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1.
Eur J Hum Genet ; 26(11): 1611-1622, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30006632

RESUMO

Acrodysostosis (MIM 101800) is a dominantly inherited condition associating (1) skeletal features (short stature, facial dysostosis, and brachydactyly with cone-shaped epiphyses), (2) resistance to hormones and (3) possible intellectual disability. Acroscyphodysplasia (MIM 250215) is characterized by growth retardation, brachydactyly, and knee epiphyses embedded in cup-shaped metaphyses. We and others have identified PDE4D or PRKAR1A variants in acrodysostosis; PDE4D variants have been reported in three cases of acroscyphodysplasia. Our study aimed at reviewing the clinical and molecular findings in a cohort of 27 acrodysostosis and 5 acroscyphodysplasia cases. Among the acrodysostosis cases, we identified 9 heterozygous de novo PRKAR1A variants and 11 heterozygous PDE4D variants. The 7 patients without variants presented with symptoms of acrodysostosis (brachydactyly and cone-shaped epiphyses), but none had the characteristic facial dysostosis. In the acroscyphodysplasia cases, we identified 2 PDE4D variants. For 2 of the 3 negative cases, medical records revealed early severe infection, which has been described in some reports of acroscyphodysplasia. Subdividing our series of acrodysostosis based on the disease-causing gene, we confirmed genotype-phenotype correlations. Hormone resistance was consistently observed in patients carrying PRKAR1A variants, whereas no hormone resistance was observed in 9 patients with PDE4D variants. All patients with PDE4D variants shared characteristic facial features (midface hypoplasia with nasal hypoplasia) and some degree of intellectual disability. Our findings of PDE4D variants in two cases of acroscyphodysplasia support that PDE4D may be responsible for this severe skeletal dysplasia. We eventually emphasize the importance of some specific assessments in the long-term follow up, including cardiovascular and thromboembolic risk factors.

2.
J Hum Genet ; 61(8): 693-9, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27193221

RESUMO

Otopalatodigital spectrum disorders (OPDSD) constitute a group of dominant X-linked osteochondrodysplasias including four syndromes: otopalatodigital syndromes type 1 and type 2 (OPD1 and OPD2), frontometaphyseal dysplasia, and Melnick-Needles syndrome. These syndromes variably associate specific facial and extremities features, hearing loss, cleft palate, skeletal dysplasia and several malformations, and show important clinical overlap over the different entities. FLNA gain-of-function mutations were identified in these conditions. FLNA encodes filamin A, a scaffolding actin-binding protein. Here, we report phenotypic descriptions and molecular results of FLNA analysis in a large series of 27 probands hypothesized to be affected by OPDSD. We identified 11 different missense mutations in 15 unrelated probands (n=15/27, 56%), of which seven were novel, including one of unknown significance. Segregation analyses within families made possible investigating 20 additional relatives carrying a mutation. This series allows refining the phenotypic and mutational spectrum of FLNA mutations causing OPDSD, and providing suggestions to avoid the overdiagnosis of OPD1.


Assuntos
Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Estudos de Associação Genética , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas da Mão/genética , Mutação , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Fenótipo , Alelos , Substituição de Aminoácidos , Éxons , Facies , Feminino , Filaminas/genética , Humanos , Masculino , Linhagem , Análise de Sequência de DNA
4.
J Clin Immunol ; 36(3): 220-34, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26951490

RESUMO

PURPOSE: Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in ACP5. We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases. METHODS: We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations. RESULTS: We observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy. CONCLUSIONS: Our data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia.


Assuntos
Doenças Autoimunes/genética , Deficiência Intelectual/genética , Lúpus Eritematoso Sistêmico/genética , Mutação , Osteocondrodisplasias/genética , Púrpura Trombocitopênica Idiopática/genética , Fosfatase Ácida Resistente a Tartarato/genética , Adolescente , Adulto , Alelos , Autoanticorpos/biossíntese , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Osso e Ossos/imunologia , Osso e Ossos/patologia , Encéfalo/imunologia , Encéfalo/patologia , Criança , Pré-Escolar , Feminino , Expressão Gênica , Genótipo , Humanos , Deficiência Intelectual/imunologia , Deficiência Intelectual/patologia , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Masculino , Osteocondrodisplasias/imunologia , Osteocondrodisplasias/patologia , Linhagem , Fenótipo , Púrpura Trombocitopênica Idiopática/imunologia , Púrpura Trombocitopênica Idiopática/patologia , Fosfatase Ácida Resistente a Tartarato/deficiência , Fosfatase Ácida Resistente a Tartarato/imunologia
5.
Pediatr Radiol ; 45(7): 965-76, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25646736

RESUMO

Disorders of post-squalene cholesterol biosynthesis are inborn errors of metabolism characterised by multiple congenital abnormalities, including significant skeletal involvement. The most frequent and best-characterised example is the Smith-Lemli-Opitz syndrome. Nine other disorders are known, namely autosomal-recessive Antley-Bixler syndrome, Greenberg dysplasia, X-linked dominant chondrodysplasia punctata, X-linked recessive male emopamil-binding protein deficiency, CHILD syndrome, CK syndrome, sterol C4 methyloxidase-like deficiency, desmosterolosis and lathosterolosis. This study provides an overview of the radiologic features observed in these diseases. A common pattern of limb abnormalities is recognisable, including polydactyly, which is typically post-axial and rarely interdigital and can involve all four limbs, and syndactyly of the toes. Chondrodysplasia punctata is specifically associated with a subgroup of disorders of cholesterol biosynthesis (Greenberg dysplasia, CHILD syndrome, X-linked dominant chondrodysplasia punctata, male emopamil-binding protein deficiency). The possible occurrence of epiphyseal stippling in the Smith-Lemli-Opitz syndrome, initially reported, does not appear to be confirmed. Stippling is also associated with other congenital disorders such as chromosomal abnormalities, brachytelephalangic chondrodysplasia punctata (X-linked recessive chondrodysplasia punctata, disruptions of vitamin K metabolism, maternal autoimmune diseases), rhizomelic chondrodysplasia punctata (peroxisomal disorders) and lysosomal storage disorders. In the differential diagnosis of epiphyseal stippling, a moth-eaten appearance of bones, asymmetry, or presence of a common pattern of limb abnormalities indicate inborn errors of cholesterol biosynthesis. We highlight the specific differentiating radiologic features of disorders of post-squalene cholesterol biosynthesis.


Assuntos
Colesterol/biossíntese , Erros Inatos do Metabolismo Lipídico/complicações , Anormalidades Musculoesqueléticas/complicações , Anormalidades Musculoesqueléticas/diagnóstico por imagem , Sistema Musculoesquelético/diagnóstico por imagem , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Gravidez , Diagnóstico Pré-Natal , Radiografia , Adulto Jovem
6.
Am J Med Genet A ; 167A(3): 461-75, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25604898

RESUMO

Type 2 collagen disorders encompass a diverse group of skeletal dysplasias that are commonly associated with orthopedic, ocular, and hearing problems. However, the frequency of many clinical features has never been determined. We retrospectively investigated the clinical, radiological, and genotypic data in a group of 93 patients with molecularly confirmed SEDC or a related disorder. The majority of the patients (80/93) had short stature, with radiological features of SEDC (n = 64), others having SEMD (n = 5), Kniest dysplasia (n = 7), spondyloperipheral dysplasia (n = 2), or Torrance-like dysplasia (n = 2). The remaining 13 patients had normal stature with mild SED, Stickler-like syndrome or multiple epiphyseal dysplasia. Over 50% of the patients had undergone orthopedic surgery, usually for scoliosis, femoral osteotomy or hip replacement. Odontoid hypoplasia was present in 56% (95% CI 38-74) and a correlation between odontoid hypoplasia and short stature was observed. Atlanto-axial instability, was observed in 5 of the 18 patients (28%, 95% CI 10-54) in whom flexion-extension films of the cervical spine were available; however, it was rarely accompanied by myelopathy. Myopia was found in 45% (95% CI 35-56), and retinal detachment had occurred in 12% (95% CI 6-21; median age 14 years; youngest age 3.5 years). Thirty-two patients complained of hearing loss (37%, 95% CI 27-48) of whom 17 required hearing aids. The ophthalmological features and possibly also hearing loss are often relatively frequent and severe in patients with splicing mutations. Based on clinical findings, age at onset and genotype-phenotype correlations in this cohort, we propose guidelines for the management and follow-up in this group of disorders.


Assuntos
Colágeno Tipo II/genética , Mutação , Osteocondrodisplasias/congênito , Fenótipo , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/genética , Radiografia , Adulto Jovem
7.
Am J Med Genet A ; 167A(1): 111-22, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25425167

RESUMO

Array comparative genomic hybridization (array CGH) has proven its utility in uncovering cryptic rearrangements in patients with X-linked intellectual disability. In 2009, Giorda et al. identified inherited and de novo recurrent Xp11.23p11.22 microduplications in two males and six females from a wide cohort of patients presenting with syndromic intellectual disability. To date, 14 females and 5 males with an overlapping microduplication have been reported in the literature. To further characterize this emerging syndrome, we collected clinical and microarray data from 17 new patients, 10 females, and 7 males. The Xp11.23p11.2 microduplications detected by array CGH ranged in size from 331 Kb to 8.9 Mb. Five patients harbored 4.5 Mb recurrent duplications mediated by non-allelic homologous recombination between segmental duplications and 12 harbored atypical duplications. The chromosomal rearrangement occurred de novo in eight patients and was inherited in six affected males from three families. Patients shared several common major characteristics including moderate to severe intellectual disability, early onset of puberty, language impairment, and age related epileptic syndromes such as West syndrome and focal epilepsy with activation during sleep evolving in some patients to continuous spikes-and-waves during slow sleep. Atypical microduplications allowed us to identify minimal critical regions that might be responsible for specific clinical findings of the syndrome and to suggest possible candidate genes: FTSJ1 and SHROOM4 for intellectual disability along with PQBP1 and SLC35A2 for epilepsy. Xp11.23p11.22 microduplication is a recently-recognized syndrome associated with intellectual disability, epilepsy, and early onset of puberty in females. In this study, we propose several genes that could contribute to the phenotype.


Assuntos
Cromossomos Humanos X/genética , Estudos de Associação Genética , Duplicações Segmentares Genômicas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Mapeamento Cromossômico , Hibridização Genômica Comparativa , Eletroencefalografia , Epilepsia/genética , Feminino , Humanos , Masculino , Fenótipo
8.
Eur J Hum Genet ; 23(1): 92-102, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24736735

RESUMO

The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features. Genotype-phenotype correlations have been found both for the location and the nature of GLI3 mutations, highlighting the bifunctional nature of GLI3 during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases). Most of mutations are novel and consistent with the previously reported genotype-phenotype correlation. Our results also show a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects. GLI3 expression studied by in situ hybridization during human development confirms its early expression in target tissues.


Assuntos
Estudos de Associação Genética , Fatores de Transcrição Kruppel-Like/genética , Mutação , Proteínas do Tecido Nervoso/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Acrocefalossindactilia/diagnóstico , Acrocefalossindactilia/genética , Estudos de Coortes , Análise Mutacional de DNA , Família , Expressão Gênica , Rearranjo Gênico , Haploinsuficiência , Humanos , Hibridização in Situ Fluorescente , Fenótipo , Proteína Gli3 com Dedos de Zinco
9.
Horm Res Paediatr ; 82(6): 355-63, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25323764

RESUMO

BACKGROUND/AIMS: Hypochondroplasia (HCH) is a skeletal dysplasia characterized by disproportionate short stature. The aims of the study are to evaluate efficacy and safety of recombinant human growth hormone (r-hGH) therapy in HCH children, when compared with a historical cohort of untreated HCH children. METHODS: Nineteen HCH patients with an initial height standard deviation score (SDS) ≤-2 and a mean age of 9.3 ± 3.1 years were treated with a mean r-hGH dose of 0.053 mg/kg/day over 3 years. Growth charts were derived from the historical cohort (n = 40). RESULTS: Height gain in the treated population was +0.62 ± 0.81 SDS greater than in the general population, and +1.39 ± 0.9 SDS greater than in the historical untreated HCH cohort (mean gain of 7.4 ± 6.6 cm gain). A negative correlation between height gain and age at treatment initiation was reported (p = 0.04). There was no significant difference in response between patients with fibroblast growth factor receptor 3 mutations and those without. No treatment-related serious adverse events were reported. CONCLUSIONS: r-hGH treatment is well tolerated and effective in improving growth in HCH patients, particularly when started early. The treatment effect varies greatly and must be evaluated for each patient during treatment to determine the value of continued therapy.


Assuntos
Osso e Ossos/anormalidades , Nanismo/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Deformidades Congênitas dos Membros/tratamento farmacológico , Lordose/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Adolescente , Estatura/efeitos dos fármacos , Criança , Desenvolvimento Infantil/efeitos dos fármacos , Pré-Escolar , Estudos de Coortes , Nanismo/genética , Feminino , Terapia de Reposição Hormonal/efeitos adversos , Hormônio do Crescimento Humano/administração & dosagem , Humanos , Injeções Subcutâneas , Deformidades Congênitas dos Membros/genética , Lordose/genética , Masculino , Proteínas Recombinantes/administração & dosagem , Resultado do Tratamento
10.
Eur J Radiol ; 83(10): 1828-42, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25043984

RESUMO

PURPOSE: The radiologist plays a critical role at all steps of the management of patients with fibrous dysplasia (FD) and McCune-Albright syndrome (MAS). The development of a standardized approach to the management of FD/MAS is crucial given the low incidence and multiple clinical presentations of these conditions. Our aim was to develop recommendations for bone imaging in FD/MAS management. MATERIALS AND METHODS: The establishment of National Reference Centers in France as part of a Health Ministry program for orphan diseases has triggered the development of recommendations for the clinical management of FD/MAS. We used a well-established robust methodological approach involving an extensive literature review by a multidisciplinary working group (20 healthcare professionals) and scoring by a peer-review group (20 healthcare professionals different from the 20 previous ones). There were four phases: a systematic literature review, drafting of initial recommendations, peer-review of this initial draft, and drafting of the final recommendations. RESULTS: Fifty-seven specific recommendations are provided as key points for the diagnosis, prognosis, and follow-up of patients with FD/MAS. Issues of special interest are highlighted in the discussion, and areas in which future research is needed are identified. CONCLUSION: We believe the dissemination of these recommendations within the radiology community may facilitate communication between radiologists and other healthcare providers, thereby substantially improving the management of patients with these rare but potentially disabling conditions.


Assuntos
Diagnóstico por Imagem , Displasia Fibrosa Poliostótica/diagnóstico , Biópsia , Diagnóstico Diferencial , França , Humanos , Guias de Prática Clínica como Assunto , Prognóstico
11.
Spine (Phila Pa 1976) ; 39(9): E564-75, 2014 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-24503682

RESUMO

STUDY DESIGN: A review of clinical publications, current knowledge, and recent developments regarding the etiology of ischiovertebral dysplasia was combined with a clinical review of the condition. OBJECTIVE: To acquaint orthopedic spine surgeons with identification patterns of ischiovertebral dysplasia in order to provide them with guidelines about spine management and which complications to expect. SUMMARY OF BACKGROUND DATA: Ischiovertebral dysplasia is a rare skeletal dysplasia that may appear in a sporadic fashion or be inherited with an autosomal dominant inheritance pattern. It is defined by the association of an ischiopubic ramus hypoplasia and a vertebral dysplasia. It leads to a specific spine deformity whose management and complications should be clarified. METHODS: Thirty consecutive patients from 0 to 31 years of age with ischiovertebral dysplasia were included from 5 centers specialized in congenital spinal deformities. Frontal and sagittal Cobb angles before treatment, natural history of the curves, therapeutic options, and their complications were systematically analyzed. RESULTS: All the patients had a vertebral dysplasia and 28 of them developed a spinal deformity. This deformity was an extremely severe thoracic kyphoscoliosis in 25 cases. The other deformities were a thoracolumbar scoliosis in 1 case and a thoracolumbar kyphosis in 2 cases. The management of the thoracic kyphoscoliosis was always challenging and complications included death by respiratory failure (3 cases) and neurological impairment (9 cases). CONCLUSION: Recognizing the occurrence of ischioverterbral dysplasia is very important to allow for dedicated treatment. The authors advocate preoperative distraction and circumferential fusion to prevent progression of the curve and to avoid the potentially fatal sequelae associated with this disorder. LEVEL OF EVIDENCE: 4.


Assuntos
Doenças do Desenvolvimento Ósseo/cirurgia , Ísquio/anormalidades , Curvaturas da Coluna Vertebral/cirurgia , Fusão Vertebral/efeitos adversos , Coluna Vertebral/anormalidades , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo/congênito , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Lactente , Recém-Nascido , Ísquio/cirurgia , Masculino , Curvaturas da Coluna Vertebral/congênito , Coluna Vertebral/cirurgia , Adulto Jovem
12.
Am J Med Genet A ; 164A(3): 769-73, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24357493

RESUMO

Dysspondyloenchondromatosis is a rare form of generalized enchondromatosis associated with spinal involvement. This skeletal dysplasia is characterized by multiple enchondromas present in vertebrae as well as in metaphyseal and diaphyseal parts of the long tubular bones, post-natal short stature, and early development of kyphoscoliosis. A novel heterozygous missense mutation in COL2A1 was recently identified in a patient with dysspondyloenchondromatosis. This suggests that dysspondyloenchondromatosis might expand the already broad spectrum of type II collagenopathies. Here, we report on a young girl with features of dysspondyloenchondromatosis, specifically short stature, thoracoscoliosis, and generalized enchondromas lesions. Sanger sequencing failed to detect a mutation in COL2A1. We therefore suggest that dysspondyloenchondromatosis is a genetically heterogeneous condition.


Assuntos
Encondromatose/diagnóstico , Encondromatose/genética , Heterogeneidade Genética , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Pré-Escolar , Colágeno Tipo II/genética , Facies , Feminino , Humanos , Mutação , Fenótipo , Radiografia , Coluna Vertebral/patologia
14.
Hum Genet ; 133(3): 367-77, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24178751

RESUMO

Oral-facial-digital syndrome type VI (OFD VI) is a recessive ciliopathy defined by two diagnostic criteria: molar tooth sign (MTS) and one or more of the following: (1) tongue hamartoma (s) and/or additional frenula and/or upper lip notch; (2) mesoaxial polydactyly of one or more hands or feet; (3) hypothalamic hamartoma. Because of the MTS, OFD VI belongs to the "Joubert syndrome related disorders". Its genetic aetiology remains largely unknown although mutations in the TMEM216 gene, responsible for Joubert (JBS2) and Meckel-Gruber (MKS2) syndromes, have been reported in two OFD VI patients. To explore the molecular cause(s) of OFD VI syndrome, we used an exome sequencing strategy in six unrelated families followed by Sanger sequencing. We identified a total of 14 novel mutations in the C5orf42 gene in 9/11 families with positive OFD VI diagnostic criteria including a severe fetal case with microphthalmia, cerebellar hypoplasia, corpus callosum agenesis, polydactyly and skeletal dysplasia. C5orf42 mutations have already been reported in Joubert syndrome confirming that OFD VI and JBS are allelic disorders, thus enhancing our knowledge of the complex, highly heterogeneous nature of ciliopathies.


Assuntos
Proteínas de Membrana/genética , Síndromes Orofaciodigitais/diagnóstico , Síndromes Orofaciodigitais/genética , Anormalidades Múltiplas , Adolescente , Adulto , Alelos , Doenças Cerebelares/diagnóstico , Doenças Cerebelares/genética , Cerebelo/anormalidades , Criança , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Exoma , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Feminino , Hamartoma/diagnóstico , Hamartoma/genética , Humanos , Doenças Hipotalâmicas/diagnóstico , Doenças Hipotalâmicas/genética , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Masculino , Mutação , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Fenótipo , Polidactilia/diagnóstico , Polidactilia/genética , Retina/anormalidades , Análise de Sequência de DNA , Adulto Jovem
15.
Eur J Med Genet ; 56(10): 556-60, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23933090

RESUMO

Kabuki syndrome (KS) is a rare syndrome associating malformations with intellectual deficiency and numerous visceral, orthopedic, endocrinological, immune and autoimmune complications. The early establishment of a diagnostic of KS leads to better care of the patients and therefore prevents complications such as perception deafness, severe complications of auto-immune diseases or obesity. However, the diagnosis of KS remains difficult because based on the appreciation of facial features combined with other highly variable features. We describe a novel sign, namely the attenuation and/or congenital absence of the IPD crease of the third and fourth fingers associated with limitation of flexion of the corresponding joints, which seems to be specific of KS and could help the clinician to diagnose KS.


Assuntos
Anormalidades Múltiplas/diagnóstico , Face/anormalidades , Dedos/anormalidades , Doenças Hematológicas/diagnóstico , Doenças Vestibulares/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino
16.
Am J Med Genet A ; 161A(12): 3023-9, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23956186

RESUMO

Multicentric carpo-tarsal osteolysis (MCTO) with or without nephropathy is a rare osteolysis disorder beginning in early childhood and involving mainly carpal and tarsal bones. Renal disease appears later in life in the majority of cases and evolves quickly to end stage renal failure. Autosomal dominant (AD) inheritance has been demonstrated, with a high frequency of sporadic cases. Recently, mutations in a highly conserved region of the MAFB gene (v-maf musculoaponeurotic fibrosarcoma oncogene ortholog B) have been identified in MCTO patients by exome sequencing. MafB, known as a regulator of various developmental processes, is essential for osteoclastogenesis and renal development. We report here the molecular screening of MAFB in eight MCTO patients from six families. We identified MAFB mutations in all, including three novel missense mutations clustering within the hot spot mutation region. Among the eight patients, six only presented renal disease. Our report confirms the genetic homogeneity of MCTO and provides data underlying the clinical variability of this disorder.


Assuntos
Ossos do Carpo/fisiopatologia , Síndrome de Hajdu-Cheney/genética , Fator de Transcrição MafB/genética , Ossos do Tarso/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Exoma , Feminino , Síndrome de Hajdu-Cheney/fisiopatologia , Humanos , Masculino , Mutação de Sentido Incorreto
17.
Acta Neurochir (Wien) ; 155(10): 1973-6, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23917744

RESUMO

Mucopolysaccharidosis type-I is caused by a deficiency of the lysosomal enzyme α-L-iduronidase, resulting in gradual deposition of glycosaminoglycans in multiple body organs, affecting physical appearance and system functioning. We present the first reported case associating MPS-I (Hurler-Scheie subtype) with craniosynostosis. A 2.5-year-old girl presented initially with macrocrania. On clinical and radiological examinations we noted a scaphocephaly with dysmorphic facial features of MPS confirmed later on. Intracranial hypertension was documented at fundoscopy (papilloedema) and ICP monitoring, and then surgically treated. This association of scaphocephaly and MPS-I highlights the importance of a meticulous physical examination performed by craniofacial, metabolic and ophthalmologic teams.


Assuntos
Craniossinostoses/cirurgia , Iduronidase/deficiência , Mucopolissacaridose I/cirurgia , Pré-Escolar , Craniossinostoses/diagnóstico , Feminino , Humanos , Mucopolissacaridose I/diagnóstico , Mucopolissacaridose I/enzimologia , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
18.
Am J Hum Genet ; 93(1): 141-9, 2013 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-23810378

RESUMO

Short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay (SHORT) syndrome is a developmental disorder with an unknown genetic cause and hallmarks that include insulin resistance and lack of subcutaneous fat. We ascertained two unrelated individuals with SHORT syndrome, hypothesized that the observed phenotype was most likely due to de novo mutations in the same gene, and performed whole-exome sequencing in the two probands and their unaffected parents. We then confirmed our initial observations in four other subjects with SHORT syndrome from three families, as well as 14 unrelated subjects presenting with syndromic insulin resistance and/or generalized lipoatrophy associated with dysmorphic features and growth retardation. Overall, we identified in nine affected individuals from eight families de novo or inherited PIK3R1 mutations, including a mutational hotspot (c.1945C>T [p.Arg649Trp]) present in four families. PIK3R1 encodes the p85α, p55α, and p50α regulatory subunits of class IA phosphatidylinositol 3 kinases (PI3Ks), which are known to play a key role in insulin signaling. Functional data from fibroblasts derived from individuals with PIK3R1 mutations showed severe insulin resistance for both proximal and distal PI3K-dependent signaling. Our findings extend the genetic causes of severe insulin-resistance syndromes and provide important information with respect to the function of PIK3R1 in normal development and its role in human diseases, including growth delay, Rieger anomaly and other ocular affections, insulin resistance, diabetes, paucity of fat, and ovarian cysts.


Assuntos
Transtornos do Crescimento/genética , Hipercalcemia/genética , Resistência à Insulina/genética , Doenças Metabólicas/genética , Nefrocalcinose/genética , Fosfatidilinositol 3-Quinases/metabolismo , Análise Mutacional de DNA , Exoma , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Predisposição Genética para Doença , Idade Gestacional , Glucose/metabolismo , Glucose/farmacologia , Humanos , Insulina/metabolismo , Insulina/farmacologia , Masculino , Mutação , Linhagem , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
19.
Am J Med Genet A ; 161A(7): 1786-91, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23720404

RESUMO

We report on two unrelated patients with a rare progeroid syndrome first described by Penttinen. Patients presented with prematurely aged appearance, delayed dental development, acro-osteolysis, diffuse keloid-like lesions, and ocular pterygia. Facial features are progressive but recognizable at birth. Premaxillary and maxillary retraction with pseudo-prognathism and palpebral malocclusion are characteristic. Thumbs and halluces are broad and spatulated. Linear growth is increased and intellectual functions are preserved. Skin retractions and joint contractures progressively developed during adolescence. Death occurred in the second decade in one of the patient due to restrictive respiratory insufficiency and cachexia. LMNA and ZMPSTE24 sequencing were normal. The molecular basis of the disorder remains unknown.


Assuntos
Acro-Osteólise/genética , Deformidades Congênitas dos Membros/etiologia , Progéria/etiologia , Acro-Osteólise/etiologia , Adolescente , Criança , Colágeno Tipo III/genética , Face/anormalidades , Humanos , Queloide/patologia , Lamina Tipo A/genética , Deformidades Congênitas dos Membros/genética , Masculino , Proteínas de Membrana/genética , Metaloendopeptidases/genética , Progéria/genética , Prognatismo/genética , Adulto Jovem
20.
Am J Hum Genet ; 92(4): 621-6, 2013 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-23541344

RESUMO

Scalp-ear-nipple (SEN) syndrome is a rare, autosomal-dominant disorder characterized by cutis aplasia of the scalp; minor anomalies of the external ears, digits, and nails; and malformations of the breast. We used linkage analysis and exome sequencing of a multiplex family affected by SEN syndrome to identify potassium-channel tetramerization-domain-containing 1 (KCTD1) mutations that cause SEN syndrome. Evaluation of a total of ten families affected by SEN syndrome revealed KCTD1 missense mutations in each family tested. All of the mutations occurred in a KCTD1 region encoding a highly conserved bric-a-brac, tram track, and broad complex (BTB) domain that is required for transcriptional repressor activity. KCTD1 inhibits the transactivation of the transcription factor AP-2α (TFAP2A) via its BTB domain, and mutations in TFAP2A cause cutis aplasia in individuals with branchiooculofacial syndrome (BOFS), suggesting a potential overlap in the pathogenesis of SEN syndrome and BOFS. The identification of KCTD1 mutations in SEN syndrome reveals a role for this BTB-domain-containing transcriptional repressor during ectodermal development.


Assuntos
Anormalidades Múltiplas/etiologia , Síndrome Brânquio-Otorrenal/etiologia , Displasia Ectodérmica/etiologia , Exoma/genética , Hipospadia/etiologia , Hipotonia Muscular/etiologia , Mutação de Sentido Incorreto/genética , Proteínas Repressoras/genética , Anormalidades Múltiplas/patologia , Sequência de Aminoácidos , Síndrome Brânquio-Otorrenal/patologia , Orelha Externa/anormalidades , Orelha Externa/patologia , Displasia Ectodérmica/patologia , Feminino , Humanos , Hipospadia/patologia , Masculino , Dados de Sequência Molecular , Hipotonia Muscular/patologia , Mamilos/anormalidades , Mamilos/patologia , Linhagem , Fenótipo , Estrutura Terciária de Proteína , Couro Cabeludo/anormalidades , Couro Cabeludo/patologia , Homologia de Sequência de Aminoácidos
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