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Sample records for achondroplasia

  1. Genetics Home Reference: achondroplasia

    ... Help Me Understand Genetics Home Health Conditions achondroplasia achondroplasia Enable Javascript to view the expand/collapse boxes. Print All Open All Close All Description Achondroplasia is a form of short-limbed dwarfism. The ...

  2. ACHONDROPLASIA AND PREGNANCY

    Richa; Arvind

    2014-01-01

    : Achondroplasia is a genetic disorder of bone growth occurring in 1:10, 000 to 1:40, 000 in all races and sexes. A 32 years old primigravida with achondroplasia at 31 weeks gestation presented to our gynae casualty with labor pain. LSCS was done in view of contracted pelvis. Baby also had achondroplasia and expired on 5th neonatal day due to prematurity. Prenatal and preimplantational diagnostic tools are available regarding termination of pregnancy, rearing of affected c...

  3. Achondroplasia and Macular Coloboma.

    Ahoor, M H; Amizadeh, Y; Sorkhabi, R

    2015-01-01

    Achondroplasia is an autosomal dominant congenital disorder of enchondral ossification. It is clinically characterized by low stature, craniofacial deformity, and vertebral malformation. Associated ophthalmic features include telecanthus, exotropia, angle anomalies, and cone-rod dystrophy. A 24-year-old male presented with decreased vision bilaterally and typical achondroplasia. The best corrected visual acuity was 20/70 in both eyes. Anterior segment examination was normal. Fundus examination revealed a well-demarcated circular paramacular lesion in both eyes. As macular coloboma and achondroplasia are developmental disorders, the funduscopic examination is required in patients with achondroplasia. PMID:26692730

  4. Achondroplasia and macular coloboma

    M H Ahoor

    2015-01-01

    Full Text Available Achondroplasia is an autosomal dominant congenital disorder of enchondral ossification. It is clinically characterized by low stature, craniofacial deformity, and vertebral malformation. Associated ophthalmic features include telecanthus, exotropia, angle anomalies, and cone-rod dystrophy. A 24-year-old male presented with decreased vision bilaterally and typical achondroplasia. The best corrected visual acuity was 20/70 in both eyes. Anterior segment examination was normal. Fundus examination revealed a well-demarcated circular paramacular lesion in both eyes. As macular coloboma and achondroplasia are developmental disorders, the funduscopic examination is required in patients with achondroplasia.

  5. ACHONDROPLASIA AND PREGNANCY

    Richa

    2014-04-01

    Full Text Available : Achondroplasia is a genetic disorder of bone growth occurring in 1:10, 000 to 1:40, 000 in all races and sexes. A 32 years old primigravida with achondroplasia at 31 weeks gestation presented to our gynae casualty with labor pain. LSCS was done in view of contracted pelvis. Baby also had achondroplasia and expired on 5th neonatal day due to prematurity. Prenatal and preimplantational diagnostic tools are available regarding termination of pregnancy, rearing of affected child at home, foster care or adoption.

  6. Achondroplasia and Macular Coloboma

    M H Ahoor; Y Amizadeh; Sorkhabi, R

    2015-01-01

    Achondroplasia is an autosomal dominant congenital disorder of enchondral ossification. It is clinically characterized by low stature, craniofacial deformity, and vertebral malformation. Associated ophthalmic features include telecanthus, exotropia, angle anomalies, and cone-rod dystrophy. A 24-year-old male presented with decreased vision bilaterally and typical achondroplasia. The best corrected visual acuity was 20/70 in both eyes. Anterior segment examination was normal. Fundus examinatio...

  7. Molecular studies of achondroplasia

    Nahar Risha; Saxena Renu; Kohli Sudha; Puri Ratna; Verma Ishwar

    2009-01-01

    Background: Achondroplasia (ACH) is the most frequent form of short-limbed dwarfi sm, caused by mutations in the FGFR3 gene. It follows an autosomal dominant inheritance, though most cases are sporadic. The molecular techniques are the only available methods to confi rm the diagnosis of a skeletal dysplasia. Clinical and radiological features are only suggestive and not confi rmatory. The present study was conducted to fi nd out how often the clinical diagnosis of achondroplasia is verifi ed ...

  8. Orofacial manifestations of achondroplasia

    Kaushik, Atul; Kumar, Munish; Rohilla, Smriti; Tanwar, Renu; Vinod, V.C.

    2012-01-01

    Achondroplasia (Online Mendelian Inheritance in Man [OMIM] 100800), is considered as a form of skeletal dysplasia dwarfism that manifests with stunted stature and disproportionate limb shortening. Achondroplasia is of special interest in the field of dentistry because of its characteristic craniofacial features which include relative macrocephaly, depressed nasal bridge and maxillary hypoplasia. Presence of large head, implanted shunt, airway obstruction and difficulty in head control r...

  9. Orofacial manifestations of achondroplasia

    Rohilla, Smriti; Kaushik, Atul; Vinod, V.C.; Tanwar, Renu; Kumar, Munish

    2012-01-01

    Achondroplasia (Online Mendelian Inheritance in Man [OMIM] 100800), is considered as a form of skeletal dysplasia dwarfism that manifests with stunted stature and disproportionate limb shortening. Achondroplasia is of special interest in the field of dentistry because of its characteristic craniofacial features which include relative macrocephaly, depressed nasal bridge and maxillary hypoplasia. Presence of large head, implanted shunt, airway obstruction and difficulty in head control requires special precautions during dental management. The current case report highlights the orofacial manifestations of Achondroplasia in a young pediatric patient, along with the multidisciplinary treatment (including the dental treatment) done for the patient which also might help the general practitioners in better understanding of the condition. PMID:27298609

  10. Achondroplasia and periodontal disease

    Chawla, Kirti; Lamba, Arundeep Kaur; Faraz, Farrukh; Tandon, Shruti

    2012-01-01

    Achondroplasia is a non-lethal form of chondrodysplasia. It is a disturbance of endochondral bone formation which results in characteristic dwarfism. It is transmitted as an autosomal dominant trait, with complete penetrance. De novo mutations cause up to 90% of cases. The mutation rate is estimated to be 0.000014 per gamete per generation. It is a rare disorder with a prevalence of 1:10,000 to 1:50,000 births worldwide. A young female patient suffering from achondroplasia reported with oral ...

  11. Molecular studies of achondroplasia

    Nahar Risha

    2009-01-01

    Full Text Available Background: Achondroplasia (ACH is the most frequent form of short-limbed dwarfi sm, caused by mutations in the FGFR3 gene. It follows an autosomal dominant inheritance, though most cases are sporadic. The molecular techniques are the only available methods to confi rm the diagnosis of a skeletal dysplasia. Clinical and radiological features are only suggestive and not confi rmatory. The present study was conducted to fi nd out how often the clinical diagnosis of achondroplasia is verifi ed on molecular studies. Materials and Methods: From 1998 through 2007, we carried out molecular analysis for the two common mutations in the FGFR3 gene in 130 cases clinically suspected to have ACH. Results: A diagnostic mutation was identifi ed in 53 (40.8% cases. The common mutation (1138G>A was present in 50 (94.7% of the positive cases, while the rare 1138 G>C substitution was found in three (5.3%. Conclusion: This study shows that confi rmation of clinical diagnosis of ACH by molecular genetic testing is essential to distinguish it from other skeletal dysplasias, to plan therapeutic options, and to offer genetic counseling. Management (medical and surgical in patients confi rmed to have ACH, is briefl y discussed.

  12. Achondroplasia Associated with Bilateral Keratoconus

    Samar A. Al-Swailem; Al Bin Ali, Ghada Y.; Al Katan, Hind M.; Al Mahmood, Ammar M.

    2012-01-01

    We report a rare case of bilateral keratoconus in association with achondroplasia. A 26-year-old male, with a known case of achondroplasia, complained of bilateral gradual deterioration in vision for the past few years. Slit lamp biomicroscopy showed bilateral central corneal protrusion and stromal thinning at the apex consistent with keratoconus. a trial of hard contact lens fitting failed to improve VA in the left eye (LE). Right eye (RE) improved to 20/25. The patient underwent penetrating...

  13. Discoid Meniscus Associated With Achondroplasia.

    Hoernschemeyer, Daniel G; Atanda, Alfred; Dean-Davis, Ellen; Gupta, Sumit K

    2016-05-01

    Achondroplasia is the most common skeletal dysplasia. This form of dwarfism is caused by a point mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, leading to inhibition of endochondral ossification for these patients. This results in a normal trunk height but shortened limbs. The discoid meniscus may be an important associated finding to better understand the common complaints of leg pain for these patients. Although the incidence for a discoid meniscus is between 3% and 5% for the general population, it is unknown with achondroplasia. This case series includes 4 patients, with ages ranging from adolescence to early adulthood, with symptoms of knee pain that were not attributable to some of the more common findings seen in this patient population. Typically, patients with achondroplasia who experience knee pain are evaluated for more common and well-known etiologies such as genu varum, ligamentous instability, and neurogenic claudication. However, the authors propose that symptomatic discoid lateral meniscus should be added to the differential diagnosis for lower-extremity pain in the achondroplasia population. A thorough history and physical examination, in combination with magnetic resonance imaging, can aid in making the diagnosis. Treatment with arthroscopic debridement, saucerization of the meniscus, and repair for unstable injuries has yielded good outcomes for this patient population. [Orthopedics. 2016; 39(3):e498-e503.]. PMID:27135452

  14. Karakteristik Dan perawatan Anomali Ortodonsia Pada Beberapa Penderita Achondroplasia

    Agustina, Nova

    2010-01-01

    Karakteristik dan Perawatan Anomali Ortodonsia pada Beberapa Penderita Achondroplasia xii + 56 halaman Kelainan genetik dapat berpengaruh terhadap gangguan dentofasial. Achondroplasia adalah salah satu kelainan genetik yang mempunyai manifestasi timbulnya gangguan dentofasial. Achondroplasia adalah salah satu bentuk dwarfisme yang sering dijumpai. Achondroplasia disebabkan oleh gangguan osifikasi endokondral akibat mutasi gen FGFR 3 (fibroblast growth factor receptor 3) pada lengan p...

  15. Intracranial MR imaging of achondroplasia

    Ueno, Shinichi; Ootsuka, Ryouichi; Hayashi, Yoshinori; Nishitani, Hiromu; Shirakawa, Norihisa; Hashimoto, Toshiaki (Tokushima Univ. (Japan). School of Medicine)

    1992-10-01

    Intracranial MR imaging was performed in five patients with achondroplasia. All patients had narrowing of the subarachnoid space at the level of the formen magnum that was mainly due to protrusion of the posterior aspect. Three patients had compressive deformities of the brainstem and/or upper cervical spine. Among them, two patients had deformities of the pons. Relative upward displacement of the brainstem was seen in all patients. Hydrocephalus was seen in three patients. (author).

  16. Intracranial MR imaging of achondroplasia

    Intracranial MR imaging was performed in five patients with achondroplasia. All patients had narrowing of the subarachnoid space at the level of the formen magnum that was mainly due to protrusion of the posterior aspect. Three patients had compressive deformities of the brainstem and/or upper cervical spine. Among them, two patients had deformities of the pons. Relative upward displacement of the brainstem was seen in all patients. Hydrocephalus was seen in three patients. (author)

  17. Achondroplasia in sibs of normal parents.

    Philip, N; Auger, M.; Mattei, J F; Giraud, F.

    1988-01-01

    A new case of recurrent achondroplasia in sibs of normal parents is reported. Two sisters and a half sister were affected. Various mechanisms can be postulated to account for unexpected recurrence of achondroplasia in the same sibship. Germinal mosaicism and unstable premutation are discussed here.

  18. Achondroplasia and enchondromatosis: report of three boys

    We report on three boys suffering from achondroplasia concurrent with enchondromatosis-like metaphyseal changes. Two boys who were examined by molecular analysis harbored a mutation of FGFR3, which occurs in most achondroplastic individuals. Given the prevalence of achondroplasia and enchondromatosis, the metaphyseal changes in these patients are less likely to represent the coincidence of both disorders, but rather to result from a rare consequence of the FGFR3 mutation. Impaired FGFs/FGFR3 signaling pathway in achondroplasia inhibits chondrocytic proliferation, which accounts for most characteristics of achondroplasia. On the other hand, it causes conflicting biological consequences that can suppress or stimulate chondrocytic maturation. In a small subset of achondroplastic individuals, the suppression of chondrocytic maturation may outweigh the stimulation, which leads to cartilaginous overgrowth into the metaphysis, eventually causing the metaphyseal dysplasia found in the present patients. (orig.)

  19. Achondroplasia and enchondromatosis: report of three boys

    Numakura, Chikahiko [Yamagata University School of Medicine, Department of Pediatrics, Yamagata (Japan); Tokyo Metropolitan Kiyose Children' s Hospital, Endocrinology and Metabolism Unit, Tokyo (Japan); Kobayashi, Hironori [Shimane University School of Medicine, Department of Pediatrics, Shimane (Japan); Hasegawa, Yukihiro [Tokyo Metropolitan Kiyose Children' s Hospital, Endocrinology and Metabolism Unit, Tokyo (Japan); Adachi, Masanori [Kanagawa Children' s Medical Center, Department of Endocrinology and Metabolism, Clinical Research Institute, Kanagawa (Japan); Kim, Ok Hwa [Ajou University Hospital, Department of Radiology, Seoul (Korea); Nishimura, Gen [Tokyo Metropolitan Kiyose Children' s Hospital, Department of Radiology, Tokyo (Japan)

    2007-06-15

    We report on three boys suffering from achondroplasia concurrent with enchondromatosis-like metaphyseal changes. Two boys who were examined by molecular analysis harbored a mutation of FGFR3, which occurs in most achondroplastic individuals. Given the prevalence of achondroplasia and enchondromatosis, the metaphyseal changes in these patients are less likely to represent the coincidence of both disorders, but rather to result from a rare consequence of the FGFR3 mutation. Impaired FGFs/FGFR3 signaling pathway in achondroplasia inhibits chondrocytic proliferation, which accounts for most characteristics of achondroplasia. On the other hand, it causes conflicting biological consequences that can suppress or stimulate chondrocytic maturation. In a small subset of achondroplastic individuals, the suppression of chondrocytic maturation may outweigh the stimulation, which leads to cartilaginous overgrowth into the metaphysis, eventually causing the metaphyseal dysplasia found in the present patients. (orig.)

  20. Optimal management of complications associated with achondroplasia

    Ireland, Penny J; Pacey, Verity; Zankl, Andreas; Edwards, Priya; Johnston, Leanne M; Savarirayan, Ravi

    2014-01-01

    Achondroplasia is the most common form of skeletal dysplasia, resulting in disproportionate short stature, and affects over 250,000 people worldwide. Individuals with achondroplasia demonstrate a number of well-recognized anatomical features that impact on growth and development, with a complex array of medical issues that are best managed through a multidisciplinary team approach. The complexity of this presentation, whereby individual impairments may impact upon multiple activity and partic...

  1. ACHONDROPLASIA AND ELLIS VAN CREVELD SYNDROME

    Ramkumar; Shanmugasundaram; Narayanan

    2014-01-01

    Stunted growth of an individual occurs in many systemic conditions and the main cause is due to defective cartilage growth in the long bones particularly in the lower extremities. In achondroplasia and Ellis Van Creveld syndrome the endochondral ossification of long bones are affected but in Ellis Van Creveld syndrome, the stunted growth is associated with ectodermal dysplasia, polydactyly and cardiac diseases. The common feature for both achondroplasia and Ellis Van Creve...

  2. Bilateral Ossiculoplasty in 1 Case of Achondroplasia

    Jung, Jongyoon; Yang, Chulwon; Lee, Sunkyu; Choi, June

    2013-01-01

    Achondroplasia is the most common skeletal dysplasia and it combines various complications with normal longevity. Hearing disturbance due to otitis media or an ossicular anomaly is one of the most common complications. Conductive hearing loss is suggested as the most common form of hearing loss. Temporal bone and middle ear structures are distorted in achondroplasia because of rotational change of the skull base. Authors experienced a case of an achondroplastic patient with bilateral hearing ...

  3. A Case of Chorioretinal Coloboma in a Patient with Achondroplasia

    Yoo, Woong Sun; Park, Yeon Jung; Yoo, Ji Myung

    2010-01-01

    Achondroplasia is a congenital disorder resulting from a specific disturbance in endochondral bone formation. The ophthalmic features reportedly associated with achondroplasia are telecanthus, exotropia, inferior oblique overaction, angle anomalies and cone-rod dystrophy. This is first report of chorioretinal coloboma in achondroplasia. An 8-year-old female was diagnosed with a developmental delay, known as achondroplasia, seven months after birth. Upon her initial visit, visual acuity was 0....

  4. Manifestasi Penyakit Achondroplasia Di Rongga Mulut Ditinjau Dari Gambaran Radiografi

    Tengku Ayu Masitah

    2009-01-01

    Achondroplasia merupakan penyakit pertumbuhan tulang yang genetik (turunan) dan biasanya terjadi satu dari setiap 20.000 kelahiran. Achondroplasia sebagian besar berasal dari tipe dwarfism (kekerdilan). Gambaran radiografi pada penderita Achondroplasia menunjukkan adanya pembesaran tengkorak, penyempitan foramen magnum, frontal bossing, penekanan nasal bridge, hipoplasia maksila, protrusi mandibula melebihi jarak normal, garis tengah muka hipoplasia, maloklusi, beberapa gigi permanen yang te...

  5. Achondroplasia

    ... early. In some cases, a surgeon needs to drain the extra fluid from a baby’s brain. Kyphosis (a small hump in the upper back). ... early. In some cases, a surgeon needs to drain the extra fluid from a baby’s brain. Kyphosis (a small hump in the upper back). ...

  6. ACHONDROPLASIA AND ELLIS VAN CREVELD SYNDROME

    Ramkumar

    2014-03-01

    Full Text Available Stunted growth of an individual occurs in many systemic conditions and the main cause is due to defective cartilage growth in the long bones particularly in the lower extremities. In achondroplasia and Ellis Van Creveld syndrome the endochondral ossification of long bones are affected but in Ellis Van Creveld syndrome, the stunted growth is associated with ectodermal dysplasia, polydactyly and cardiac diseases. The common feature for both achondroplasia and Ellis Van Creveld syndrome is the individual’s trunk is normal but the lower extremities are short. Though there is a cartilage dysfunction in these two cases, different clinical manifestation occurs in the body and these things are recorded from two case reports of Achondroplasia and Ellis Van Creveld syndrome and submitted the clinical differences with explanation and discussion.

  7. Optimal management of complications associated with achondroplasia

    Irel

    2014-06-01

    Full Text Available Penny J Ireland,1 Verity Pacey,2,3 Andreas Zankl,4 Priya Edwards,1 Leanne M Johnston,5 Ravi Savarirayan6 1Queensland Paediatric Rehabilitation Service, Royal Children’s Hospital, Herston, Brisbane, Queensland, 2Physiotherapy Department, The Children’s Hospital at Westmead, Sydney, New South Wales, 3Department of Health Professions, Macquarie University, Sydney, New South Wales, 4Genetic Medicine, Children’s Hospital, Westmead, Sydney, New South Wales, 5School of Health and Rehabilitation Sciences, University of Queensland, Brisbane, Queensland, 6Victorian Clinical Genetics Service, Royal Children’s Hospital, Melbourne, Victoria, Australia Abstract: Achondroplasia is the most common form of skeletal dysplasia, resulting in disproportionate short stature, and affects over 250,000 people worldwide. Individuals with achondroplasia demonstrate a number of well-recognized anatomical features that impact on growth and development, with a complex array of medical issues that are best managed through a multidisciplinary team approach. The complexity of this presentation, whereby individual impairments may impact upon multiple activity and participation areas, requires consideration and discussion under a broad framework to gain a more thorough understanding of the experience of this condition for individuals with achondroplasia. This paper examines the general literature and research evidence on the medical and health aspects of individuals with achondroplasia and presents a pictorial model of achondroplasia based on The International Classification of Functioning, Disability, and Health (ICF. An expanded model of the ICF will be used to review and present the current literature pertaining to the musculoskeletal, neurological, cardiorespiratory, and ear, nose, and throat impairments and complications across the lifespan, with discussion on the impact of these impairments upon activity and participation performance. Further research is required to

  8. Surgical treatment of lumbar stenosis in achondroplasia

    Thomeer, RTWM; Van Dijk, JMC

    2002-01-01

    Object. The authors conducted a study to evaluate the results of a unique surgical procedure for treating primary lumbar stenosis in patients with achondroplasia, based on its distorted anatomical dimensions. Methods. A consecutive single-center series of 36 achondroplastic dwarfs with symptomatic l

  9. Limb Lengthening in Patients with Achondroplasia

    Park, Kwang-Won; Garcia, Rey-an Niño; Rejuso, Chastity Amor; Choi, Jung-Woo; Song, Hae-Ryong

    2015-01-01

    Purpose Although bilateral lower-limb lengthening has been performed on patients with achondroplasia, the outcomes for the tibia and femur in terms of radiographic parameters, clinical results, and complications have not been compared with each other. We proposed 1) to compare the radiological outcomes of femoral and tibial lengthening and 2) to investigate the differences of complications related to lengthening. Materials and Methods We retrospectively reviewed 28 patients (average age, 14 y...

  10. Breathing abnormalities in sleep in achondroplasia.

    Waters, K A; Everett, F; Sillence, D; Fagan, E.; Sullivan, C E

    1993-01-01

    Overnight sleep studies were performed in 20 subjects with achondroplasia to document further the respiratory abnormalities present in this group. Somatosensory evoked potentials (SEPs) were recorded in 19 of the subjects to screen for the presence of brainstem abnormalities, which are one of the potential aetiological mechanisms. Fifteen children aged 1 to 14 years, and five young adults, aged 20 to 31 years were included. All had upper airway obstruction and 15 (75%) had a pathological apno...

  11. Achondroplasia: Craniofacial manifestations and considerations in dental management

    Al-Saleem, Afnan; Al-Jobair, Asma

    2010-01-01

    Achondroplasia is the most common form of skeletal dysplasia dwarfism that manifests with stunted stature and disproportionate limb shortening. Achondroplasia is of dental interest because of its characteristic craniofacial features which include relative macrocephaly, depressed nasal bridge and maxillary hypoplasia. Presence of large head, implanted shunt, airway obstruction and difficulty in head control require special precautions during dental management. Craniofacial manifestations and c...

  12. Prenatal Diagnosis of Concurrent Achondroplasia and Klinefelter Syndrome

    Esther Perez-Carbajo

    2015-01-01

    Full Text Available Achondroplasia is the most frequent nonlethal skeletal dysplasia, with a prevalence of 1 : 5000 to 1 : 40,000 live births, and it is caused by a fibroblast growth factor receptor alteration. The combination of achondroplasia and Klinefelter syndrome is extremely rare and just four reports have been published in the literature, which were all diagnosed postnatally. We report the fifth case described of this uncommon association and its prenatal diagnosis. In cases of prenatal diagnosis of achondroplasia with additional suspicious morphological abnormalities, an invasive test such as amniocentesis must be carried out to assess the karyotype normality.

  13. Prenatal diagnosis of concurrent achondroplasia and klinefelter syndrome.

    Perez-Carbajo, Esther; Zapardiel, Ignacio; Sanfrutos-Llorente, Luis; Cruz-Melguizo, Sara; Martinez-Payo, Cristina; Iglesias-Goy, Enrique

    2015-01-01

    Achondroplasia is the most frequent nonlethal skeletal dysplasia, with a prevalence of 1 : 5000 to 1 : 40,000 live births, and it is caused by a fibroblast growth factor receptor alteration. The combination of achondroplasia and Klinefelter syndrome is extremely rare and just four reports have been published in the literature, which were all diagnosed postnatally. We report the fifth case described of this uncommon association and its prenatal diagnosis. In cases of prenatal diagnosis of achondroplasia with additional suspicious morphological abnormalities, an invasive test such as amniocentesis must be carried out to assess the karyotype normality. PMID:25789188

  14. Achondroplasia: Current Options and Future Perspective.

    Bouali, Houda; Latrech, Hanane

    2015-06-01

    Achondroplasia is a human bone genetic disorder of the growth plate and is the most common form of inherited disproportionate short stature. It is inherited as an autosomal dominant disease with essentially complete penetrance. Of these most have the same point mutation in the gene for fibroblast growth factor receptor 3 (FGFR3) which is a negative regulator of bone growth. The clinical and radiological features of achondroplasia can easily be identified; they include disproportionate short stature with rhizomelic shortening, macrocephaly with frontal bossing, midface hypoplasia, lumbar hyperlordosis, and a trident hand configuration. The majority of achondroplasts have a normal intelligence, but many social and medical complications may compromise a full and productive life. Some of them have serious health consequences related to hydrocephalus, craniocervical junction compression, or upper-airway obstruction. In this article, we discuss a number of treatments from the surgical limb lengthening approach and the Recombinant Growth Hormone (rhGH) treatment, to future treatments, which include the Natriuretic Peptide C-type (CNP). The discussion is a comparative study of the complications and drawbacks of various experiments using numerous strategies. PMID:26182483

  15. Physeal growth arrest after tibial lengthening in achondroplasia

    Song, Sang-Heon; Agashe, Mandar Vikas; Huh, Young-Jae; Hwang, Soon-Young; Song, Hae-Ryong

    2012-01-01

    Background and purpose Bilateral tibial lengthening has become one of the standard treatments for upper segment-lower segment disproportion and to improve quality of life in achondroplasia. We determined the effect of tibial lengthening on the tibial physis and compared tibial growth that occurred at the physis with that in non-operated patients with acondroplasia. Methods We performed a retrospective analysis of serial radiographs until skeletal maturity in 23 achondroplasia patients who und...

  16. Achondroplasia with oligodontia: Report of a rare case

    Lata Kale; Neha Khambete; Sonia Sodhi; Rahul Kumar

    2013-01-01

    Achondroplasia is considered as a form of skeletal dysplasia/dwarfism that manifests with stunted stature and disproportionate limb shortening. Achondroplasia is of special interest in the field of dentistry because of its characteristic craniofacial features. It has been considered as the most common short-limbed dwarfism syndrome. Very few authors have reported the presence of oligodontia in achondroplastic patients. The present paper reports a rare case of oligodontia in a young, female, a...

  17. Achondroplasia with oligodontia: Report of a rare case

    Lata Kale

    2013-01-01

    Full Text Available Achondroplasia is considered as a form of skeletal dysplasia/dwarfism that manifests with stunted stature and disproportionate limb shortening. Achondroplasia is of special interest in the field of dentistry because of its characteristic craniofacial features. It has been considered as the most common short-limbed dwarfism syndrome. Very few authors have reported the presence of oligodontia in achondroplastic patients. The present paper reports a rare case of oligodontia in a young, female, achondroplastic patient.

  18. Achondroplasia Presenting with Pneumonia in a Two Months Old Boy

    Huseyin Bilgin

    2014-01-01

    Achondroplasia is one of the common chondrodysplasias with an inheritance is autosomal dominant, but in around 85% the phenotype is the result of a new mutation. Achondroplasia develops as a result of dysplasia of enchondral formation due to the mutation of fibroblast growth factor receptor 3. A 2-month-old boy was referred to the our hospital with cough and fever. Craniofacially the head appeared large and also frontal bossing and depressed nasal bridge was demonstrated. Narrow lumbar interp...

  19. Achondroplasia Presenting with Pneumonia in a Two Months Old Boy

    Huseyin Bilgin

    2014-03-01

    Full Text Available Achondroplasia is one of the common chondrodysplasias with an inheritance is autosomal dominant, but in around 85% the phenotype is the result of a new mutation. Achondroplasia develops as a result of dysplasia of enchondral formation due to the mutation of fibroblast growth factor receptor 3. A 2-month-old boy was referred to the our hospital with cough and fever. Craniofacially the head appeared large and also frontal bossing and depressed nasal bridge was demonstrated. Narrow lumbar interpedicular distances, normal trunk length, short-wide pelvis, micromelic upper extremities and rhizomelic lower extremities were seen on x-ray examination. The clinically and radiographically diagnosis of achondroplasia with heart failure secondary to pneumonia was performed. Achondroplasia, presenting with respiratory disorders and short limb should be differentiated from metatropic dysplasia and campomelic dysplasia. Achondroplasia may had similar findings with other dwarfism and differentiate diagnosis from other achondroplasia like diseases needs team work which includes pediatry, radiology and medical genetic for better patient care and family counseling.

  20. Two sibs who are double heterozygotes for achondroplasia and pseudoachondroplastic dysplasia.

    Woods, C G; Rogers, J G; Mayne, V

    1994-01-01

    We report a family in which two sibs have both achondroplasia and pseudoachondroplastic dysplasia. The mother has achondroplasia and the father has pseudoachondroplastic dysplasia, which he had inherited from his father. Both children appeared typical of achondroplasia at birth. By 1 1/2 years they had developed a fixed lumbar kyphosis with gibbus and had additional x ray changes unusual for just achondroplasia and suggestive of pseudoachondroplastic dysplasia. Subsequently both children have...

  1. Advances in research on and diagnosis and treatment of achondroplasia in China

    Wang, Yao; Liu, Zeying; Liu, Zhenxing; Zhao, Heng; Zhou, Xiaoyan; Cui, Yazhou; Han, Jinxiang

    2013-01-01

    Achondroplasia is a rare autosomal dominant genetic disease. Research on achondroplasia in China, however, has received little emphasis. Around 80–90% of cases of neonatal achondroplasia result from mutations in fibroblast growth factor receptor 3 (FGFR3) according to polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). Recently, genetic research on achondroplasia in China made a major breakthrough by revealing two novel mutations located on the FGFR3 gene, thus helpi...

  2. Prenatal Diagnosis of Concurrent Achondroplasia and Klinefelter Syndrome

    Esther Perez-Carbajo; Ignacio Zapardiel; Luis Sanfrutos-Llorente; Sara Cruz-Melguizo; Cristina Martinez-Payo; Enrique Iglesias-Goy

    2015-01-01

    Achondroplasia is the most frequent nonlethal skeletal dysplasia, with a prevalence of 1 : 5000 to 1 : 40,000 live births, and it is caused by a fibroblast growth factor receptor alteration. The combination of achondroplasia and Klinefelter syndrome is extremely rare and just four reports have been published in the literature, which were all diagnosed postnatally. We report the fifth case described of this uncommon association and its prenatal diagnosis. In cases of prenatal diagnosis of acho...

  3. Development in Children with Achondroplasia: A Prospective Clinical Cohort Study

    Ireland, Penelope J.; Donaghey, Samantha; McGill, James; Zankl, Andreas; Ware, Robert S.; Pacey, Verity; Ault, Jenny; Savarirayan, Ravi; Sillence, David; Thompson, Elizabeth; Townshend, Sharron; Johnston, Leanne M.

    2012-01-01

    Aim: Achondroplasia is characterized by delays in the development of communication and motor skills. While previously reported developmental profiles exist across gross motor, fine motor, feeding, and communication skills, there has been no prospective study of development across multiple areas simultaneously. Method: This Australasian…

  4. Functional Performance in Young Australian Children with Achondroplasia

    Ireland, Penelope Jane; McGill, James; Zankl, Andreas; Ware, Robert S.; Pacey, Verity; Ault, Jenny; Savarirayan, Ravi; Sillence, David; Thompson, Elizabeth M.; Townshend, Sharron; Johnston, Leanne Marie

    2011-01-01

    Aim: The aim of this study was to determine population-specific developmental milestones for independence in self-care, mobility, and social cognitive skills in children with achondroplasia, the most common skeletal dysplasia. Methods: Population-based recruitment from October 2008 to October 2010 identified 44 Australian children with…

  5. Advances in treatment of achondroplasia and osteoarthritis.

    Klag, Kendra A; Horton, William A

    2016-04-15

    Achondroplasia (ACH) is the prototype and most common of the human chondrodysplasias. It results from gain-of-function mutations that exaggerate the signal output of the fibroblast growth factor receptor 3 (FGFR3), a receptor tyrosine kinase that negatively regulates growth plate activity and linear bone growth. Several approaches to reduce FGFR3 signaling by blocking receptor activation or inhibiting downstream signals have been proposed. Five show promise in preclinical mouse studies. Two candidate therapies target the extracellular domain of FGFR3. The first is a decoy receptor that competes for activating ligands. The second is a synthetic blocking peptide that prevents ligands from binding and activating FGFR3. Two established drugs, statins and meclozine, improve growth of ACH mice. The strongest candidate therapy employs an analog of C-type natriuretic peptide (CNP), which antagonizes the mitogen-activated-protein (MAP) kinase pathway downstream of the FGFR3 receptor and may also act independently in the growth plate. Only the CNP analog has reached clinical trials. Preliminary results of Phase 2 studies show a substantial increase in growth rate of ACH children after six months of therapy with no serious adverse effects. A challenge for drug therapy in ACH is targeting agents to the avascular growth plate. The application of gene therapy in osteoarthritis offers insights because it faces similar technical obstacles. Major advances in gene therapy include the emergence of recombinant adeno-associated virus as the vector of choice, capsid engineering to target vectors to specific tissues, and development of methods to direct vectors to articular chondrocytes. PMID:26443596

  6. Association of achondroplasia with sagittal synostosis and scaphocephaly in two patients, an underestimated condition?

    Accogli, Andrea; Pacetti, Mattia; Fiaschi, Pietro; Pavanello, Marco; Piatelli, Gianluca; Nuzzi, Daniele; Baldi, Maurizia; Tassano, Elisa; Severino, Maria Savina; Allegri, Anna; Capra, Valeria

    2015-03-01

    We report on two patients with an unusual combination of achondroplasia and surgically treated sagittal synostosis and scaphocephaly. The most common achondroplasia mutation, p.Gly380Arg in fibroblast growth factor receptor 3 (FGFR3), was detected in both patients. Molecular genetic testing of FGFR1, FGFR2, FGFR3 and TWIST1 genes failed to detect any additional mutations. There are several reports of achondroplasia with associated craniosynostosis, but no other cases of scaphocephaly in children with achondroplasia have been described. Recently it has been demonstrated that FGFR3 mutations affect not only endochondral ossification but also membranous ossification, providing new explanations for the craniofacial hallmarks in achondroplasia. Our report suggests that the association of isolated scaphocephaly and other craniosynostoses with achondroplasia may be under recognized. PMID:25691418

  7. Achondroplasia and Down syndrome in the same patient. Report of a case

    Achondroplasia and trisomy 21 are, within their respective categories, conditions the most frequent genetic diseases found in newborns. The simultaneous presence of both conditions in the same patient, has been however, reported only once in the world literature. In this paper we present a patient affected by both entities (Achondroplasia and Trisomy 21). The clinical findings (using, among other, achondroplasia radiography), and the reasons for the rare reported frequency of these cases are discussed

  8. Congenital lumbar spinal stenosis with ossification of the ligamentum flavum in achondroplasia: a case report

    Saito, Kimio; Miyakoshi, Naohisa; Hongo, Michio; Kasukawa, Yuji; Ishikawa, Yoshinori; Shimada, Yoichi

    2014-01-01

    Introduction Achondroplasia is a genetic disorder of bone growth. Congenital spinal stenosis is a well-known complication of this disease, but, to the best of our knowledge, no cases involving combined stenosis with congenital lumbar spinal stenosis and ossification of the ligamentum flavum in achondroplasia have been reported previously. In this report, we describe a case of a patient with congenital spinal stenosis with achondroplasia combined with ossification of the ligamentum flavum at t...

  9. FGFR3 Heterodimerization in Achondroplasia, the Most Common Form of Human Dwarfism*

    He, Lijuan; Shobnam, Nadia; Wimley, William C.; Hristova, Kalina

    2011-01-01

    The G380R mutation in the transmembrane domain of fibroblast growth factor receptor 3 (FGFR3) causes achondroplasia, the most common form of human dwarfism. Achondroplasia is a heterozygous disorder, and thus the affected individuals express both wild-type and mutant FGFR3. Yet heterodimerization in achondroplasia has not been characterized thus far. To investigate the formation of FGFR3 heterodimers in cellular membranes, we designed an FGFR3 construct that lacks the kinase domain, and we mo...

  10. Achondroplasia and Down’s Syndrome – Case Report of a Rare Association

    Santos, S; Silva, T.; Pinto, M.

    2011-01-01

    The association of achondroplasia and Down’s syndrome is very rare and only five cases have been reported in the literature so far. These two genetic alterations have overlapping features such as short stature, developmental delay or hypotonia that complicate management and follow up. We report the case of a girl that is unique since she was born from a mother with achondroplasia and a healthy father. Achondroplasia was dominantly inherited from the mother but at birth she had featur...

  11. Physeal growth arrest after tibial lengthening in achondroplasia

    2012-01-01

    Background and purpose Bilateral tibial lengthening has become one of the standard treatments for upper segment-lower segment disproportion and to improve quality of life in achondroplasia. We determined the effect of tibial lengthening on the tibial physis and compared tibial growth that occurred at the physis with that in non-operated patients with acondroplasia. Methods We performed a retrospective analysis of serial radiographs until skeletal maturity in 23 achondroplasia patients who underwent bilateral tibial lengthening before skeletal maturity (lengthening group L) and 12 achondroplasia patients of similar height and age who did not undergo tibial lengthening (control group C). The mean amount of lengthening of tibia in group L was 9.2 cm (lengthening percentage: 60%) and the mean age at the time of lengthening was 8.2 years. The mean duration of follow-up was 9.8 years. Results Skeletal maturity (fusion of physis) occurred at 15.2 years in group L and at 16.0 years in group C. The actual length of tibia (without distraction) at skeletal maturity was 238 mm in group L and 277 mm in group C (p = 0.03). The mean growth rates showed a decrease in group L relative to group C from about 2 years after surgery. Physeal closure was most pronounced on the anterolateral proximal tibial physis, with relative preservation of the distal physis. Interpretation Our findings indicate that physeal growth rate can be disturbed after tibial lengthening in achondroplasia, and a close watch should be kept for such an occurrence—especially when lengthening of more than 50% is attempted. PMID:22489887

  12. Correction of anterior open bite in a case of achondroplasia

    Karpagam S; Rabin K; Mathew George; Koshy Santhosh

    2005-01-01

    Treatment planning for patients with skeletal deformities is often considered challenging. This article reports a female patient with achondroplasia who presented with severe maxillary retrognathism and vertical excess along with anterior open bite. The clinical and cephalometric findings of the patient are detailed here. The treatment plan consisted of modified anterior maxillary osteotomy for simultaneous vertical and sagittal augmentation along with orthodontic intervention. The course of ...

  13. The prevalence of thoracolumbar kyphosis in achondroplasia: a systematic review

    Engberts, Alexander C.; Jacobs, Wilco C. H.; Castelijns, Sanne J. A. M.; Castelein, Rene M; Vleggeert-Lankamp, Carmen L.A.

    2011-01-01

    Purpose Thoracolumbar kyphosis (TLK) is described as a common presentation in children with achondroplasia. However, the prevalence and development of TLK are ill-defined, as well as its clinical implications. The goal of this study was to assess the existing evidence on the prevalence and development of TLK from the literature. Methods A systematic literature review was performed in PubMed, EMBASE, and Thomson Reuters (ISI) Web of Knowledge. Articles were selected and evaluated with the Newc...

  14. The sagging rope sign in achondroplasia - different from Perthes' disease

    The sagging rope sign is a radio-opaque line, seen on radiographs of the hips, with Perthes' disease. The main purpose of this study was to determine the incidence, cause and importance of this sign in achondroplasia, and to reveal how it differs from in Perthes' disease. Serial radiograms, along with 2-dimensional and 3-dimensional CT images were studied in 42 achondroplasic patients. Forty-two achondroplasic patients, reported at our institute (for routine outpatient consultation, spine surgeries, deformity corrections, limb-lengthening procedures) were included in this study. There were 26 males and 16 females. The sign was observed bilaterally, in all patients. Evaluation of CT images revealed spherical heads, with presence of circumferential overhang in all hips. This circumferential overhang, seen on 3-D CT scan, corresponded to the sagging rope sign on radiographs. Presence of the sagging rope sign in bilateral hips is a characteristic feature of achondroplasia. It usually appears before epiphyseal closure. Its cause, incidence, and nature differ from Perthes' disease, and its presence does not carry a bad prognosis in achondroplasia. (orig.)

  15. Correction of anterior open bite in a case of achondroplasia

    Karpagam S

    2005-01-01

    Full Text Available Treatment planning for patients with skeletal deformities is often considered challenging. This article reports a female patient with achondroplasia who presented with severe maxillary retrognathism and vertical excess along with anterior open bite. The clinical and cephalometric findings of the patient are detailed here. The treatment plan consisted of modified anterior maxillary osteotomy for simultaneous vertical and sagittal augmentation along with orthodontic intervention. The course of surgical-orthodontic treatment and the results are presented. This treatment is to be followed by correction of vertical maxillary excess after completion of growth. This paper concludes that the dentoalveolar component of a skeletal deformity can be handled independent of the craniofacial management.

  16. Nonrandom association of a type II procollagen genotype with achondroplasia

    Eng, C E; Pauli, R. M.; C. M. Strom

    1986-01-01

    Achondroplasia is an autosomal dominant disorder that involves defective endochondral bone formation. Type II collagen is the predominant collagen of cartilage. We found a HindIII polymorphic site in the normal Caucasian population by using the type II procollagen gene probe pgHCol(II)A. The presence of this site yields a 7.0-kilobase (kb) band; its absence yields a 14.0-kb band. We found a significant deviation in genotype distribution and allele frequencies in a population of unrelated indi...

  17. Fixator-Assisted Lengthening and Deformity Correction Over an Intramedullary Nail in a Patient with Achondroplasia

    Erdal Uzun

    2014-12-01

    Full Text Available Achondroplasia is the most frequently encountered form of nonlethal skeletal dysplasia and a type of rhizomelic dwarfism. It results in considerable physical and psychologic handicaps owing to the disproportionate stature of the body and difficulty in performing routine activities of daily living. They also have major musculoskeletal problems including symptomatic malalignment of the lower limbs. Limb lengthening has been used in patients with achondroplasia by different techniques (Intramedullar nailing, monolateral or circular external fixator. We report our treatment of a patient 17 years of age with achondroplasia for bilateral lower limb length discrepancy and bilateral tibial varus deformity.

  18. Effect of the G375C and G346E Achondroplasia Mutations on FGFR3 Activation

    He, Lijuan; Serrano, Christopher; Niphadkar, Nitish; Shobnam, Nadia; Hristova, Kalina

    2012-01-01

    Two mutations in FGFR3, G380R and G375C are known to cause achondroplasia, the most common form of human dwarfism. The G380R mutation accounts for 98% of the achondroplasia cases, and thus has been studied extensively. Here we study the effect of the G375C mutation on the phosphorylation and the cross-linking propensity of full-length FGFR3 in HEK 293 cells, and we compare the results to previously published results for the G380R mutant. We observe identical behavior of the two achondroplasia...

  19. Coronary artery surgery in a man with achondroplasia: a case report

    Daskalopoulos Marios E

    2010-10-01

    Full Text Available Abstract Introduction Achondroplasia is a musculoskeletal disorder associated with short stature. Despite an estimated prevalence of 1:25,000 in the general population, there is little literature concerning the diagnostic and treatment challenges faced by doctors dealing with a heart operation on a patient with this condition. Case presentation We present the case of a 41-year-old Caucasian man of Greek ethnicity with achondroplasia, who underwent bypass heart surgery. Conclusions The surgery was successful and did not present particular difficulties, showing that heart surgery can be safely performed on people with achondroplasia.

  20. De novo achondroplasia causing four consecutive unsuccessful pregnancies: a case report

    Igwegbe Anthony; Eleje George; Ugwueke Ikechukwu

    2012-01-01

    Abstract Introduction The incidence of achondroplasia is very low, and the birth of two or more consecutive babies with achondroplasia to unaffected parents is a rarity. We report a rare case of recurrent achondroplasia in babies of unaffected parents. Case presentation A 29-year-old Nigerian Igbo woman who has had three consecutive dead achondroplastic babies presented at a gestational age of 31 weeks with a two-hour history of drainage of liquor and vaginal bleeding. Neither she nor her hus...

  1. Growth hormone treatment in 35 prepubertal children with achondroplasia

    Hertel, Niels Thomas; Eklöf, Ole; Ivarsson, Sten;

    2005-01-01

    BACKGROUND: Achondroplasia is a skeletal dysplasia with extreme, disproportionate, short stature. AIM: In a 5-y growth hormone (GH) treatment study including 1 y without treatment, we investigated growth and body proportion response in 35 children with achondroplasia. METHODS: Patients were...... randomized to either 0.1 IU/kg (n = 18) or 0.2 IU/kg (n = 17) per day. GH treatment was interrupted for 12 mo after 2 y of treatment in prepubertal patients to study catch-down growth. Mean height SDS (HSDS) at start was -5.6 and -5.2 for the low- and high-dose groups, respectively, and mean age 7.3 and 6.......6 y. RESULTS: Mean growth velocity (baseline 4.5/4.6 cm/y for the groups) increased significantly by 1.9/3.6 cm/y during the first year and by 0.5/1.5 cm/y during the second year. During the third year, a decrease of growth velocity was observed at 1.9/1.3 cm/y below baseline values. HSDS increased...

  2. Achondroplasia is defined by recurrent G380R mutations of FGFR3

    Bellus, G.A.; Hefferon, T.W.; Luna, R.I.O. de; McIntosh, I. [Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States); Hecht, J.T. [Univ. of Texas Medical School, Houston, TX (United States); Horton, W.A.; Machado, M. [Shriners Hospital for Crippled Children, Portland, OR (United States); Kaitila, I. [Helsinki Univ. Hospital (Finland); Francomano, C.A. [Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States)]|[National Institutes of Health, Bethesda, MD (United States)

    1995-02-01

    Genomic DNA from 154 unrelated individuals with achondroplasia was evaluated for mutations in the fibroblast growth factor receptor 3 (FGFR3) transmembrane domain. All but one, an atypical case, were found to have a glycine-to-arginine substitution at codon 380. Of these, 150 had a G-to-A transition at nt 1138, and 3 had a G-to-C transversion at this same position. On the basis of estimates of the prevalence of achondroplasia, the mutation rate at the FGFR3 1138 guanosine nucleotide is two to three orders of magnitude higher than that previously reported for transversions and transitions in CpG dinucleotides. To date, this represents the most mutable single nucleotide reported in the human genome. The homogeneity of mutations in achondroplasia is unprecedented for an autosomal dominant disorder and may explain the relative lack of heterogeneity in the achondroplasia phenotype. 52 refs., 1 fig., 1 tab.

  3. A common FGFR3 gene mutation is present in achondroplasia but not in hypochondroplasia

    Stoilov, I.; Kilpatrick, M.W.; Tsipouras, P. [Univ. of Connecticut Health Center, Farmington, CT (United States)

    1995-01-02

    Achondroplasia is the most common type of genetic dwarfism. It is characterized by disproportionate short stature and other skeletal anomalies resulting from a defect in the maturation of the chondrocytes in the growth plate of the cartilage. Recent studies mapped the achondroplasia gene on chromosome region 4p16.3 and identified a common mutation in the gene encoding the fibroblast growth factor receptor 3 (FGFR3). In an analysis of 19 achondroplasia families from a variety of ethnic backgrounds we confirmed the presence of the G380R mutation in 21 of 23 achondroplasia chromosomes studied. In contrast, the G380R mutation was not found in any of the 8 hypochondroplasia chromosomes studied. Futhermore, linkage studies in a 3-generation family with hypochondroplasia show discordant segregation with markers in the 4p16.3 region suggesting that at least some cases of hypochondroplasia are caused by mutations in a gene other than FGFR3. 27 refs., 2 figs.

  4. Magnetic resonance evaluation of the knee in children and adolescents with achondroplasia

    Achondroplasia is the most common form of skeletal dysplasia. Although the radiographic features are well described, MRI features of the knee in achondroplasia have not been reported. To describe common MRI characteristics of the knee joint in symptomatic children and adolescents with achondroplasia. We retrospectively evaluated 10 knee MRI examinations in 8 children and young adults (age range 11-20 years, mean 16.3 years) with achondroplasia. We measured modified Insall-Salvati index, knee flexion angle, anterior cruciate ligament (ACL)-Blumensaat line angle, ACL-tibial angle, posterior cruciate ligament (PCL) angle, intercondylar notch width index, and intercondylar notch depth index. We compared our findings with an age- and gender-matched control group of 20 children (age range 15-18 years; mean 16 years) with normal knee MRIs. All 10 knees in the achondroplasia group had discoid lateral meniscus; 8 meniscal tears were identified. Patella baja was present in half of the study cases. Greater knee flexion and increased ACL-Blumensaat line and PCL angles were seen in all achondroplasia knees. ACL-tibial angle was similar in the study and in the control group. Children with achondroplasia had deeper A-shape femoral notches that extended more anteriorly than those seen in the control group. MRI findings were confirmed in all seven knees with arthroscopic correlation. Discoid lateral meniscus, often with tear, is a consistent feature in knee MRIs of symptomatic children and adolescents with achondroplasia. Other findings include patella baja, knee flexion, deep A-shape intercondylar notch, increased ACL-Blumensaat line angle and taut PCL. (orig.)

  5. Analysis of the chondroitin sulfate proteoglycan core protein (CSPGCP) gene in achondroplasia and pseudoachondroplasia.

    Finkelstein, J E; Doege, K; Yamada, Y; Pyeritz, R E; Graham, J M; Moeschler, J.B.; Pauli, R. M.; Hecht, J T; Francomano, C A

    1991-01-01

    Achondroplasia and pseudoachondroplasia are autosomal dominant skeletal dysplasias resulting in short-limbed dwarfism. Histologic and ultrastructural studies of the cartilage in pseudoachondroplasia and in homozygous achondroplasia have suggested a structural abnormality in chondroitin sulfate proteoglycan (CSPG), a major structural protein in the extra-cellular matrix. The gene encoding CSPG core protein (CSPGCP) is thus a logical "candidate gene" for analysis in these conditions. cDNA probe...

  6. A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3

    Wang, Yingcai; Spatz, Michal K.; Kannan, Karuppiah; Hayk, Hovhannisyan; Avivi, Aaron; Gorivodsky, Marat; Pines, Mark; Yayon, Avner; Lonai, Peter; Givol, David

    1999-01-01

    Achondroplasia, the most common form of dwarfism in man, is a dominant genetic disorder caused by a point mutation (G380R) in the transmembrane region of fibroblast growth factor receptor 3 (FGFR3). We used gene targeting to introduce the human achondroplasia mutation into the murine FGFR3 gene. Heterozygotes for this point mutation that carried the neo cassette were normal whereas neo+ homozygotes had a phenotype similar to FGFR3-deficient mice, exhibiting bone overgrowth. This was because o...

  7. Lumbar Nerve Root Occupancy in the Foramen in Achondroplasia: A Morphometric Analysis

    Modi, Hitesh N; Suh, Seung Woo; Song, Hae-Ryong; Yang, Jae Hyuk

    2008-01-01

    Lumbar stenosis is common in patients with achondroplasia because of narrowing of the neural canal. However, it is unclear what causes stenosis, narrowing of the central canal or foramina. We performed a morphometric analysis of the lumbar nerve roots and intervertebral foramen in 17 patients (170 nerve roots and foramina) with achondroplasia (eight symptomatic, nine asymptomatic) and compared the data with that from 20 (200 nerve roots and foramina) asymptomatic patients without achondroplas...

  8. Fixator-Assisted Lengthening and Deformity Correction Over an Intramedullary Nail in a Patient with Achondroplasia

    Erdal Uzun

    2014-01-01

    Achondroplasia is the most frequently encountered form of nonlethal skeletal dysplasia and a type of rhizomelic dwarfism. It results in considerable physical and psychologic handicaps owing to the disproportionate stature of the body and difficulty in performing routine activities of daily living. They also have major musculoskeletal problems including symptomatic malalignment of the lower limbs. Limb lengthening has been used in patients with achondroplasia by different techniques (Intramed...

  9. Achondroplasia manifesting as enchondromatosis and ossification of the spinal ligaments: a case report

    Al Kaissi Ali; Ganger Rudolf; Klaushofer Klaus; Rumpler Monika; Grill Franz

    2008-01-01

    Abstract Introduction A girl presented with achondroplasia manifested as mild knee pain associated with stiffness of her back. A skeletal survey showed enchondroma-like metaphyseal dysplasia and ossification of the spinal ligaments. Magnetic resonance imaging of the spine further clarified the pathological composites. Case presentation A 7-year-old girl presented with the classical phenotypic features of achondroplasia. Radiographic documentation showed the co-existence of metaphyseal enchond...

  10. Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis

    Chen, Lin; Adar, Rivka; Yang, Xiao; Monsonego, Efrat O.; Li, Cuiling; Hauschka, Peter V; Yayon, Avner; Deng, Chu-Xia

    1999-01-01

    Missense mutations in fibroblast growth factor receptor 3 (FGFR3) result in several human skeletal dysplasias, including the most common form of dwarfism, achondroplasia. Here we show that a glycine-to-cysteine substitution at position 375 (Gly375Cys) in human FGFR3 causes ligand-independent dimerization and phosphorylation of FGFR3 and that the equivalent substitution at position 369 (Gly369Cys) in mouse FGFR3 causes dwarfism with features mimicking human achondroplasia. Accordingly, homozyg...

  11. Treatment of Varus Deformities of the Lower Limbs in Patients with Achondroplasia and Hypochondroplasia

    Kaissi, Ali Al; Farr, Sebastian; Ganger, Rudolf; Hofstaetter, Jochen G; Klaushofer, Klaus; Grill, Franz

    2013-01-01

    Angular deformities of the lower limbs are a common clinical problem encountered in pediatric orthopaedic practices particularly in patients with osteochondrodysplasias. The varus deformity is more common than the valgus deformity in achondroplasia and hypochondroplasia patients because of the unusual growth of the fibulae than that of the tibiae. We retrospectively reviewed six patients (four patients with achondroplasia and two patients with hypochondroplsia) with relevant limb deformities ...

  12. Prospective assessment of risks for cervicomedullary-junction compression in infants with achondroplasia.

    Pauli, R. M.; Horton, V K; Glinski, L. P.; Reiser, C A

    1995-01-01

    Achondroplasia, the most common heritable skeletal dysplasia, may result in abnormality at the craniocervical junction, which is a potentially lethal problem in a subset of young infants with this disorder. We evaluated and followed an unbiased and unselected consecutive series of infants with achondroplasia, to better document the occurrence, frequency, and clinical presentation of craniocervical abnormalities. Of 53 prospectively ascertained infants, 5 were judged to have sufficient cranioc...

  13. Coronary artery surgery in a man with achondroplasia: a case report

    Daskalopoulos Marios E; Tsantsaridou Angeliki; Desimonas Nicholas; Baddour Andony J; Karangelis Dimos; Tagarakis Georgios I; Papadopoulos Dimitrios; Tsilimingas Nikolaos B

    2010-01-01

    Abstract Introduction Achondroplasia is a musculoskeletal disorder associated with short stature. Despite an estimated prevalence of 1:25,000 in the general population, there is little literature concerning the diagnostic and treatment challenges faced by doctors dealing with a heart operation on a patient with this condition. Case presentation We present the case of a 41-year-old Caucasian man of Greek ethnicity with achondroplasia, who underwent bypass heart surgery. Conclusions The surgery...

  14. Magnetic resonance evaluation of the knee in children and adolescents with achondroplasia

    Akyol, Yakup; Averill, Lauren W. [Nemours/Alfred I. duPont Hospital for Children, Department of Medical Imaging, Wilmington, DE (United States); Atanda, Alfred; Mackenzie, William G. [Nemours/Alfred I. duPont Hospital for Children, Department of Orthopedics, Wilmington, DE (United States); Kecskemethy, Heidi H. [Nemours/Alfred I. duPont Hospital for Children, Department of Medical Imaging, Wilmington, DE (United States); Nemours/Alfred I. duPont Hospital for Children, Department of Biomedical Research, Wilmington, DE (United States); Bober, Michael B. [Nemours/Alfred I. duPont Hospital for Children, Division of Genetics, Department of Pediatrics, Wilmington, DE (United States)

    2015-06-15

    Achondroplasia is the most common form of skeletal dysplasia. Although the radiographic features are well described, MRI features of the knee in achondroplasia have not been reported. To describe common MRI characteristics of the knee joint in symptomatic children and adolescents with achondroplasia. We retrospectively evaluated 10 knee MRI examinations in 8 children and young adults (age range 11-20 years, mean 16.3 years) with achondroplasia. We measured modified Insall-Salvati index, knee flexion angle, anterior cruciate ligament (ACL)-Blumensaat line angle, ACL-tibial angle, posterior cruciate ligament (PCL) angle, intercondylar notch width index, and intercondylar notch depth index. We compared our findings with an age- and gender-matched control group of 20 children (age range 15-18 years; mean 16 years) with normal knee MRIs. All 10 knees in the achondroplasia group had discoid lateral meniscus; 8 meniscal tears were identified. Patella baja was present in half of the study cases. Greater knee flexion and increased ACL-Blumensaat line and PCL angles were seen in all achondroplasia knees. ACL-tibial angle was similar in the study and in the control group. Children with achondroplasia had deeper A-shape femoral notches that extended more anteriorly than those seen in the control group. MRI findings were confirmed in all seven knees with arthroscopic correlation. Discoid lateral meniscus, often with tear, is a consistent feature in knee MRIs of symptomatic children and adolescents with achondroplasia. Other findings include patella baja, knee flexion, deep A-shape intercondylar notch, increased ACL-Blumensaat line angle and taut PCL. (orig.)

  15. Mutations in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome.

    Wilkin, D J; Szabo, J K; Cameron, R; Henderson, S; Bellus, G A; Mack, M L; Kaitila, I; Loughlin, J.; Munnich, A; Sykes, B; Bonaventure, J.; Francomano, C A

    1998-01-01

    More than 97% of achondroplasia cases are caused by one of two mutations (G1138A and G1138C) in the fibroblast growth factor receptor 3 (FGFR3) gene, which results in a specific amino acid substitution, G380R. Sporadic cases of achondroplasia have been associated with advanced paternal age, suggesting that these mutations occur preferentially during spermatogenesis. We have determined the parental origin of the achondroplasia mutation in 40 sporadic cases. Three distinct 1-bp polymorphisms we...

  16. De novo achondroplasia causing four consecutive unsuccessful pregnancies: a case report

    Igwegbe Anthony

    2012-08-01

    Full Text Available Abstract Introduction The incidence of achondroplasia is very low, and the birth of two or more consecutive babies with achondroplasia to unaffected parents is a rarity. We report a rare case of recurrent achondroplasia in babies of unaffected parents. Case presentation A 29-year-old Nigerian Igbo woman who has had three consecutive dead achondroplastic babies presented at a gestational age of 31 weeks with a two-hour history of drainage of liquor and vaginal bleeding. Neither she nor her husband had features of achondroplasia. Fundal height was compatible with the gestational age. Fetal heart activity was present. An abdominal ultrasound examination showed a viable fetus with short long bones, oligohydramnios, and a fundal placenta with a small retroplacental blood clot. Our patient was stabilized and had an emergency Cesarean section for grade 1 abruptio placentae. A live male baby with Apgar scores of 4 at one minute and 5 at 10 minutes was delivered. The baby had classic features of achondroplasia and died shortly after birth. Conclusions To the best of our knowledge, this is the first reported case of recurrent achondroplasia in siblings of unaffected parents in Nigeria. Management is challenging, and the outcomes of future pregnancies appear bleak. However, proper counseling and follow-up are needed. There is also a need to establish preconception clinics and facilities for prenatal genetic diagnosis and gene therapy in developing countries.

  17. A case report of recurrent achondroplasia in fetuses of normal parents

    Anbumani TL

    2015-06-01

    Full Text Available Achondroplasia, a skeletal dysplasia has an incidence of 1 in 15000 to 1 in 30000 live births. It is inherited in an autosomal dominant manner. The occurrence of recurrent achondroplasia in babies born to normal parents is rare. The present case report is one such type. A female fetus of 27 weeks gestational age was brought to the Department of Anatomy, Karpaga Vinayaga Institute of Medical Sciences, Maduranthagam. There was frontal bossing of forehead, rhizomelic type of limb shortening with limitation of elbow extension in the fetus. The mother of the fetus, who is 26 years old, gave history of recurrence of such condition. Her first pregnancy was a twin pregnancy, conceived by natural methods, where one of the twins was a male baby who also had achondroplasia and died 2 hours after delivery. The other twin is a girl and the child has delayed developmental milestones. Her second pregnancy was uneventful. The present fetus under study is from her third pregnancy. Her marriage is of second degree consanguineous type. The age of her husband is 36 years old. Germinal mosaicism has been attributed for the causation of recurrent achondroplasia in children, whose parents are normal. 80% of achondroplasia is due to a new mutation. Only 20% of achondroplasia is inherited. Increased paternal age is a risk factor for new mutations to occur. The other investigations of the case and the genetic analysis are described further in the article. [Int J Res Med Sci 2015; 3(6.000: 1533-1537

  18. Effect of the G375C and G346E achondroplasia mutations on FGFR3 activation.

    Lijuan He

    Full Text Available Two mutations in FGFR3, G380R and G375C are known to cause achondroplasia, the most common form of human dwarfism. The G380R mutation accounts for 98% of the achondroplasia cases, and thus has been studied extensively. Here we study the effect of the G375C mutation on the phosphorylation and the cross-linking propensity of full-length FGFR3 in HEK 293 cells, and we compare the results to previously published results for the G380R mutant. We observe identical behavior of the two achondroplasia mutants in these experiments, a finding which supports a direct link between the severity of dwarfism phenotypes and the level and mechanism of FGFR3 over-activation. The mutations do not increase the cross-linking propensity of FGFR3, contrary to previous expectations that the achondroplasia mutations stabilize the FGFR3 dimers. Instead, the phosphorylation efficiency within un-liganded FGFR3 dimers is increased, and this increase is likely the underlying cause for pathogenesis in achondroplasia. We further investigate the G346E mutation, which has been reported to cause achondroplasia in one case. We find that this mutation does not increase FGFR3 phosphorylation and decreases FGFR3 cross-linking propensity, a finding which raises questions whether this mutation is indeed a genetic cause for human dwarfism.

  19. Impact of three genetic musculoskeletal diseases: a comparative synthesis of achondroplasia, Duchenne muscular dystrophy and osteogenesis imperfecta

    Dogba, Maman Joyce; Rauch, Frank; Douglas, Erin; Bedos, Christophe

    2014-01-01

    Achondroplasia, Duchenne muscular dystrophy, and osteogenesis imperfecta are among the most frequent rare genetic disorders affecting the musculoskeletal system in children. Rare genetic disorders are severely disabling and can have substantial impacts on families, children, and on healthcare systems. This literature review aims to classify, summarize and compare these non-medical impacts of achondroplasia, Duchenne muscular dystrophy and osteogenesis imperfecta.

  20. Limb shortening osteotomy in a patient with achondroplasia and leg length difference after total hip arthroplasty

    Christian L. Galata

    2013-07-01

    Full Text Available Introduction: Achondroplasia is the most common reason for disproportionate short stature. Normally, orthopedic limb lengthening procedures must be discussed in the course of this genetic disorder and have been successful in numerous achondroplastic patients in the past. In some cases, the disease may lead to leg length differences with need for surgical correction. Case Report: We report a case of achondroplastic dysplastic coxarthrosis with symptomatic leg length difference after bilateral total hip arthroplasty in a 52-year-old female patient, in which a distal femoral shortening osteotomy was successfully performed. Conclusion: Femoral shortening osteotomy is very uncommon in patients with achondroplasia. We conclude, however, that in rare cases it can be indicated and provide the advantage of shorter operation time, less perioperative complications and faster recovery compared to leg lengthening procedures. Keywords: Achondroplasia, dysplastic coxarthrosis, limb shortening, distal femur osteotomy.

  1. Achondroplasia is defined by recurrent G380R mutations of FGFR3.

    Bellus, G A; Hefferon, T W; Ortiz de Luna, R I; Hecht, J T; Horton, W A; Machado, M.; Kaitila, I; McIntosh, I; Francomano, C A

    1995-01-01

    Genomic DNA from 154 unrelated individuals with achondroplasia was evaluated for mutations in the fibroblast growth factor receptor 3 (FGFR3) transmembrane domain. All but one, an atypical case, were found to have a glycine-to-arginine substitution at codon 380. Of these, 150 had a G-to-A transition at nt 1138, and 3 had a G-to-C transversion at this same position. On the basis of estimates of the prevalence of achondroplasia, the mutation rate at the FGFR3 1138 guanosine nucleotide is two to...

  2. Age-related X-ray feature of the spine in patients with achondroplasia

    Age-related X-ray features of the spine in patients with achondroplasia are studied. It gives the time course of changes in the shape of vertebrae, the specific features of apophyseal ossification, provides a quantitative account of the shorter caudal lumbar vertebral arch root distance symptom. The time course of changes in the size of the lumbosacral angle was examined. The findings suggest that there are not only considerable static changes in the spine of patients with achondroplasia, but also significant age-related features of vertebral tissue growth and differentiation

  3. A case report of recurrent achondroplasia in fetuses of normal parents

    Anbumani TL; Anthony Ammal S; Thamarai Selvi .A

    2015-01-01

    ABSTRACT Achondroplasia, a skeletal dysplasia has an incidence of 1 in 15000 to 1 in 30000 live births. It is inherited in an autosomal dominant manner. The occurrence of recurrent achondroplasia in babies born to normal parents is rare. The present case report is one such type. A female fetus of 27 weeks gestational age was brought to the Department of Anatomy, Karpaga Vinayaga Institute of Medical Sciences, Maduranthagam. There was frontal bossing of forehead, rhizome...

  4. C-Type Natriuretic Peptide Analog as Therapy for Achondroplasia.

    Legeai-Mallet, Laurence

    2016-01-01

    Fibroblast growth factor receptor 3 (FGFR3) is an important regulator of bone formation. Gain-of-function mutations in the FGFR3 gene result in chondrodysplasias which include achondroplasia (ACH), the most common form of dwarfism, in which skull, appendicular and axial skeletons are affected. The skeletal phenotype of patients with ACH showed defective proliferation and differentiation of the chondrocytes in the growth plate cartilage. Both endochondral and membranous ossification processes are disrupted during development. At cellular level, Fgfr3 mutations induce increased phosphorylation of the tyrosine kinase receptor FGFR3, which correlate with an enhanced activation of its downstream signaling pathways. Potential therapeutic strategies have emerged for ACH. Several preclinical studies have been conducted such as the C-type natriuretic peptide (CNP) analog (BMN111), intermittent parathyroid hormone injections, soluble FGFR3 therapy, and meclozine and statin treatments. Among the putative targets to antagonize FGFR3 signaling, CNP (or BMN111) is one of the most promising strategies. BMN111 acts as a key regulator of longitudinal bone growth by downregulating the mitogen-activated protein kinase pathway, which is activated as a result of a FGFR3 gain-of-function mutation. Preclinical studies showed that BMN111 treatment led to a large improvement in skeletal parameters in Fgfr3Y367C/+ mice mimicking ACH. In 2014, a clinical trial (phase 2) of BMN111 in pediatric patients with ACH has started. This first clinical trial marks the first big step towards real treatment for these patients. PMID:26684019

  5. Rotational profile of the lower extremity in achondroplasia: computed tomographic examination of 25 patients

    Song, Hae-Ryong; Suh, Seung-Woo [Korea University Guro Hospital, Department of Orthopaedic Surgery, Rare Diseases Institute, Seoul (Korea); Choonia, Abi-Turab [Laud Clinic, Department of Orthopaedic Surgery, Mumbai (India); Hong, Suk Joo; Cha, In Ho [Korea University Guro Hospital, Department of Radiology, Seoul (Korea); Lee, Seok-Hyun [Dongguk University Ilsan Buddist Hospital, Department of Orthopaedic Surgery, Goyang (Korea); Park, Jong-Tae [Korea University Ansan Hospital, Department of Occupational and Enviornmental Medicine, Ansan (Korea)

    2006-12-15

    To evaluate lower-extremity rotational abnormalities in subjects with achondroplasia using computed tomography (CT) scans. CT scans were performed in 25 subjects with achondroplasia (13 skeletally immature, mean age 8.7 years; 12 skeletally mature, mean age 17.6 years). In a total of 50 bilateral limbs, CT images were used to measure the angles of acetabular anteversion, femoral anteversion, and tibial external torion. Measurement was performed by three examiners and then repeated by one examiner. Inter- and intraobserver agreements were analyzed, and results were compared with previously reported normal values. Mean values for skeletally immature and skeletally mature subjects were 13.6{+-}7.5 and 21.5{+-}6.4 respectively for acetabular anteversion, 27.1{+-}20.8 and 30.5{+-}20.1 for femoral torsion, and 21.6{+-}10.6 and 22.5{+-}10.8 for tibial torsion. Intra- and interobserver agreements were good to excellent. Acetabular anteversion and femoral anteversion in skeletally mature subjects were greater than normal values in previous studies. Both skeletally immature and mature subjects with achondroplasia had decreased tibial torsion compared to normal skeletally immature and mature subjects. Lower-extremity rotational abnormalities in subjects with achondroplasia include decreased tibial external torsion in both skeletally immature and mature subjects, as well as increased femoral and acetabular anteversion in skeletally mature subjects. (orig.)

  6. Is there a correlation between sleep disordered breathing and foramen magnum stenosis in children with achondroplasia?

    White, Klane K; Parnell, Shawn E; Kifle, Yemiserach; Blackledge, Marcella; Bompadre, Viviana

    2016-01-01

    Children with achondroplasia have midface hypoplasia, frontal bossing, spinal stenosis, rhizomelia, and a small foramen magnum. Central sleep apnea, with potential resultant sudden death, is thought to be related to compression of the spinal cord at the cervicomedullary junction in these patients. Screening polysomnography and/or cervical spine MRI are often performed for infants with achondroplasia. Decompressive suboccipital craniectomy has been performed in selected cases. We aim to better delineate the relationship between polysomnography, cervical spine MRI, and indications for surgical decompression in achondroplasia.We retrospectively review electronic medical records of all children with achondroplasia in our IRB-approved skeletal dysplasia registry who had received screening polysomnography and cervical spine MRI examination was performed. We explored correlations of polysomnography, MRI parameters, and need for decompressive surgery. Seventeen patients with both polysomnography and MRI of the cervical spine met inclusion criteria. The average age at time of the sleep study was 2.4 ± 3.6 years. An abnormal apnea-hypopnea index was found in all patients, with central sleep apnea found in 6/17. Five patients (29%) required foramen magnum decompression. We found no statistically significant correlation between central sleep apnea and abnormal MRI findings suggestive of foramen magnum stenosis. Screening polysomnography is an important tool but does not appear to correlate with MRI findings of foramen magnum stenosis. Cord compression, with either associated T2 cord signal abnormality or clinical findings of clonus, was most predictive of subsequent surgical decompression. PMID:26394798

  7. Roentgenodiagnostics of soft tissue condition in achondroplasia cases in limb lengthening after Ilizarov

    Muscles and subcutaneous cellular tissue of upper and lower limbs have been studied in 14 patients with achondroplasia treated after Ilizarov in various periods of lengthening employing contrast roentgenography. The technique applied has allowed to reveal anatomic and topographic features of muscles and subcutaneous cellular tissue in achodroplasia cases and observe changes of morphological parameters in different stages of elongation. 8 refs.; 8 figs

  8. Rotational profile of the lower extremity in achondroplasia: computed tomographic examination of 25 patients

    To evaluate lower-extremity rotational abnormalities in subjects with achondroplasia using computed tomography (CT) scans. CT scans were performed in 25 subjects with achondroplasia (13 skeletally immature, mean age 8.7 years; 12 skeletally mature, mean age 17.6 years). In a total of 50 bilateral limbs, CT images were used to measure the angles of acetabular anteversion, femoral anteversion, and tibial external torion. Measurement was performed by three examiners and then repeated by one examiner. Inter- and intraobserver agreements were analyzed, and results were compared with previously reported normal values. Mean values for skeletally immature and skeletally mature subjects were 13.6±7.5 and 21.5±6.4 respectively for acetabular anteversion, 27.1±20.8 and 30.5±20.1 for femoral torsion, and 21.6±10.6 and 22.5±10.8 for tibial torsion. Intra- and interobserver agreements were good to excellent. Acetabular anteversion and femoral anteversion in skeletally mature subjects were greater than normal values in previous studies. Both skeletally immature and mature subjects with achondroplasia had decreased tibial torsion compared to normal skeletally immature and mature subjects. Lower-extremity rotational abnormalities in subjects with achondroplasia include decreased tibial external torsion in both skeletally immature and mature subjects, as well as increased femoral and acetabular anteversion in skeletally mature subjects. (orig.)

  9. Lethal skeletal dysplasia owing to double heterozygosity for achondroplasia and spondyloepiphyseal dysplasia congenita.

    Young, I D; Ruggins, N R; Somers, J M; Zuccollo, J M; N. Rutter

    1992-01-01

    A male infant with lethal short limbed dwarfism is described. His father had spondyloepiphyseal dysplasia congenita and his mother had achondroplasia. It is believed that the infant inherited both of these disorders and that their combined effects resulted in early death owing primarily to severe pulmonary hypoplasia.

  10. Evidence against the structural gene encoding type II collagen (COL2A1) as the mutant locus in achondroplasia.

    Ogilvie, D.; Wordsworth, P; Thompson, E.; Sykes, B

    1986-01-01

    The structure of the locus encoding the major cartilage collagen gene (COL2A1) was studied in a total of 19 cases of achondroplasia. No gross rearrangements were seen. The segregation of COL2A1 was examined in three affected kindreds using restriction site and length variants as genetic markers. In two kindreds discordant segregation between the achondroplasia and COL2A1 loci was demonstrated. Paternity/maternity was confirmed using a 'minisatellite' core sequence probe which reveals cross hy...

  11. Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia.

    Webster, M K; Donoghue, D J

    1996-01-01

    Achondroplasia, the most common genetic form of dwarfism, is an autosomal dominant disorder whose underlying mechanism is a defect in the maturation of the cartilage growth plate of long bones. Achondroplasia has recently been shown to result from a Gly to Arg substitution in the transmembrane domain of the fibroblast growth factor receptor 3 (FGFR3), although the molecular consequences of this mutation have not been investigated. By substituting the transmembrane domain of the Neu receptor t...

  12. A high-resolution linkage map of the achondroplasia critical region on human chromosome 4q16.3

    Tiller, G.E.; Polumbo, P.A. [Vanderbilt Univ. School of Medicine, Nashville, TN (United States)

    1994-09-01

    Achondroplasia is the most common nonlethal skeletal dysplasia, with an incidence of greater than 1/40,000 births. Recently, a random search of the genome using highly polymorphic autosomal markers has localized the gene for achondroplasia to the distal portion of human chromosome 4p. We report here the construction of a high-resolution linkage map of the critical region including the achondroplasia locus. The CEPH panel of pedigrees was genotyped at several loci using highly polymorphic markers, including the Huntington locus (IT15), D4S43, D4S115, and the gene for the {beta}-subunit of rod cGMP phosphodiesterase (PDEB). These data were incorporated into the CEPH v.6.6 database and a multipoint map was generated using the LINKAGE programs v.5.1. Based on reported recombination events in achondroplasia pedigrees, the gene for achondroplasia lies distal to the anonymous marker D4S43, in the 8 cM region defined as follows: cen-IT15-D4S43-D4S98-[D4S115-D4S111]-D4S90-PDEB. The disparity between the genetic distance and the physical distance (2 mB) among these markers likely reflects the high rate of recombination within the region. Extension of this linkage map further toward the telomere and identification of distal recombinant markers should expedite efforts directed toward isolation of the gene for achondroplasia.

  13. Limb shortening osteotomy in a patient with achondroplasia and leg length difference after total hip arthroplasty

    Galata, Christian L.; Rieger, Bertram; Friederich, Niklaus F.

    2013-01-01

    Introduction: Achondroplasia is the most common reason for disproportionate short stature. Normally, orthopedic limb lengthening procedures must be discussed in the course of this genetic disorder and have been successful in numerous achondroplastic patients in the past. In some cases, the disease may lead to leg length differences with need for surgical correction. Case Report: We report a case of achondroplastic dysplastic coxarthrosis with symptomatic leg length difference after bilateral total hip arthroplasty in a 52-year-old female patient, in which a distal femoral shortening osteotomy was successfully performed. Conclusion: Femoral shortening osteotomy is very uncommon in patients with achondroplasia. We conclude, however, that in rare cases it can be indicated and provide the advantage of shorter operation time, less perioperative complications and faster recovery compared to leg lengthening procedures. PMID:27298915

  14. Deceleration in maturation of bone during adolescent age in achondroplasia - a retrospective study using RUS scoring system

    Knowledge of bone age in achondroplasia is required for the prediction of adult height, timings of limb lengthening, and epiphysiodesis procedures. The purpose of this investigation was to determine the differences in skeletal age in achondroplasia and a control population with the Tanner-Whitehouse 3 method using the RUS score and to determine the right age for the interventional procedure for limb lengthening procedure or deformity correction in these patients. Left hand radiographs of 34 patients (age range, 5-18 years) with achondroplasia were evaluated for skeletal age using the RUS scoring system, which were compared with the left hand radiographs of 41 patients (age range, 5-18 years) without achondroplasia measuring skeletal age. The difference in chronological age and RUS bone age were evaluated statistically according to gender and age group. In the achondroplasia group, chronological age were 10.5±4.3 years for males and 10.1±3.6 years for females and RUS bone age were 9.2±4.0 years for males and 8.9±3.4 years for females, which showed statistically significantly difference (males p=0.0003 and females p 10 years in the study group, while 0.1±1.1 for 10 years in the control group, which also showed >statistically significant difference (10 years p10 years in achondroplasia patients compared to nonachondroplasia patients. We recommend the use of the Tanner-Whitehouse 3 method especially the radius, ulna, short bone score to measure the skeletal age and to wait for a longer time before interventional procedures in achondroplasia patients. (orig.)

  15. Achondroplasia manifesting as enchondromatosis and ossification of the spinal ligaments: a case report

    Al Kaissi Ali

    2008-08-01

    Full Text Available Abstract Introduction A girl presented with achondroplasia manifested as mild knee pain associated with stiffness of her back. A skeletal survey showed enchondroma-like metaphyseal dysplasia and ossification of the spinal ligaments. Magnetic resonance imaging of the spine further clarified the pathological composites. Case presentation A 7-year-old girl presented with the classical phenotypic features of achondroplasia. Radiographic documentation showed the co-existence of metaphyseal enchondromatosis and development of spinal bony ankylosis. Magnetic resonance imaging showed extensive ossification of the anterior and posterior spinal ligaments. Additional features revealed by magnetic resonance imaging included calcification of the peripheral vertebral bodies associated with anterior end-plate irregularities. Conclusion Enchondromas are metabolically active and may continue to grow and evolve throughout the patient's lifetime; thus, progressive calcification over a period of years is not unusual. Ossification of the spinal ligaments has a specific site of predilection and often occurs in combination with senile ankylosing vertebral hyperostosis. Nevertheless, ossification of the spinal ligaments has been encountered in children with syndromic malformation complex. It is a multifactorial disease in which complex genetic and environmental factors interact, potentially leading to chronic pressure on the spinal cord and nerve roots with subsequent development of myeloradiculopathy. Our patient presented with a combination of achondroplasia, enchondroma-like metaphyseal dysplasia and calcification of the spinal ligaments. We suggest that the development of heterotopic bone formation along the spinal ligaments had occurred through an abnormal ossified enchondral mechanism. We postulate that ossification of the spinal ligaments and metaphyseal enchondromatous changes are related to each other and represent impaired terminal differentiation of

  16. Aspects of achondroplasia in the skulls of dwarf transgenic mice: a cephalometric study.

    Bloom, Melissa Wadler; Murakami, Shunichi; Cody, Dianna; Montufar-Solis, Dina; Duke, Pauline Jackie

    2006-03-01

    Achondroplasia, the most common short-limbed dwarfism in humans, results from a single nucleotide substitution in the gene for fibroblast growth factor receptor 3 (FGFR3). FGFR3 regulates bone growth in part via the mitogen-activated protein kinase pathway (MAPK). To examine the role of this pathway in chondrocyte differentiation, a transgenic mouse was generated that expresses a constitutively active mutant of MEK1 in chondrocytes and exhibits dwarfing characteristics typical of human achondroplasia, i.e., shortened axial and appendicular skeletons, mid-facial hypoplasia, and dome-shaped cranium. In this study, cephalometrics of the MEK1 mutant skulls were assessed to determine if the MEK1 mice are a good model of achondroplasia. Skull length, arc of the cranial vault, and area, maximum and minimum diameters of the brain case were measured on digitized radiographs of skulls of MEK1 and control mice. Cranial base and nasal bone length and foramen magnum diameter were measured on midsagittal micro-CT sections. Data were normalized by dividing by the cube root of each animal's weight. Transgenic mice exhibited a domed skull, deficient midface, and (relatively) prognathic mandible and had a shorter cranial base and nasal bone than the wild-type. Skull length was significantly less in transgenic mice, but cranial arc was significantly greater. The brain case was larger and more circular and minimum diameter of the brain case was significantly greater in transgenic mice. The foramen magnum was displaced anteriorly but not narrowed. MEK1 mouse cephalometrics confirm these mice as a model for achondroplasia, demonstrating that the MAP kinase signaling pathway is involved in FGF signaling in skeletal development. PMID:16463380

  17. Intraoperative Computed Tomography for Cervicomedullary Decompression of Foramen Magnum Stenosis in Achondroplasia: Two Case Reports

    Arishima, Hidetaka; Tsunetoshi, Kenzo; KODERA, Toshiaki; Kitai, Ryuhei; Takeuchi, Hiroaki; Kikuta, Ken-ichiro

    2013-01-01

    The authors report two cases of cervicomedullary decompression of foramen magnum (FM) stenosis in children with achondroplasia using intraoperative computed tomography (iCT). A 14-month-old girl with myelopathy and retarded motor development, and a 10-year-old girl who had already undergone incomplete FM decompression was presented with myelopathy. Both patients underwent decompressive sub-occipitalcraniectomy and C1 laminectomy without duraplasty using iCT. It clearly showed the extent of FM...

  18. Alternative technique in atypical spinal decompression: the use of the ultrasonic scalpel in paediatric achondroplasia.

    Woodacre, Timothy; Sewell, Matthew; Clarke, Andrew J; Hutton, Mike

    2016-01-01

    Spinal stenosis can be a very disabling condition. Surgical decompression carries a risk of dural tear and neural injury, which is increased in patients with severe stenosis or an atypical anatomy. We present an unusual case of symptomatic stenosis secondary to achondroplasia presenting in a paediatric patient, and highlight a new surgical technique used to minimise the risk of dural and neural injury during decompression. PMID:27288205

  19. EMERGENC Y CAESARIAN SECTION IN A PATIENT WITH ACHONDROPLASIA : A CASE REPORT

    Praveen Kumar; Srinivasa Rao; Nagarjun Reddy

    2015-01-01

    The word Achondroplasia literally means “Without Cartilage Formation ” . It results from abnormal cartilage formation at epiphyseal growth plates. It is the most common form of short limbed dwarfism. Since it is a congenital short statured disease patient can have respiratory, neurological and cardiac problems associated with and poses many challenges to anaesthesiologists to choose best anaesthetic choice. CASE REPORT: A 27 year s old parturient with short st...

  20. Neutron Diffraction Studies of Fluid Bilayers with Transmembrane Proteins: Structural Consequences of the Achondroplasia Mutation

    Han, Xue; Mihailescu, Mihaela; Hristova, Kalina

    2006-01-01

    Achondroplasia, the most common form of human dwarfism, is due to a G380R mutation in the transmembrane domain of fibroblast growth factor receptor 3 (FGFR3) in >97% of the studied cases. While the molecular mechanism of pathology induction is under debate, the structural consequences of the mutation have not been studied. Here we use neutron diffraction to determine the disposition of FGFR3 transmembrane domain in fluid lipid bilayers, and investigate whether the G380R mutation affects the t...

  1. HOMOLOGY MODELLING AND DOCKING STUDIES OF FGFR3 PROTEIN TO SEARCH MOST EFFECTIVE DRUG AGAINST ACHONDROPLASIA

    Chauhan Nutan; Ahmad Faizan; Siddiqui M. A; Amir Asad; Singh Priyansha; Sahu Sarika

    2010-01-01

    The present investigation was carried out with the aim of modeling the 3D structure of FGFR3 protein and predicting the most effective drug using SU5402 and its analogues. FGFR3 protein, responsible for long bone growth, causes Achondroplasia in H. sapiens when it becomes mutated. When mutated, the dimmer of FGFR3 stabilizes without interacting with its ligand results in constitutive activation of downstream pathway and inhibits the bone growth. No known structure of FGFR3 was available. The ...

  2. Limb shortening osteotomy in a patient with achondroplasia and leg length difference after total hip arthroplasty

    Galata, Christian L.; Bertram Rieger; Friederich, Niklaus F

    2013-01-01

    Introduction: Achondroplasia is the most common reason for disproportionate short stature. Normally, orthopedic limb lengthening procedures must be discussed in the course of this genetic disorder and have been successful in numerous achondroplastic patients in the past. In some cases, the disease may lead to leg length differences with need for surgical correction. Case Report: We report a case of achondroplastic dysplastic coxarthrosis with symptomatic leg length difference after bilater...

  3. Concomitant achondroplasia and Chiari II malformation: A double-hit at the cervicomedullary junction

    Awad, Al-Wala; Aleck, Kyrieckos A.; Bhardwaj, Ratan D

    2014-01-01

    We report the first case of a neonate with concurrent Chiari II malformation and achondroplasia. Although rare, both these conditions contribute to several deleterious anatomical changes at the cervicomedullary junction and thus predispose to acute hydrocephalus. Although our patient was initially asymptomatic, hydrocephalus ensued several weeks after birth and required cerebral spinal fluid diversion. We discuss the potential links between the two conditions, the pathophysiology, and the imp...

  4. Physical Basis behind Achondroplasia, the Most Common Form of Human Dwarfism*

    He, Lijuan; Horton, William; Hristova, Kalina

    2010-01-01

    Fibroblast growth factor receptor 3 (FGFR3) is a receptor tyrosine kinase that plays an important role in long bone development. The G380R mutation in FGFR3 transmembrane domain is known as the genetic cause for achondroplasia, the most common form of human dwarfism. Despite many studies, there is no consensus about the exact mechanism underlying the pathology. To gain further understanding into the physical basis behind the disorder, here we measure the activation of wild-type and mutant FGF...

  5. Defective lysosomal targeting of activated fibroblast growth factor receptor 3 in achondroplasia

    Cho, Jay Y.; Guo, Changsheng; Torello, Monica; Lunstrum, Gregory P.; Iwata, Tomoko; Deng, Chuxia; Horton, William A.

    2003-01-01

    Mutations of fibroblast growth factor receptor 3 (FGFR3) are responsible for achondroplasia (ACH) and related dwarfing conditions in humans. The pathogenesis involves constitutive activation of FGFR3, which inhibits proliferation and differentiation of growth plate chondrocytes. Here we report that activating mutations in FGFR3 increase the stability of the receptor. Our results suggest that the mutations disrupt c-Cbl-mediated ubiquitination that serves as a targeting signal for lysosomal de...

  6. Best practices in the evaluation and treatment of foramen magnum stenosis in achondroplasia during infancy.

    White, Klane K; Bompadre, Viviana; Goldberg, Michael J; Bober, Michael B; Campbell, Jeffrey W; Cho, Tae-Joon; Hoover-Fong, Julie; Mackenzie, William; Parnell, Shawn E; Raggio, Cathleen; Rapoport, David M; Spencer, Samantha A; Savarirayan, Ravi

    2016-01-01

    Achondroplasia is the most common inherited disorder of bone growth (skeletal dysplasia). Despite this fact, consistent and evidence-based management approaches to recognized, life-threatening complications, such as foramen magnum stenosis, are lacking. This study aims to outline best practice, based on evidence and expert consensus, regarding the diagnosis, assessment, and management of foramen magnum stenosis in achondroplasia during infancy. A panel of 11 multidisciplinary international experts on skeletal dysplasia was invited to participate in a Delphi process. They were: 1) presented with a list of 26 indications and a thorough literature review, 2) given the opportunity to anonymously rate the indications and discuss in face to face discussion; 3) edit the list and rate it in a second round. Those indications with more than 80% agreement were considered as consensual. After two rounds of rating and a face-to-face meeting, consensus was reached to support 22 recommendations for the evaluation and treatment of foramen magnum stenosis in infants with achondroplasia. These recommendations include indications for surgical decompression, ventriculomegaly, and hydrocephalus, sleep-disordered breathing, physical exams and the use of polysomnography and imaging in this condition. We present a consensus-based best practice guidelines consisting of 22 recommendations. It is hoped that these guidelines will lead to more uniform and structured evaluation, standardizing care pathways, and improving mortality and morbidity outcomes for this cohort. PMID:26394886

  7. Achondroplasia and hypochondroplasia. Comments on frequency, mutation rate, and radiological features in skull and spine.

    Oberklaid, F; Danks, D M; Jensen, F; Stace, L; Rosshandler, S

    1979-04-01

    An attempt was made to ascertain all the dwarfs in the State of Victoria. The incidence of achondroplasia proved to be approximately 1 in 26,000 live births in the period 1969 to 1975 when ascertainment was nearly complete. This indicates a mutation rate of 1.93 X 10(-5) per generation in this locus. Paternal age was shown to influence mutation. Ascertainment in earlier years of the study was low despite the very great effort made to find all cases. Patients with hypochondroplasia were particularly difficult to find. However, 25 cases were found for study. Overlap between hypochondroplasia and achondroplasia was found in all features except the facial appearance (which was the basis of definition). Achondroplasia was more severe in all regards, but some individuals with hypochondroplasia were very short and some had extreme degrees of spinal canal stenosis. The classical measurements used to describe the skull changes in acondroplasia failed to distinguish this condition from hypochondroplasia. More efficient indices were devised, but visual assessment of the size of the facial region compared to that of the cranial valult proved more reliable than any index. The clinical distinction based upon facial appearance remains the arbitrary basis of definition. PMID:458831

  8. The sagging rope sign in achondroplasia - different from Perthes' disease

    Shingade, Viraj U. [Korea University, Department of Paediatric Orthopaedics, College of Medicine, Guro Hospital, Seoul (Korea); Song, Hae-Ryong [Korea University, Department of Paediatric Orthopaedic Surgery, College of Medicine, Guro Hospital, Seoul (Korea); Lee, Seok-Hyun; Suh, Seung-Woo [Korea University, Department of Orthopaedic Surgery, College of Medicine, Guro Hospital, Seoul (Korea); Oh, Chang-Wug [Kyungpook National University Hospital, Department of Orthopaedic Surgery, Daegu (Korea); Hong, Jun-Seok [Ansan Hospital, Department of Orthopaedic Surgery, Korea University, Ansan, Gyeonggi do (Korea)

    2006-12-15

    The sagging rope sign is a radio-opaque line, seen on radiographs of the hips, with Perthes' disease. The main purpose of this study was to determine the incidence, cause and importance of this sign in achondroplasia, and to reveal how it differs from in Perthes' disease. Serial radiograms, along with 2-dimensional and 3-dimensional CT images were studied in 42 achondroplasic patients. Forty-two achondroplasic patients, reported at our institute (for routine outpatient consultation, spine surgeries, deformity corrections, limb-lengthening procedures) were included in this study. There were 26 males and 16 females. The sign was observed bilaterally, in all patients. Evaluation of CT images revealed spherical heads, with presence of circumferential overhang in all hips. This circumferential overhang, seen on 3-D CT scan, corresponded to the sagging rope sign on radiographs. Presence of the sagging rope sign in bilateral hips is a characteristic feature of achondroplasia. It usually appears before epiphyseal closure. Its cause, incidence, and nature differ from Perthes' disease, and its presence does not carry a bad prognosis in achondroplasia. (orig.)

  9. EMERGENC Y CAESARIAN SECTION IN A PATIENT WITH ACHONDROPLASIA : A CASE REPORT

    Praveen Kumar

    2015-05-01

    Full Text Available The word Achondroplasia literally means “Without Cartilage Formation ” . It results from abnormal cartilage formation at epiphyseal growth plates. It is the most common form of short limbed dwarfism. Since it is a congenital short statured disease patient can have respiratory, neurological and cardiac problems associated with and poses many challenges to anaesthesiologists to choose best anaesthetic choice. CASE REPORT: A 27 year s old parturient with short stature (3 feet 8 inches weighing 45.5 Kgs came to the hospital in early labor with 37 weeks of gestation. Patient presen ting cephalopelvic disproportion and foetal distress. She had mild lumbar lordosis and very mild scoliosis and the patient known hypothyroid since the beginning of the pregnancy and on treatment. There is no previous history of exposure to anaesthesia and no previous surgical history. Family history reveals, no person in the family has got Achondroplasia. We used low dose Bupivacaine 1.2ml (6mg along with fentanyl 0.2ml of fentanyl (10 micrograms for spinal anaesthesia. First attempt was a dry tap followe d a successful spinal anaesthesia with adequate block achieved. CONCLUSION: In spite of not many case reports of spinal anaesthesia in Achondroplasia, spinal anaesthesia remains an appropriate option in emergency caesarian section.

  10. Association of achondroplasia with Down syndrome: difficulty in prenatal diagnosis by sonographic and 3-D helical computed tomographic analyses.

    Kaga, Akimune; Murotsuki, Jun; Kamimura, Miki; Kimura, Masato; Saito-Hakoda, Akiko; Kanno, Junko; Hoshi, Kazuhiko; Kure, Shigeo; Fujiwara, Ikuma

    2015-05-01

    Achondroplasia and Down syndrome are relatively common conditions individually. But co-occurrence of both conditions in the same patient is rare and there have been no reports of fetal analysis of this condition by prenatal sonographic and three-dimensional (3-D) helical computed tomography (CT). Prenatal sonographic findings seen in persons with Down syndrome, such as a thickened nuchal fold, cardiac defects, and echogenic bowel were not found in the patient. A prenatal 3-D helical CT revealed a large head with frontal bossing, metaphyseal flaring of the long bones, and small iliac wings, which suggested achondroplasia. In a case with combination of achondroplasia and Down syndrome, it may be difficult to diagnose the co-occurrence prenatally without typical markers of Down syndrome. PMID:25385298

  11. Deceleration in maturation of bone during adolescent age in achondroplasia - a retrospective study using RUS scoring system

    Lee, Suk-Ha [Konkuk University Hospital, Department of Orthopedics, Seoul (Korea); Modi, Hitesh N.; Suh, Seung Woo [Korea University Guro Hospital, Scoliosis Research Institute, Department of Orthopedics, Seoul (Korea); Song, Hae-Ryong; Hazra, Sunit; Modi, Chetna [Korea University Guro Hospital, Rare Disease Institute, Department of Orthopedics, Seoul (Korea)

    2009-02-15

    Knowledge of bone age in achondroplasia is required for the prediction of adult height, timings of limb lengthening, and epiphysiodesis procedures. The purpose of this investigation was to determine the differences in skeletal age in achondroplasia and a control population with the Tanner-Whitehouse 3 method using the RUS score and to determine the right age for the interventional procedure for limb lengthening procedure or deformity correction in these patients. Left hand radiographs of 34 patients (age range, 5-18 years) with achondroplasia were evaluated for skeletal age using the RUS scoring system, which were compared with the left hand radiographs of 41 patients (age range, 5-18 years) without achondroplasia measuring skeletal age. The difference in chronological age and RUS bone age were evaluated statistically according to gender and age group. In the achondroplasia group, chronological age were 10.5{+-}4.3 years for males and 10.1{+-}3.6 years for females and RUS bone age were 9.2{+-}4.0 years for males and 8.9{+-}3.4 years for females, which showed statistically significantly difference (males p=0.0003 and females p < 0.0001), while in the control group, chronological age were 11.1{+-}2.9 years for males and 10.7{+-}3.4 years for females and RUS bone age were 11.2{+-}3.4 years for males and 10.7{+-}3.3 years for females, which did not show statistically significantly difference (males p=0.54 and females p=0.76). Our finding suggested a delay of 1.4 years for males and 1.2 years for females in the maturation of bone in achondroplasia patients. Difference between chronological age and RUS bone age was 0.9{+-}1.1 for <10 years and 1.6{+-}0.9 for >10 years in the study group, while 0.1{+-}1.1 for <10 years and -0.2 {+-} 0.6 for >10 years in the control group, which also showed >statistically significant difference (<10 years p=0.04 and >10 years p<0.0001). These differences indicate that there was a delay in the maturation of bones by 1 year in the group <10

  12. MR imaging of the craniocervical junction, cranium, and brain in children with achondroplasia

    Ten children with achondroplasia underwent MR imaging of the craniocervical junction, cranium and brain. All patients had narrowing of the subarachnoid space at the level of foramen magnum with apparent upward displacement of the brain stem. Hydrocephalus was seen in five patients, bifrontal widening of subarachnoid space in four, skull asymmetry in two, and an empty sella in one. One patient showed abnormal signal in the central gray matter of the cervicomedullary region. MR is a noninvasive modality for the evaluation of cranial, cerebral, and cervicomedullary is achondroplastic children

  13. Favorable Growth Hormone Treatment Response in a Young Boy with Achondroplasia

    Krstevska-Konstantinova, Marina; Stamatova, Ana; Gucev, Zoran

    2016-01-01

    Background: Achondroplasia is a skeletal dysplasia, the most common cause of rhizomelic dwarfism. Case presentation: This is a ten year old boy who was first diagnosed prenatally. He had a mutation c1138G>A in the gene FGFR3 in a heterozygotic constellation. His IGF1 and IGFBP3 levels were normal. Two stimulation tests for growth hormone were performed with values within the reference range. His psychomotor development was adequate for his age except for speech difficulty. He started with rec...

  14. The observed human sperm mutation frequency cannot explain the achondroplasia paternal age effect

    Tiemann-Boege, Irene; Navidi, William; Grewal, Raji; Cohn, Dan; Eskenazi, Brenda; Wyrobek, Andrew J.; Arnheim, Norman

    2002-01-01

    The lifelong spermatogonial stem cell divisions unique to male germ cell production are thought to contribute to a higher mutation frequency in males. The fact that certain de novo human genetic conditions (e.g., achondroplasia) increase in incidence with the age of the father is consistent with this idea. Although it is assumed that the paternal age effect is the result of an increasing frequency of mutant sperm as a man grows older, no direct molecular measurement of the germ-line mutation ...

  15. Chest wall deformity and respiratory distress in a 17-year-old patient with achondroplasia: CT and MRI evaluation

    A marked thoracic deformity associated with intrathoracic tracheal narrowing was seen in a 17-year old with achondroplasia and dyspnea. The role of chest deformity and its evaluation by CT and MRI in achondroplastic patients with respiratory symptoms are considered. (orig.)

  16. Chest wall deformity and respiratory distress in a 17-year-old patient with achondroplasia: CT and MRI evaluation

    Herman, T.E.; Siegel, M.J.; McAlister, W.H. (Washington Univ. School of Medicine, St. Louis, MO (United States). Mallinckrodt Inst. of Radiology)

    1992-06-01

    A marked thoracic deformity associated with intrathoracic tracheal narrowing was seen in a 17-year old with achondroplasia and dyspnea. The role of chest deformity and its evaluation by CT and MRI in achondroplastic patients with respiratory symptoms are considered. (orig.).

  17. Achondroplasia with 47, xxy karyotype: a case report of the neonatal diagnosis of an extremely unusual association

    Ros-Pérez Purificación

    2012-06-01

    Full Text Available Abstract Background The association of achondroplasia and Klinefelter syndrome is extremely rare. To date, five cases have been previously reported, all of them diagnosed beyond the postnatal period, and only one was molecularly characterized. We describe the first case of this unusual association diagnosed in the neonatal period, the clinical findings and the molecular studies undertaken. Case presentation The boy was born at term with clinical and radiological features indicating the diagnosis of achondroplasia or hypochondroplasia combined with the prenatal karyotype of Klinefelter syndrome (47,XXY. Neonatal FGFR3 mutation screening showed that the newborn was heterozygous for the classic achondroplasia G340R mutation. Microsatellite marker analysis showed that the sex chromosome aneuploidy had arisen from a non-disjunction error in paternal meiosis I, with a recombination event in the pseudoautosomal region 1 (PAR1. Conclusion Specific mutation analysis is appropriate to confirm the clinical diagnosis of achondroplasia for appropriate diagnosis, prognosis, and genetic counseling, especially when the karyotype does not explain the abnormal prenatal sonographic findings. In the present case, a recombination event was observed in the PAR1 region, although recombinational events in paternally derived Klinefelter syndrome cases are much rarer than expected.

  18. Magnetic resonance imaging study determining cord level and occupancy at thoracolumbar junction in achondroplasia - A prospective study

    Hitesh N Modi

    2011-01-01

    Conclusion: Our results indicated high level of spinal cord in achondroplasia patients compared to nonachondroplasia individuals. High prevalence of neurological symptoms at TL level in such patients can be associated with high cord level and developing progressive kyphosis at TL level along with degenerative process.

  19. Achondroplasia among ancient populations of mesoamerica and South America: Iconographic and Archaeological Evidence.

    Rodríguez, Carlos A

    2012-09-01

    Full Text Available Introduction: Achondroplasia is the most frequent form of short-limb dwarfism. Affected individuals exhibit short stature caused by rhizomelic shortening of the limbs, characteristic facies with frontal bossing and mid-face hypoplasia, genu varum, and trident hand.Although the etiology of this disease was reported in 1994, evidence of this disease in ancient populations has been found in populations of ancient Egypt (2500 BC and it has been documented in ancient American populations. Objective: To analyze the presence of individuals with achondroplasia in the Mayan state society of Mexico and Guatemala, during the Classical (100-950 AC and Post-Classical (950 - 1519 AC periods; likewise, in the hierarchical-chieftain society of Tumaco-la Tolita (300 BC – 600 AC from the Colombia-Ecuador Pacific coast, and the Moche state society (100 - 600 AC from the northern coast of Peru.Materials and methods: Iconographic and clinical-morphological studies of some of the most important artistic representations of individuals of short stature in these three cultures. Conclusion: We present the hypothesis that the individuals with short stature were somehow associated with the political and religious power elite.

  20. Achondroplasia among ancient populations of mesoamerica and South America: Iconographic and Archaeological Evidence.

    Carlos A. Rodríguez

    2012-09-01

    Full Text Available 14.00 800x600 Normal 0 21 false false false ES-CO X-NONE X-NONE MicrosoftInternetExplorer4  Introduction: Achondroplasia is the most frequent form of short-limb dwarfism. Affected individuals exhibit short stature caused by rhizomelic shortening of the limbs, characteristic facies with frontal bossing and mid-face hypoplasia, genu varum, and trident hand. Although the etiology of this disease was reported in 1994, evidence of this disease in ancient populations has been found in populations of ancient Egypt (2500 BC and it has been documented in ancient American populations. Objective: To analyze the presence of individuals with achondroplasia in the Mayan state society of Mexico and Guatemala, during the Classical (100-950 AC and Post-Classical (950 - 1519 AC periods; likewise, in the hierarchical-chieftain society of Tumaco-la Tolita (300 BC – 600 AC from the Colombia-Ecuador Pacific coast, and the Moche state society (100 - 600 AC from the northern coast of Peru. Materials and methods: Iconographic and clinical-morphological studies of some of the most important artistic representations of individuals of short stature in these three cultures. Conclusion: We present the hypothesis that the individuals with short stature were somehow associated with the political and religious power elite.. 

  1. Droplet Digital PCR combined with minisequencing, a new approach to analyze fetal DNA from maternal blood: application to the non-invasive prenatal diagnosis of achondroplasia.

    Orhant, Lucie; Anselem, Olivia; Fradin, Mélanie; Becker, Pierre Hadrien; Beugnet, Caroline; Deburgrave, Nathalie; Tafuri, Gilles; Letourneur, Franck; Goffinet, François; Khattabi, Laïla Allach El; Leturcq, France; Bienvenu, Thierry; Tsatsaris, Vassilis; Nectoux, Juliette

    2016-01-01

    Achondroplasia is generally detected by abnormal prenatal ultrasound-findings in the third trimester of pregnancy, and then confirmed by molecular genetic testing of fetal genomic DNA obtained by aspiration of amniotic fluid. This invasive procedure presents a small but significant risk for both the fetus and mother. Therefore, non-invasive procedures using cell-free-fetal DNA in maternal plasma have been developed for the detection of the fetal achondroplasia mutations.MethodsTo determine wh...

  2. NMR images of non-communicating hydrocephalus associated with Dandy-Walker variant and achondroplasia

    Two cases of non-communicating hydrocephalus caused by a relatively rare etiology were reported. They were both diagnosed by means of nuclear magnetic resonance (NMR). The first patient, a 4-month-old boy, had Dandy-Walker variant, showing hypoplasia of the corpus callosum and the inferior vermis, and a large cyst behind the vermis, communicating with the subarachnoid space, as well as hydrocephalus; the fourth ventricle was partially reserved. The second patient, also a 4-month-old boy, had achondroplasia, resulting in a narrow foramen magnum; the disturbance of the outflow of the cerebro-spinal fluid around the cisterna magna was thought to be the cause of hydrocephalus in his case. The validity of NMR was demonstrated in the diagnoses of these conditions, for a high resolution was needed in examining the complicated structure of the posterior fossa. (author)

  3. NMR images of non-communicating hydrocephalus associated with Dandy-Walker variant and achondroplasia

    Sato, Masaharu; Kuroda, Ryotaro; Watanabe, Masaru; Nakatani, Jiro; Ioku, Masahiko; Irisawa, Minoru; Hamada, Tatsumi; Ishida, Osamu

    1988-06-01

    Two cases of non-communicating hydrocephalus caused by a relatively rare etiology were reported. They were both diagnosed by means of nuclear magnetic resonance (NMR). The first patient, a 4-month-old boy, had Dandy-Walker variant, showing hypoplasia of the corpus callosum and the inferior vermis, and a large cyst behind the vermis, communicating with the subarachnoid space, as well as hydrocephalus; the fourth ventricle was partially reserved. The second patient, also a 4-month-old boy, had achondroplasia, resulting in a narrow foramen magnum; the disturbance of the outflow of the cerebro-spinal fluid around the cisterna magna was thought to be the cause of hydrocephalus in his case. The validity of NMR was demonstrated in the diagnoses of these conditions, for a high resolution was needed in examining the complicated structure of the posterior fossa.

  4. [Achondroplasia: a pilot study on the psychosocial and medical features of a sample in Puerto Rico].

    Rodriguez-Gomez, José; Aldarondo, Ariadna; Vidot, Frances; Quiñones, Ana; Rivera, Maily; Cintrón, Eledy; Gonzilez, Natalie; Trujillo, Rodolfo F; Lopez-Cordova, Nanet M; Colón, Natalia

    2015-01-01

    This study explores the psychological wellbeing of twenty-two (n = 22) adults with achondroplasia. The sample was composed of seven (n = 7) males and fifteen (n = 15) females between the ages of 21 and 75 (mean age = 39.6). Each individual completed four self-administered questionnaires: the Beck Depression Inventory (BDI-l), the Beck Anxiety Inventory (BAI), the Beck Hopelessness Scale (BHS), and Derogatis Symptom Check-list-90-Revisited (SCL-90-R). They also filled out a socio-demographic questionnaire. We found that 31.8% of the sample reported at least one comorbid condition such as, hypertension, diabetes, rheumatoid arthritis, asthma, scoliosis, thyroid problems, neuropathy, psoriasis, gastritis and/or sleep apnea; 32% reported mild to severe depressive symp- toms; 55% reported mild to severe symptoms associated to anxiety and 18% reported mild to severe symptoms associated with hopelessness; 22.7% reported mild to severe symptoms in at least one of the sub-scales in Derogatis Symptom Checklist-90-Revisited (SCL-90-R) particularly the obsessive-compulsive, paranoid and depressive subscales. Chi Square correlations (X2) were made to observe if there was interdependence between the socio-demographic variables and the administered tests. In general, no significant correlations were found between BDI-Il, BAI, BHS, SCL-90-R and civil status, gender, income and age. However, a significant correlation was found between age and the somatization sub-scale of the SCL-90-R (rs = 0.510, p achondroplasia. The development of preventive and cultural sensitive interventions is suggested in order to protect and treat individuals with the condition. PMID:26742198

  5. Bilateral humeral lengthening in achondroplasia with unilateral external fixators: is it safe and does it improve daily life?

    Balci, H I; Kocaoglu, M; Sen, C; Eralp, L; Batibay, S G; Bilsel, K

    2015-11-01

    A retrospective study was performed in 18 patients with achondroplasia, who underwent bilateral humeral lengthening between 2001 and 2013, using monorail external fixators. The mean age was ten years (six to 15) and the mean follow-up was 40 months (12 to 104). The mean disabilities of the arm, shoulder and hand (DASH) score fell from 32.3 (20 to 40) pre-operatively to 9.4 (6 to 14) post-operatively (p = 0.037). A mean lengthening of 60% (40% to 95%) was required to reach the goal of independent perineal hygiene. One patient developed early consolidation, and fractures occurred in the regenerate bone of four humeri in three patients. There were three transient radial nerve palsies. Humeral lengthening increases the independence of people with achondroplasia and is not just a cosmetic procedure. PMID:26530664

  6. Magnetic resonance imaging study determining cord level and occupancy at thoracolumbar junction in achondroplasia – A prospective study

    Modi, Hitesh N; Seung-Woo Suh; Jae-Young Hong; Jae-Hyuk Yang

    2011-01-01

    Background: Thoracolumbar (TL) stenosis in achondroplasia is frequently reported, and becomes symptomatic in adulthood. Hence we conducted a prospective study to determine cord level and occupancy at TL junction in symptomatic or asymptomatic achondroplasis patients in comparision to normal population by magnetic resonance imaging (MRI). Materials and Methods: Cord level with its occupancy rate and TL kyphosis were measured on MRI and standing radiogram, respectively. We prospectively stu...

  7. Achondroplasia with 47, xxy karyotype: a case report of the neonatal diagnosis of an extremely unusual association

    Ros-Pérez Purificación; Regidor Francisco J; Colino Esmeralda; Martínez-Payo Cristina; Barroso Eva; Heath Karen E

    2012-01-01

    Abstract Background The association of achondroplasia and Klinefelter syndrome is extremely rare. To date, five cases have been previously reported, all of them diagnosed beyond the postnatal period, and only one was molecularly characterized. We describe the first case of this unusual association diagnosed in the neonatal period, the clinical findings and the molecular studies undertaken. Case presentation The boy was born at term with clinical and radiological features indicating the diagno...

  8. Common mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism

    Bonaventure, J.; Rousseau, F.; Legeai-Mallet, L.; LeMerrer, M.; Munnich, A.; Maroteaux, P. [INSERM, Paris (France)

    1996-05-03

    The mapping of the achondroplasia locus to the short arm of chromosome 4 and the subsequent identification of a recurrent missense mutation (G380R) in the fibroblast growth factor receptor 3 (FGFR-3) gene has been followed by the detection of common FGFR-3 mutations in two clinically related disorders: thanatophoric dwarfism (types I and II) and hypochondroplasia. The relative clinical homogeneity of achondroplasia was substantiated by demonstration of its genetic homogeneity as more than 98% of all patients hitherto reported exhibit mutations in the transmembrane receptor domain. Although most hypochondroplasia cases were accounted for by a recurrent missense substitution (N540K) in the first tyrosine kinase (TK 1) domain of the receptor, a significant proportion (40%) of our patients did not harbor the N540K mutation and three hypochondroplasia families were not linked to the FGFR-3 locus, thus supporting clinical heterogeneity of this condition. In thanatophoric dwarfism (TD), a recurrent FGFR-3 mutation located in the second tyrosine kinase (TK 2) domain of the receptor was originally detected in 100% of TD II cases; in our series, seven distinct mutations in three different protein domains were identified in 25 of 26 TD I patients, suggesting that TD, like achondroplasia, is a genetically homogenous skeletal disorder. 31 refs., 4 figs., 2 tabs.

  9. ANÁLISIS MUTACIONAL DE LA ACONDROPLASIA EN 20 PACIENTES COLOMBIANOS Mutational analysis of achondroplasia in 20 Colombian patients

    Ángela Castro

    2010-07-01

    Full Text Available Antecedentes. La acondroplasia es la más común de las displasias esqueléticas. Se trata de una enfermedad autosómica dominante con penetrancia completa. Esta enfermedad se debe a una mutación en el gen del receptor 3 del factor de crecimiento fibroblástico (FGFR3. El 90% o más de los casos se deben a mutaciones nuevas que se originan en las células germinales de padres sanos, asociada a una edad incrementada. Se ha calculado una frecuencia al nacimiento de 1:10.000 a 1:30.000. En la mayoría de los casos (97% la mutación presente es la transición G1138A, en el dominio transmembranal de gen. En el resto se presenta la transversión en el mismo nucleótido, G1138C. Objetivo. Detectar mutaciones del gen FGFR3 en un grupo de pacientes colombianos con acondroplasia. Material y métodos. Estudiamos un grupo de 20 pacientes con diagnóstico clínico de acondroplasia. Se utilizó el método, ARMS-PCR (Amplification Refractory Mutation System - Polymerase Chain Reaction que emplea dos pares primers diseñados específicamente para amplificar respectivamente los dos diferentes nucleótidos de una mutación puntual. Resultados. 19 pacientes (95%, presentaron la mutación G1138A y un paciente presentó la mutación G1138C (5%. Conclusión. No obstante la acondroplasia presentar un fenotipo considerado distinguible de otras displasias esqueléticas, algunas veces la hipocondroplasia, que se presenta por mutaciones en el mismo gen FGFR3, puede ser difícil de discriminar clínicamente, por lo que el análisis mutacional permite la correcta clasificación, así como de eventualmente otras displasias esqueléticas por mutaciones en otros genes.Background. Achondroplasia is the most common skeletal dysplasia, mainly affecting tubular bones, vertebrae and skull. This is an autosomal dominant syndrome with complete penetrance, due to a mutation in the fibroblast growth factor receptor 3 (FGFR3 gene. Approximately 90% of the achondroplasia cases, are due

  10. Ser217Cys mutation in the Ig Ⅱ domain of FGFR3 in a Chinese family with autosomal dominant achondroplasia

    ZHANG Shi-rong; ZHOU Xiao-qing; REN Xiang; WANG Tian-tian; YUAN Ming-xiong; WANG Qing; LIU Jing-yu; LIU Mu-gen

    2007-01-01

    @@ Achondroplasia (ACH) is the most common form of skeletal dysplasia characterized by disproportionately short stature, lumbar lordosis, relative macrocephaly and other skeletal anomalies resulting from a defect in the maturation of the chondrocytes in the growth plate of the cartilage. The combined frequency of the disease has been estimated to be 1 in 15 000 live births.1 ACH is inherited in autosomal dominant fashion with a complete penetrance, more than 80% of affected individuals have de novo mutations associated with increased paternal age.

  11. Direct Assessment of the Effect of the Gly380Arg Achondroplasia Mutation on FGFR3 Dimerization Using Quantitative Imaging FRET

    Placone, Jesse; Hristova, Kalina

    2012-01-01

    The Gly380Arg mutation in FGFR3 is the genetic cause for achondroplasia (ACH), the most common form of human dwarfism. The mutation has been proposed to increase FGFR3 dimerization, but the dimerization propensities of wild-type and mutant FGFR3 have not been compared. Here we use quantitative imaging FRET to characterize the dimerization of wild-type FGFR3 and the ACH mutant in plasma membrane-derived vesicles from HEK293T cells. We demonstrate a small, but statistically significant increase...

  12. Atypical radiological findings in achondroplasia with uncommon mutation of the fibroblast growth factor receptor-3 (FGFR-3) gene (Gly to Cys transition at codon 375)

    Nishimuri, Gen [Dokkyo Univ. School of Medicine, Tochigi (Japan); Fukushima, Yoshimitsu; Ohashi, Hirofumi [Saitama Children`s Medical Center, Saitama (Japan); Ikegawa, Shiro [Tokyo Univ. (Japan)

    1995-11-20

    The recent discovery of mutations in the FGFR-3 (fibroblast growth factor receptor-3) gene (FGFR3) as the cause of achondroplasia has provided new insight into understanding genetic diseases. It was surprising from the viewpoint of molecular genetics that most patients with achondroplasia showed the same mutation at nucleotide 1138, leading to a single amino acid substitution from glycine to arginine at codon 380 (Gly380Arg). All 39 patients examined by two groups had the Gly380Arg; 38 patients and the other demonstrated a G to A and a G to C transition at nucleotide 1138, respectively. Subsequently another group disclosed a G to A transition at the same nucleotide 1138 in 21/23 patients of diverse ethnic origin, although mutations were not identified in two patients. To date, a total of 193 patients with the mutation of the G380Arg have been reported; a single patient with another mutation resulting in a substitution from glycine to cysteine at codon 375 (Gly375Cys) has been described. The presence of this common mutation is consistent with the clinical fact that achondroplastic individuals show less phenotypic variability than is unusual for autosomal dominant diseases. We encountered a Japanese boy with the Gly375Cys. His mother with achondroplasia has the same mutation. The molecular investigation of these patients was reported elsewhere. Here we report the clinical and radiological findings in this boy who demonstrated some atypical manifestations from those of typical achondroplasia. 8 refs., 1 fig.

  13. Psychosocial Adjustment of Children with Short Stature (Achondroplasia): Social Competence, Behavior Problems, Self-Esteem, Family Functioning, Body Image, and Reaction to Frustrations.

    Csapo, Marg

    1991-01-01

    This evaluation of 16 children (ages 7-12) with achondroplasia from Transkei, Hungary, and Nigeria found that, compared to controls, subjects had more behavior problems and less self-esteem. Subjects were socially withdrawn, internalized emotional problems, had lower academic performance, found less adaptive solutions to frustration, and faced…

  14. Callus features of regenerate fracture cases in femoral lengthening in achondroplasia

    We studied the callus features seen in cases of regenerate fracture in femoral lengthening using a monolateral fixator in achondroplasia to determine whether callus types and shapes can predict the probability of callus fracture. The radiographs of 28 cases of femoral lengthening in 14 patients, 14 cases of callus fracture, and 14 cases without callus fracture were retrospectively analyzed by four observers and classified into different shapes and types in concordance with the Ru Li classification. The average lengthening of 9.4 cm (range 7.5-11.8 cm) was achieved, which was 41% (range 30-55%) of the original length and the average timing of callus fracture was 470 days (range 440-545 days) after surgery in the callus fracture group. While the average lengthening of 9.1 cm (range 8-9.7 cm) was achieved, this was 30% (range 28-32%) of the original length in the group of patients without callus fracture. The callus was atypically shaped, there was a 48% average (range 30-72%) reduction of the callus width compared with the natural width of the femur, and a lucent pathway was present in all cases of regenerate fracture. A lucent pathway was seen in all fracture cases with concave, lateral, and atypical shapes, and there was more than 30% lengthening and 30% reduction of the callus width compared with the natural width of the femur, which are the warning signs for regenerate fractures. These signs help the surgeon to predict the outcome and guide him in planning for any additional interventions. The Ru Li classification is an effective method for the evaluation of the chance of callus fracture. (orig.)

  15. Callus features of regenerate fracture cases in femoral lengthening in achondroplasia

    Devmurari, Kamlesh N.; Song, Hae Ryong; Modi, Hitesh N.; Venkatesh, K.P.; Ju, Kim Seung; Song, Sang Heon [Korea University Medical College, Institute for Rare Diseases and Department of Orthopedic Surgery, Seoul (Korea)

    2010-09-15

    We studied the callus features seen in cases of regenerate fracture in femoral lengthening using a monolateral fixator in achondroplasia to determine whether callus types and shapes can predict the probability of callus fracture. The radiographs of 28 cases of femoral lengthening in 14 patients, 14 cases of callus fracture, and 14 cases without callus fracture were retrospectively analyzed by four observers and classified into different shapes and types in concordance with the Ru Li classification. The average lengthening of 9.4 cm (range 7.5-11.8 cm) was achieved, which was 41% (range 30-55%) of the original length and the average timing of callus fracture was 470 days (range 440-545 days) after surgery in the callus fracture group. While the average lengthening of 9.1 cm (range 8-9.7 cm) was achieved, this was 30% (range 28-32%) of the original length in the group of patients without callus fracture. The callus was atypically shaped, there was a 48% average (range 30-72%) reduction of the callus width compared with the natural width of the femur, and a lucent pathway was present in all cases of regenerate fracture. A lucent pathway was seen in all fracture cases with concave, lateral, and atypical shapes, and there was more than 30% lengthening and 30% reduction of the callus width compared with the natural width of the femur, which are the warning signs for regenerate fractures. These signs help the surgeon to predict the outcome and guide him in planning for any additional interventions. The Ru Li classification is an effective method for the evaluation of the chance of callus fracture. (orig.)

  16. Effect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta

    Orioli, I.M. [Universidade Federal do Rio de Janeiro (Brazil); Castilla, E.E. [Centro de Educacion Medica e Investigacion Clinica, Buenos Aires (Argentina); Scarano, G.; Mastroiacovo, P. [Universita Cattolica, Rome (Italy)

    1995-11-06

    The paternal ages of nonfamilial cases of achondroplasia (AC) (n = 78), thanatophoric dysplasia (TD) (n = 64), and osteogenesis imperfecta (OI) (n = 106), were compared with those of matched controls, from an Italian Indagine Policentrica Italiana sulle Malformazioni Congenite (IPIMC) and a South American Estudio Colaborativo Latinoamericano de Malformaciones Congenitas (ECLAMC) series. The degree of paternal age effect on the origin of these dominant mutations differed among the three conditions. Mean paternal age was highly elevated in AC, 36.30 {plus_minus} 6.74 years in the IPIMC, and 37.19 {plus_minus} 10.53 years in the ECLAMC; less consistently elevated in TD, 33.60 {plus_minus} 7.08 years in the IPIMC, and 36.41 {plus_minus} 9.38 years in the ECLAMC; and only slightly elevated in OI in the ECLAMC, 31.15 {plus_minus} 9.25 years, but not in the IPIMC, 32.26 {plus_minus} 6.07 years. Increased maternal age or birth order in these conditions disappeared when corrected for paternal age. Approximately 50% of AC and TD cases, and only 30% of OI cases, were born to fathers above age 35 years. For AC and TD, the increase in relative incidence with paternal age fitted an exponential curve. The variability of paternal age effect in these new mutations could be due, among other reasons, to the high proportion of germ-line mosaicism in OI parents, or to the localization of the AC gene, mapped to the 4p16.3 region, in the neighborhood of an unstable DNA area. 28 refs., 1 fig., 6 tabs.

  17. Localisation of the gene for achondroplasia to the telomeric region of chromosome 4p

    Stoilov, I.; Velinov, M.; Kilpatrick, M.W. [and others

    1994-09-01

    Achondroplasia (ACH), the most common type of genetic dwarfism, is characterized by a variety of skeletal anomalies including disproportionate short stature and rhizomelic shortening of the extremities. The disorder is inherited as an autosomal dominant trait, with a prevalence of 1-15 per 100,000 live births. The etiology of ACH remains unknown, although evidence points to a defect in the maturation of the chondrocytes in the growth plate of the cartilage. To determine the location of the gene responsible for ACH, a panel of 14 families with a total of 43 meioses was genotyped for 40 polymorphic markers for loci randomly distributed throughout the genome. The first significant positive Lod score was obtained for the locus D4S127 (Zmax=3.65 at {theta}=0.03). A series of 20 markers for chromosome 4p16.3 loci were then used to determine the most likely position of the ACH gene. Two additional loci, D4S412 and IDUA, showed strong linkage to the disease (Zmax=3.34 at {theta}=0.03 and Zmax=3.35 at {theta}=0.0, respectively). Multipoint analysis and direct counting of recombinants places the ACH gene in a 2.5 cM region between the marker D4S43 and the chromosome 4p telomere. No evidence was found for genetic heterogeneity. The ACH region contains a number of genes, including that for the fibroblast growth factor receptor FGFR3, which are being evaluated as candidates for the ACH gene. This identification of tightly linked polymorphic markers, as well as being the first step in the characterization of the ACH gene, offers the possibility of DNA based prenatal diagnosis of this disorder.

  18. Functional characteristics of mesenchymal stem cells derived from the adipose tissue of a patient with achondroplasia.

    Park, Jeong-Ran; Lee, Hanbyeol; Kim, Chung-Hyo; Hong, Seok-Ho; Ha, Kwon-Soo; Yang, Se-Ran

    2016-05-01

    Mesenchymal stem cells (MSCs) can be isolated from various tissues including bone marrow, adipose tissue, skin dermis, and umbilical Wharton's jelly as well as injured tissues. MSCs possess the capacity for self-renewal and the potential for differentiation into adipogenic, osteogenic, and chondrogenic lineages. However, the characteristics of MSCs in injured tissues, such as achondroplasia (ACH), are not well known. In this study, we isolated MSCs from human subcutaneous adipose (ACH-SAMSCs) tissue and circumjacent human adipose tissue of the cartilage (ACH-CAMSCs) from a patient with ACH. We then analyzed the characterization of ACH-SAMSCs and ACH-CAMSCs, compared with normal human dermis-derived MSCs (hDMSCs). In flow cytometry analysis, the isolated ACH-MSCs expressed low levels of CD73, CD90, and CD105, compared with hDMSCs. Moreover, both ACH- SAMSCs and ACH-CAMSCs had constitutionally overactive fibroblast growth factor receptor 3 (FGFR3) and exhibited significantly reduced osteogenic differentiation, compared to enhanced adipogenic differentiation. The activity of extracellular signal-regulated kinases 1/2 (ERK1/2) and p38 mitogen-activated protein kinases (p38 MAPK) was increased in ACH-MSCs. In addition, the efficacy of osteogenic differentiation was slightly restored in osteogenic differentiation medium with MAPKs inhibitors. These results suggest that they play essential roles in MSC differentiation toward adipogenesis in ACH pathology. In conclusion, the identification of the characteristics of ACH-MSCs and the favoring of adipogenic differentiation via the FGFR3/MAPK axis might help to elucidate the pathogenic mechanisms relevant to other skeletal diseases and could provide targets for therapeutic interventions. PMID:27059327

  19. Meclozine facilitates proliferation and differentiation of chondrocytes by attenuating abnormally activated FGFR3 signaling in achondroplasia.

    Masaki Matsushita

    Full Text Available Achondroplasia (ACH is one of the most common skeletal dysplasias with short stature caused by gain-of-function mutations in FGFR3 encoding the fibroblast growth factor receptor 3. We used the drug repositioning strategy to identify an FDA-approved drug that suppresses abnormally activated FGFR3 signaling in ACH. We found that meclozine, an anti-histamine drug that has long been used for motion sickness, facilitates chondrocyte proliferation and mitigates loss of extracellular matrix in FGF2-treated rat chondrosarcoma (RCS cells. Meclozine also ameliorated abnormally suppressed proliferation of human chondrosarcoma (HCS-2/8 cells that were infected with lentivirus expressing constitutively active mutants of FGFR3-K650E causing thanatophoric dysplasia, FGFR3-K650M causing SADDAN, and FGFR3-G380R causing ACH. Similarly, meclozine alleviated abnormally suppressed differentiation of ATDC5 chondrogenic cells expressing FGFR3-K650E and -G380R in micromass culture. We also confirmed that meclozine alleviates FGF2-mediated longitudinal growth inhibition of embryonic tibia in bone explant culture. Interestingly, meclozine enhanced growth of embryonic tibia in explant culture even in the absence of FGF2 treatment. Analyses of intracellular FGFR3 signaling disclosed that meclozine downregulates phosphorylation of ERK but not of MEK in FGF2-treated RCS cells. Similarly, meclozine enhanced proliferation of RCS cells expressing constitutively active mutants of MEK and RAF but not of ERK, which suggests that meclozine downregulates the FGFR3 signaling by possibly attenuating ERK phosphorylation. We used the C-natriuretic peptide (CNP as a potent inhibitor of the FGFR3 signaling throughout our experiments, and found that meclozine was as efficient as CNP in attenuating the abnormal FGFR3 signaling. We propose that meclozine is a potential therapeutic agent for treating ACH and other FGFR3-related skeletal dysplasias.

  20. HOMOLOGY MODELLING AND DOCKING STUDIES OF FGFR3 PROTEIN TO SEARCH MOST EFFECTIVE DRUG AGAINST ACHONDROPLASIA

    Chauhan Nutan

    2010-10-01

    Full Text Available The present investigation was carried out with the aim of modeling the 3D structure of FGFR3 protein and predicting the most effective drug using SU5402 and its analogues. FGFR3 protein, responsible for long bone growth, causes Achondroplasia in H. sapiens when it becomes mutated. When mutated, the dimmer of FGFR3 stabilizes without interacting with its ligand results in constitutive activation of downstream pathway and inhibits the bone growth. No known structure of FGFR3 was available. The 3D modeling of FGFR3 was done using Robetta server and from the various model predicted, model 5 was selected as the best model after evaluating the models using PROCHECK. . The total number of residues in selected model was found as: 589 (86.5% residues in most favored region, 84 (12.3% in additional allowed region, 8 (1.2% in generously allowed region and 0 (0.0% in disallowed region of the Ramachandran plot. Three analogues were constructed by using the existing FGFR3 specific inhibitor SU5402. Receptor-analogue interaction study was performed in FlexX3 docking software. Ligand 3 (IUPAC Name: 3-{2-[Z-(4-hydroxy-2-oxo-1,2-dihydro-3Hindol- 3-ylidene methyl]-4-oxo-4,5-dihydro-1H-pyrrol-3-yl} propanoic acid was showing the best binding energy (-10.458 KJ/Mol that can be predicted the most effective inhibitor for FGFR3. It should be noted that these predicted data should be validated using suitable assays for further consideration.

  1. Direct assessment of the effect of the Gly380Arg achondroplasia mutation on FGFR3 dimerization using quantitative imaging FRET.

    Jesse Placone

    Full Text Available The Gly380Arg mutation in FGFR3 is the genetic cause for achondroplasia (ACH, the most common form of human dwarfism. The mutation has been proposed to increase FGFR3 dimerization, but the dimerization propensities of wild-type and mutant FGFR3 have not been compared. Here we use quantitative imaging FRET to characterize the dimerization of wild-type FGFR3 and the ACH mutant in plasma membrane-derived vesicles from HEK293T cells. We demonstrate a small, but statistically significant increase in FGFR3 dimerization due to the ACH mutation. The data are consistent with the idea that the ACH mutation causes a structural change which affects both the stability and the activity of FGFR3 dimers in the absence of ligand.

  2. Analysis of callus pattern of tibia lengthening in achondroplasia and a novel method of regeneration assessment using pixel values

    To relate morphology of new bone formation to outcome after tibial lengthening performed in patients with achondroplasia. A retrospective analysis of 60 tibial segments in 30 achondroplasia patients was performed. There were 22 female patients and eight male patients, with a mean age of 9.8 years. New bone formation was classified by shape, homogeneity and density. Pixel values in relation to original bone were measured using a picture-archiving communication system (PACS). Clinical outcome was described by the external fixator and maturation indices. Mean lengthening was 9.2 cm (range 3-12.7 cm). The mean external fixator index was 23.4 (range 15.1-50). The mean maturation index was 12.3 days/cm (range 6-40 days/cm). Homogeneous pathways were associated with the best clinical results (fixator index 20.4, maturation index 10.8), followed by heterogeneous pathway (external fixator index 26.5, maturation index 16.8) and radiolucent pathway (fixator index 31.2, maturation index 21.4). Both cylindrical (external fixator index 25.2, maturation index 14.5) and concave (external fixator index 26.6, maturation index 16.3) callus shapes were favourable. Mineralization of new bone became equal to that of normal bone within 16 weeks (mean) for homogeneous pathway, 12 weeks for heterogeneous pathway and 32 weeks for lucent pathway. The type of new bone formation seen on radiographs is related to clinical outcome, with homogeneous pathways being the most favourable ones. (orig.)

  3. Analysis of callus pattern of tibia lengthening in achondroplasia and a novel method of regeneration assessment using pixel values

    Singh, Suryaudai; Song, Hae-Ryong; Venkatesh, K.P.; Modi, Hitesh N.; Jang, Ki-Mo; Kim, Seung J. [Korea University Guro Hospital, Rare Diseases Institute, Department of Orthopedic Surgery, Seoul (Korea); Park, Man Sik [Korea University, Department of Biostatistics, College of Medicine, Seoul (Korea)

    2010-03-15

    To relate morphology of new bone formation to outcome after tibial lengthening performed in patients with achondroplasia. A retrospective analysis of 60 tibial segments in 30 achondroplasia patients was performed. There were 22 female patients and eight male patients, with a mean age of 9.8 years. New bone formation was classified by shape, homogeneity and density. Pixel values in relation to original bone were measured using a picture-archiving communication system (PACS). Clinical outcome was described by the external fixator and maturation indices. Mean lengthening was 9.2 cm (range 3-12.7 cm). The mean external fixator index was 23.4 (range 15.1-50). The mean maturation index was 12.3 days/cm (range 6-40 days/cm). Homogeneous pathways were associated with the best clinical results (fixator index 20.4, maturation index 10.8), followed by heterogeneous pathway (external fixator index 26.5, maturation index 16.8) and radiolucent pathway (fixator index 31.2, maturation index 21.4). Both cylindrical (external fixator index 25.2, maturation index 14.5) and concave (external fixator index 26.6, maturation index 16.3) callus shapes were favourable. Mineralization of new bone became equal to that of normal bone within 16 weeks (mean) for homogeneous pathway, 12 weeks for heterogeneous pathway and 32 weeks for lucent pathway. The type of new bone formation seen on radiographs is related to clinical outcome, with homogeneous pathways being the most favourable ones. (orig.)

  4. Constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype

    Murakami, Shunichi; Balmes, Gener; McKinney, Sandra; Zhang, Zhaoping; Givol, David; de Crombrugghe, Benoit

    2004-01-01

    We generated transgenic mice that express a constitutively active mutant of MEK1 in chondrocytes. These mice showed a dwarf phenotype similar to achondroplasia, the most common human dwarfism, caused by activating mutations in FGFR3. These mice displayed incomplete hypertrophy of chondrocytes in the growth plates and a general delay in endochondral ossification, whereas chondrocyte proliferation was unaffected. Immunohistochemical analysis of the cranial base in transgenic embryos showed redu...

  5. A simple and rapid quantitative method of detection of the common achondroplasia mutation: Analysis in mismatch repair deficient cells

    Grewal Raji

    2004-01-01

    Full Text Available Achondroplasia is the most common form of dwarfism and has an incidence of approximately 1/7,500. In more than 97% of cases, it is caused by a recurrent point mutation, a G to A substitution at nucleotide position 1138 (G1138A of the fibroblast growth factor receptor 3 gene. Although this is an autosomal dominant condition, more than 90% of all mutations occur sporadically making this one of the most mutagenic sites in the human genome. The reasons for the high spontaneous G1138A mutation rate are not known. This investigation was performed by developing a simple and rapid semi-quantitative allele specific PCR based assay capable of reliably detecting more than 25 mutant G1138A copies in a pool of 300,000 wild type molecules. Using this assay, the G1138A mutation frequency was measured in cell lines deficient in mismatch repair (LoVo, SW48 and comparing it with controls. No differences were found in the frequency of this point mutation between the mismatch repair deficient and wild type cell lines.

  6. Myelography in achondroplasia: value of a lateral C1-2 puncture and non-ionic, water-soluble contrast medium

    Suss, R.A.; Udvarhelyi, G.B.; Wang, H.; Kumar, A.J.; Zinreich, S.J.; Rosenbaum, A.E.

    1983-10-01

    Because of technical difficulties and diagnostic limitations encountered with other myelographic techniques in patients with achondroplasia, the authors employed a lateral C1-2 puncture and non-ionic, water-soluble contrast medium in 18 achondroplastic patients with spinal compression (21 procedures). This technique proved most appropriate for identifying the upper limit of degenerative osteophytes causing exacerbation of congenital spinal stenosis, which is crucial in planning decompressive surgery. A potentially important additional finding was the presence of degenerative lower cervical spine disease in the majority of patients. There were no serious complications. The authors recommend this technique as safe and effective in achondroplastic patients with severe congenital spinal stenosis.

  7. Myelography in achondroplasia: value of a lateral C1-2 puncture and non-ionic, water-soluble contrast medium

    Because of technical difficulties and diagnostic limitations encountered with other myelographic techniques in patients with achondroplasia, the authors employed a lateral C1-2 puncture and non-ionic, water-soluble contrast medium in 18 achondroplastic patients with spinal compression (21 procedures). This technique proved most appropriate for identifying the upper limit of degenerative osteophytes causing exacerbation of congenital spinal stenosis, which is crucial in planning decompressive surgery. A potentially important additional finding was the presence of degenerative lower cervical spine disease in the majority of patients. There were no serious complications. The authors recommend this technique as safe and effective in achondroplastic patients with severe congenital spinal stenosis

  8. Effect of the achondroplasia mutation on FGFR3 dimerization and FGFR3 structural response to fgf1 and fgf2: A quantitative FRET study in osmotically derived plasma membrane vesicles.

    Sarabipour, Sarvenaz; Hristova, Kalina

    2016-07-01

    The G380R mutation in the transmembrane domain of FGFR3 is a germline mutation responsible for most cases of Achondroplasia, a common form of human dwarfism. Here we use quantitative Fӧster Resonance Energy Transfer (FRET) and osmotically derived plasma membrane vesicles to study the effect of the achondroplasia mutation on the early stages of FGFR3 signaling in response to the ligands fgf1 and fgf2. Using a methodology that allows us to capture structural changes on the cytoplasmic side of the membrane in response to ligand binding to the extracellular domain of FGFR3, we observe no measurable effects of the G380R mutation on FGFR3 ligand-bound dimer configurations. Instead, the most notable effect of the achondroplasia mutation is increased propensity for FGFR3 dimerization in the absence of ligand. This work reveals new information about the molecular events that underlie the achondroplasia phenotype, and highlights differences in FGFR3 activation due to different single amino-acid pathogenic mutations. PMID:27040652

  9. Limb lengthening in achondroplasia

    Sanjay K Chilbule

    2016-01-01

    Full Text Available Background: Stature lengthening in skeletal dysplasia is a contentious issue. Specific guidelines regarding the age and sequence of surgery, methods and extent of lengthening at each stage are not uniform around the world. Despite the need for multiple surgeries, with their attendant complications, parents demanding stature lengthening are not rare, due to the social bias and psychological effects experienced by these patients. This study describes the outcome and complications of extensive stature lengthening performed at our center. Materials and Methods: Eight achondroplasic and one hypochondroplasic patient underwent bilateral transverse lengthening for tibiae, humeri and femora. Tibia lengthening was carried out using a ring fixator and bifocal corticotomy, while a monolateral pediatric limb reconstruction system with unifocal corticotomy was used for the femur and humerus. Lengthening of each bone segment, height gain, healing index and complications were assessed. Subgroup analysis was carried out to assess the effect of age and bone segment on the healing index. Results: Nine patients aged five to 25 years (mean age 10.2 years underwent limb lengthening procedures for 18 tibiae, 10 femora and 8 humeri. Four patients underwent bilateral lengthening of all three segments. The mean length gain for the tibia, femur and humerus was 15.4 cm (100.7%, 9.9 cm (52.8% and 9.6 cm (77.9%, respectively. Healing index was 25.7, 25.6 and 20.6 days/cm, respectively, for the tibia, femur and humerus. An average of 33.3% height gain was attained. Lengthening of both tibia and femur added to projected height achieved as the 3 rd percentile of standard height in three out of four patients. In all, 33 complications were encountered (0.9 complications per segment. Healing index was not affected by age or bone segment. Conclusion: Extensive limb lengthening (more than 50% over initial length carries significant risk and should be undertaken only after due consideration.

  10. Meclozine promotes longitudinal skeletal growth in transgenic mice with achondroplasia carrying a gain-of-function mutation in the FGFR3 gene.

    Matsushita, Masaki; Hasegawa, Satoru; Kitoh, Hiroshi; Mori, Kensaku; Ohkawara, Bisei; Yasoda, Akihiro; Masuda, Akio; Ishiguro, Naoki; Ohno, Kinji

    2015-02-01

    Achondroplasia (ACH) is one of the most common skeletal dysplasias causing short stature owing to a gain-of-function mutation in the FGFR3 gene, which encodes the fibroblast growth factor receptor 3. We found that meclozine, an over-the-counter drug for motion sickness, inhibited elevated FGFR3 signaling in chondrocytic cells. To examine the feasibility of meclozine administration in clinical settings, we investigated the effects of meclozine on ACH model mice carrying the heterozygous Fgfr3(ach) transgene. We quantified the effect of meclozine in bone explant cultures employing limb rudiments isolated from developing embryonic tibiae from Fgfr3(ach) mice. We found that meclozine significantly increased the full-length and cartilaginous primordia of embryonic tibiae isolated from Fgfr3(ach) mice. We next analyzed the skeletal phenotypes of growing Fgfr3(ach) mice and wild-type mice with or without meclozine treatment. In Fgfr3(ach) mice, meclozine significantly increased the body length after 2 weeks of administration. At skeletal maturity, the bone lengths including the cranium, radius, ulna, femur, tibia, and vertebrae were significantly longer in meclozine-treated Fgfr3(ach) mice than in untreated Fgfr3(ach) mice. Interestingly, meclozine also increased bone growth in wild-type mice. The plasma concentration of meclozine during treatment was within the range that has been used in clinical settings for motion sickness. Increased longitudinal bone growth in Fgfr3(ach) mice by oral administration of meclozine in a growth period suggests potential clinical feasibility of meclozine for the improvement of short stature in ACH. PMID:25456072

  11. Optimal management of complications associated with achondroplasia

    Irel; PJ; Pacey V; Zankl A; Edwards P; Johnston LM; Savarirayan R

    2014-01-01

    Penny J Ireland,1 Verity Pacey,2,3 Andreas Zankl,4 Priya Edwards,1 Leanne M Johnston,5 Ravi Savarirayan6 1Queensland Paediatric Rehabilitation Service, Royal Children’s Hospital, Herston, Brisbane, Queensland, 2Physiotherapy Department, The Children’s Hospital at Westmead, Sydney, New South Wales, 3Department of Health Professions, Macquarie University, Sydney, New South Wales, 4Genetic Medicine, Children’s Hospital, Westmead, Sydney, New South Wales, 5School of Health and R...

  12. Optimal management of complications associated with achondroplasia

    Ireland, Penny

    2014-01-01

    Penny J Ireland,1 Verity Pacey,2,3 Andreas Zankl,4 Priya Edwards,1 Leanne M Johnston,5 Ravi Savarirayan6 1Queensland Paediatric Rehabilitation Service, Royal Children’s Hospital, Herston, Brisbane, Queensland, 2Physiotherapy Department, The Children’s Hospital at Westmead, Sydney, New South Wales, 3Department of Health Professions, Macquarie University, Sydney, New South Wales, 4Genetic Medicine, Children’s Hospital, Westmead, Sydney, New South Wales, 5School of ...

  13. [Anesthetic Management for Cervicomedullary Decompression in a Patient with Achondroplasia--A Case Report].

    Furuichi, Yuko; Nakazato, Keiko; Suzuki, Norihito; Hongo, Takashi; Sakamoto, Atsuhiro

    2015-12-01

    This is a case report of a 42-year-old man who underwent suboccipital craniectomy and C-1 laminoplasty under general anesthesia. His weight and height were 32 kg and 110 cm, respectively. The patient had short limbs, a protruding forehead, a large tongue, and a short neck. Preoperative magnetic resonance imaging showed marked stenosis of the foramen magnum and cervicomedullary compression and malacia, with the smallest anteroposterior diameter of 4.5 mm. Mask ventilation and tracheal intubation were not feasible; therefore, an Airtraq® laryngoscope and a bronchial fiberscope were used. Anesthesia was maintained with propofol, remifentanil, and fentanyl. After intubation and postural change, the patient was awakened, and we confirmed the absence of any limb movement disorder. Intraoperative motor evoked potentials were normal. After extubation, he experienced numbness of the limbs. Postoperative magnetic resonance imaging revealed an enlargement of the foramen magnum and the foramen of the atlas. However, the cervicomedullary malacia remained unchanged. The cause of numbness was unknown. After rehabilitation, he became ambulatory and could walk continuously for about 300 m at a slow pace. PMID:26790327

  14. Genetics Home Reference: SADDAN

    ... All Open All Close All Description SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) is a ... address the diagnosis or management of SADDAN: GeneReview: Achondroplasia Genetic Testing Registry: Severe achondroplasia with developmental delay ...

  15. ANÁLISIS MUTACIONAL DE LA ACONDROPLASIA EN 20 PACIENTES COLOMBIANOS Mutational analysis of achondroplasia in 20 Colombian patients

    Ángela Castro; Andrés Gutiérrez; Luisa Fernanda Rodríguez; Pineda Tatiana; Harvy Velasco; Clara Arteaga; Hugo Sotomayor; Alejandro Giraldo

    2010-01-01

    Antecedentes. La acondroplasia es la más común de las displasias esqueléticas. Se trata de una enfermedad autosómica dominante con penetrancia completa. Esta enfermedad se debe a una mutación en el gen del receptor 3 del factor de crecimiento fibroblástico (FGFR3). El 90% o más de los casos se deben a mutaciones nuevas que se originan en las células germinales de padres sanos, asociada a una edad incrementada. Se ha calculado una frecuencia al nacimiento de 1:10.000 a 1:30.000. En la mayoría ...

  16. Effects of diadenosine tetraphosphate on FGF9-induced chloride flux changes in achondroplastic chondrocytes

    Huete, Fernando; Guzman-Aranguez, Ana; Ortín, Javier; Hoyle, Charles H. V.; Pintor, Jesús

    2011-01-01

    Achondroplasia, the most common type of dwarfism, is characterized by a mutation in the fibroblast growth factor receptor 3 (FGFR3). Achondroplasia is an orphan pathology with no pharmacological treatment so far. However, the possibility of using the dinucleotide diadenosine tetraphosphate (Ap4A) with therapeutic purposes in achondroplasia has been previously suggested. The pathogenesis involves the constitutive activation of FGFR3, resulting in altered biochemical and physiological processes...

  17. The radiographic manifestations of hypochondroplasia

    Hypochrondroplasia is an inherited skeletal dysplasia that resembles achondroplasia in mild degree. Radiographic manifestations encountered in 12 affected individuals in South Africa include slight shortening of all segments of the tubular bones, moderate caudal diminution of the lumbar interpedicular distances, increased lumbar lordosis with cacral tilt and distal prolongation of the fibular. Hypochondroplasia can be distinguished from other osteochondrodystrophies such as achondroplasia, pseudo-achondroplasia and metaphyseal chondroplasia by the recognition of it clinical and radiographic manifestations. (author)

  18. Preserved fertility in a non-mosaic Klinefelter patient with a mutation in the fibroblast growth factor receptor 3 gene

    Juul, A; Aksglaede, L; Lund, A M; Duno, M; Skakkebaek, N E; Rajpert-De Meyts, E

    2007-01-01

    receptor 3 (FGFR3) gene, which is a gain-of-function mutation resulting in achondroplasia. The patient had phenotypic characteristics of achondroplasia (e.g. short limbed dwarfism and frontal bossing). Testicular volume was 8 ml at 27 years of age and repeated semen samples showed sperm concentrations of 0...

  19. Specific Genetic Disorders

    ... links from the National Institutes of Health. Specific Genetic Disorders Many human diseases have a genetic component. ... Condition in an Adult The Undiagnosed Diseases Program Genetic Disorders Achondroplasia Alpha-1 Antitrypsin Deficiency Antiphospholipid Syndrome ...

  20. Genetics Home Reference: pseudoachondroplasia

    ... related to another disorder of bone growth called achondroplasia , but without that disorder's characteristic facial features. More ... Additional Information & Resources MedlinePlus (1 link) Health Topic: Dwarfism Genetic and Rare Diseases Information Center (1 link) ...

  1. Genetics Home Reference: hypochondroplasia

    ... Description Hypochondroplasia is a form of short-limbed dwarfism. This condition affects the conversion of cartilage into ... Hypochondroplasia is similar to another skeletal disorder called achondroplasia , but the features tend to be milder. All ...

  2. Achondroplastic dog breeds have no mutations in the transmembrane domain of the FGFR-3 gene.

    S. Martínez; Valdés, J; R. A. Alonso

    2000-01-01

    One of the most common skeletal affections in humans is achondroplasia, a short-limbed dwarfism that is, in most cases, caused by mutations in the transmembrane domain of the fibroblast growth factor receptor-3 (FGFR-3) gene. Due to the lack of sufficient radiological, genetic, and molecular studies, most types of skeletal anomalies in dogs are classified as achondroplasia. To initiate the molecular characterization of some osteochondrodysplastic dog breeds, we obtained the DNA sequence of th...

  3. Coronary artery bypass grafting in an achondroplastic dwarf.

    Balaguer, J M; Perry, D; Crowley, J; Moran, J. M.

    1995-01-01

    To our knowledge, coronary bypass for complications of coronary artery disease in achondroplasia has not previously been described. Achondroplasia, in and of itself, is not a contraindication to coronary bypass. Although the anatomic reserve of saphenous vein is less in achondroplastic dwarfs than in people of normal stature, that vessel and the internal mammary artery can be harvested in routine fashion. A 60-year-old woman with several risk factors for coronary artery disease underwent succ...

  4. An Achondroplasic Case with Foramen Magnum Stenosis, Hydrocephaly, Cortical Atrophy, Respiratory Failure and Sympathetic Dysfunction

    Bulent Karapinar; Mehmet Tayip Arslan; Mustafa Ozcetin

    2012-01-01

    Background: Achondroplasia is a relatively frequent genetic disorder that may lead to limb weakness, motor-mental retardation, hydrocephaly, and respiratory disorders. In this pathology, foramen magnum stenosis and accompanying disorders like respiratory depression is well documented.Case Presentation: A 2.5 year-old child with the diagnosis of achondroplasia admitted to our clinic with severe respiratory depression, limb weakness, and motor mental retardation as well as sympathetic dysfuncti...

  5. Problémy lidí malého vzrůstu, postižených achondroplazií a pseudoachondroplazií, v běžných životních situacích

    BLÁHOVÁ, Vendula

    2009-01-01

    The work deals with the problems of people of small stature, affected by achondroplasia and pseudoachondroplasia, current life situations. The theoretical part is characterized by achondroplasia, pseudoachnodroplasia, health problems of people of small stature, their education, employment, the barriers, difficulties and limitations in their lives. Furthermore describes the socio-legal sphere in the Czech Republic and the civic association Palecek. The practical part contains the research. Obj...

  6. Genetic inactivation of ERK1 and ERK2 in chondrocytes promotes bone growth and enlarges the spinal canal

    Sebastian, Arjun; Matsushita, Takehiko; Kawanami, Aya; Mackem, Susan; Landreth, Gary; Murakami, Shunichi

    2010-01-01

    Activating mutations in FGFR3 cause the most common forms of human dwarfism: achondroplasia and thanatophoric dysplasia. In mouse models of achondroplasia, recent studies have implicated the ERK MAPK pathway, a pathway activated by FGFR3, in creating reduced bone growth. Our recent studies have indicated that increased Fgfr3 and ERK MAPK signaling in chondrocytes also causes premature synchondrosis closure in the cranial base and vertebrae, accounting for the sometimes fatal stenosis of the f...

  7. FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway

    Matsushita, Takehiko; Wilcox, William R.; Chan, Yuk Yu; Kawanami, Aya; Bükülmez, Hülya; Balmes, Gener; Krejci, Pavel; Mekikian, Pertchoui B.; Otani, Kazuyuki; Yamaura, Isakichi; Warman, Matthew L; Givol, David; Murakami, Shunichi

    2008-01-01

    Activating mutations in FGFR3 cause achondroplasia and thanatophoric dysplasia, the most common human skeletal dysplasias. In these disorders, spinal canal and foramen magnum stenosis can cause serious neurologic complications. Here, we provide evidence that FGFR3 and MAPK signaling in chondrocytes promote synchondrosis closure and fusion of ossification centers. We observed premature synchondrosis closure in the spine and cranial base in human cases of homozygous achondroplasia and thanatoph...

  8. Confirmatory linkage of hypochondroplasia to chromosome arm 4p

    Hectht, J.T.; Herrera, C.A.; Greenhaw, G.A. [Univ. of Texas Medical School, Houston, TX (United States)] [and others

    1995-07-03

    Hypochondroplasia is an inherited chondrodystrophy that is characterized by disproportionate short stature. A recent linkage study by LeMerrer et al. suggested that hypochondroplasia and achondroplasia are allelic conditions. Three groups have now mapped the achondroplasia locus to the telomeric region of chromosome 4. Recently, two mutations in fibroblast growth factor receptor 3 (FGFR3) at nucleotide 1138, in the transmembrane domain, were identified in 169 of 170 unrelated individuals with achondroplasia. Here, we report the results of a linkage study in 4 multigenerational families with hypochondroplasia and mutational analysis of nucleotide 1138 in one individual from each of these families, two nonfamilial hypochondroplasia individuals and sequencing of the transmembrane domain of the FGFR3 in three affected unrelated individuals. 13 refs., 1 tab.

  9. Homozygous N540K hypochondroplasia--first report: radiological and clinical features.

    De Rosa, M Laura Garcia; Fano, Virginia; Araoz, H Verónica; Chertkoff, Lilien; Obregon, M Gabriela

    2014-07-01

    We describe a 16-month-old male with N540K homozygous mutation in the FGFR3 gene who showed a more severe phenotype than hypochondroplasia (HCH). To our knowledge, a homozygous state for this mutation causing HCH has not been reported before. The clinical and radiological characteristics of our patient represent an intermediate condition between achondroplasia and achondroplasia/hypochondroplasia compound heterozygosity. This case represents a new expression of FGFR3 spectrum and it is of considerable importance for the genetic counseling in cases where both parents are affected with HCH. PMID:24715719

  10. Selfish spermatogonial selection

    Lim, Jasmine; Maher, Geoffrey J; Turner, Gareth D H; Dudka-Ruszkowska, Wioleta; Taylor, Stephen; Meyts, Ewa Rajpert-De; Goriely, Anne; Wilkie, Andrew O M

    2012-01-01

    The dominant congenital disorders Apert syndrome, achondroplasia and multiple endocrine neoplasia-caused by specific missense mutations in the FGFR2, FGFR3 and RET proteins respectively-represent classical examples of paternal age-effect mutation, a class that arises at particularly high frequenc......The dominant congenital disorders Apert syndrome, achondroplasia and multiple endocrine neoplasia-caused by specific missense mutations in the FGFR2, FGFR3 and RET proteins respectively-represent classical examples of paternal age-effect mutation, a class that arises at particularly high...

  11. Confirmatory linkage study of hypochondroplasia

    Hecht, J.T.; Herrera, C.; Greenhaw, G.A. [Univ. of Texas Medical School, Houston, TX (United States)] [and others

    1994-09-01

    Hypochondroplasia is an autosomal dominant form of disproportionate short stature disorder that has clinical and radiographic findings similar to but milder than achondroplasia. Based on these findings it has been suggested that achondroplasia and hypochondroplasia are allelic conditions. We and others have mapped the achondroplasia locus to telomeric region of chromosome 4. Tested linkage to 4p markers in 6 hypochondroplasia families and a maximum LOD score of 1.7 at {theta} = 0 was found for IUDA. Here we report the results of a linkage study in 4 multigenerational families with hypochondroplasia using 7 short tandem repeat markers (D4S127, D4S412, D4S43, D4S115, IUDA, D4S227, D4S169) from the short arm of chromosome 4. These families have been well characterized and show the typical clinical and radiographic features of hypochondroplasia. One family was Afro-American, one Hispanic and two were Caucasian. We found a maximum multipoint LOD score of 2.9 at D4S115. The results of this study provide confirmatory evidence that achondroplasia and hypochondroplasia map to the same chromosomal location and suggests that they are indeed allelic conditions.

  12. Abnormal cartilage from the mandibular condyle of stumpy (stm) mutant mice.

    Johnson, D.R.

    1983-01-01

    The mammalian mandibular condyle is composed of secondary cartilage and may thus be susceptible to genes causing achondroplasia and which result in abnormal++ primary cartilage formation. This paper describes the secondary cartilage in the mandible of the stumpy achondroplastic mutation in the mouse: both primary and secondary cartilage are affected by the gene.

  13. Cloverleaf skull with generalised bone dysplasia

    A case of cloverleaf skull with generalised bone dysplasia is reported. The authors believe that bone dysplasia associated with cloverleaf is neither identical with thanatophoric dysplasia nor achondroplasia. Until identity of thanatophoric dysplasia and cloverleaf skull with generalised bone dysplasia is proved the diseases should be looked upon as separate entities and the wording ''thanatophoric dysplasia with cloverleaf skull'' should be abolished. (orig.)

  14. Achondroplastic dog breeds have no mutations in the transmembrane domain of the FGFR-3 gene.

    Martínez, S; Valdés, J; Alonso, R A

    2000-10-01

    One of the most common skeletal affections in humans is achondroplasia, a short-limbed dwarfism that is, in most cases, caused by mutations in the transmembrane domain of the fibroblast growth factor receptor-3 (FGFR-3) gene. Due to the lack of sufficient radiological, genetic, and molecular studies, most types of skeletal anomalies in dogs are classified as achondroplasia. To initiate the molecular characterization of some osteochondrodysplastic dog breeds, we obtained the DNA sequence of the transmembrane domain of the FGFR-3 gene from the dachshund, basset hound, bulldog, and German shepherd dogs. All 4 breeds showed no mutation in the evaluated region. This indicates that the mutation responsible for the osteochondrodysplastic phenotype in the tested dog breeds lies either elsewhere in the FGFR-3 gene or in other ones involved in the formation and development of endochondral bone. PMID:11041504

  15. FGFR3-related condition: a skeletal dysplasia with similarities to thanatophoric dysplasia and SADDAN due to Lys650Met.

    Farmakis, Shannon G; Shinawi, Marwan; Miller-Thomas, Michelle; Radmanesh, Alireza; Herman, Thomas E

    2015-03-01

    Mutations in the fibroblast growth factor receptor 3 (FGFR3) gene account for six related skeletal dysplasia conditions: achondroplasia, hypochondroplasia, thanatophoric dysplasia types 1 and 2, SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans), and platyspondylic lethal skeletal dysplasia, San Diego type. This group of disorders has very characteristic clinical and radiologic features, which distinguish them from other skeletal dysplasias. They display a spectrum of severity in the skeletal findings, ranging from relatively mild hypochondroplasia to lethal thanatophoric dysplasia. We report a patient who has the missense FGFR3 mutation, Lys650Met, previously reported in association only with SADDAN, who exhibits some findings similar to both thanatophoric dysplasia (types 1 and 2) in addition to those findings characteristic of SADDAN. PMID:25119967

  16. Osteochondral Diseases and Fibrodysplasia Ossificans Progressiva

    Kaplan, Frederick S.

    2016-01-01

    Osteochondrodysplasias like thanatophoric dysplasia, osteogenesis imperfecta, achondroplasia, and other genetic skeletal disorders like fibrodysplasia ossificans progressiva are infrequently seen in clinical practice. In cases of sporadic achondroplasia as well as in fibrodysplasia ossificans progressiva, there is a strong association with paternal age, a relationship that is less evident in other genetic osteochondral diseases. No other constitutional or environmental factor has proven to be associated with these disorders. The use of prenatal ultrasonography as a routine component of prenatal care is crucial in the early suspicion of osteochondrodysplasias whereas definitive diagnosis is usually obtained by pre-natal molecular analysis. In the case of fibrodysplasia ossificans progressiva, recognition of congenital great toe malformations associated with rapidly–appearing soft tissue swelling is sufficient to make the proper clinical diagnosis, which can be confirmed by genetic testing. Large regional centres will improve diagnosis performance, provide accurate genetic counselling, and ensure an integral assistance for these often severe and incapacitating conditions. PMID:20824454

  17. Volume reduction of the jugular foramina in Cavalier King Charles Spaniels with syringomyelia

    Schmidt Martin; Ondreka Nele; Sauerbrey Maren; Volk Holger; Rummel Christoph; Kramer Martin

    2012-01-01

    Abstract Background Understanding the pathogenesis of the chiari-like malformation in the Cavalier King Charles Spaniel (CKCS) is incomplete, and current hypotheses do not fully explain the development of syringomyelia (SM) in the spinal cords of affected dogs. This study investigates an unconventional pathogenetic theory for the development of cerebrospinal fluid (CSF) pressure waves in the subarachnoid space in CKCS with SM, by analogy with human diseases. In children with achondroplasia th...

  18. Dwarfism and gigantism in historical picture postcards.

    Enderle, A

    1998-01-01

    A collection of 893 historical picture postcards from 1900 to 1935, depicting dwarfs and giants, was analysed from medical and psychosocial viewpoints. In conditions such as 'bird headed dwarfism', achondroplasia, cretinism, so-called Aztecs or pinheads, Grebe chondrodysplasia, and acromegalic gigantism, the disorder could be diagnosed easily. In hypopituitary dwarfism, exact diagnosis was more difficult because of heterogeneity. The most common conditions depicted were pituitary dwarfism and...

  19. The prevalence of thanatophoric dysplasia and lethal osteogenesis imperfecta type II in Northern Ireland - a complete population study

    Donnelly, Deirdre E; McConnell, Vivienne; Paterson, Anne; Morrison, Patrick J

    2010-01-01

    The minimum prevalence of lethal Osteogenesis imperfecta type II, thanatophoric dysplasia and achondroplasia were derived following detailed case note review of all perinatal lethal skeletal dysplasias (SD) in Northern Ireland over a 12 year period. Multiple sources of ascertainment, including genetic notes, radiological reports and post mortem findings, were used. 39 cases were identified. Thanatophoric dysplasia was the commonest diagnosis made (22), followed by osteogenesis imperfecta type...

  20. Cloverleaf skull with generalised bone dysplasia

    Kozlowski, K.; Warren, P.S.; Fisher, C.C.

    1985-09-01

    A case of cloverleaf skull with generalised bone dysplasia is reported. The authors believe that bone dysplasia associated with cloverleaf is neither identical with thanatophoric dysplasia nor achondroplasia. Until identity of thanatophoric dysplasia and cloverleaf skull with generalised bone dysplasia is proved the diseases should be looked upon as separate entities and the wording ''thanatophoric dysplasia with cloverleaf skull'' should be abolished.

  1. Multiple exostotic hypochondroplasia: Syndrome of combined hypochondroplasia and multiple exostoses

    This is a report of a family with major focus on the daughter who had short stature. The mother had hypochondroplasia and the father had multiple exostoses. The daughter's skeletal roentgenograms show features of both hypochondroplasia and multiple exostoses. The roentgenographic, clinical and genetic aspects of these skeletal dysplasias are reviewed and hypochrondroplasia is contrasted with achondroplasia. The genetic and counseling implications of the association of hypochondroplasia and multiple exostoses are discussed. (orig.)

  2. Chromosomal aberrations in children exposed to diagnostic x-rays

    Among children who have received high x-ray doses congenital dislocation of the hip joint is the predominating diagnosis. In a series of 9 children who had received high x-ray doses (8 with luxation of the hip joint and one with achondroplasia) a significant increase of chromosomal aberrations was found. The increase concerned mainly chromosome type aberrations. The shorter the time since the last x-ray investigation the higher was the frequency of chromosome type aberrations. (author)

  3. Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias

    Foldynova-Trantirkova, Silvie; Wilcox, William R.; Krejci, Pavel

    2011-01-01

    In 1994, the field of bone biology was significantly advanced by the discovery that activating mutations in the FGFR3 receptor tyrosine kinase account for the common genetic form of dwarfism in humans, achondroplasia. Other conditions soon followed, with the list of human disorders caused by FGFR3 mutations now reaching at least 10. An array of vastly different diagnoses is caused by similar mutations in FGFR3, including syndromes affecting skeletal development (hypochondroplasia, achondropla...

  4. Den molekylaergenetiske baggrund for en raekke arvelige kraniosynostoser og kondrodysplasier

    Hertz, Jens Michael; juncker, Inger; Christensen, L; Østergaard, J R; Jensen, P K

    2001-01-01

    Fibroblast growth factors are structurally related proteins associated with cell growth, differentiation, migration, wound healing, angiogenesis, and oncogenesis. At the cellular level, their function is mediated by transmembrane tyrosinekinase receptors, fibroblast growth factor receptors. Four ......, ACS. The same mutation can cause different syndromes, and the same syndrome can be caused by mutations in different genes. The chondrodysplasias: achondroplasia, hypochondroplasia, and thanatophoric dysplasia are all caused by mutations in FGFR3....

  5. Multiple exostotic hypochondroplasia: Syndrome of combined hypochondroplasia and multiple exostoses

    Dominguez, R.; Young, L.W.; Girdany, B.R.; Steele, M.W.

    1984-07-01

    This is a report of a family with major focus on the daughter who had short stature. The mother had hypochondroplasia and the father had multiple exostoses. The daughter's skeletal roentgenograms show features of both hypochondroplasia and multiple exostoses. The roentgenographic, clinical and genetic aspects of these skeletal dysplasias are reviewed and hypochrondroplasia is contrasted with achondroplasia. The genetic and counseling implications of the association of hypochondroplasia and multiple exostoses are discussed.

  6. Not all hypochondroplasia families are linked to chromosome 4p16.3

    Rousseau, F.; Munnich, A.; Merrer, M.Le. [INSERM, Paris (France)] [and others

    1994-09-01

    Achondroplasia (ACH, MIM 100800) and hypochondroplasia (HCH, MIM 146000) are short limb dwarfism with enlarged head sharing some specific radiological features. Inter- and intrafamilial clinical variability and histolopathological aspects of the growth cartilage suggested that ACH and HCH are allelic disorders. Recently, the gene for achondroplasia was mapped to chromosome 4p and no recombinants were found in 9 families with hypochondroplasia between D4S111 and the telomere (Zmax=1.70, {theta}=0). By using an additional polymorphic DNA marker which detects VNTR-like polymorphism at the D4S227 locus and a new microsatellite at locus D4S? (AFM163yc1), we observed recombinant events with markers of the chromosome 4p16.3 in 3/10 hypochondroplasia families, indicating that not all hypochondroplasia families are linked to chromosome 4p. A fibroblast growth factor receptor (FGFR3) expressed in chondrocytes during endochondral ossification which is located in the 2.5 Mb candidate region for achondroplasia was regarded as a good candidate gene. No major rearrangement of the FGFR3 gene was detected by Southern blot analysis using an FGFR3 cDNA probe. Further investigations will be required to conclude as to the possible involvement of this gene in ACH.

  7. Llizarov technique

    This paper illustrates the radiographic manifestations of the Ilizarov distraction technique for the correction of short and deformed limbs. The radiographs of 130 patients who underwent Ilizarov distraction at 160 sites since December 1986 were reviewed retrospectively. Reasons for correction included fracture nonunion and malunion idiopathic leg length discrepancy, achondroplasia, and neurofibromatosis with tibial pseudarthrosis. Ninety patients were adults, and 40 were children. In order to assess cortical bone development during the fixation phase, CT of the regenerate bone was performed in 17 patients. Conventional tomograms were obtained in 20 patients for the evaluation of delayed or hypoplastic union at the distraction site

  8. Systemically induced changes in skeletal structure

    The number of systemic designs leading the radiographically detectable bone and joint changes is legion. Some disorders (notably the arthridites), while qualifying as diseases with protean systemic manifestations are discussed elsewhere in this book. Other disorders (e.g., achondroplasia), while not representing diseases per se, are included in this chapter for the sake of completeness and due to their relative frequency and their interesting radiographic characteristics. The author focuses on a number of selected conditions, some commonly seen and some relatively infrequently encountered. They are classified into he following categories: endocrinologic; metabolic; hematologic and reticuloendothelial; and dysplastic

  9. Sheathless transradial coronary angioplasty in an achondroplasic patient with ST elevation myocardial infarction.

    Rahman, Nasir; Nabi, Amjad; Gul, Ibrahim

    2015-01-01

    We present a case of a 50-year-old man with achondroplasia, who presented with anterior ST segment myocardial infarction (STEMI). He was taken urgently to the catheterisation laboratory. Owing to his short stature, it was not possible to insert a radial artery sheath so he underwent a sheathless primary percutaneous coronary intervention (PCI) through the right radial artery, with no complication. He was shifted to the coronary care unit and had an uneventful hospital course. He was discharged in stable condition and follows up regularly as an outpatient. PMID:26508119

  10. Anesthesia for an achondroplastic individual with coexisting atlantoaxial dislocation.

    Kaushal, Ashutosh; Haldar, Rudrashish; Ambesh, Paurush

    2015-01-01

    Achondroplasia is a congenital, disfiguring condition which is the most common form of short-limbed dwarfism. Defective cartilage formation is the hallmark of this condition, which results in a wide spectrum of skeletal abnormalities including spinal defects. Various other systems such as cardiac, pulmonary, and neurological can be simultaneously affected adversely including airway defects. Anesthetic management of such individuals is complicated because of their multisystem affliction. Concomitant atlantoaxial dislocation can further amplify the difficulty during the administration of anesthesia in such patients. We report the successful anesthetic conduct of such a patient with the positive outcome. PMID:26712995

  11. Coronary bypass using bilateral internal mammary arteries in an achondroplast.

    Alassal, Mohamed Abdulwahab; Youssef, Mostafa; Koudieh, Mohammed

    2015-01-01

    Coronary bypass grafting for ischemic heart disease in achondroplastic dwarfs is very rare. Shortage of veins and inadequate vein quality may cause difficulties during surgery. Only 2 cases of coronary bypass surgery in an achondroplastic dwarf, in which the left internal mammary artery and vein grafts were used, have been reported. We describe the case of a 55-year-old male achondroplastic dwarf who had triple-vessel coronary disease and underwent successful coronary bypass surgery using one saphenous vein graft and bilateral internal mammary artery grafts. The anatomic and surgical challenges in achondroplasia are highlighted. PMID:24887865

  12. Ovarian Spigelian hernia: A radiological diagnosis

    We describe that case of a 54 year old lady with achondroplasia who presented with ongoing left sided abdominal pain. Ultrasound and abdominal computerized tomography images demonstrated an enlarged left ovary and Fallopian tube trapped between the rectus abdominus and the lateral semilunar line under cover of the external oblique aponeurosis. A left sided salpingoophrectomy with mesh herniorrhaphy was performed and histological analysis confirmed the hernia contents were a hydrosalpinx and normal ovary. This case report presents the unusual radiographic images and intraoperative photographs of an ovarian Speglian hernia.

  13. Fixed cord in spinal stenosis

    This paper evaluates patients with cervical spinal canal compromise due to congenital anomalies (achondroplasia, Chiari malformation) and degenerative diseases using MR cord motion and cerebrospinal fluid (CSF) flow studies. Pulsatile longitudinal motion of the cervical cord was determined by means of cardiac-gated velocity phase contrast methods, including cine. Pathology included dwarfism (n = 15), Chiari malformation (n = 10), spondylosis (n = 10), and acute cord compression (n = 9). Symptomatic cases of congenital cervical stenosis had decreased cord motion, although CSF flow was not always significantly compromised. Postoperative cases demonstrated good cord and CSF motion, unless compression or obstruction was present

  14. Tópicos sobre displasias óseas

    Guillermo Lay-Son R.

    2012-02-01

    Full Text Available It is important to recognize skeletal dysplasia as a heterogeneous group of conditions with many classifications all of which have shortcomings. In consequence, it is very important to obtain anthropometric measurements and a complete skeletal work-up so as to properly establish phenotype. Once this is done patients can be assigned to diagnostic groups and diagnosis may be established. Diagnosing conditions that do not belong to the more common and well known diseases – such as achondroplasia – is more challenging and requires a multi-disciplinary approach.

  15. SSCP and segregation analysis of the human type X collagen gene (COL10A1) in heritable forms of chondrodysplasia

    Sweetman, W.A.; Rash, B.; Thomas, J.T.; Boot-Handford, R.; Grant, M.E.; Wallis, G.A. (Univ. of Manchester (United Kingdom)); Sykes, B. (Univ. of Oxford (United Kingdom)); Beighton, P. (Univ. of Cape Town (South Africa)); Hecht, J.T. (Univ. of Texas, Houston, TX (United States)); Zabell, B. (Johannes Gutenburg Universitaet, Mainz (Germany))

    1992-10-01

    Type X collagen is a homotrimeric, short chain, nonfibrillar collagen that is expressed exclusively by hypertrophic chondrocytes at the sites of endochondral ossification. The distribution and pattern of expression of the type X collagen gene (COL10A1) suggests that mutations altering the structure and synthesis of the protein may be responsible for causing heritable forms of chondrodysplasia. The authors investigated whether mutations within the human COL10A1 gene were responsible for causing the disorders achondroplasia, hypochondroplasia, pseudoachondroplasia, and thanatophoric dysplasia, by analyzing the coding regions of the gene by using PCR and the single-stranded conformational polymorphism technique. By this approach, seven sequence changes were identified within and flanking the coding regions of the gene of the affected persons. The authors demonstrated that six of these sequence changes were not responsible for causing these forms of chondrodysplasia but were polymorphic in nature. The sequence changes were used to demonstrate discordant segregation between the COL10A1 locus and achondroplasia and pseudoachondroplasia, in nuclear families. This lack of segregation suggests that mutations within or near the COL101A1 locus are not responsible for these disorders. The seventh sequence change resulted in a valine-to-methionine substitution in the carboxyl-terminal domain of the molecule and was identified in only two hypochondroplasic individuals from a single family. Segregation analysis in this family was inconclusive, and the significance of this substitution remains uncertain. 47 refs., 3 figs., 2 tabs.

  16. Severe spinal stenosis in an adult achondroplastic dwarf – case report

    B. Iliescu1, S. Gaivas1, C. Apetrei1, I. Poeată1,2

    2010-11-01

    Full Text Available Achondroplasia is the most commonform of human short-limbed dwarfism andis one of a spectrum of diseases caused bymutations in the FGFR3 gene.Achondroplasia is estimated to occur in 1 in10,000–30,000 live births4,7. The disease isautosomal dominant, but 80% of patientshave new mutations. It is commonlyassociated with several neurologicalconditions such as hydrocephalus,cervicomedullary compression, cervical orthoracic cord compression, and lumbarspinal compression due to bone stenosisalong the neuraxis. We report a case withsevere spinal stenosis at the lumbar andthoracic levels, with minimal involvementof the cervical spine with late neurologicalonset in an adult patient withachondroplasia. Neurological andradiological findings and surgicalprocedures are discussed. The patient wasadmitted with profound spastic lowerparaparesis and urinary incontinence. In thefirst operation we performed lumbardecompression and the patient improvedand on the fifth day she was able to take ashort walk. 3 months after the first surgerywe intervened on the thoracic spine with amulti-level decompression which allowedfor further neurological improvement,continued in a specialized medical facility.The case stands out as the clinical picturewas dominated by the lumbar stenosis(although both lumbar and thoracicstenosis were severe at the time ofpresentation with a late onset and sparingof the cervical spine.

  17. Experience of a skeletal dysplasia registry in Turkey: a five-years retrospective analysis.

    Kurt-Sukur, Eda Didem; Simsek-Kiper, Pelin Ozlem; Utine, Gülen Eda; Boduroglu, Koray; Alanay, Yasemin

    2015-09-01

    This study shares data on 417 patients with genetic disorders of skeleton including 10 fetal autopsies encountered in a 5-year period at a tertiary university hospital in Ankara, Turkey. We included patients with osteochondrodysplasias, excluding overgrowth syndromes, dysostoses, and craniofacial syndromes. When grouped according to the "International Skeletal Dysplasia Society 2010 classification" the most frequent group is "FGFR3 group" (achondroplasia). "Decreased bone density group" takes the second place, consistent with the literature. We also demonstrated, a relatively higher frequency of recessively inherited skeletal dysplasias when the diagnosis is an entity other than achondroplasia or osteogenesis imperfecta. The literature on the incidence of genetic disorders of skeleton from the Middle East and Eastern Mediterranean is limited to fetal and neonatal autopsies or birth prevelance reports. The higher rate of consanguineous marriages which increases the frequency of autosomal recessive entities makes it difficult to apply data from other parts of the world. Total consanguinity rate among parents in our study was 53% and there were regional differences. The highest (79%) was among parents from South-east Anatolia. This study is the first broad retrospective analysis of genetic disorders of skeleton from our region. We aim to provide a descriptive source for future studies and discuss our findings in comparison to reports from other parts of the world. PMID:25931420

  18. Hypochondroplasia with Foramen Magnum Stenosis: a Case Report

    Nazik Aşılıoğlu

    2011-09-01

    Full Text Available Hypochondroplasia was first reported in the English literature by Beals (1969. The features are similar to those of achondroplasia but are less severe and are usually reported not to involve the skull. The foramen magnum and whole spinal canal are reduced in diameter in achondroplasia, but less so in hypochondroplasia. In this study, we present an unique case of a seven month old child with hypochondroplasia with symptomatic foramen magnum stenosis which required surgical decompression. This 7-month-old child with hypochondroplasia presented with hypotonia and severe respiratory disabilities, including apneic episodes requiring continuous positive airway pressure. Magnetic resonance imaging revealed marked foramen magnum stenosis. Foramen magnum decompression was performed. Postoperatively, steady motor improvement has been observed and the patient no longer requires ventilatory support. To the our knowledge, this is the first report of hypochondroplasia and symptomatic foramen magnum stenosis. In this case we wish to emphasize the necessity of the radiological imaging of foramen magnum and spinal cord for the patient who has respiratory distress and hypotonia with skeletal dysplasia.

  19. Total spinal anesthesia in an achondroplasic patient: case report

    Amiri H R

    2008-06-01

    Full Text Available Background: Total spinal anesthesia is a complication of lumbar epidural anesthesia following undiagnosed subarachnoid or subdural injection of local anesthetic. Although many achondroplastic dwarfs have a normal spine, catheter insertion may be more problematic with a narrow epidural space making a subarachnoid tap more probable.  Other malformations associated with achondroplasia, such as prolapsed intervertebral discs, reduced interpedicular distance, shortened pedicles, and osteophyte formation, combined with a narrow epidural space may make identification of the space difficult and increases the risk of dural puncture. Furthermore, subarachnoid tap or dural puncture may be hard to recognize if a free flow of CSF is difficult to achieve due spinal stenosis. Yet, for those who meet the criteria, epidural regional anesthesia is frequently preferred over other forms, which often have more or more dangerous side effects in this type of patient.Case report: A 22-year-old achondroplastic male dwarf patient was scheduled for pelvic mass resection and was considered a candidate for continuous epidural anesthesia. The anesthesia became complicated by total spinal anesthesia, which was reversed following supportive management for about two hours.Conclusion: There is significant debate over the composition and volume of the test dose, especially for patients with achondroplasia. We nevertheless recommend repeated test-doses during the accomplishment of epidural anesthesia to exclude unintended intravascular, intrathecal or subdural injection, keeping in mind that a test dose of local anesthetic does not completely prevent complications.

  20. Mutant activated FGFR3 impairs endochondral bone growth by preventing SOX9 downregulation in differentiating chondrocytes.

    Zhou, Zi-Qiang; Ota, Sara; Deng, Chuxia; Akiyama, Haruhiko; Hurlin, Peter J

    2015-03-15

    Fibroblast growth factor receptor 3 (FGFR3) plays a critical role in the control of endochondral ossification, and bone growth and mutations that cause hyperactivation of FGFR3 are responsible for a collection of developmental disorders that feature poor endochondral bone growth. FGFR3 is expressed in proliferating chondrocytes of the cartilaginous growth plate but also in chondrocytes that have exited the cell cycle and entered the prehypertrophic phase of chondrocyte differentiation. Achondroplasia disorders feature defects in chondrocyte proliferation and differentiation, and the defects in differentiation have generally been considered to be a secondary manifestation of altered proliferation. By initiating a mutant activated knockin allele of FGFR3 (FGFR3K650E) that causes Thanatophoric Dysplasia Type II (TDII) specifically in prehypertrophic chondrocytes, we show that mutant FGFR3 induces a differentiation block at this stage independent of any changes in proliferation. The differentiation block coincided with persistent expression of SOX9, the master regulator of chondrogenesis, and reducing SOX9 dosage allowed chondrocyte differentiation to proceed and significantly improved endochondral bone growth in TDII. These findings suggest that a proliferation-independent and SOX9-dependent differentiation block is a key driving mechanism responsible for poor endochondral bone growth in achondroplasia disorders caused by mutations in FGFR3. PMID:25432534

  1. Advances on circulating fetal DNA in maternal plasma

    FU Xian-hu; CHEN Han-ping

    2007-01-01

    @@ The discovery of cell-free fetal DNA in maternal plasma in 1997 has opened up new possibilities for noninvasive diagnosis.1 By RT-PCR, circulating fetal DNA can be detected in the plasma of pregnant women,even in the first trimester of pregnancy,2,3 and thus can be used for noninvasive prenatal diagnosis of sex-linked disorders,4-6 the RhD status of fetuses,7 and single gene disorders such as beta-thalassaemia,8,9 congenital adrenal hyperplasia,10 and achondroplasia.11 In addition,quantitative aberrations of circulating fetal DNA may indicate various pregnancy-associated disorders,including1 Preeclampsia,12-14 preterm labor15,16 and fetal trisomy 21.17

  2. Paleopathological Study of Dwarfism-Related Skeletal Dysplasia in a Late Joseon Dynasty (South Korean) Population

    Woo, Eun Jin; Lee, Won-Joon; Hu, Kyung-Seok; Hwang, Jae Joon

    2015-01-01

    Skeletal dysplasias related to genetic etiologies have rarely been reported for past populations. This report presents the skeletal characteristics of an individual with dwarfism-related skeletal dysplasia from South Korea. To assess abnormal deformities, morphological features, metric data, and computed tomography scans are analyzed. Differential diagnoses include achondroplasia or hypochondroplasia, chondrodysplasia, multiple epiphyseal dysplasia, thalassemia-related hemolytic anemia, and lysosomal storage disease. The diffused deformities in the upper-limb bones and several coarsened features of the craniofacial bones indicate the most likely diagnosis to have been a certain type of lysosomal storage disease. The skeletal remains of EP-III-4-No.107 from the Eunpyeong site, although incomplete and fragmented, provide important clues to the paleopathological diagnosis of skeletal dysplasias. PMID:26488291

  3. Interpretation and value of MR CSF flow studies for paediatric neurosurgery

    Samukelisiwe Sithembile Mbonane

    2013-03-01

    Full Text Available Imaging techniques may be underutilised when clinicians are unaware of the technique or do not recognise its potential. Phase-contrast MR imaging (PC-MRI is a rapid, simple and non-invasive technique that is sensitive to CSF flow. It demonstrates a mechanical coupling between cerebral blood and CSF flow throughout the cardiac cycle. Neurosurgeons should be able to request this procedure routinely as part of an MRI request. This paper gives an overview of the indications, technical requirements, technique and interpretation, using image examples. Indications for CSF flow studies include assessment and functionality of shunt treatment in patients with hydrocephalus; hydrocephalus associated with achondroplasia; Chiari I malformation; confirmation of aqueductal stenosis; and determining patency of a third ventriculostomy.

  4. The gene for the Ellis-van Creveld syndrome is located on chromosome 4p16

    Polymeropoulos, M.H.; Ide, S.E. [National Institute of Health, Bethesda, MD (United States); Wright, M. [Univ. of Newcastle Upon Tyne (United Kingdom)] [and others

    1996-07-01

    Ellis-van Creveld syndrome (EVC) is an autosomal recessive disorder characterized by disproportionate dwarfism, polydactyly, and congenital heart disease. This rare disorder is found with increased frequency among the Old Order Amish community in Lancaster County, Pennsylvania. We have used linkage analysis to localize the gene responsible for the EVC phenotype in nine interrelated Amish pedigrees and three unrelated families from Mexico, Ecuador, and Brazil. We now report the linkage for the Ellisvan Creveld syndrome gene to markers on the distal short arm of human chromosome 4, with Z{sub max} = 6.91 at {theta} = 0.02 for marker HOX7, in a region proximal to the FGFR3 gene responsible for the achondroplasia phenotype. 17 refs., 2 figs., 1 tab.

  5. Failed rapid sequence induction in an achondroplastic dwarf

    Jasleen Kaur

    2011-01-01

    Full Text Available Achondroplasia, a common cause of short limbed type of dwarfism is due to quantitative decrease in rate of endochondral ossification. This abnormal bone growth leads to disproportionate body and head structure, thus placing them under high risk for anaesthetic management. There is paucity in literatures, regarding appropriate drug dosage selection in these patients. Use of drugs as per standard dosage recommendations based on body weight or body surface area, may not be adequate in these patients owing to discrepancies in overall body weight and lean body weight, especially during rapid sequence induction. Here, we report a case of failed rapid sequence induction due to abnormal response to administered drugs in an adult achondroplastic dwarf. Standard doses of thiopentone and rocuronium had to be repeated thrice to achieve adequate conditions for intubation.

  6. Ellis Van Creveld Syndrome: Report of a Case and Brief Literature Review

    Gholamhossein Amirhakimi

    2008-04-01

    Full Text Available Objective: Ellis van Creveld syndrome (EvCS is a rare autosomal recessive (AR disorder first described in 1940. The syndrome manifests with several skeletal, oral mucosal and dental anomalies, congenital cardiac defects and nail dysplasia. EvCs should be differentiated from other chondrodystrophies such as achondroplasia and Morquios syndrome.Case Presentation: A nine-year old girl was referred with short stature. In physical examination her height was 105 cm. She had normal intelligence, small teeth, abnormal crown and adontia in mandibular incisors. Other findings included bilateral postaxial polydactyly in hands, narrow thorax, hypoplastic nails in hands and feet and genu valgum.Conclusion: Ellis van Creveld syndrome is a rare autosmal disorder with a high mortality in early life. As the condition is easily diagnosed at birth, early treatment can prevent patients from various complications and undue psychological trauma.

  7. Atlantoaxial Subluxation due to an Os Odontoideum in an Achondroplastic Adult: Report of a Case and Review of the Literature

    Abolfazl Rahimizadeh

    2015-01-01

    Full Text Available The authors report the first example of an adult achondroplastic dwarf with progressive quadriparesis secondary to atlantoaxial subluxation as a consequence of an os odontoideum. Actually, craniocervical region is a frequent site of compression and myelopathy in achondroplasia particularly in children as a result of small foramen magnum and hypertrophied opisthion. Moreover, very rarely in achondroplastic patients, coexistence of atlantoaxial instability as the sequel of os odontoideum can result in further compression of the already compromised cervicomedullary neural tissues, the scenario that has been reported only in five achondroplastic children. Herein, a 39-year-old achondroplastic male suffering such an extremely rare combination is presented. With C1-C2 screw rod instrumentation, atlas arch laminectomy, limited suboccipital craniectomy, and release of dural fibrous bands, reduction, decompression, and stabilization could be achieved properly resulting in steady but progressive recovery.

  8. Acute upper airway obstruction and emergency front of neck access in an achondroplastic patient.

    McCaffer, Craig James; Douglas, Catriona; Wickham, Matthew H; Picozzi, Gerard L

    2015-01-01

    Dwarfism is defined as a failure to attain a height of 148 cm in adulthood. Achondroplasia is the most common form of short-limbed dwarfism. Although this condition is relatively rare, with an incidence of 0.5-1.5 per 10,000 live births, most medical professionals will come across the achondroplastic dwarf (AD) during their career. Faulty endochondral ossification produces the characteristic short stature phenotype, as well as severe craniofacial, central nervous system, spinal, respiratory and cardiac anomalies. These unusual characteristics may present airway management difficulties in elective as well as emergency situations. Within the literature there is very little information regarding the emergency insertion of a surgical airway in an adult AD. We present our experience of this situation in the form of a case report and a review of the relevant literature. PMID:25827920

  9. Perceval S aortic valve implantation in an achondroplastic Dwarf.

    Baikoussis, Nikolaos G; Argiriou, Michalis; Argiriou, Orestis; Dedeilias, Panagiotis

    2016-01-01

    Despite cardiovascular disease in patients with dwarfism is not rare; there is a lack of reports referring to cardiac interventions in such patients. Dwarfism may be due to achondroplasia or hormonal growth disorders. We present a 58-year-old woman with episodes of dyspnea for several months. She underwent on transthoracic echocardiography, and she diagnosed with severe aortic valve stenosis. She referred to our department for surgical treatment of this finding. In accordance of her anthropometric characteristics and her very small aortic annulus, we had the dilemma of prosthesis selection. We decided to implant a stentless valve to optimize her effective orifice area. Our aim is to present the successful Perceval S valve implantation and the descriptions of the problems coming across in operating on these special patients. To our knowledge, this is the first case patient in which a Perceval S valve is implanted according to the international bibliography. PMID:26750695

  10. Novel approaches to short stature therapy.

    Wit, Jan M; Oostdijk, Wilma

    2015-06-01

    Besides growth hormone, several pharmaceutical products have been investigated for efficacy and safety in increasing short term growth or adult height. Short-term treatment with testosterone esters in boys with constitutional delay of growth and puberty is efficacious in generating secondary sex characteristics and growth acceleration. The addition of oxandrolone to growth hormone (GH) in Turner syndrome has an additive effect on adult height gain. Treatment with GnRH analogs is the established treatment of central precocious puberty, and its addition to GH therapy appears effective in increasing adult height in GH deficient children, and possibly short children born SGA or with SHOX deficiency, who are still short at pubertal onset. Aromatase inhibitors appear effective in several rare disorders, but their value in increasing adult height in early pubertal boys with GH deficiency or idiopathic short stature is uncertain. A trial with a C-natriuretic peptide analog offers hope for children with achondroplasia. PMID:26051296

  11. Atlantoaxial Subluxation due to an Os Odontoideum in an Achondroplastic Adult: Report of a Case and Review of the Literature.

    Rahimizadeh, Abolfazl; Soufiani, Housain F; Hassani, Valiolah; Rahimizadeh, Ava

    2015-01-01

    The authors report the first example of an adult achondroplastic dwarf with progressive quadriparesis secondary to atlantoaxial subluxation as a consequence of an os odontoideum. Actually, craniocervical region is a frequent site of compression and myelopathy in achondroplasia particularly in children as a result of small foramen magnum and hypertrophied opisthion. Moreover, very rarely in achondroplastic patients, coexistence of atlantoaxial instability as the sequel of os odontoideum can result in further compression of the already compromised cervicomedullary neural tissues, the scenario that has been reported only in five achondroplastic children. Herein, a 39-year-old achondroplastic male suffering such an extremely rare combination is presented. With C1-C2 screw rod instrumentation, atlas arch laminectomy, limited suboccipital craniectomy, and release of dural fibrous bands, reduction, decompression, and stabilization could be achieved properly resulting in steady but progressive recovery. PMID:26693369

  12. Chondroectodermal dysplasia (Ellis van Creveld syndrome: A report of three cases with review of literature

    Kurian K

    2007-01-01

    Full Text Available Chondroectodermal dysplasia is a rare mesenchymal - ectodermal dysplasia first described in 1940 by Richard W.B. Ellis and Simon van Creveld now known as Ellis van Creveld syndrome. It is also known as Mesvectodermal dysplasia. Majority of cases were characteristically seen in one particular inbred population from the Amish community of Lancaster County, Pennsylvania, U.S.A. The syndrome manifests with several skeletal anomalies, oral mucosal and dental anomalies, congenital cardiac defects and nail dysplasia. Ellis van Creveld syndrome may be differentiated from other chondrodystrophies like achondroplasia, chondroplasia punctata, asphyxiating thorasic dystrophy and Morquio′s syndrome. The presence of oral mucosal and dental alterations like notching of the lower alveolar process, fusion of the upper lip with gingival mucosal margin, occasional presence of neonatal teeth, oligodontia and conical shape of anterior teeth will confirm the diagnosis of Ellis van Creveld syndrome and hence its importance to dentists.

  13. Future directions in research

    New studies of the effects of ionizing radiation on the human genome must include not only its effect on the sequence of a particular gene, but must also consider the possible location, complete structure, regulation, and function of the gene as well. Historically, genetic disorders have been characterized as single gene disorders, chromosomal aberrations, and multifactorial disorders. Now, however, the following have to be considered: mosaicism, genomic imprinting, uniparental disomy, cytoplasmic inheritance, allelic expansion. Molecular techniques that may be useful in analyzing radiation damage include Fluorescent In Situ Hybridization and the Polymerase Chain Reaction. The effect of radiation on the fibroblast growth factor receptor 3, damage to which is associated with the development of achondroplasia, is recommended as a fruitful, if complicated, research topic

  14. Paleopathological Study of Dwarfism-Related Skeletal Dysplasia in a Late Joseon Dynasty (South Korean Population.

    Eun Jin Woo

    Full Text Available Skeletal dysplasias related to genetic etiologies have rarely been reported for past populations. This report presents the skeletal characteristics of an individual with dwarfism-related skeletal dysplasia from South Korea. To assess abnormal deformities, morphological features, metric data, and computed tomography scans are analyzed. Differential diagnoses include achondroplasia or hypochondroplasia, chondrodysplasia, multiple epiphyseal dysplasia, thalassemia-related hemolytic anemia, and lysosomal storage disease. The diffused deformities in the upper-limb bones and several coarsened features of the craniofacial bones indicate the most likely diagnosis to have been a certain type of lysosomal storage disease. The skeletal remains of EP-III-4-No.107 from the Eunpyeong site, although incomplete and fragmented, provide important clues to the paleopathological diagnosis of skeletal dysplasias.

  15. Anaesthetic Management of Caesarean Section in an Achondroplastic Dwarf

    Kirti N Saxena

    2008-01-01

    A twenty year old parturient with short stature presented to the hospital in early labour. An elective lower segment caesarean section(LSCS was planned in view of cephalopelvic disproportion. She had papers which suggested that she had been diagnosed as a case of achondroplasia though details were not available. Combined spinal epidural(CSE anaesthesia was planned in the patient in view of the death of her first baby following caesarean section under general anaesthesia. Repeatedly dry taps were achieved on attempting dural puncture. Dural puncture was abandoned and an 18 G epidural catheter was threaded via the Tuohy needle. Sensory block till T 6 was achieved with 6ml of local anaesthetic solution. The patient was stable during the intraoperative and postoperative period.

  16. Perceval S aortic valve implantation in an achondroplastic Dwarf

    Nikolaos G Baikoussis

    2016-01-01

    Full Text Available Despite cardiovascular disease in patients with dwarfism is not rare; there is a lack of reports referring to cardiac interventions in such patients. Dwarfism may be due to achondroplasia or hormonal growth disorders. We present a 58-year-old woman with episodes of dyspnea for several months. She underwent on transthoracic echocardiography, and she diagnosed with severe aortic valve stenosis. She referred to our department for surgical treatment of this finding. In accordance of her anthropometric characteristics and her very small aortic annulus, we had the dilemma of prosthesis selection. We decided to implant a stentless valve to optimize her effective orifice area. Our aim is to present the successful Perceval S valve implantation and the descriptions of the problems coming across in operating on these special patients. To our knowledge, this is the first case patient in which a Perceval S valve is implanted according to the international bibliography.

  17. Homozygous FIBP nonsense variant responsible of syndromic overgrowth, with overgrowth, macrocephaly, retinal coloboma and learning disabilities.

    Thauvin-Robinet, C; Duplomb-Jego, L; Limoge, F; Picot, D; Masurel, A; Terriat, B; Champilou, C; Minot, D; St-Onge, J; Kuentz, P; Duffourd, Y; Thevenon, J; Rivière, J-B; Faivre, L

    2016-05-01

    The acidic fibroblast growth factor (FGF) intracellular binding protein (FIBP) interacts directly with the fibroblast growth factor FGF1. Although FIBP is known to be implicated in the FGF signaling pathway, its precise function remains unclear. Gain-of-function variants in several FGF receptors (FGFRs) are implicated in a wide spectrum of growth disorders from achondroplasia to overgrowth syndromes. In a unique case from a consanguineous union presenting with overgrowth, macrocephaly, retinal coloboma, large thumbs, severe varicose veins and learning disabilities, exome sequencing identified a homozygous nonsense FIBP variant. The patient's fibroblasts exhibit FIBP cDNA degradation and an increased proliferation capacity compared with controls. The phenotype defines a new multiple congenital abnormalities (MCA) syndrome, overlapping with the heterogeneous group of overgrowth syndromes with macrocephaly. The different clinical features can be explained by the alteration of the FGFR pathway. Taken together, these results suggest the implication of FIBP in a new autosomal recessive MCA. PMID:26660953

  18. Lumbar gibbus in storage diseases and bone dysplasias

    Levin, T.L. [Department of Radiology, Division of Pediatric Radiology, Columbia-Presbyterian Medical Center, Babies and Children`s Hospital of New York, NY (United States); Berdon, W.E. [Department of Radiology, Division of Pediatric Radiology, Columbia-Presbyterian Medical Center, Babies and Children`s Hospital of New York, NY (United States); Lachman, R.S. [International Skeletal Dysplasia Registry, Los Angeles, CA (United States); Anyane-Yeboa, K. [Department of Pediatrics, Columbia-Presbyterian Medical Center, Babies and Children`s Hospital of New York, NY (United States); Ruzal-Shapiro, C. [Department of Radiology, Division of Pediatric Radiology, Columbia-Presbyterian Medical Center, Babies and Children`s Hospital of New York, NY (United States); Roye, D.P. Jr. [Department of Orthopedic Surgery, Columbia-Presbyterian Medical Center, Babies and Children`s Hospital of New York, NY (United States)

    1997-04-01

    Objective. The objective of this study was to review the problem of lumbar gibbus in children with storage diseases and bone dysplasias utilizing plain films and MR imaging. Materials and methods. Clinical histories and radiographic images in five patients with storage diseases [four mucopolysaccharidosis (MPS) and one mucolipidosis] and two with achondroplasia were reviewed. The International Skeletal Dysplasia Registry (Los Angeles, Calif.), surveyed for all patients with lumbar gibbus and skeletal dysplasias, provided 12 additional cases. Results. All patients had localized gibbus of the upper lumbar spine, characterized by anterior wedging and posterior displacement of the vertebrae at the apex of the curve, producing a beaked appearance. The curve, exaggerated in the sitting or standing position, was most severe in the two patients with MPS-IV (one of whom died). Both developed severe neurologic signs and symptoms requiring surgical intervention. In four patients, MR images demonstrated the apex of the curve to be at or below the conus. Two patients demonstrated anterior herniation of the intervertebral discs at the apex of the curve, though the signal intensity of the intervertebral discs was normal. Conclusion. Lumbar gibbus has important neurologic and orthopedic implications, and is most severe in patients with MPS. The etiology of the gibbus with vertebral beaking is multifactorial and includes poor truncal muscle tone, weight-bearing forces, growth disturbance and anterior disc herniation. The curve is generally at or below the conus. Neurologic complications are unusual, although orthopedic problems can arise. Due to their longer survival, patients with achondroplasia or Morquio`s disease are more vulnerable to eventual gibbus-related musculoskeletal complications. (orig.). With 6 figs., 2 tabs.

  19. Lumbar gibbus in storage diseases and bone dysplasias

    Objective. The objective of this study was to review the problem of lumbar gibbus in children with storage diseases and bone dysplasias utilizing plain films and MR imaging. Materials and methods. Clinical histories and radiographic images in five patients with storage diseases [four mucopolysaccharidosis (MPS) and one mucolipidosis[ and two with achondroplasia were reviewed. The International Skeletal Dysplasia Registry (Los Angeles, Calif.), surveyed for all patients with lumbar gibbus and skeletal dysplasias, provided 12 additional cases. Results. All patients had localized gibbus of the upper lumbar spine, characterized by anterior wedging and posterior displacement of the vertebrae at the apex of the curve, producing a beaked appearance. The curve, exaggerated in the sitting or standing position, was most severe in the two patients with MPS-IV (one of whom died). Both developed severe neurologic signs and symptoms requiring surgical intervention. In four patients, MR images demonstrated the apex of the curve to be at or below the conus. Two patients demonstrated anterior herniation of the intervertebral discs at the apex of the curve, though the signal intensity of the intervertebral discs was normal. Conclusion. Lumbar gibbus has important neurologic and orthopedic implications, and is most severe in patients with MPS. The etiology of the gibbus with vertebral beaking is multifactorial and includes poor truncal muscle tone, weight-bearing forces, growth disturbance and anterior disc herniation. The curve is generally at or below the conus. Neurologic complications are unusual, although orthopedic problems can arise. Due to their longer survival, patients with achondroplasia or Morquio's disease are more vulnerable to eventual gibbus-related musculoskeletal complications. (orig.). With 6 figs., 2 tabs

  20. Drugs Used in Paediatric Bone and Calcium Disorders.

    Cheung, Moira S

    2015-01-01

    Calcium and bone disorders in children and adolescents are treated with a wide variety of drugs. Several of these drugs have been used for many years on the basis of accepted practice, without being subjected to rigorous trials. Bisphosphonates are the mainstay treatment for children with osteoporosis, but newer, more potent compounds such as zoledronate and risedronate have begun to replace the older-generation bisphosphonates. Hypocalcaemia is managed with calcium and vitamin D and its metabolites. In difficult cases that are secondary to hypoparathyroidism, subcutaneous injections or infusions of parathyroid hormone have been used. Multiple daily phosphate supplements and calcitriol are the standard treatment for hypophosphataemic rickets, but trials of an anti-fibroblast growth factor 23 antibody appear promising, and the results are eagerly awaited. Many new medications are undergoing clinical trials and are starting to emerge as viable treatment options for children. Some of these drugs target specific diseases, such as recombinant alkaline phosphatase for hypophosphatasia and a C-type natriuretic peptide analogue for achondroplasia. Other drugs, such as denosumab and odanacatib, have been used successfully in the adult population, and the appropriate use of these drugs in children is now being evaluated. PMID:26138848

  1. Molecular, Phenotypic Aspects and Therapeutic Horizons of Rare Genetic Bone Disorders

    Taha Faruqi

    2014-01-01

    Full Text Available A rare disease afflicts less than 200,000 individuals, according to the National Organization for Rare Diseases (NORD of the United States. Over 6,000 rare disorders affect approximately 1 in 10 Americans. Rare genetic bone disorders remain the major causes of disability in US patients. These rare bone disorders also represent a therapeutic challenge for clinicians, due to lack of understanding of underlying mechanisms. This systematic review explored current literature on therapeutic directions for the following rare genetic bone disorders: fibrous dysplasia, Gorham-Stout syndrome, fibrodysplasia ossificans progressiva, melorheostosis, multiple hereditary exostosis, osteogenesis imperfecta, craniometaphyseal dysplasia, achondroplasia, and hypophosphatasia. The disease mechanisms of Gorham-Stout disease, melorheostosis, and multiple hereditary exostosis are not fully elucidated. Inhibitors of the ACVR1/ALK2 pathway may serve as possible therapeutic intervention for FOP. The use of bisphosphonates and IL-6 inhibitors has been explored to be useful in the treatment of fibrous dysplasia, but more research is warranted. Cell therapy, bisphosphonate polytherapy, and human growth hormone may avert the pathology in osteogenesis imperfecta, but further studies are needed. There are still no current effective treatments for these bone disorders; however, significant promising advances in therapeutic modalities were developed that will limit patient suffering and treat their skeletal disabilities.

  2. A single nucleotide mutation in Nppc is associated with a long bone abnormality in lbab mice

    Roe Bruce A

    2007-04-01

    Full Text Available Abstract Background The long bone abnormality (lbab mouse is a new autosomal recessive mutant characterized by overall smaller body size with proportionate dwarfing of all organs and shorter long bones. Previous linkage analysis has located the lbab mutation on chromosome 1 between the markers D1Mit9 and D1Mit488. Results A genome-based positional approach was used to identify a mutation associated with lbab disease. A total of 122 genes and expressed sequence tags at the lbab region were screened for possible mutation by using genomic DNA from lbabl/lbab, lbab/+, and +/+ B6 mice and high throughput temperature gradient capillary electrophoresis. A sequence difference was identified in one of the amplicons of gene Nppc between lbab/lbab and +/+ mice. One-step reverse transcriptase polymerase chain reaction was performed to validate the difference of Nppc in different types of mice at the mRNA level. The mutation of Nppc was unique in lbab/lbab mice among multiple mouse inbred strains. The mutation of Nppc is co-segregated with lbab disease in 200 progenies produced from heterozygous lbab/+ parents. Conclusion A single nucleotide mutation of Nppc is associated with dwarfism in lbab/lbab mice. Current genome information and technology allow us to efficiently identify single nucleotide mutations from roughly mapped disease loci. The lbab mouse is a useful model for hereditary human achondroplasia.

  3. A systematic review of genetic skeletal disorders reported in Chinese biomedical journals between 1978 and 2012

    Cui Yazhou

    2012-08-01

    Full Text Available Abstract Little information is available on the prevalence, geographic distribution and mutation spectrum of genetic skeletal disorders (GSDs in China. This study systematically reviewed GSDs as defined in “Nosology and Classification of genetic skeletal disorders (2010 version” using Chinese biomedical literature published over the past 34 years from 1978 to 2012. In total, 16,099 GSDs have been reported. The most frequently reported disorders were Marfan syndrome, osteogenesis imperfecta, fibrous dysplasia, mucopolysaccharidosis, multiple cartilaginous exostoses, neurofibromatosis type 1 (NF1, osteopetrosis, achondroplasia, enchondromatosis (Ollier, and osteopoikilosis, accounting for 76.5% (12,312 cases of the total cases. Five groups (group 8, 12, 14, 18, 21 defined by “Nosology and Classification of genetic skeletal disorders” have not been reported in the Chinese biomedical literature. Gene mutation testing was performed in only a minor portion of the 16,099 cases of GSDs (187 cases, 1.16%. In total, 37 genes for 41 different GSDs were reported in Chinese biomedical literature, including 43 novel mutations. This review revealed a significant imbalance in rare disease identification in terms of geographic regions and hospital levels, suggesting the need to create a national multi-level network to meet the specific challenge of care for rare diseases in China.

  4. The time of onset of abnormal calcification in spondylometaepiphyseal dysplasia, short limb-abnormal calcification type

    Tueysuez, Beyhan [Istanbul University, Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul (Turkey); Gazioglu, Nurperi [Istanbul University, Department of Neurosurgery, Cerrahpasa Medical School, Istanbul (Turkey); Uenguer, Savas [Istanbul University, Department of Pediatric Radiology, Cerrahpasa Medical School, Istanbul (Turkey); Aji, Dolly Yafet [Istanbul University, Department of Pediatrics, Cerrahpasa Medical School, Istanbul (Turkey); Tuerkmen, Seval [Istanbul University, Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul (Turkey); Universitatsklinikum Berlin, Charite Virchow-Klinik, Berlin (Germany)

    2009-01-15

    A 1-month-old boy with shortness of extremities on prenatal US was referred to our department with a provisional diagnosis of achondroplasia. His height was normal but he had short extremities and platyspondyly, premature carpal epiphyses on both hands, and short tubular bones with irregular metaphyses on radiographs. Re-evaluation of the patient at the age of 1 year revealed very short height and premature calcification of the costal cartilages and epiphyses. Spondylometaepiphyseal dysplasia (SMED), short limb-abnormal calcification type was diagnosed. This condition is a very rare autosomal recessively inherited disorder, and most of the patients die in early childhood due to neurological involvement. At the age of 2 years and 5 months, a CT scan showed narrowing of the cervical spinal canal. One month later he died suddenly because of spinal cord injury. In conclusion early diagnosis is very important because the recurrence risk is high and patients may die due to early neurological complications. The time of onset of abnormal calcifications, a diagnostic finding of the disease, is at the age of around 1 year in most patients. When abnormal calcifications are not yet present, but radiological changes associated with SMED are present, this rare disease must be considered. (orig.)

  5. The time of onset of abnormal calcification in spondylometaepiphyseal dysplasia, short limb-abnormal calcification type.

    Tüysüz, Beyhan; Gazioğlu, Nurperi; Ungür, Savaş; Aji, Dolly Yafet; Türkmen, Seval

    2009-01-01

    A 1-month-old boy with shortness of extremities on prenatal US was referred to our department with a provisional diagnosis of achondroplasia. His height was normal but he had short extremities and platyspondyly, premature carpal epiphyses on both hands, and short tubular bones with irregular metaphyses on radiographs. Re-evaluation of the patient at the age of 1 year revealed very short height and premature calcification of the costal cartilages and epiphyses. Spondylometaepiphyseal dysplasia (SMED), short limb-abnormal calcification type was diagnosed. This condition is a very rare autosomal recessively inherited disorder, and most of the patients die in early childhood due to neurological involvement. At the age of 2 years and 5 months, a CT scan showed narrowing of the cervical spinal canal. One month later he died suddenly because of spinal cord injury. In conclusion early diagnosis is very important because the recurrence risk is high and patients may die due to early neurological complications. The time of onset of abnormal calcifications, a diagnostic finding of the disease, is at the age of around 1 year in most patients. When abnormal calcifications are not yet present, but radiological changes associated with SMED are present, this rare disease must be considered. PMID:19002453

  6. The time of onset of abnormal calcification in spondylometaepiphyseal dysplasia, short limb-abnormal calcification type

    A 1-month-old boy with shortness of extremities on prenatal US was referred to our department with a provisional diagnosis of achondroplasia. His height was normal but he had short extremities and platyspondyly, premature carpal epiphyses on both hands, and short tubular bones with irregular metaphyses on radiographs. Re-evaluation of the patient at the age of 1 year revealed very short height and premature calcification of the costal cartilages and epiphyses. Spondylometaepiphyseal dysplasia (SMED), short limb-abnormal calcification type was diagnosed. This condition is a very rare autosomal recessively inherited disorder, and most of the patients die in early childhood due to neurological involvement. At the age of 2 years and 5 months, a CT scan showed narrowing of the cervical spinal canal. One month later he died suddenly because of spinal cord injury. In conclusion early diagnosis is very important because the recurrence risk is high and patients may die due to early neurological complications. The time of onset of abnormal calcifications, a diagnostic finding of the disease, is at the age of around 1 year in most patients. When abnormal calcifications are not yet present, but radiological changes associated with SMED are present, this rare disease must be considered. (orig.)

  7. The acrophysis: a unifying concept for understanding enchondral bone growth and its disorders. II. Abnormal growth

    Oestreich, Alan E. [Department of Radiology, Cincinnati Children' s Hospital Medical Center, 3333 Burnet Avenue, OH 45229-3039, Cincinnati (United States)

    2004-03-01

    In order to discuss and illustrate the effects common to normal and abnormal enchondral bone at the physes and at all other growth plates of the developing child, the term ''acrophysis'' was proposed. Acrophyses include the growth plates of secondary growth centers including carpals and tarsals and apophyses, and the growth plates at the nonphyseal ends of small tubular bones. Abnormalities at acrophyseal sites are analogous to those at the physeal growth plates and their metaphyses. For example, changes relating to the zone of provisional calcification (ZPC) are often important to the demonstration of such similarities. Lead lines were an early example of the concept of analogy from abnormality due to physeal and to acrophyseal disturbance. The ZPC is a key factor in understanding patterns of rickets and its healing. Examples (including hypothyroidism, scurvy and other osteoporosis, Ollier disease, achondroplasia, and osteopetrosis, as well as the family of frostbite, Kashin-Beck disease, and rat bite fever) illustrate the acrophysis principle and in turn their manifestations are explained by that principle. (orig.)

  8. Pseudoachondroplasia: A case report

    Radlović Vladimir

    2013-01-01

    Full Text Available Introduction. Pseudoachondroplasia (PSACH is an autosomal dominant osteochondrodysplasia due to mutations in the gene encoding cartilage oligomeric matrix protein. It is characterized by rhizomelic dwarfism, limb and vertebral deformity, joint laxity and early onset osteoarthrosis. We present the girl with the early expressed and severe PSACH born to clinically and radiographically unaffected parents. Case Outline. A 6.5-year-old girl presented with short-limbed dwarfism (body height 79.5 cm, achondroplasia-like rhizomelic dwarfism recognized by the absence of abnormality at birth, normal craniofacial appearance, characteristic epiphyseal and metaphyseal radiographic finding and joint hyperlaxity.

  9. Progressive postnatal pansynostosis: an insidious and pernicious form of craniosynostosis.

    Wood, Benjamin C; Oh, Albert K; Keating, Robert F; Boyajian, Michael J; Myseros, John S; Magge, Suresh N; Rogers, Gary F

    2015-09-01

    OBJECT Progressive postnatal pansynostosis (PPP) is a rare form of craniosynostosis that is characterized by a normal head shape, insidious decrease in percentile head circumference, and high rates of elevated intracranial pressure (ICP). This investigation describes the clinical, radiographic, and genetic features of this entity. METHODS The authors' craniofacial database for the period 1997-2013 was retrospectively culled to identify patients who had a normal or near-normal head shape and CT-confirmed multiple-suture synostosis. Patients with kleeblatt-schädel or previous craniofacial surgery were excluded. All demographic information was collected and analyzed. RESULTS Seventeen patients fit the inclusion criteria. Nine patients had a syndromic diagnosis: Crouzon syndrome (n = 4), Pfeiffer syndrome (n = 2), Saethre-Chotzen syndrome (n = 1), Apert syndrome (n = 1), and achondroplasia (n = 1). With the exception of 3 patients with mild turricephaly, all patients had a relatively normal head shape. Patients were diagnosed at an average age of 62.9 months. Nearly all patients had some combination of clinical, radiographic, or ophthalmological evidence of increased ICP. CONCLUSIONS PPP is insidious; diagnosis is typically delayed because the clinical signs are subtle and appear gradually. All normocephalic infants or children with a known or suspected craniosynostotic disorder should be carefully monitored; any decrease in percentile head circumference or signs/symptoms of increased ICP should prompt CT evaluation. PMID:26046691

  10. All Madelung deformities are not endocrine

    Ajay Kumar

    2013-01-01

    Full Text Available Madelung deformity is a rare inherited disorder associated with endocrine disorders like Turner′s syndrome, pseudohypoparathyroidism, but can be seen with short stature homeobox deficiency conditions such as Leri-Weill dyschondrosteosis (LWD and Langers mesomelic dysplasia. It has also been reported following trauma to the distal radius epiphysis neoplasia mucopolysaccharidosis (MPS and achondroplasia. Madelung deformity is an abnormality of distal radial epiphysis where in progressive ulnar and volar tilt of the articular surface occurring in association with distal subluxation of ulna. A 13-year-old girl was referred to us for evaluation of bilateral deformity of wrist and short stature. There was ulnar deviation and dorsal tilt of bilateral hands without history of pain to the joint trauma and family history of similar illness. On X-ray, wrist showed malformed distal radial epiphysis with dorsal and ulnar shift and with increased length of phalanges suggestive of Madelung deformity. X-ray spine was normal. Ultrasound abdomen showed normal uterus and ovary and her follicle stimulating hormone. Luteinizing hormone was normal and so was urine MPS screening. Based on the above points the diagnosis of LWD was made.

  11. Neutral endopeptidase-resistant C-type natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3-related dwarfism.

    Wendt, Daniel J; Dvorak-Ewell, Melita; Bullens, Sherry; Lorget, Florence; Bell, Sean M; Peng, Jeff; Castillo, Sianna; Aoyagi-Scharber, Mika; O'Neill, Charles A; Krejci, Pavel; Wilcox, William R; Rimoin, David L; Bunting, Stuart

    2015-04-01

    Achondroplasia (ACH), the most common form of human dwarfism, is caused by an activating autosomal dominant mutation in the fibroblast growth factor receptor-3 gene. Genetic overexpression of C-type natriuretic peptide (CNP), a positive regulator of endochondral bone growth, prevents dwarfism in mouse models of ACH. However, administration of exogenous CNP is compromised by its rapid clearance in vivo through receptor-mediated and proteolytic pathways. Using in vitro approaches, we developed modified variants of human CNP, resistant to proteolytic degradation by neutral endopeptidase, that retain the ability to stimulate signaling downstream of the CNP receptor, natriuretic peptide receptor B. The variants tested in vivo demonstrated significantly longer serum half-lives than native CNP. Subcutaneous administration of one of these CNP variants (BMN 111) resulted in correction of the dwarfism phenotype in a mouse model of ACH and overgrowth of the axial and appendicular skeletons in wild-type mice without observable changes in trabecular and cortical bone architecture. Moreover, significant growth plate widening that translated into accelerated bone growth, at hemodynamically tolerable doses, was observed in juvenile cynomolgus monkeys that had received daily subcutaneous administrations of BMN 111. BMN 111 was well tolerated and represents a promising new approach for treatment of patients with ACH. PMID:25650377

  12. Multikinase activity of fibroblast growth factor receptor (FGFR) inhibitors SU5402, PD173074, AZD1480, AZD4547 and BGJ398 compromises the use of small chemicals targeting FGFR catalytic activity for therapy of short-stature syndromes.

    Gudernova, Iva; Vesela, Iva; Balek, Lukas; Buchtova, Marcela; Dosedelova, Hana; Kunova, Michaela; Pivnicka, Jakub; Jelinkova, Iva; Roubalova, Lucie; Kozubik, Alois; Krejci, Pavel

    2016-01-01

    Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) cause the most common genetic form of human dwarfism, achondroplasia (ACH). Small chemical inhibitors of FGFR tyrosine kinase activity are considered to be viable option for treating ACH, but little experimental evidence supports this claim. We evaluated five FGFR tyrosine kinase inhibitors (TKIs) (SU5402, PD173074, AZD1480, AZD4547 and BGJ398) for their activity against FGFR signaling in chondrocytes. All five TKIs strongly inhibited FGFR activation in cultured chondrocytes and limb rudiment cultures, completely relieving FGFR-mediated inhibition of chondrocyte proliferation and maturation. In contrast, TKI treatment of newborn mice did not improve skeletal growth and had lethal toxic effects on the liver, lungs and kidneys. In cell-free kinase assays as well as in vitro and in vivo cell assays, none of the tested TKIs demonstrated selectivity for FGFR3 over three other FGFR tyrosine kinases. In addition, the TKIs exhibited significant off-target activity when screened against a panel of 14 unrelated tyrosine kinases. This was most extensive in SU5402 and AZD1480, which inhibited DDR2, IGF1R, FLT3, TRKA, FLT4, ABL and JAK3 with efficiencies similar to or greater than those for FGFR. Low target specificity and toxicity of FGFR TKIs thus compromise their use for treatment of ACH. Conceptually, different avenues of therapeutic FGFR3 targeting should be investigated. PMID:26494904

  13. Ellis-van Creveld syndrome associated with chronic intestinal pseudo-obstruction.

    Iwakura, Hideo; Fujii, Katsunori; Furutani, Yoshiyuki; Takatani, Tomozumi; Ebata, Ryota; Nakanishi, Toshio; Mitsunaga, Tetsuya; Saito, Takeshi; Kishimoto, Takashi; Yoshida, Hideo; Shimojo, Naoki

    2016-01-01

    Ellis-van Creveld (EVC) syndrome is a rare autosomal recessive disorder characterized by hypoplastic nails, polydactyly, and achondroplasia. Patients usually exhibit normal cognitive function and no remarkable developmental delay. We herein present an unusual case of EVC syndrome. A Japanese 2-year-old boy was born at term, but immediately developed severe respiratory failure due to thorax deformity, postaxial polydactyly and nail hypoplasia. We identified a novel pattern of germinal compound heterozygous nonsense EVC2 mutations of c.1814C > A (p. S605X) and c.2653C > T (p. R885X), leading to the diagnosis of EVC syndrome. Interestingly, he also had severe developmental delay, and suddenly developed excessive abdominal distension at the age of 2. On surgery, extensive necrotic bowel with chronic intestinal pseudo-obstruction was noted. This is, to our knowledge, a most severe phenotype of EVC syndrome, illustrating that the specific pattern of EVC2 compound heterozygous mutations may cause severe developmental delay and intestinal malfunction. PMID:26818569

  14. The acrophysis: a unifying concept for understanding enchondral bone growth and its disorders. II. Abnormal growth

    In order to discuss and illustrate the effects common to normal and abnormal enchondral bone at the physes and at all other growth plates of the developing child, the term ''acrophysis'' was proposed. Acrophyses include the growth plates of secondary growth centers including carpals and tarsals and apophyses, and the growth plates at the nonphyseal ends of small tubular bones. Abnormalities at acrophyseal sites are analogous to those at the physeal growth plates and their metaphyses. For example, changes relating to the zone of provisional calcification (ZPC) are often important to the demonstration of such similarities. Lead lines were an early example of the concept of analogy from abnormality due to physeal and to acrophyseal disturbance. The ZPC is a key factor in understanding patterns of rickets and its healing. Examples (including hypothyroidism, scurvy and other osteoporosis, Ollier disease, achondroplasia, and osteopetrosis, as well as the family of frostbite, Kashin-Beck disease, and rat bite fever) illustrate the acrophysis principle and in turn their manifestations are explained by that principle. (orig.)

  15. MORPHOMETRIC ANALYSIS OF FORAMEN MAGNUM

    Muralidhar P Shepur

    2014-03-01

    Full Text Available Background: Diameters of foramen magnum are important because vital structures passing through it and for sex determination of skulls. The dimensions of the foramen magnum are clinically important because vital structures passing through it may endure compression such as in cases of foramen magnum herniation, foramen magnum meningiomas and foramen magnum achondroplasia. The knowledge of foramen magnum diameters is needed to determine some malformations such as Arnold Chiari syndrome, which shows expansion of transverse diameter. Objectives: To study longitudinal diameter, transverse diameter and area of foramen magnum in relation to sex. Methods: 150 dry skulls and 30 CT scan images of living subjects were studied. Diameters of foramen magnum were measured by vernier calipers and its area was calculated by formula. Diameters and area of foramen were measured automatically. Results: The mean longitudinal diameter of foramen magnum in male was 33.4mm and female was 33.1mm and by CT Imaging method in male was 38.5mm and female was 35.2mm. The mean transverse diameter of foramen magnum in male was 28.5mm and female was 27.3mm and by CT Imaging method in male was 29.1mm and female was 27.6mm. Conclusion: longitudinal and transverse diameters and area of foramen magnum of male skulls were greater than females.

  16. Genomic organization of the mouse fibroblast growth factor receptor 3 (Fgfr3) gene

    Perez-Castro, A.V.; Wilson, J.; Altherr, M.R. [Los Alamos National Lab., NM (United States)

    1995-11-20

    The fibroblast growth factor receptor 3 (Fgfr3) protein is a tyrosine kinase receptor involved in the signal transduction of various fibroblast growth factors. Recent studies suggest its important role in normal development. In humans, mutation in Fgfr3 is responsible for growth disorders such as achondroplasia, hypoachondroplasia, and thanatophoric dysplasia. Here, we report the complete genomic organization of the mouse Fgfr3 gene. The murine gene spans approximately 15 kb and consists of 19 exons and 18 introns. One major and one minor transcription initiation site were identified. Position +1 is located 614 nucleotides upstream from the ATG initiation codon. The translation initiation and termination sites are located in exons 2 and 19, respectively. Five Sp1 sites, two AP2 sites, one Zeste site, and one Krox 24 site were observed in the 5{prime}-flanking region. The Fgfr3 promoter appears to be contained within a CpG island and, as is common in genes having multiple Sp1-binding sites, lacks a TATA box. 35 refs., 3 figs., 1 tab.

  17. The Radiograph of the Pelvis as a Window to Skeletal Dysplasias.

    Gajarajulu, Vijayalakshmi; Natarajan, Balakrishnan; Muralinath, S

    2016-06-01

    Skeletal dysplasias are disorders of bone formation. There are many dysplasias that have been identified and studied over the years and long lists of radiological features have been documented; it is not possible to remember all of them, most of which are common to more than one dysplasia. This article is about a practical approach to the radiological diagnosis of skeletal dysplasias by viewing only a few radiographs rather than the entire skeletal survey. The radiographs that are to be studied are AP view of the pelvis, dorsolumbar spine- AP and lateral view and both hands PA view, in that order. The skull lateral view and both knees AP view are sometimes required. The authors advice to set out with the pelvis that provides information of not only the pelvic bones but also parts of the lumbar spine and the upper ends of the femur including their epiphyses, metaphyses and a part of the diaphyses. Sometimes the diagnosis is reached with only this one radiograph, as in achondroplasia or it may indicate a group like mucopolysaccharidoses which can be sorted out with radiographs of the spine and hands or the upper part of the femur can provide a cue to epiphyseal and metaphyseal dysplasias. Gamuts and atlases can be consulted for the rare dysplasias. PMID:26821546

  18. Spell Checking Nature: Versatility of CRISPR/Cas9 for Developing Treatments for Inherited Disorders.

    Wojtal, Daria; Kemaladewi, Dwi U; Malam, Zeenat; Abdullah, Sarah; Wong, Tatianna W Y; Hyatt, Elzbieta; Baghestani, Zahra; Pereira, Sergio; Stavropoulos, James; Mouly, Vincent; Mamchaoui, Kamel; Muntoni, Francesco; Voit, Thomas; Gonorazky, Hernan D; Dowling, James J; Wilson, Michael D; Mendoza-Londono, Roberto; Ivakine, Evgueni A; Cohn, Ronald D

    2016-01-01

    Clustered regularly interspaced short palindromic repeat (CRISPR) has arisen as a frontrunner for efficient genome engineering. However, the potentially broad therapeutic implications are largely unexplored. Here, to investigate the therapeutic potential of CRISPR/Cas9 in a diverse set of genetic disorders, we establish a pipeline that uses readily obtainable cells from affected individuals. We show that an adapted version of CRISPR/Cas9 increases the amount of utrophin, a known disease modifier in Duchenne muscular dystrophy (DMD). Furthermore, we demonstrate preferential elimination of the dominant-negative FGFR3 c.1138G>A allele in fibroblasts of an individual affected by achondroplasia. Using a previously undescribed approach involving single guide RNA, we successfully removed large genome rearrangement in primary cells of an individual with an X chromosome duplication including MECP2. Moreover, removal of a duplication of DMD exons 18-30 in myotubes of an individual affected by DMD produced full-length dystrophin. Our findings establish the far-reaching therapeutic utility of CRISPR/Cas9, which can be tailored to target numerous inherited disorders. PMID:26686765

  19. Atlantoaxial subluxation. Radiography and magnetic resonance imaging correlated to myelopathy

    Yamashita, Y.; Takahashi, M.; Sakamoto, Y.; Kojima, R.

    Twenty-nine patients with atlantoaxial subluxation (18 with rheumatoid arthritis, 2 due to trauma, 4 with os odontoideum, and one each with polyarteritis nodosa, rheumatic fever, Klippel-Feil syndrome, achondroplasia, and cause unknown) were evaluated using a 0.22 tesla resistive MRI unit. Cord compression was classified into four grades according to the degree on magnetic resonance imaging. There were 7 patients with no thecal sac compression (grade 0), 10 with a minimal degree of subarachnoid space compression without cord compression (grade 1), 7 with mild cord compression (grade 2), and 5 with severe cord compression or cord atrophy (grade 3). Although the severity of myelopathy showed poor correlation with the atlantodental interval on conventional radiography, high correlation was observed between MR grading and the degree of myelopathy. The high signal intensity foci were observed in 7 or 12 patients with cord compression (grades 2 and 3) on T2 weighted images. Other frequently observed findings in rheumatoid arthritis included soft tissue masses of low to intermediate signal intensity in the paraodontoid space, erosions of the odontoid processes, and atlanto-axial impaction on T1 and T2 weighted images.

  20. Perinatal Diagnostic Approach to Fetal Skeletal Dysplasias: Six Years Experience of a Tertiary Center.

    Toru, Havva Serap; Nur, Banu Guzel; Sanhal, Cem Yasar; Mihci, Ercan; Mendilcioğlu, İnanç; Yilmaz, Elanur; Yilmaz, Gulden Tasova; Ozbudak, Irem Hicran; Karaali, Kamil; Alper, Ozgul M; Karaveli, Fatma Şeyda

    2015-01-01

    Skeletal dysplasias (SDs) constitute a group of heterogeneous disorders affecting growth morphology of the chondro-osseous tissues. Prenatal diagnosis of SD is a considerable clinical challenge due to phenotypic variability. We performed a retrospective analysis of the fetal autopsies series conducted between January 2006 and December 2012 at our center. SD was detected in 54 (10%) out of 542 fetal autopsy cases which included; 11.1% thanatophoric dysplasia (n = 6), 7.4% achondroplasia (n = 4), 3.7% osteogenesis imperfect (n = 2), 1.9% Jarcho-Levin Syndrome (n = 1), 1.9% arthrogryposis (n = 1), 1.9% Dyggve-Melchior-Clausen syndrome (n = 1), 72.1% of dysostosis cases (n = 39). All SD cases were diagnosed by ultrasonography. In 20 of the cases, amniocentesis was performed, 4 cases underwent molecular genetic analyses. Antenatal identification of dysplasia is important in the management of pregnancy and in genetic counseling. Our data analysis showed that SD is usually detected clinically after the 20th gestational week. Genetic analyses for SD may provide early diagnosis and management. PMID:26376227

  1. Prenatal diagnosis of single gene disorders using amniotic fluid as the starting material for PCR.

    Huang, Huan; Li, Shuo; Lu, Shuolian; Ge, Hongshan; Sun, Lizhou

    2016-01-01

    A rapid and inexpensive method for fetal genetic diagnosis using amniotic fluid (AF) as the starting material was demonstrated in this study. Raw AF was added directly to polymerase chain reaction (PCR) mixtures with HpH buffer (a high pH buffer), without any pre-treatment. Amplified products were detected by gel electrophoresis and then subjected to Sanger sequencing. The AF from four fetuses, each expressing a single gene disorder (achondroplasia, hypochondroplasia, thanatophoric dysplasia, or X-linked hypohidrotic ectodermal dysplasia), were analyzed. DNA fragments of different lengths were efficiently amplified from 8 μl of AF, allowing each of these single gene disorders to be successfully diagnosed. Although the amplification efficiency of the AF-PCR method is comparable to that of the Chelex method, the amount of the AF sample required was considerably lower than that required for the Chelex method (10 ml). This proposed method of diagnosis is more efficient, simpler, and less expensive, and reduces the chance of cross-contamination relative to the Chelex method, which requires purified DNA or other pre-treatment processes. Our method offers a promising tool that can be used for the diagnosis of various gene disorders in fetuses. PMID:26587643

  2. Combined spinal epidural anesthesia in achondroplastic dwarf for femur surgery

    Rochana Girish Bakhshi

    2011-11-01

    Full Text Available Achondroplasia is the commonest form of short-limbed dwarfism and occurs in 1:26,000- 40,000 live births. This is an autosomal dominant disorder with abnormal endochondral ossification whereas periosteal and intramembranous ossification are normal. The basic abnormality is a disturbance of cartilage formation mainly at the epiphyseal growth plates and at the base of the skull. The anesthetic management of achondroplastic dwarfs is a challenge to the anesthesiologist. Both regional as well as general anesthesia have their individual risks and consequences. We report a case of an achondroplastic dwarf in whom combined spinal epidural anesthesia was used for fixation of a fractured femur. The patient had undergone previous femur surgery under general anesthesia since he had been informed that spinal anesthesia could be very problematic. There was no technical difficulty encountered during the procedure and an adequate level was achieved with low-dose local anesthetics without any problem. Postoperative pain relief was offered for three consecutive postoperative days using epidural tramadol. We discuss the anesthetic issues and highlight the role of combined spinal epidural anesthesia with low-dose local anesthetics in this patient. This approach also helped in early ambulation and postoperative pain relief.

  3. Hypochondroplasia, Acanthosis Nigricans, and Insulin Resistance in a Child with FGFR3 Mutation: Is It Just an Association?

    Manal Mustafa

    2014-01-01

    Full Text Available FGFR3 mutations cause wide spectrum of disorders ranging from skeletal dysplasias (hypochondroplasia, achondroplasia, and thanatophoric dysplasia, benign skin tumors (epidermal nevi, seborrhaeic keratosis, and acanthosis nigricans, and epithelial malignancies (multiple myeloma and prostate and bladder carcinoma. Hypochondroplasia is the most common type of short-limb dwarfism in children resulting from fibroblast growth factor receptor 3 (FGFR3 mutation. Acanthosis nigricans might be seen in severe skeletal dysplasia, including thanatophoric dysplasia and SADDAN syndrome, without a biochemical evidence of hyperinsulinemia. Insulin insensitivity and acanthosis nigricans are uncommonly seen in hypochondroplasia patients with FGFR3 mutations which may represent a new association. We aim to describe the association of hypochondroplasia, acanthosis nigricans, and insulin resistance in a child harboring FGFR3 mutation. To our knowledge, this is the first case report associating the p.N540 with acanthosis nigricans and the second to describe hyperinsulinemia in hypochondroplasia. This finding demonstrates the possible coexistence of insulin insensitivity and acanthosis nigricans in hypochondroplasia patients.

  4. Generation of Fgfr3 Conditional Knockout Mice

    Nan Su, Xiaoling Xu, Cuiling Li, Qifen He, Ling Zhao, Can Li, Siyu Chen, Fengtao Luo, Lingxian Yi, Xiaolan Du, Haiyang Huang, Chuxia Deng, Lin Chen

    2010-01-01

    Full Text Available Fibroblast growth factor receptor 3 (FGFR3, highly conserved in both humans and murine, is one of key tyrosine kinase receptors for FGF. FGFR3 is expressed in different tissues, including cartilage, brain, kidney, and intestine at different development stages. Conventional knockout of Fgfr3 alleles leads to short life span, and overgrowth of bone. In clinic, human FGFR3 mutations are responsible for three different types of chondrodysplasia syndromes including achondroplasia (ACH, hypochondroplasia (HCH and thanatophoric dysplasia (TD. For better understanding of the roles of FGFR3 in different tissues at different stages of development and in pathological conditions, we generated Fgfr3 conditional knockout mice in which loxp sites flank exons 9-10 in the Fgfr3 allele. We also demonstrated that Cre-mediated recombination using Col2a1-Cre, a Cre line expressed in chondrocyte during bone development, results in specific deletion of the gene in tissues containing cartilage. This animal model will be useful to study distinct roles of FGFR3 in different tissues at different ages.

  5. Atlantoaxial subluxation

    Twenty-nine patients with atlantoaxial subluxation (18 with rheumatoid arthritis, 2 due to trauma, 4 with os odontoideum, and one each with polyarteritis nodosa, rheumatic fever, Klippel-Feil syndrome, achondroplasia, and cause unknown) were evaluated using a 0.22 tesla resistive MRI unit. Cord compression was classified into four grades according to the degree on magnetic resonance imaging. There were 7 patients with no thecal sac compression (grade 0), 10 with a minimal degree of subarachnoid space compression without cord compression (grade 1), 7 with mild cord compression (grade 2), and 5 with severe cord compression or cord atrophy (grade 3). Although the severity of myelopathy showed poor correlation with the atlantodental interval on conventional radiography, high correlation was observed between MR grading and the degree of myelopathy. The high signal intensity foci were observed in 7 or 12 patients with cord compression (grades 2 and 3) on T2 weighted images. Other frequently observed findings in rheumatoid arthritis included soft tissue masses of low to intermediate signal intensity in the paraodontoid space, erosions of the odontoid processes, and atlanto-axial impaction on T1 and T2 weighted images. (orig.)

  6. Frequency of the allelic variant c.1150T > C in exon 10 of the fibroblast growth factor receptor 3 (FGFR3 gene is not increased in patients with pathogenic mutations and related chondrodysplasia phenotypes

    Thatiane Yoshie Kanazawa

    2014-12-01

    Full Text Available Mutations in the FGFR3 gene cause the phenotypic spectrum of FGFR3 chondrodysplasias ranging from lethal forms to the milder phenotype seen in hypochondroplasia (Hch. The p.N540K mutation in the FGFR3 gene occurs in ~70% of individuals with Hch, and nearly 30% of individuals with the Hch phenotype have no mutations in the FGFR3, which suggests genetic heterogeneity. The identification of a severe case of Hch associated with the typical mutation c.1620C > A and the occurrence of a c.1150T > C change that resulted in a p.F384L in exon 10, together with the suspicion that this second change could be a modulator of the phenotype, prompted us to investigate this hypothesis in a cohort of patients. An analysis of 48 patients with FGFR3 chondrodysplasia phenotypes and 330 healthy (control individuals revealed no significant difference in the frequency of the C allele at the c.1150 position (p = 0.34. One patient carrying the combination `pathogenic mutation plus the allelic variant c.1150T > C' had a typical achondroplasia (Ach phenotype. In addition, three other patients with atypical phenotypes showed no association with the allelic variant. Together, these results do not support the hypothesis of a modulatory role for the c.1150T > C change in the FGFR3 gene.

  7. A pilot study of gene testing of genetic bone dysplasia using targeted next-generation sequencing.

    Zhang, Huiwen; Yang, Rui; Wang, Yu; Ye, Jun; Han, Lianshu; Qiu, Wenjuan; Gu, Xuefan

    2015-12-01

    Molecular diagnosis of genetic bone dysplasia is challenging for non-expert. A targeted next-generation sequencing technology was applied to identify the underlying molecular mechanism of bone dysplasia and evaluate the contribution of these genes to patients with bone dysplasia encountered in pediatric endocrinology. A group of unrelated patients (n=82), characterized by short stature, dysmorphology and X-ray abnormalities, of which mucopolysacharidoses, GM1 gangliosidosis, mucolipidosis type II/III and achondroplasia owing to FGFR3 G380R mutation had been excluded, were recruited in this study. Probes were designed to 61 genes selected according to the nosology and classification of genetic skeletal disorders of 2010 by Illumina's online DesignStudio software. DNA was hybridized with probes and then a library was established following the standard Illumina protocols. Amplicon library was sequenced on a MiSeq sequencing system and the data were analyzed by MiSeq Reporter. Mutations of 13 different genes were found in 44 of the 82 patients (54%). Mutations of COL2A1 gene and PHEX gene were found in nine patients, respectively (9/44=20%), followed by COMP gene in 8 (18%), TRPV4 gene in 4 (9%), FBN1 gene in 4 (9%), COL1A1 gene in 3 (6%) and COL11A1, TRAPPC2, MATN3, ARSE, TRPS1, SMARCAL1, ENPP1 gene mutations in one patient each (2% each). In conclusion, mutations of COL2A1, PHEX and COMP gene are common for short stature due to bone dysplasia in outpatient clinics in pediatric endocrinology. Targeted next-generation sequencing is an efficient way to identify the underlying molecular mechanism of genetic bone dysplasia. PMID:26377240

  8. New insight on FGFR3-related chondrodysplasias molecular physiopathology revealed by human chondrocyte gene expression profiling.

    Laurent Schibler

    Full Text Available Endochondral ossification is the process by which the appendicular skeleton, facial bones, vertebrae and medial clavicles are formed and relies on the tight control of chondrocyte maturation. Fibroblast growth factor receptor (FGFR3 plays a role in bone development and maintenance and belongs to a family of proteins which differ in their ligand affinities and tissue distribution. Activating mutations of the FGFR3 gene lead to craniosynostosis and multiple types of skeletal dysplasia with varying degrees of severity: thanatophoric dysplasia (TD, achondroplasia and hypochondroplasia. Despite progress in the characterization of FGFR3-mediated regulation of cartilage development, many aspects remain unclear. The aim and the novelty of our study was to examine whole gene expression differences occurring in primary human chondrocytes isolated from normal cartilage or pathological cartilage from TD-affected fetuses, using Affymetrix technology. The phenotype of the primary cells was confirmed by the high expression of chondrocytic markers. Altered expression of genes associated with many cellular processes was observed, including cell growth and proliferation, cell cycle, cell adhesion, cell motility, metabolic pathways, signal transduction, cell cycle process and cell signaling. Most of the cell cycle process genes were down-regulated and consisted of genes involved in cell cycle progression, DNA biosynthesis, spindle dynamics and cytokinesis. About eight percent of all modulated genes were found to impact extracellular matrix (ECM structure and turnover, especially glycosaminoglycan (GAG and proteoglycan biosynthesis and sulfation. Altogether, the gene expression analyses provide new insight into the consequences of FGFR3 mutations in cell cycle regulation, onset of pre-hypertrophic differentiation and concomitant metabolism changes. Moreover, impaired motility and ECM properties may also provide clues about growth plate disorganization. These

  9. Volume reduction of the jugular foramina in Cavalier King Charles Spaniels with syringomyelia

    Schmidt Martin

    2012-09-01

    Full Text Available Abstract Background Understanding the pathogenesis of the chiari-like malformation in the Cavalier King Charles Spaniel (CKCS is incomplete, and current hypotheses do not fully explain the development of syringomyelia (SM in the spinal cords of affected dogs. This study investigates an unconventional pathogenetic theory for the development of cerebrospinal fluid (CSF pressure waves in the subarachnoid space in CKCS with SM, by analogy with human diseases. In children with achondroplasia the shortening of the skull base can lead to a narrowing of the jugular foramina (JF between the cranial base synchondroses. This in turn has been reported to cause a congestion of the major venous outflow tracts of the skull and consequently to an increase in the intracranial pressure (ICP. Amongst brachycephalic dog breeds the CKCS has been identified as having an extremely short and wide braincase. A stenosis of the JF and a consequential vascular compromise in this opening could contribute to venous hypertension, raising ICP and causing CSF jets in the spinal subarachnoid space of the CKCS. In this study, JF volumes in CKCSs with and without SM were compared to assess a possible role of this pathologic mechanism in the development of SM in this breed. Results Computed tomography (CT scans of 40 CKCSs > 4 years of age were used to create three-dimensional (3D models of the skull and the JF. Weight matched groups (7–10 kg of 20 CKCSs with SM and 20 CKCSs without SM were compared. CKCSs without SM presented significantly larger JF -volumes (median left JF: 0.0633 cm3; median right JF: 0.0703 cm3; p 3; median right JF: 0.0434 cm3; p Conclusion A stenosis of the JF and consecutive venous congestion may explain the aetiology of CSF pressure waves in the subarachnoid space, independent of cerebellar herniation, as an additional pathogenetic factor for the development of SM in this breed.

  10. Selfish spermatogonial selection: evidence from an immunohistochemical screen in testes of elderly men.

    Jasmine Lim

    Full Text Available The dominant congenital disorders Apert syndrome, achondroplasia and multiple endocrine neoplasia-caused by specific missense mutations in the FGFR2, FGFR3 and RET proteins respectively-represent classical examples of paternal age-effect mutation, a class that arises at particularly high frequencies in the sperm of older men. Previous analyses of DNA from randomly selected cadaveric testes showed that the levels of the corresponding FGFR2, FGFR3 and RET mutations exhibit very uneven spatial distributions, with localised hotspots surrounded by large mutation-negative areas. These studies imply that normal testes are mosaic for clusters of mutant cells: these clusters are predicted to have altered growth and signalling properties leading to their clonal expansion (selfish spermatogonial selection, but DNA extraction eliminates the possibility to study such processes at a tissue level. Using a panel of antibodies optimised for the detection of spermatocytic seminoma, a rare tumour of spermatogonial origin, we demonstrate that putative clonal events are frequent within normal testes of elderly men (mean age: 73.3 yrs and can be classed into two broad categories. We found numerous small (less than 200 cells cellular aggregations with distinct immunohistochemical characteristics, localised to a portion of the seminiferous tubule, which are of uncertain significance. However more infrequently we identified additional regions where entire seminiferous tubules had a circumferentially altered immunohistochemical appearance that extended through multiple serial sections that were physically contiguous (up to 1 mm in length, and exhibited enhanced staining for antibodies both to FGFR3 and a marker of downstream signal activation, pAKT. These findings support the concept that populations of spermatogonia in individual seminiferous tubules in the testes of older men are clonal mosaics with regard to their signalling properties and activation, thus fulfilling