Recurrence risks in families with nonsydromic cleft lip and palate

Purpose: Estimate the recurrence risks for the proband’s children in the different groups of nonsyndromic cleft lip and palate (NSCLP). Methods: The retrospective and prospective study was based on a sample of 841 individuals, registered at the Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo (HRAC/USP). The minimum criteria used for inclusion were: presence of NSCLP and the existence of biological children of the proband’s. The sample was divided into two groups, Group I: proband’s with cleft lip with or without cleft palate (CL+/-CP) and Group II: proband’s with cleft palate (CP). Results: From the total of 841 individuals, 660(237M and 423F) constituted Group I and 181(41M and 140F), Group II. The frequency of familial cases in Group I was 14.0%, while in Group II it was 11%. By estimation of the recurrence risk, a risk of 5.3% SR (statistical reliability) 95% (4.2%-6.7%) and of 4.3% SR 95% (2.6%- 6.8%) was determined for the proband’s child in Group I and II respectively, with one affected parent, independent of the proband’s gender. On the other hand, considering the proband’s gender, in Group I a recurrence risk of 2.7% SR 95% (1.6%-4.0%) was obtained for the child of a female proband and a recurrence risk of 6,2% SR 95% (4.3%- 8.7%) for the child of a male probando. In Group II a recurrence risk of 4.5% SR 95% (2.4%-7.4%) was observed for a female proband and a risk of 3.9% SR 95% (1.1%- 9.7%) for a male proband. Conclusion: The recurrence risk in the Group I was similar when compared to the Group II, without taking into account the gender of the proband; the recurrence risk, in Group I was twice as high a male proband as for a female proband, while in Group II the recurrence risk was similar for the proband’s of either gender

Clinical evidence for a mandibular to maxillary transformation in auriculocondylar syndrome

Université Sorbonne Paris-Cité Pôle - project number SPC/JFG/2013-031ANR - project EvoDevoMut 2010E-Rare CRANIRARE gran

Novel variants in GNAI3 associated with auriculocondylar syndrome strengthen a common dominant negative effect

Auriculocondylar syndrome is a rare craniofacial disorder comprising core features of micrognathia, condyle dysplasia and question mark ear. Causative variants have been identified in PLCB4, GNAI3 and EDN1, which are predicted to function within the EDN1-EDNRA pathway during early pharyngeal arch patterning. To date, two GNAI3 variants in three families have been reported. Here we report three novel GNAI3 variants, one segregating with affected members in a family previously linked to 1p21.1-q23.3 and two de novo variants in simplex cases. Two variants occur in known functional motifs, the G1 and G4 boxes, and the third variant is one amino acid outside of the G1 box. Structural modeling shows that all five altered GNAI3 residues identified to date cluster in a region involved in GDP/GTP binding. We hypothesize that all GNAI3 variants lead to dominant negative effects.CRANIRAREUniversite Paris Descartes-Sorbonne Paris Cite Pole de Recherche et d'Enseignement SuperieurAgence Nationale de la Recherche (project EvoDevoMut)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)National Health and Medical Research Council of AustraliaUniv São Paulo, Inst Biociencias, Dept Genet & Biol Evolut, Ctr Pesquisas Genoma Humano & Celulas Tronco, BR-05508090 São Paulo, BrazilUniv Paris 05, Sorbonne Paris Cite, INSERM, U1163, Paris, FranceUniv São Paulo, HRCA, Dept Clin Genet, Bauru, BrazilUniv Melbourne, Royal Childrens Hosp, Murdoch Childrens Res Inst, Victorian Clin Genet Serv, Melbourne, Vic, AustraliaUniv Melbourne, Dept Paediat, Melbourne, Vic, AustraliaRoyal Childrens Hosp, Dept Plast & Maxillofacial Surg, Melbourne, Vic, AustraliaHosp Sick Children, Dept Otolaryngol Head & Neck Surg, Toronto, ON M5G 1X8, CanadaUniv São Paulo, Inst Biosci, BR-05508090 São Paulo, BrazilLeiden Univ, Med Ctr, Leiden Genome Technol Ctr, Leiden, NetherlandsUniversidade Federal de São Paulo, Inst Ciencia & Tecnol, Sao Jose Dos Campos, BrazilHop Necker Enfants Malad, AP HP, Dept Genet, Paris, FranceUniversidade Federal de São Paulo, Inst Ciencia & Tecnol, Sao Jose Dos Campos, BrazilUniversite Paris Descartes-Sorbonne Paris Cite Pole de Recherche et d'Enseignement Superieur: SPC/JFG/2013-031National Health and Medical Research Council of Australia: 607431Web of Scienc

Clinical-genetic study of 144 patients with nonsyndromic hearing loss

A deficiência auditiva constitui uma importante categoria de defeitos congênitos que podem se manifestar isoladamente ou fazer parte do espectro fenotípico de várias síndromes. O presente trabalho refere-se ao estudo genéticoclínico de pacientes portadores de deficiência auditiva não sindrômica, com os objetivos de estabelecer a razão sexual, tipo, grau, simetria, lateralidade e progressão da deficiência auditiva; determinar diagnósticos etiológicos prováveis da deficiência auditiva, estabelecendo, quando possível, o padrão de herança genética e fornecer meios para o aconselhamento genético. Foram avaliados 306 pacientes no serviço de Genética Clínica do Centro de Atendimento aos Distúrbios da Audição, Linguagem e Visão do Hospital de Reabilitação de Anomalias Craniofaciais-USP, no período de dezoito meses. Dos 306 pacientes avaliados, 278 eram portadores de deficiência auditiva, 27 portadores de distúrbio de linguagem e 1 portador de deficiência visual. De acordo com o critério estabelecido (presença de deficiência auditiva isolada), 144 pacientes foram selecionados para este estudo, através da história clínica, história familial, dados pré, peri e pós-natais e audiometria (dados de prontuário). A análise estatística não mostrou associação significativa entre a ocorrência de deficiência auditiva não sindrômica e o sexo dos propósitos. Dos 144 pacientes estudados, 95.8% dos casos tinham etiologia genética e 4.2% etiologia ambiental. Nos portadores de deficiência auditiva de etiologia genética, o padrão de herança indefinido (53.6%) foi o mais freqüente, seguido o de herança autossômica recessiva (23.9%) e autossômica dominante (22.5%); as anomalias maiores e menores associadas à deficiência auditiva não estavam relacionadas com esta deficiência. O tipo de perda auditiva predominante foi o neurossensorial (99.3%) e deficiência auditiva severa a profunda foi a mais freqüente (34.8%). Da amostra, 68.1% dos casos apresentaram perda auditiva pré-lingüística, 54.9% apresentaram perda auditiva assimétrica, 95.8% perda auditiva bilateral e 95.1% perda auditiva não progressiva. O estudo permitiu concluir que história clínica e familial são informações importantes no diagnóstico etiológico da deficiência auditiva; que as configurações da curva audiométrica são avaliações de apoio ao esclarecimento diagnóstico da deficiência auditiva; que o aconselhamento genético é dificultado nos casos com padrão de herança indefinido e que análises moleculares são dados subsidiários à definição etiológica da deficiência auditiva.Hearing loss constitutes an important category of congenital defects that can be expressed isolately or making part of the phenotypical spectrum of several syndromes. The aim of this study is to establish the sex-ratio, type, degree, symmetry, laterality, progression , and to find out the etiology of non syndromic hearing loss, establishing, when possible, the inheritance pattern providing ways to genetic couseling. During 18 months, 306 patients were evaluated at Centro de Atendimento aos Distúrbios da Audição, Linguagem e Visão of the Hospital de Reabilitação de Anomalias Craniofaciais-USP. Nonsyndromic hearing loss was observed in 144 of them; syndromic hearing loss in 134; only speech impairment in 27, and only visual impairment in 1. According criteria only the 144 patients with nonsyndromic were selected for this study. There were 83 females (57.6%) and 61males (42.4%); genetic etiology was found in 95.8% of the sample and environmental etiology in 4.2%; major and minor associated anomalies were not related with hearing loss. Sensorineural hearing loss was found in 99.3% and severeprofound hearing loss was the most frequent (34.8%). Others results were: asymmetrical hearing loss in 54.9%, bilateral hearing loss in 95.8%, and non progressive in 95.1%. This study allow to conclude that the familial and clinical data were important to define etiological diagnosis; the shape of audiograms were evaluations that help to clarify, but not define, the diagnosis. Genetic counseling is difficult when the pattern of inheritance is unknown; and molecular studies are important subsidiary test to define the etiology of the hearing loss

Genetic and environmental syndromes in hearing loss disturbance

Objetivos: estabelecer o diagnóstico de uma amostra de indivíduos com deficiência auditiva (DA) e comprometimento de outras estruturas anatômicas e/ou sistemas fisiológicos, cadastrados no CEDALVI/HRAC-USP-Bauru; verificar possíveis fatores etiológicos envolvidos e investigar possível correlação do tipo de DA com as diferentes síndromes encontradas. Local: Serviço de Genética Clínica do CEDALVI/HRAC-USP, Bauru-SP. Participantes: 93 indivíduos com DA e comprometimento de outras estruturas anatômicas e/ou sistemas fisiológicos. Intervenções: Avaliação genética-clínica; estudo citogenético; avaliações radiológica, oftalmológica, otorrinolaringológica, audiológica e outras. Resultados: Dos 93 indivíduos, 51 eram do sexo masculino e 42, do feminino. Recorrência familial foi observada em 31 casos e, consangüinidade parental em 8. Na amostra, 25 síndromes gênicas conhecidas, 5 síndromes cromossômicas, 5 quadros de etiologia ambiental e 2 quadros de etiologia heterogênea foram estabelecidos em 87 indivíduos. Em 1 caso, não foi possível definir entre 2 condições gênicas e em 5, não foi possível se chegar a um diagnóstico. Conclusões: a casuística se compôs de síndromes etiologicamente heterogêneas, com maior freqüência de etiologia genética; o tipo de DA nas síndromes gênicas foi condizente com o quadro diagnosticado; 3 indivíduos apresentaram síndromes ambientais clássicas, com diferentes tipos de DA; 2 indivíduos apresentaram quadro clínico, possivelmente decorrente de efeito teratogênico; implicação direta de fatores de risco para DA, na etiologia dessa, nos indivíduos com síndromes gênicas conhecidas sem DA; 1 caso, possivelmente, representa uma síndrome nova de padrão único, de etiologia desconhecida; o aconselhamento genético está na dependência da fase em que se encontra o processo de delineamento das diferentes condições estabelecidas.Objectives: The purposes of this study were to establish the diagnostic of the individuals with hearing loss and presenting other additional anatomic structures and/or physiologic systems involvement, recorded in the CEDALVI/HRAC-USP-Bauru; to verify possible etiologic factors involved and to investigate a possible correlation of the hearing loss type with the different diagnosis syndromes. Setting: Clinical genetic service of the CEDALVI/HRAC-USP, Bauru- P. Participants: The sample was comprised of 93 individuals with hearing loss and involvement of other anatomic structures and/or physiologic systems. Interventions: Clinical genetic evaluation; cytogenetic study; radiological, ophtalmological, othorinolaryngological, audiologycal evaluation, etc. Results: From the total of the sample, 51 were male and 42 were female. Familial recurrence was observed in 31 cases and parental consanguinity in 8. In the present sample, 25 known genic syndromes, 5 chromosomal syndromes, 5 environmental conditions, and 2 heterogeneous conditions were established in 87 individuals. The diagnosis was not established in 5 individuals and in 1 case it was not possible to define between 2 genic conditions. Conclusions: The casuistic was composed of etiologically heterogeneous syndromes with greater frequency of genetic etiology; the type of hearing loss in the genic syndromes was concordant with the diagnosed condition; 3 individuals presented classic environmental syndromes with different types of hearing loss; 2 individuals presented clinical picture, possibly due to teratogenic effect; hearing impairment related to risk factors of the hearing loss in the individuals with known genic syndromes without hearing loss; probable a new unique-pattern syndrome, of unknown etiology in 1 case; the genetic counseling will depend on the step of delineation process of the different diagnosed condition

Clinical-genetic study of 144 patients with nonsyndromic hearing loss

A deficiência auditiva constitui uma importante categoria de defeitos congênitos que podem se manifestar isoladamente ou fazer parte do espectro fenotípico de várias síndromes. O presente trabalho refere-se ao estudo genéticoclínico de pacientes portadores de deficiência auditiva não sindrômica, com os objetivos de estabelecer a razão sexual, tipo, grau, simetria, lateralidade e progressão da deficiência auditiva; determinar diagnósticos etiológicos prováveis da deficiência auditiva, estabelecendo, quando possível, o padrão de herança genética e fornecer meios para o aconselhamento genético. Foram avaliados 306 pacientes no serviço de Genética Clínica do Centro de Atendimento aos Distúrbios da Audição, Linguagem e Visão do Hospital de Reabilitação de Anomalias Craniofaciais-USP, no período de dezoito meses. Dos 306 pacientes avaliados, 278 eram portadores de deficiência auditiva, 27 portadores de distúrbio de linguagem e 1 portador de deficiência visual. De acordo com o critério estabelecido (presença de deficiência auditiva isolada), 144 pacientes foram selecionados para este estudo, através da história clínica, história familial, dados pré, peri e pós-natais e audiometria (dados de prontuário). A análise estatística não mostrou associação significativa entre a ocorrência de deficiência auditiva não sindrômica e o sexo dos propósitos. Dos 144 pacientes estudados, 95.8% dos casos tinham etiologia genética e 4.2% etiologia ambiental. Nos portadores de deficiência auditiva de etiologia genética, o padrão de herança indefinido (53.6%) foi o mais freqüente, seguido o de herança autossômica recessiva (23.9%) e autossômica dominante (22.5%); as anomalias maiores e menores associadas à deficiência auditiva não estavam relacionadas com esta deficiência. O tipo de perda auditiva predominante foi o neurossensorial (99.3%) e deficiência auditiva severa a profunda foi a mais freqüente (34.8%). Da amostra, 68.1% dos casos apresentaram perda auditiva pré-lingüística, 54.9% apresentaram perda auditiva assimétrica, 95.8% perda auditiva bilateral e 95.1% perda auditiva não progressiva. O estudo permitiu concluir que história clínica e familial são informações importantes no diagnóstico etiológico da deficiência auditiva; que as configurações da curva audiométrica são avaliações de apoio ao esclarecimento diagnóstico da deficiência auditiva; que o aconselhamento genético é dificultado nos casos com padrão de herança indefinido e que análises moleculares são dados subsidiários à definição etiológica da deficiência auditiva.Hearing loss constitutes an important category of congenital defects that can be expressed isolately or making part of the phenotypical spectrum of several syndromes. The aim of this study is to establish the sex-ratio, type, degree, symmetry, laterality, progression , and to find out the etiology of non syndromic hearing loss, establishing, when possible, the inheritance pattern providing ways to genetic couseling. During 18 months, 306 patients were evaluated at Centro de Atendimento aos Distúrbios da Audição, Linguagem e Visão of the Hospital de Reabilitação de Anomalias Craniofaciais-USP. Nonsyndromic hearing loss was observed in 144 of them; syndromic hearing loss in 134; only speech impairment in 27, and only visual impairment in 1. According criteria only the 144 patients with nonsyndromic were selected for this study. There were 83 females (57.6%) and 61males (42.4%); genetic etiology was found in 95.8% of the sample and environmental etiology in 4.2%; major and minor associated anomalies were not related with hearing loss. Sensorineural hearing loss was found in 99.3% and severeprofound hearing loss was the most frequent (34.8%). Others results were: asymmetrical hearing loss in 54.9%, bilateral hearing loss in 95.8%, and non progressive in 95.1%. This study allow to conclude that the familial and clinical data were important to define etiological diagnosis; the shape of audiograms were evaluations that help to clarify, but not define, the diagnosis. Genetic counseling is difficult when the pattern of inheritance is unknown; and molecular studies are important subsidiary test to define the etiology of the hearing loss

Oculoauriculovertebral spectrum: report of nine familial cases with evidence of autosomal dominant inheritance and review of the literature

Oculoauriculovertebral spectrum (OAVS; OMIM 164210) is a complex condition characterized by defects of aural, oral, mandibular and vertebral development. The aetiology of this condition is likely to be heterogeneous; most cases are sporadic, however, familial cases suggesting autosomal recessive end autosomal dominant inheritance have been reported. In this study, we describe the clinical aspects of nine familial cases with evidence of autosomal dominant inheritance and compare them with reports in the literature. Interfamilial and intrafamilial clinical variabilities were observed in this study (reinforcing the necessity of careful examination of familial members). We suggest that oculoauriculovertebral spectrum with autosomal dominant inheritance is characterized mainly by bilateral auricular involvement and rarely presents extracranial anomalies. Clin Dysmorphol 18:67-77 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

22q11 deletion syndrome and limb anomalies: Report on two Brazilian patients

Objective: To report on two Brazilian patients with chromosome 22q11 deletion who presented with velopharyngeal insufficiency, congenital heart anomalies, developmental delay, and limb anomalies. The pattern of limb anomalies in these patients, which range from ectrodactyly to limb synostosis, is very uncommon in 22q11 deletion syndrome. Conclusion: These patients widen the spectrum of clinical signs of the 22q11 deletion syndrome and alert researchers to conduct additional investigation in patients with limb involvement with velopharyngeal insufficiency and/or cardiac anomalies, along with developmental delay.CNPq[309030/2003-0