Abstract Objective: To evaluate the impact of the Universal Neonatal Hearing Screening (UNHS) on the age at diagnosis, beginning of treatment, and first cochlear implant surgery. Methods: A retrospective cohort study with children up to 12 years old with bilateral hearing loss were divided into two groups: patients who underwent UNHS and the ones who didn't. The groups were compared according to their age at the beginning of the evaluation at a specialized center, at the beginning of the intervention, and, for the ones who had indication, at the cochlear implant surgery. The group who underwent UNHS was divided between the ones who passed the screening test and the ones who didn’t. They were compared according to their ages at the same moments as the first two groups. Results: 135 patients were included. The median age at the first appointment in a specialized center was 1.42 (0.50 and 2.50) years, at the beginning of treatment 2.00 (1.00 and 3.52) years, and the cochlear implant surgery 2.83 (1.83 and 4.66) years. Children who underwent UNHS were younger than those who didn't, at the three evaluated moments (p < 0.001). In a subanalysis, children who passed the UNHS but were later diagnosed with hearing loss reached the first appointment with a specialist and started treatment older than those who failed the tests. Conclusion: Performing UNHS interfered with the timing of deafness diagnosis and treatment. However, children who passed the screening but were later diagnosed with hearing loss were the category with the most important delay.

Abstract Introduction Hearing loss etiology depends on the population studied as well as on the ethnicity and the socio-economic condition of the analyzed region. Etiological diagnosis contributes to the improvement of preventive measures and to the early identification of this deficiency. Objective To identify the etiological factors of hearing loss and its prevalence in a tertiary hospital in southern Brazil, to verify the frequency of mutations in GJB2 and GJB6 genes, and to correlate the degree of hearing loss with the etiological factors of deafness. Methods This prevalence study involved 140 children with bilateral sensorineural or mixed hearing loss. Medical history, physical examination, audiometry, and evoked auditory brainstem response were conducted. Imaging and genetic examinations were also performed. Results Etiologies and their prevalence were as follows: (a) indeterminate causes, 31.4%; (b) conditions related to neonatal period, 22.1%; (c) genetic, 22.1%; (d) auditory neuropathy, 10%; (e) other factors (cortical malformation, intracranial hemorrhage, and internal ear malformations), 7.9% and (f) congenital infections, 6.4%. Within the genetic cases, ten homozygous and seven heterozygotes of the 35delG mutation were identified, besides two cases of rare variants of GJB2: p.Try172* and p.Arg184Pro. One case with homozygosis of del(GJB6-D13S1830) was found. Regarding severity of hearing loss, in 78.6% of the cases the degree of hearing loss was profound and there were no significant differences when comparing between etiologies. Conclusion The number of indeterminate etiologies is still high and congenital CMV infection may be a possible cause of undiagnosed etiology for hearing loss. The predominance of etiologies related to neonatal conditions and infectious causes are characteristic of developing countries. The most prevalent mutation was 35delG, the main GJB2 gene, probably because of the European influence in the genotype of our population.

Resumo Introdução A etiologia da perda auditiva depende da população estudada, da etnia e da condição socioeconômica da região analisada. O diagnóstico etiológico contribui para o aprimoramento das medidas preventivas e para a identificação precoce dessa deficiência. Objetivos Identificar os fatores etiológicos da perda auditiva e sua prevalência em um hospital terciário do sul do Brasil, verificar a frequência de mutações nos genes GJB2 e GJB6 e correlacionar o grau da perda auditiva com os fatores etiológicos da deficiência auditiva. Método Este estudo de prevalência avaliou 140 crianças com perda auditiva neurossensorial bilateral ou mista. Foram submetidos a anamnese com histórico médico, exame físico, audiometria e potencial evocado auditivo de tronco encefálico. Exames de imagem e genéticos também foram feitos. Resultados As etiologias e sua prevalência foram as seguintes: (a) causas indeterminadas, 31,4%; (b) condições relacionadas ao período neonatal, 22,1%; (c) genética, 22,1%; (d) neuropatia auditiva, 10%; (e) outros fatores (malformação cortical, hemorragia intracraniana e malformações da orelha interna), 7,9% e (f) infecções congênitas, 6,4%. Entre os casos genéticos, foram identificados dez casos homozigotos e sete heterozigotos da mutação 35delG, além de dois casos de variantes raras do GJB2: p.Try172* e p.Arg184Pro. Foi encontrado um caso homozigoto da mutação del (GJB6‐D13S1830). Em relação à gravidade da perda auditiva, em 78,6% dos casos o grau da perda auditiva foi profundo e não houve diferenças significantes na comparação entre as etiologias. Conclusão O número de etiologias indeterminadas ainda é elevado e a infecção congênita por CMV pode ser uma possível causa de etiologia não diagnosticada para perda auditiva. A predominância das etiologias relacionadas às condições neonatais e às causas infecciosas são características de países em desenvolvimento. A mutação mais prevalente foi a 35delG e o principal gene foi o GJB2, provavelmente devido à influência europeia no genótipo de nossa população.

Objective: To define the list of priority congenital anomalies for improving the registration in the Brazilian Live Birth Information System (Sinasc). Methods: Based on International Classification of Diseases, Tenth Revision (ICD-10), internation protocols and meetings with specialists, the list of priority anomalies was built considering two main criteria: being diagnosable at birth and having intervention available at different levels. The list was submitted for consideration by the Brazilian Society of Medical Genetics and Genomics. Results: The list comprised eight groups of congenital anomalies distributed according to the type of anomaly related, as well as the affect body part, all of which were related to some code of chapter XVII of ICD-10. Conclusion: The list of priority congenital anomalies for notification provides subsidies for improving registration at Sinasc.

Objetivo: Definir a lista de anomalias congênitas prioritárias para o aprimoramento do registro no Sistema de Informações sobre Nascidos Vivos (Sinasc). Métodos: A partir da Décima Revisão da Classificação Estatística Internacional de Doenças e Problemas Relacionados à Saúde (CID-10), protocolos internacionais e reuniões com especialistas, a lista de anomalias prioritárias foi construída considerando-se dois critérios principais: ser diagnosticável ao nascimento; e possuir intervenção disponível em diferentes níveis. A lista foi submetida a apreciação da Sociedade Brasileira de Genética Médica e Genômica. Resultados: Compuseram a lista oito grupos de anomalias distribuídos de acordo com o tipo de anomalia relacionada, bem como a parte do corpo afetada e sua correspondência ao código do capítulo XVII da CID-10. Conclusão: A lista de anomalias congênitas prioritárias para notificação fornece subsídios para o aprimoramento do registro no Sinasc.

Resumo Objetivo Definir a lista de anomalias congênitas prioritárias para o aprimoramento do registro no Sistema de Informações sobre Nascidos Vivos (Sinasc). Métodos A partir da Décima Revisão da Classificação Estatística Internacional de Doenças e Problemas Relacionados à Saúde (CID-10), protocolos internacionais e reuniões com especialistas, a lista de anomalias prioritárias foi construída considerando-se dois critérios principais: ser diagnosticável ao nascimento; e possuir intervenção disponível em diferentes níveis. A lista foi submetida a apreciação da Sociedade Brasileira de Genética Médica e Genômica. Resultados Compuseram a lista oito grupos de anomalias congênitas distribuídos de acordo com o tipo de anomalia relacionada, bem como a parte do corpo afetada e sua correspondência ao código do capítulo XVII da CID-10. Conclusão A lista de anomalias congênitas prioritárias para notificação fornece subsídios para o aprimoramento do registro no Sinasc.

Abstract Objective To define the list of priority congenital anomalies for improving their recording on the Brazilian Live Birth Information System (Sinasc). Methods Based on the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10), international protocols and meetings with specialists, the list of priority anomalies was built considering two main criteria: being diagnosable at birth and having intervention available at different levels. The list was submitted for consideration by the Brazilian Medical Genetics and Genomics Society. Results The list comprised eight groups of congenital anomalies distributed according to the type of related anomaly, as well as the affected part of the body and its corresponding code in ICD-10 Chapter XVII. Conclusion The list of priority congenital anomalies for notification provides a basis for improving case recording on Sinasc.

Resumen Objetivo Definir la lista de anomalías congénitas prioritarias para perfeccionar el registro en el Sistema de Información de Nacidos Vivos (Sinasc). Métodos Con base en la Clasificación Internacional de Enfermedades, Décima Revisión (CIE-10), protocolos internacionales y reuniones con especialistas, la lista de anomalías prioritarias se construyó considerando dos criterios principales: ser diagnosticables al nacer y tener intervención disponible en diferentes niveles. La lista fue sometida a la consideración de la Sociedad Brasileña de Genética y Genómica Médica. Resultados La lista comprendía ocho grupos de anomalías congénitas distribuidos según el tipo de anomalía relacionada, así como la parte del cuerpo afectada, todos ellos relacionados con algún código del capítulo XVII de la CIE-10. Conclusión La lista de anomalías congénitas prioritarias para notificación proporciona subsidios para mejorar el registro en Sinasc.

Resumo Objetivo Definir a lista de anomalias congênitas prioritárias para o aprimoramento do registro no Sistema de Informações sobre Nascidos Vivos (Sinasc). Métodos A partir da Décima Revisão da Classificação Estatística Internacional de Doenças e Problemas Relacionados à Saúde (CID-10), protocolos internacionais e reuniões com especialistas, a lista de anomalias prioritárias foi construída considerando-se dois critérios principais: ser diagnosticável ao nascimento; e possuir intervenção disponível em diferentes níveis. A lista foi submetida a apreciação da Sociedade Brasileira de Genética Médica e Genômica. Resultados Compuseram a lista oito grupos de anomalias congênitas distribuídos de acordo com o tipo de anomalia relacionada, bem como a parte do corpo afetada e sua correspondência ao código do capítulo XVII da CID-10. Conclusão A lista de anomalias congênitas prioritárias para notificação fornece subsídios para o aprimoramento do registro no Sinasc.

Abstract Objective To define the list of priority congenital anomalies for improving their recording on the Brazilian Live Birth Information System (Sinasc). Methods Based on the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10), international protocols and meetings with specialists, the list of priority anomalies was built considering two main criteria: being diagnosable at birth and having intervention available at different levels. The list was submitted for consideration by the Brazilian Medical Genetics and Genomics Society. Results The list comprised eight groups of congenital anomalies distributed according to the type of related anomaly, as well as the affected part of the body and its corresponding code in ICD-10 Chapter XVII. Conclusion The list of priority congenital anomalies for notification provides a basis for improving case recording on Sinasc.

Resumen Objetivo Definir la lista de anomalías congénitas prioritarias para perfeccionar el registro en el Sistema de Información de Nacidos Vivos (Sinasc). Métodos Con base en la Clasificación Internacional de Enfermedades, Décima Revisión (CIE-10), protocolos internacionales y reuniones con especialistas, la lista de anomalías prioritarias se construyó considerando dos criterios principales: ser diagnosticables al nacer y tener intervención disponible en diferentes niveles. La lista fue sometida a la consideración de la Sociedad Brasileña de Genética y Genómica Médica. Resultados La lista comprendía ocho grupos de anomalías congénitas distribuidos según el tipo de anomalía relacionada, así como la parte del cuerpo afectada, todos ellos relacionados con algún código del capítulo XVII de la CIE-10. Conclusión La lista de anomalías congénitas prioritarias para notificación proporciona subsidios para mejorar el registro en Sinasc.

Abstract Treatment of moderate and severe forms of osteogenesis imperfecta (OI) with cyclic pamidronate at the Reference Center for OI Treatment in Southern Brazil was studied. A retrospective cohort study was conducted from 2002 to 2012. Data were obtained during inpatient (drug infusion) and outpatient care. Clinical data, including the presence of blue sclerae, dentinogenesis imperfecta, history and site of the fractures, biochemical data, including calcium, phosphorus, and alkaline phosphatase levels, were systematically collected. Bone mineral density (BMD) was measured using dual energy X-ray absorptiometry (DXA). Forty-five patients (26 females) were included in the study, and the age of the patients at the time of diagnosis ranged from 1 to 144 months, with a median age (p25-p75) of 38 (5-96) months. Most cases presented OI-4 (51.1%), and the median age of the patients at the start of treatment was 3.3 years (25-75 percentiles: 0.5 - 8.7 years). Twenty-four patients (54.5%) had some adverse events or intercurrences during treatment, and the treatment compliance mean was 92.3% (± 10.7). The treatment with intravenous pamidronate has shown to be safe, well-tolerated, and effective in regard to the improvement of BMD and the reduction of the number of fractures in children and adolescents with OI.

Resumo Objetivo: Identificar desequilíbrios genômicos patogênicos em pacientes que apresentam cardiopatias congênitas (CC) e anomalias extracardíacas e exclusão da síndrome de deleção 22q11.2 (SD22q11.2). Métodos: Foram avaliados por microarray cromossômico (CMA) 78 pacientes negativos para a deleção 22q11.2, previamente testados por hibridação in situ com fluorescência (FISH) e/ou amplificação de múltiplas sondas dependentes de ligação (MLPA). Resultados: Foram identificadas variações do número de cópias de DNA (CNVs) clinicamente significativas (≥ 300 kb) em 10% (8/78) dos casos, além de CNVs potencialmente relevantes em dois casos (duplicação de 993 kb em 15q21.1 e duplicação de 706 kb em 2p22.3). Genes envolvidos como IRX4, BMPR1A, SORBS2, ID2, ROCK2, E2F6, GATA4, SOX7, SEMAD6D, FBN1 e LTPB1 são conhecidos por atuar no desenvolvimento cardíaco e podem ser genes candidatos a CC. Conclusão: Esses dados mostram que pacientes que apresentam CC, com anomalias extracardíacas e exclusão da SD22q11.2, devem ser investigados por CMA. Ainda, este estudo enfatiza a possível função das CNVs nas CC.

Abstract Objective: To identify pathogenic genomic imbalances in patients presenting congenital heart disease (CHD) with extra cardiac anomalies and exclusion of 22q11.2 deletion syndrome (22q11.2 DS). Methods: 78 patients negative for the 22q11.2 deletion, previously screened by fluorescence in situ hybridization (FISH) and/or multiplex ligation probe amplification (MLPA) were tested by chromosomal microarray analysis (CMA). Results: Clinically significant copy number variations (CNVs ≥300 kb) were identified in 10% (8/78) of cases. In addition, potentially relevant CNVs were detected in two cases (993 kb duplication in 15q21.1 and 706 kb duplication in 2p22.3). Genes inside the CNV regions found in this study, such as IRX4, BMPR1A, SORBS2, ID2, ROCK2, E2F6, GATA4, SOX7, SEMAD6D, FBN1, and LTPB1 are known to participate in cardiac development and could be candidate genes for CHD. Conclusion: These data showed that patients presenting CHD with extra cardiac anomalies and exclusion of 22q11.2 DS should be investigated by CMA. The present study emphasizes the possible role of CNVs in CHD.

RESUMO Objetivo: Caracterizar o padrão de fraturas e a história clínica no momento do diagnóstico de osteogênese imperfeita. Métodos: Neste estudo retrospectivo, foram incluídos todos os pacientes com osteogênese imperfeita de ambos os sexos, com idades entre 0 e 18 anos, que realizaram tratamento entre 2002 e 2014. Os prontuários médicos foram revisados para coleta de dados clínicos, incluindo presença de escleras azuladas, dentinogênese imperfeita, história familiar positiva para a doença e locais das fraturas, além de achados radiográficos no momento do diagnóstico. Resultados: Foram incluídos no estudo 76 pacientes (42 do sexo feminino), com idade, no momento do diagnóstico, entre 0 e 114 meses [mediana (p25-p75) de idade de 38 (6-96) meses]. Escleras azuladas estavam presentes em 93,4% dos pacientes, dentinogênese imperfeita foi observada em 27,6% e ossos wormianos em 29,4%. O número de fraturas ao diagnóstico variou entre 0 e 17, com uma mediana de 3 (2-8) fraturas. Em 40 (57%) pacientes, as fraturas eram de membros superiores e inferiores no momento do diagnóstico e, em 9 pacientes também havia fratura vertebral. O diagnóstico foi realizado ao nascimento em 85,7% dos pacientes com o tipo 3 e em 39,3% daqueles com tipo 4/5 da doença. Conclusões: Osteogênese imperfeita é uma doença genética com características clínicas distintas, tais como fragilidade óssea, fraturas recorrentes, escleras azuladas e dentinogênese imperfeita. É importante saber identificar essas características, facilitando o diagnóstico, otimizando o tratamento e diferenciando de outras doenças que também podem causar fraturas.

ABSTRACT Objective: To characterize the fracture pattern and the clinical history at the time of diagnosis of osteogenesis imperfecta. Methods: In this retrospective study, all patients with osteogenesis imperfecta, of both genders, aged 0-18 years, who were treated between 2002 and 2014 were included. Medical records were assessed to collect clinical data, including the presence of blue sclerae, dentinogenesis imperfecta, positive familial history of osteogenesis imperfecta, and the site of the fractures. In addition, radiographic findings at the time of the diagnosis were reviewed. Results: Seventy-six patients (42 females) were included in the study. Individuals’ age ranged from 0 to 114 months, with a median (interquartile range) age of 38 (6-96) months. Blue sclerae were present in 93.4% of patients, dentinogenesis imperfecta was observed in 27.6% of patients, and wormian bones in 29.4% of them. The number of fractures at diagnosis ranged from 0 to 17, with a median of 3 (2-8) fractures. Forty (57%) patients had fractures of the upper and lower extremities, and 9 patients also had spinal fractures. The diagnosis was performed at birth in 85.7% of patients with type 3, and 39.3% of those with type 4/5 of the disorder. Conclusions: Osteogenesis imperfecta is a genetic disorder with distinctive clinical features such as bone fragility, recurrent fractures, blue sclerae, and dentinogenesis imperfecta. It is important to know how to identify these characteristics in order to facilitate the diagnosis, optimize the treatment, and differentiate osteogenesis imperfecta from other disorders that also can lead to fractures.

Holoprosencephaly (HPE) is a spectrum of brain and facial malformations primarily reflecting genetic factors, such as chromosomal abnormalities and gene mutations. Here, we present a clinical and molecular analysis of 195 probands with HPE or microforms; approximately 72% of the patients were derived from the Latin American Collaborative Study of Congenital Malformations (ECLAMC), and 82% of the patients were newborns. Alobar HPE was the predominant brain defect in almost all facial defect categories, except for patients without oral cleft and median or lateral oral clefts. Ethmocephaly, cebocephaly, and premaxillary agenesis were primarily observed among female patients. Premaxillary agenesis occurred in six of the nine diabetic mothers. Recurrence of HPE or microform was approximately 19%. The frequency of microdeletions, detected using Multiplex Ligation-dependant Probe Amplification (MLPA) was 17% in patients with a normal karyotype. Cytogenetics or QF-PCR analyses revealed chromosomal anomalies in 27% of the probands. Mutational analyses in genes SHH, ZIC2, SIX3 and TGIF were performed in 119 patients, revealing eight mutations in SHH, two mutations in SIX3 and two mutations in ZIC2. Thus, a detailed clinical description of new HPE cases with identified genetic anomalies might establish genotypic and phenotypic correlations and contribute to the development of additional strategies for the analysis of new cases.

We report a study of TGFA/ Taq I polymorphisms and environmental factors in non-syndromic oral cleft in Southern Brazil. Nonsyndromic cleft case-parent triads were recruited to participate. Clinical data was collected with an emphasis on tobacco and alcohol use during pregnancy. DNA was extracted from peripheral blood and TGFA/ Taq I polymorphisms were analyzed by PCR/RFLP with Taq I restriction enzyme. Association of clefts and TGFA/ Taq I polymorphisms was determined using a transmission disequilibrium test (TDT). Association of environmental factors, clefts, and genotypes was evaluated with Fisher's exact test. The minor allele frequency was 0.064. We found no evidence of association between TGFA/ Taq I polymorphisms and clefting (TDT p = 0.335). We also found no association between TGFA/ TaqI polymorphisms and environmental factors (alcohol and/or tobacco). Therefore, no evidence was found that TGFA/ Taq I polymorphisms play a role in clefting in this population. No evidence was found that tobacco or alcohol exposure during pregnancy was related to clefting, however a larger sample size is needed to confirm these results.

Prenatal alcohol exposure can have serious and permanent adverse effects. The developing brain is the most vulnerable organ to the insults of prenatal alcohol exposure. A behavioral phenotype of prenatal alcohol exposure including conduct disorders is also described. This study on a sample of Brazilian adolescents convicted for criminal behavior aimed to evaluate possible clinical features of Fetal Alcohol Syndrome (FAS). These were compared to a control group of school adolescents, as well as tested for other environmental risk factors for antisocial behavior. A sample of 262 institutionalized male adolescents due to criminal behavior and 154 male students aged between 13 and 21 years comprised the study population. Maternal use of alcohol was admitted by 48.8% of the mothers of institutionalized adolescents and by 39.9% of the school students. In this sample of adolescents we could not identify -individual cases with a clear diagnosis of FAS, but signs suggestive of FASD were more common in the institutionalized adolescents. Social factors like domestic and family violence were frequent in the risk group, this also being associated to maternal drinking during pregnancy. The inference is that in our sample, criminal behavior is more related to complex interactions between environmental and social issues including prenatal alcohol exposure.

Três famílias com a síndrome do X frágil foram estudadas com o objetivo de estabelecer as características clínicas mais frequentes nos indivíduos afetados e nas mulheres heterozigotas. Avaliação clínica, de nível intelectual e citogenética visando a expressão do sítio frágil do cromosssomo X na região Xq27.3 foram empregadas em 40 indivíduos, 20 do sexo masculino e 20 do sexo feminino. Foi confirmado o diagnóstico da síndrome do X frágil em todos os indivíduos do sexo masculino com deficiência mental. Nos indivíduos pós-puberais as características clínicas mais frequentes foram: distância intercantal interna inferior a 3,5 cm, macroorquidia, face estreita e alongada, e palato alto. Nos indivíduos pré-puberais as características de comportamento como hiperatividade e pobre contato ocular foram observadas em todos os pacientes. Vinte e seis por cento das mulheres heterozigotas apresentaram deficiência mental e nestas as características clínicas foram mais importantes. Todos os indivíduos do sexo masculino com deficiência mental apresentaram o cromossomo X frágil [fra(X)] em cultura de linfócitos. Sessenta e três por cento das mulheres demonstraram o fra(X). Houve correlação positiva entre a frequência de fra(X) e as características clínicas. Enfatizamos a importância da avaliação clínica no estudo de deficiência mental familial e na triagem de casos isolados com suspeita da síndrome do X frágil.

Three families with the fragile X syndrome were studied with the aim to establish the most frequent clinical signs in the affected individuals and heterozygous women. The clinical evaluation, IQ level measurements and cytogenetic studies were performed in 40 subjects, 20 males and 20 females. The fragile X diagnosis was confirmed in all the male individuals with mental retardation. In the postpubertal subjects the most frequent clinical signs were inner canthal distance < 3.5 cm, macro-orchidism, long and narrow face and high arched palate while in the prepubertal subjects the behavioral characteristics as hyperactivity and poor eye contact were the most frequent and were observed in all patients. Twenty six percent of the heterozygous women presented with mental retardation and showed clinical signs rather than behavioral ones. All male individuals with mental retardation were observed as having fragile X [fra(X)] in lymphocytes culture. Sixty three percent of women showed fra(X). There was a positive correlation between the frequency of fra(X) and the clinical characteristics. We emphasize the importance of the clinical evaluation in the study of familial mental retardation and in the screening of isolated cases with suspect of having the fragile X syndrome.