Epidemiological characterization of rare diseases in Brazil: A retrospective study of the Brazilian Rare Diseases Network.

BACKGROUND: The Brazilian Policy for Comprehensive Care for People with Rare Diseases was implemented in 2014; however, national epidemiological data on rare diseases (RDs) are scarce and mainly focused on specific disorders. To address this gap, University Hospitals, Reference Services for Neonatal Screening, and Reference Services for Rare Diseases, all of which are public health institutions, established the Brazilian Rare Diseases Network (RARAS) in 2020. The objective of this study was to perform a comprehensive nationwide epidemiological investigation of individuals with RDs in Brazil. This retrospective survey collected data from patients receiving care in 34 healthcare facilities affiliated with RARAS in 2018 and 2019. RESULTS: The survey included 12,530 participants with a median age of 15.0 years, with women representing 50.5% of the cohort. Classification according to skin color demonstrated that 5044 (47.4%) participants were admixed. Most had a confirmed diagnosis (63.2%), with a predominance of phenylketonuria (PKU), cystic fibrosis (CF), and acromegaly. Common clinical manifestations included global developmental delay and seizures. The average duration of the diagnostic odyssey was 5.4 years (± 7.9 years). Among the confirmed diagnoses, 52.2% were etiological (biochemical: 42.5%; molecular: 30.9%), while 47.8% were clinical. Prenatal diagnoses accounted for 1.2%. Familial recurrence and consanguinity rates were 21.6% and 6.4%, respectively. Mainstay treatments included drug therapy (55.0%) and rehabilitation (15.6%). The Public Health System funded most diagnoses (84.2%) and treatments (86.7%). Hospitalizations were reported in 44.5% of cases, and the mortality rate was 1.5%, primarily due to motor neuron disease and CF. CONCLUSION: This study marks a pioneering national-level data collection effort for rare diseases in Brazil, offering novel insights to advance the understanding, management, and resource allocation for RDs. It unveils an average diagnostic odyssey of 5.4 years and a higher prevalence of PKU and CF, possibly associated with the specialized services network, which included newborn screening services.

Identifying Genetic Etiology in Patients with Intellectual Disability: An Experience in Public Health Services in Northeastern Brazil.

Intellectual disability (ID) is considered a common neuropsychiatric disorder that affects up to 3% of the population. The etiologic origin of ID may be genetic, environmental, and multifactorial. Chromosomopathies are relatively common among the genetic causes of ID, especially in the most severe cases and those associated with dysmorphic features. Currently, the application of new molecular cytogenetics technologies has increasingly allowed the identification of microdeletions, microduplications, and unbalanced translocations as causes of ID. The objective of this study was to investigate the etiology of ID in patients admitted to a public hospital in Northeastern Brazil. In total, 119 patients with ID who had normal karyotypes and fragile X exams participated in this study. The patients were initially physically examined for microdeletion syndromes and then tested using fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), methylation-sensitive polymerase chain reaction (MS-PCR), and chromosome microarray analysis (CMA), according to clinical suspicion. Patients with no diagnoses after FISH, MLPA, and/or MS-PCR evaluations were subsequently tested by CMA. The rate of etiologic diagnoses of ID in the current study was 28%. FISH diagnosed 25 out of 79 tested (31%), MLPA diagnosed 26 out of 79 tested (32%), MS-PCR diagnosed 7 out of 20 tested (35%), and the single nucleotide polymorphism array diagnosed 6 out of 27 tested (22%). Although the CMA is the most complete and recommended tool for the diagnosis of microdeletions, microduplications, and unbalance translocations in patients with ID, FISH, MLPA, and MS-PCR testing can be used as the first tests for specific syndromes, as long as the patients are first physically screened clinically, especially in the public health networks system in Brazil, where resources are scarce.

ELMO2 biallelic pathogenic variants in a patient with gingival hypertrophy and cherubism phenotype: Case report and molecular review.

Ramon syndrome (OMIM #266270) was first described in a patient with cherubism, gingival fibromatosis, epilepsy, intellectual disability, hypertrichosis, and stunted growth. In 2018, Mehawej et al. described a patient with Ramon syndrome in whom a homozygous variant in ELMO2 was identified, suggesting that this gene may be the causative for this syndrome. ELMO2 biallelic pathogenic variants were also described in patients with a primary intraosseous vascular malformation (PIVM; OMIM #606893). These patients presented gingival bleeding and cherubism phenotype. Herein, a patient with gingival hypertrophy, neurodevelopmental delay, and cherubism phenotype with a novel homozygous predicted loss-of-function (LOF) variant in the ELMO2 gene and family recurrence was reported. A surgical approach to treat gingival bleeding and mandible vascular malformation was also described. Furthermore, this study includes a comprehensive literature review of molecular data regarding the ELMO2 gene. All the variants, except one described in the ELMO2, were predicted as LOF, including our patient's variant. There is an overlapping between PIVM, also caused by LOF biallelic variants in the ELMO2 gene, and Ramon syndrome, which can suggest that they are not different entities. However, due to a limited number of cases described with molecular evaluation, it is hard to establish a genotype-phenotype correlation. Our study supports that LOF pathogenic biallelic variants in the ELMO2 gene cause a phenotype that has cherubism and gingival hypertrophy as main characteristics.

Temporal trends in prevalence and infant mortality of birth defects in Brazil, from 2001 to 2018. / Tendência temporal da prevalência e mortalidade infantil das anomalias congênitas no Brasil, de 2001 a 2018.

Congenital anomalies (CA) are a relevant problem for global public health, affecting about 3% to 6% of newborns worldwide. In Brazil, these are the second main cause of infant mortality. Thus, extensive studies are needed to demonstrate the impact of these anomalies on births and deaths. The present study describes the temporal trends of prevalence and infant mortality due to CA among live births in Brazil and regions, from 2001 to 2018, using the related data between the Live Birth Information System (SINASC, acronym in Portuguese) and the Mortality Information System (SIM, acronym in Portuguese). The prevalence and infant mortality due to CA has increased in Brazil and in most regions, especially in the Northeast and North. CAs in the musculoskeletal system were the most frequent at birth (29.8/10,000 live births), followed by those in the circulatory system (12.7/10,000 live births), which represented the primary cause of death in this group. The applied linkage technique made it possible to correct the national prevalence of CA by 17.9% during the analyzed period, after retrieving the anomalies reported in SIM, thereby proving to be a good tool to improve the quality of information on anomalies in Brazil.

As anomalias congênitas (AC) configuram um relevante problema para a saúde pública global, afetando em média de 3% a 6% dos recém-nascidos em todo o mundo. No Brasil, ocupam a segunda posição entre os principais grupos de causas de óbito infantil. Assim, estudos amplos são necessários para mostrar o impacto das AC na saúde infantil. O presente estudo descreve a tendência temporal da prevalência e da mortalidade infantil por AC entre nascidos vivos (NV) no Brasil e em suas cinco regiões de 2001 a 2018, utilizando dados vinculados entre as bases de dados do Sistema de Informações sobre Nascidos Vivos (SINASC) e do Sistema de Informações sobre Mortalidade (SIM). A prevalência e mortalidade infantil por AC mostrou-se crescente no Brasil na maioria das regiões, principalmente no Norte e no Nordeste. Aquelas do aparelho osteomuscular foram as mais prevalentes ao nascimento (29,8/10.000 NV); as do aparelho circulatório passaram para a segunda posição (12,7/10.000 NV) após a vinculação das bases e representam a primeira causa de morte desse grupo. A técnica de vinculação de dados aplicada corrigiu a prevalência nacional das AC em 17,9% no período analisado, após serem recuperadas as AC notificadas no SIM, mostrando ser uma boa ferramenta para melhorar a qualidade das informações das AC.

Tendência temporal da prevalência e mortalidade infantil das anomalias congênitas no Brasil, de 2001 a 2018 / Temporal trends in prevalence and infant mortality of birth defects in Brazil, from 2001 to 2018

Resumo As anomalias congênitas (AC) configuram um relevante problema para a saúde pública global, afetando em média de 3% a 6% dos recém-nascidos em todo o mundo. No Brasil, ocupam a segunda posição entre os principais grupos de causas de óbito infantil. Assim, estudos amplos são necessários para mostrar o impacto das AC na saúde infantil. O presente estudo descreve a tendência temporal da prevalência e da mortalidade infantil por AC entre nascidos vivos (NV) no Brasil e em suas cinco regiões de 2001 a 2018, utilizando dados vinculados entre as bases de dados do Sistema de Informações sobre Nascidos Vivos (SINASC) e do Sistema de Informações sobre Mortalidade (SIM). A prevalência e mortalidade infantil por AC mostrou-se crescente no Brasil na maioria das regiões, principalmente no Norte e no Nordeste. Aquelas do aparelho osteomuscular foram as mais prevalentes ao nascimento (29,8/10.000 NV); as do aparelho circulatório passaram para a segunda posição (12,7/10.000 NV) após a vinculação das bases e representam a primeira causa de morte desse grupo. A técnica de vinculação de dados aplicada corrigiu a prevalência nacional das AC em 17,9% no período analisado, após serem recuperadas as AC notificadas no SIM, mostrando ser uma boa ferramenta para melhorar a qualidade das informações das AC.

Abstract Congenital anomalies (CA) are a relevant problem for global public health, affecting about 3% to 6% of newborns worldwide. In Brazil, these are the second main cause of infant mortality. Thus, extensive studies are needed to demonstrate the impact of these anomalies on births and deaths. The present study describes the temporal trends of prevalence and infant mortality due to CA among live births in Brazil and regions, from 2001 to 2018, using the related data between the Live Birth Information System (SINASC, acronym in Portuguese) and the Mortality Information System (SIM, acronym in Portuguese). The prevalence and infant mortality due to CA has increased in Brazil and in most regions, especially in the Northeast and North. CAs in the musculoskeletal system were the most frequent at birth (29.8/10,000 live births), followed by those in the circulatory system (12.7/10,000 live births), which represented the primary cause of death in this group. The applied linkage technique made it possible to correct the national prevalence of CA by 17.9% during the analyzed period, after retrieving the anomalies reported in SIM, thereby proving to be a good tool to improve the quality of information on anomalies in Brazil.

Respiratory function of children and adolescents with osteogenesis imperfecta: respiratory muscle strength, forced vital capacity, and peak expiratory flow.

OBJECTIVE: This study aims to evaluate the respiratory function of children and adolescents with osteogenesis imperfecta (OI) followed up at a referral center. METHODS: A cross-sectional study was conducted with a non-probabilistic sample. Manovacuometry was performed with the measurement of maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP), and in addition, peak expiratory flow (PEF) and ventilometry were performed to measure forced vital capacity (FVC). RESULTS: In total, 23 individuals were evaluated, with a mean age of 11.6±3.4 years, 56.5% of whom were females. Regarding the classification of OI, 56.5% of the sample belonged to type IV, 30.5% to type III, and 13% to type I. The mean MIP was 64.4% of the predicted, and the mean MEP was 56.2% of the predicted. Overall, the mean PEF was 213.9 L/min, but only 140.6 L/min in the OI type III group. Median FVC was 1.9 L, corresponding to 110% of the predicted. CONCLUSIONS: Respiratory function of the study subjects was altered, with respiratory muscle strength values lower than expected in the whole sample, and peak expiratory flow was significantly reduced in the OI type III group.

Aspectos clínicos e diagnósticos, qualidade de vida, utilidade, adesão terapêutica e custos para angioedema hereditário associado à deficiência de C1-esterase / Clinical and diagnostic aspects, quality of life, usefulness, therapeutic adherence and costs for hereditary angioedema associated with C1-esterase deficiency

Introdução: O angioedema hereditário associado à deficiência de C1 esterase (AEH-C1-INH) é uma doença rara (DR) que se manifesta com a ocorrência de episódios recorrentes de angioedema não pruriginoso subcutâneo ou submucoso, o que gera impactos em todos os aspectos da vida dos indivíduos. Objetivo: Avaliar a qualidade de vida e a jornada clínica e assistencial dos pacientes com AEH-C1-INH. Material e Métodos: Trata-se de um estudo observacional ambispectivo em que foram aplicados questionários relacionados à qualidade de vida e jornada assistencial, além da coleta de dados clínicos dos prontuários nos tempos 0, 6 e 12 meses. Resultados: Foram recrutados 15 indivíduos com AEH-C1-INH e a mediana (I.I.Q) de idade da amostra foi de 38 anos (30-43). O tempo médio entre os primeiros sintomas e o diagnóstico foi de 8 anos. Os dados clínicos demonstraram história familiar positiva expressiva, ocorrência importante de edema de laringe em algum momento da vida e altos índices de recorrência das crises de angioedema durante os 12 meses de estudo. A qualidade de vida apresentou prejuízo importante principalmente em aspectos físicos, emocionais e vitalidade, sem variações significativas no tempo de estudo. Além disso, vale destacar a perda de produtividade expressiva associada a gastos médios de R$3.017,00 para medicamentos e R$598,00 para exames complementares em 12 meses. Conclusão: Observa-se um panorama de perda significativa de qualidade de vida relacionada ao AEH-C1-INH, principalmente por impactos da saúde física e emocional no exercício das atividades rotineiras. Ressaltam-se os impactos econômicos da jornada terapêutica, tanto pela perda de produtividade quanto pela necessidade de financiar medicamentos e exames que deveriam ser responsabilidade do Estado por meio do Sistema Único de Saúde (SUS). Portanto, fica clara a importância de medidas públicas que busquem amenizar os impactos causados pela doença nos indivíduos acometidos.

Introduction: Hereditary Angioedema associated with C1 esterase deficiency (HAE-C1-INH) is a rare disease (RD) that manifests with recurrent episodes of non-pruritic subcutaneous or submucosal angioedema, which impacts on all aspects of the individual's life. Objective: To evaluate the quality of life and the clinical and care journey of patients with HAE-C1-INH. Material and Methods: This is an ambispective observational study in which questionnaires related to quality of life and care journey were applied, in addition to the clinical data collection from medical records at 0, 6 and 12 months. Results: 15 subjects with HAE-C1-INH were recruited and the median (IQR) age of the sample was 38 years (30-43). The average time between the first symptoms and diagnosis was 8 years. The clinical data showed a substantial positive family history, considerable occurrence of laryngeal edema at some point in life and high rates of recurring angioedema crises during the 12 months of the study. Quality of life was significantly impaired, especially in terms of physical and emotional aspects and vitality, with no significant variations over the study period. It is also worth noting the major loss of productivity associated with average costs of R$3,017.00 for medication and R$598.00 for complementary tests over 12 months. Conclusion: There is a noticeable loss of quality of life related to HAE-C1-INH, mainly due to the impact on physical and emotional health when carrying out routine activities. The economic impacts of the therapeutic journey stand out, both due to the loss of productivity and the need to finance medicines and tests that should be the responsibility of the State through the Unified Health System (SUS). Therefore, the importance of public measures that seek to mitigate the impacts caused by the disease on affected individuals is evident.

Functional status of individuals with osteogenesis imperfecta: data from a reference center

Abstract Objective: To evaluate the functional status of individuals with Osteogenesis Imperfecta (OI) followed up at a reference center in the state of Bahia. Materials and methods: This is an observational, cross-sectional, descriptive study, which evaluated individuals with OI, based on a non-probabilistic sampling. To assess motor function, the Motor Function Measure (MFM) score was used, in addition to the measurement of muscle strength using the Medical Research Council (MRC) score. Functional performance was measured using the Pediatric Assessment of Disability Inventory, Computerized Adaptive Testing (PEDI-CAT). Results: Thirty-one individuals aged between two and 18 years old were evaluated. The overall score of MFM was 74.2%, and the lowest score was found in participants with type III OI (56.3%). The median of the MRC index was 80. The mobility domain was the most affected in the PEDI-CATevaluation, with a mean T score of 23.9, (14.2 in type III OI). Conclusions: Among the evaluated individuals, functional alterations were identified, reduced global gross motor functionality and muscle strength, impacting the mobility domain, with the most relevant findings in individuals with type III OI.

Functional status of individuals with osteogenesis imperfecta: data from a reference center.

OBJECTIVE: To evaluate the functional status of individuals with Osteogenesis Imperfecta (OI) followed up at a reference center in the state of Bahia. MATERIALS AND METHODS: This is an observational, cross-sectional, descriptive study, which evaluated individuals with OI, based on a non-probabilistic sampling. To assess motor function, the Motor Function Measure (MFM) score was used, in addition to the measurement of muscle strength using the Medical Research Council (MRC) score. Functional performance was measured using the Pediatric Assessment of Disability Inventory, Computerized Adaptive Testing (PEDI-CAT). RESULTS: Thirty-one individuals aged between two and 18 years old were evaluated. The overall score of MFM was 74.2%, and the lowest score was found in participants with type III OI (56.3%). The median of the MRC index was 80. The mobility domain was the most affected in the PEDI-CAT evaluation, with a mean T score of 23.9, (14.2 in type III OI). CONCLUSIONS: Among the evaluated individuals, functional alterations were identified, reduced global gross motor functionality and muscle strength, impacting the mobility domain, with the most relevant findings in individuals with type III OI.

Respiratory function of children and adolescents with osteogenesis imperfecta: respiratory muscle strength, forced vital capacity, and peak expiratory flow / Função respiratória de crianças e adolescentes com osteogênese imperfeita: força muscular respiratória, capacidade vital forçada e pico de fluxo expiratório

Abstract Objective: This study aims to evaluate the respiratory function of children and adolescents with osteogenesis imperfecta (OI) followed up at a referral center. Methods: A cross-sectional study was conducted with a non-probabilistic sample. Manovacuometry was performed with the measurement of maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP), and in addition, peak expiratory flow (PEF) and ventilometry were performed to measure forced vital capacity (FVC). Results: In total, 23 individuals were evaluated, with a mean age of 11.6±3.4 years, 56.5% of whom were females. Regarding the classification of OI, 56.5% of the sample belonged to type IV, 30.5% to type III, and 13% to type I. The mean MIP was 64.4% of the predicted, and the mean MEP was 56.2% of the predicted. Overall, the mean PEF was 213.9 L/min, but only 140.6 L/min in the OI type III group. Median FVC was 1.9 L, corresponding to 110% of the predicted. Conclusions: Respiratory function of the study subjects was altered, with respiratory muscle strength values lower than expected in the whole sample, and peak expiratory flow was significantly reduced in the OI type III group.

RESUMO Objetivo: Avaliar a função respiratória de crianças e adolescentes com osteogênese imperfeita (OI) acompanhados em um centro de referência. Métodos: Realizou-se um estudo de corte transversal, com amostragem não probabilística. Foi realizada manovacuometria com mensuração da pressão inspiratória máxima (PIM) e pressão expiratória máxima (PEM), além do pico de fluxo expiratório (PFE) e da ventilometria para a medida da capacidade vital forçada (CVF). Resultados: Foram avaliados 23 indivíduos, com média de idade de 11,6±3,4 anos, sendo 56,5% do sexo feminino. Com relação à classificação da OI, 56,5% da amostra pertencia ao tipo IV, 30,5% ao tipo III e 13% ao tipo I. A média de PIM foi de 64,4% do previsto, e a PEM foi de 56,2% do previsto. A média de PFE foi de 213,9 L/min, sendo 140,6 L/min no grupo de OI tipo III. A mediana da CVF foi de 1,9 L, correspondendo a 110% do previsto. Conclusões: A função respiratória dos indivíduos estudados encontrava-se alterada, com valores abaixo do esperado em toda a amostra para força muscular respiratória, além do PFE reduzido no grupo OI tipo III.

Hearing Loss in Mucopolysaccharidosis.

Introduction Mucopolysaccharidosis (MPS) is a set of rare diseases caused by deficiency of lysosomal enzymes that lead to the accumulation of glycosaminoglycans (GAG) in tissues and organs, which, in turn, is responsible for the multisystemic clinical, chronic, and progressive symptoms. Objective To describe the profile of the otorhinolaryngological clinical examination and audiology tests of patients with MPS disease. Methods The present study is a case series. The evaluation was performed, initially, in 24 patients with MPS types I, II, IIIA, IV and VI. Results The most common hearing complaint was hearing loss, which was confirmed by audiology tests in almost 100% of the patients, most of whom presented conductive hearing loss. Conclusions It is important to evaluate the complaints, physical examination, and audiology tests in patients with MPS. The otorhinolaryngologistshould be part of the group of professionals that follows these patients to better monitor their hearing and provide early hearing rehabilitation.

Case of 15q26-qter deletion associated with a Prader-Willi phenotype.

Prader-Willi syndrome (PWS) is one of the common neurogenetic disorders associated with intellectual disability. PWS involves a complex inheritance pattern and is caused by an absence of gene expression on the paternally inherited 15q11.2-q13 region, either due to deletion, maternal uniparental disomy or imprinting defect. The syndrome is characterized principally by severe neonatal hypotonia, a weak suck in infancy that is later followed by hyperphagia and obesity, developmental delay, intellectual disability and short stature. In the case of the chromosome 15q26-qter deletion syndrome or Drayer's syndrome, very few reports have been published. Its characteristics include intrauterine growth restriction, postnatal growth failure, varying degrees of intellectual disability, developmental delay, typical facial appearance and diaphragmatic hernia. The present paper describes a female patient in whom clinical findings were suggestive of PWS and deletion in the 15q26-qter region. Both karyotyping and methylation-specific polymerase chain reaction were shown to be normal. Nevertheless, fluorescence in situ hybridization showed a 15qter deletion that was later mapped by single nucleotide polymorphism (SNP)-array. The deleted genomic region involves the insulin-like growth factor-1 receptor (IGF1R) gene, which is related to short stature, developmental delay and intellectual disability. This case had various clinical characteristics in common with the cases of 15q26-qter deletionand characteristics compatible with PWS.

Identificação de doenças genéticas na Atenção Primária à Saúde: experiência de um município de porte médio no Brasil / Identification of genetic diseases in Primary Health Care: experience of a medium county in Brazil / Identificación de enfermedades genéticas en la Atención Primaria de Salud: experiencia de un municipio mediano en Brasil

Problema: Embora individualmente raras, somadas, as doenças genéticas têm prevalência global estimada de 31,5 a 73,0 por 1.000 indivíduos. Além disto, doenças genéticas e defeitos congênitos representam a segunda causa de mortalidade infantil no Brasil. Diante deste cenário, foi instituída a Política Nacional de Atenção Integral às Pessoas com Doenças Raras no Sistema Único de Saúde. Esta política prevê funções específicas para Atenção Primária à Saúde (APS) que incluem diagnóstico precoce e mapeamento de pessoas com ou sob-risco de desenvolver doenças genéticas raras e/ou defeitos congênitos para encaminhamento regulado. Essa experiência objetivou colaborar com o desenvolvimento de métodos para o reconhecimento de indivíduos com ou sob-risco de desenvolver doenças genéticas na APS. Métodos: Através de visitas domiciliares e por meio do preenchimento de uma ficha específica, realizou-se busca ativa de casos de doença genética e/ou defeito congênito em uma amostra probabilística aleatória, representativa de uma Unidade de Saúde da Família de um município brasileiro de porte médio. Resultados: Foram investigados 295 domicílios, totalizando 1.160 indivíduos e 238 casais. A média de filhos por casal foi de 2,7, a frequência de consanguinidade foi 3,8% e de abortamento espontâneo foi 8,7%. Foram identificadas 29 pessoas (2,5%) com doenças congênitas, 11 (0,9%) com deficiências auditivas, 10 (0,9%) com deficiência mental e 6 (0,5%) com déficits visuais importantes. Atraso no desenvolvimento neuropsicomotor foi relatado em 8,8% das crianças e adolescentes. Doze indivíduos (1%) possuíam câncer e 9,6% relataram história familiar positiva para câncer. Conclusão: Os profissionais da APS estão em posição privilegiada para identificar e organizar uma rede de cuidados para indivíduos com doenças genéticas e/ou defeitos congênitos. A utilização sistemática de instrumentos que facilitem o reconhecimento de fatores de risco e de situações suspeitas pode ser uma estratégia útil a ser incorporada pela APS.

Problem: Although individually rare, when added together, genetic diseases have an estimated overall prevalence of 31.5 to 73.0 per 1,000 individuals. In addition, genetic diseases and birth defects represent the second cause of infant mortality in Brazil. In this context, the National Policy on Comprehensive Care of People with Rare Diseases was established in the Brazilian National Health System. This policy provides specific Primary Health Care (PHC) assignments that includes early diagnosis and mapping people with or at risk of developing rare genetic disease and/or birth defects for regulated referral. This experience aimed to collaborate with developing methods for recognizing individuals with or at risk of developing genetic diseases in PHC. Methods: Through home visits and filling out a specific form, an active search for cases of genetic disease and/or birth defect was carried out in a random probabilistic sample, representative of a Family Health Unit in a Brazilian medium-sized county. Results: A total of 295 households were surveyed, totalling 1,160 individuals and 238 couples. The mean number of children per couple was 2.7, the inbreeding rate was 3.8% and the frequency of miscarriage was estimated in 8.7%. Twenty-nine individuals (2.5%) with congenital disorders, 11 (0.9%) with hearing impairment, 10 (0.9%) with mental disability, and 6 (0.5%) with significant visual deficits were identified. Neuropsychomotor developmental delay was presented in 8.8% of the children and teenagers. Twelve individuals (1%) had cancer and 9.6% reported a positive family history of cancer. Conclusion: PHC professionals are in a privileged position to identify and organize a care network for individuals with genetic diseases and/or birth defects. The systematic use of instruments that facilitate the recognition of risk factors and suspicious situations can be a useful strategy to be incorporated by PHC.

Genética na atenção primária à saúdeRev Bras Med Fam Comunidade. Rio de Janeiro, 2020 Jan-Dez; 15(42):23472INTRODUÇÃOEstima-se que existam cerca de 6 a 7 mil doenças genéticas diferentes e, embora a maior parte destas sejam individualmente raras, somadas, as doenças genéticas têm prevalência global estimada de 31,5 a 73,0 por 1.000 indivíduos.1 Doenças genéticas podem ser congênitas ou podem se manifestar ao longo da vida, impactando nas diferentes faixas etárias: alterações cromossômicas estão presentes em cerca de 50% dos abortamentos espontâneos de primeiro trimestre; entre recém-nascidos, 3 a 5% apresentam algum defeito congênito, determinado total ou parcialmente por fatores genéticos; deficiências físicas, intelectuais e sensoriais em crianças e jovens frequentemente fazem parte do quadro clínico de síndromes genéticas; nos adultos, aproximadamente 5 a 10% dos cânceres possuem forte componente genético hereditário.1,2 Doenças genéticas podem ser hereditárias, sendo transmitidas ao longo das gerações de uma família, ou não hereditárias, ocorrendo por "mutação de novo".2 São sabidamente fatores de risco para doenças genéticas idades materna e/ou paterna avançadas, consanguinidade e história familiar positiva para doenças genéticas previamente reconhecidas.2-5 Além destes, a exposição de gestantes a teratógenos é fator de risco para defeitos congênitos.6Problema: Aunque individualmente raras, las enfermedades genéticas combinadas tienen prevalencia general estimada de 31.5 a 73.0 por 1,000 individuos. Además, enfermedades genéticas y anomalías congénitas representan la segunda causa de mortalidad infantil en Brasil. Ante este escenario, se instituyó la Política Nacional de Atención Integral a Personas con Enfermedades Raras en el Sistema Único de Salud. Esta Política proporciona funciones específicas para Atención Primaria de Salud (APS) que incluyen diagnóstico precoz y mapeo de personas con o en riesgo de desarrollar enfermedades genéticas raras y/o anomalías congénitas para derivación regulada. Esta experiencia tuvo como objetivo colaborar con el desarrollo de métodos para el reconocimiento de individuos con o en riesgo de desarrollar enfermedades genéticas en la APS. Método: Mediante visitas domiciliarias y completando un formulario específico, se realizó búsqueda activa de casos de enfermedades genéticas y/o defectos congénitos en una muestra probabilística aleatoria, representativa de una Unidad de Salud Familiar en un municipio brasileño de tamaño mediano. Resultados: Se investigaron un total de 295 hogares, 1,160 personas y 238 parejas. El número promedio de hijos por pareja fue de 2.7, la frecuencia de consanguinidad 3.8% y el aborto espontáneo 8.7%. Se identificaron 29 personas (2.5%) con enfermedades congénitas, 11 (0.9%) con discapacidad auditiva, 10 (0.9%) con discapacidad mental y 6 (0.5%) con déficits visuales significativos. Se informó retraso psicomotor en 8.8% de los niños y adolescentes. Doce personas (1%) tenían cáncer y 9.6% reportaron antecedentes familiares de cáncer. Conclusión: Los profesionales de la APS están en posición privilegiada para identificar y organizar una red de atención para personas con enfermedades genéticas y/o defectos congénitos. El uso sistemático de instrumentos que facilitan el reconocimiento de factores de riesgo y situaciones sospechosas puede ser una estrategia útil para la APS.

Neurodevelopmental delay in normocephalic children with in utero exposure to Zika virus.

Neurodevelopment in 29 normocephalic children with in utero exposure to Zika virus (ZIKV) was evaluated by the Bayley Scales of Infant and Toddler Development-Third Edition. Ten (35%) infants presented neurodevelopment delay. Language, cognitive and motor delays were identified in 9 (31%), 4 (14%) and 1 (3%) infants, respectively. Children exposed to ZIKV in utero must undergo careful evaluations for the early detection of any neurodevelopment delays in order to implement prompt intervention.

Population medical genetics: translating science to the community.

Rare genetic disorders are currently in the spotlight due to the elevated number of different conditions and significant total number of affected patients. The study of these disorders is extremely helpful for the elucidation of physiological processes related with complex disorders. Isolated populations are instrumental for the study of genetic disorders, considering their homogeneity and high proportion of affected patients in a small geographic area. These favorable conditions lead to the creation of a new discipline, known as "population medical genetics", which integrates medical genetics, population genetics, epidemiological genetics and community genetics. In order to develop practical activities in this new discipline, the National Institute of Population Medical Genetics (INaGeMP) was created in 2008 in Brazil. INaGeMP has developed several tools and funded numerous research activities. In this review, we highlight three successful projects developed in the first 10 years of INaGeMP activities (2008-2018): a newborn screening pilot study for MPS VI in Northeast Brazil, the study of Machado-Joseph disease in Brazilian families with Azorian ancestry, and the high twinning rate in a small town in southern Brazil. The results of these projects in terms of scientific output and contributions to the affected communities highlight the success and importance of INaGeMP.

Mortality for Critical Congenital Heart Diseases and Associated Risk Factors in Newborns. A Cohort Study / Mortalidade para Cardiopatias Congênitas e Fatores de Risco Associados em Recém-Nascidos. Um Estudo de Coorte

Abstract Background: Congenital heart diseases are the most common type of congenital defects, and account for more deaths in the first year of life than any other condition, when infectious etiologies are ruled out. Objectives: To evaluate survival, and to identify risk factors in deaths in newborns with critical and/or complex congenital heart disease in the neonatal period. Methods: A cohort study, nested to a randomized case-control, was performed, considering the Confidence Interval of 95% (95% CI) and significance level of 5%, paired by gender of the newborn and maternal age. Case-finding, interviews, medical record analysis, clinical evaluation of pulse oximetry (heart test) and Doppler echocardiogram were performed, as well as survival analysis, and identification of death-related risk factors. Results: The risk factors found were newborns younger than 37 weeks (Relative Risk - RR: 2.89; 95% CI [1.49-5.56]; p = 0.0015), weight of less than 2,500 grams (RR: 2.33 [; 95% CI 1.26-4.29]; p = 0.0068), occurrence of twinning (RR: 11.96 [95% CI 1.43-99.85]; p = 0.022) and presence of comorbidity (RR: 2.27 [95% CI 1.58-3.26]; p < 0.0001). The incidence rate of mortality from congenital heart disease was 81 cases per 100,000 live births. The lethality attributed to critical congenital heart diseases was 64.7%, with proportional mortality of 12.0%. The survival rate at 28 days of life decreased by almost 70% in newborns with congenital heart disease. The main cause of death was cardiogenic shock. Conclusion: Preterm infants with low birth weight and comorbidities presented a higher risk of mortality related to congenital heart diseases. This cohort was extinguished very quickly, signaling the need for greater investment in assistance technology in populations with this profile.

Resumo Fundamento: As cardiopatias congênitas configuram o tipo mais comum de defeitos congênitos, sendo responsáveis por mais mortes no primeiro ano de vida do que em qualquer outra condição, quando etiologias infecciosas são excluídas. Objetivo: Avaliar a sobrevida e identificar os fatores de risco nos óbitos em recém-nascidos com cardiopatia congênita crítica e/ou complexa no período neonatal. Métodos: Realizou-se um estudo de coorte, aninhado a um caso-controle aleatorizado, considerando Intervalo de Confiança de 95% (IC95%) e nível de significância de 5%, pareado por sexo do recém-nascido e idade materna. Foram feitas buscas ativas de casos, entrevistas, análise de prontuário, avaliação clínica da oximetria de pulso (teste do coraçãozinho) e do ecoDopplercardiograma, bem como análise de sobrevida e identificação dos fatores de risco relacionados ao óbito. Resultados: Os fatores de risco encontrados foram recém-nascidos com menos de 37 semanas (Risco Relativo − RR: 2,89; IC95% 1,49-5,56; p = 0,0015), peso inferior a 2.500 g (RR: 2,33; IC95% 1,26-4,29; p = 0,0068), ocorrência de gemelaridade (RR: 11,96; IC95% 1,43-99,85; p = 0,022) e presença de comorbidade (RR: 2,27; IC95% 1,58-3,26; p < 0,0001). A taxa de incidência de mortalidade por cardiopatias congênitas foi de 81 casos por 100 mil nascidos vivos. A letalidade atribuída às cardiopatias congênitas críticas foi de 64,7%, com mortalidade proporcional de 12,0%. A taxa de sobrevida aos 28 dias de vida diminuiu em quase 70% nos recém-nascidos com cardiopatias congênitas. A principal causa de óbito foi o choque cardiogênico. Conclusão: Recém-nascidos prematuros, com baixo peso e presença de comorbidades apresentaram maior risco de mortalidade relacionada às cardiopatias congênitas. Esta coorte se extinguiu muito rapidamente, sinalizando para a necessidade de maior investimento em tecnologia assistencial em populações com este perfil.

Mortality for Critical Congenital Heart Diseases and Associated Risk Factors in Newborns. A Cohort Study.

BACKGROUND: Congenital heart diseases are the most common type of congenital defects, and account for more deaths in the first year of life than any other condition, when infectious etiologies are ruled out. OBJECTIVES: To evaluate survival, and to identify risk factors in deaths in newborns with critical and/or complex congenital heart disease in the neonatal period. METHODS: A cohort study, nested to a randomized case-control, was performed, considering the Confidence Interval of 95% (95% CI) and significance level of 5%, paired by gender of the newborn and maternal age. Case-finding, interviews, medical record analysis, clinical evaluation of pulse oximetry (heart test) and Doppler echocardiogram were performed, as well as survival analysis, and identification of death-related risk factors. RESULTS: The risk factors found were newborns younger than 37 weeks (Relative Risk - RR: 2.89; 95% CI [1.49-5.56]; p = 0.0015), weight of less than 2,500 grams (RR: 2.33 [; 95% CI 1.26-4.29]; p = 0.0068), occurrence of twinning (RR: 11.96 [95% CI 1.43-99.85]; p = 0.022) and presence of comorbidity (RR: 2.27 [95% CI 1.58-3.26]; p < 0.0001). The incidence rate of mortality from congenital heart disease was 81 cases per 100,000 live births. The lethality attributed to critical congenital heart diseases was 64.7%, with proportional mortality of 12.0%. The survival rate at 28 days of life decreased by almost 70% in newborns with congenital heart disease. The main cause of death was cardiogenic shock. CONCLUSION: Preterm infants with low birth weight and comorbidities presented a higher risk of mortality related to congenital heart diseases. This cohort was extinguished very quickly, signaling the need for greater investment in assistance technology in populations with this profile.

Mutation screening in the genes PAX-8, NKX2-5, TSH-R, HES-1 in cohort of 63 Brazilian children with thyroid dysgenesis.

OBJECTIVE: To evaluate the candidate genes PAX-8, NKX2-5, TSH-R and HES-1 in 63 confirmed cases of thyroid dysgenesis. SUBJECTS AND METHODS: Characterization of patients with congenital hypothyroidism into specific subtypes of thyroid dysgenesis with hormone levels (TT4 and TSH), thyroid ultrasound and scintigraphy. DNA was extracted from peripheral blood leukocytes and the genetic analysis was realized by investigating the presence of mutations in the transcription factor genes involved in thyroid development. RESULTS: No mutations were detected in any of the candidate genes. In situ thyroid gland represented 71.1% of all cases of permanent primary congenital hypothyroidism, followed by hypoplasia (9.6%), ectopia (78%), hemiagenesis (6.0%) and agenesis (5.5%). The highest neonatal screening TSH levels were in the agenesis group (p < 0.001). CONCLUSIONS: Thyroid dysgenesis is possibly a polygenic disorder and epigenetic factors could to be implicated in these pathogeneses.

Diagnosis of Atelosteogenesis Type I suggested by Fetal Ultrasonography and Atypical Paternal Phenotype with Mosaicism.

Atelosteogenesis type I (AOI) is an autosomal dominant skeletal dysplasia caused by mutations in the filaminB (FLNB) gene with classic and well-recognizable clinical findings. However, parents affected with a mild phenotype, probably with somatic mosaicism, can generate offspring with a much more severe phenotype of AOI. In the present report, we describe a female newborn with classic AOI leading to early neonatal death, whose diagnostic was based on prenatal radiological findings and on the physical examination of the father. Since her father had limb deformities and corporal asymmetry, suggesting somatic mosaicism, his biological samples were analyzed through a gene panel for skeletal dysplasias. A missense mutation not previously described in the literature was detected in the FLNB gene, affecting ∼ 20% of the evaluated cells and, therefore, confirming the diagnosis of mosaic AOI in the father. The molecular analysis of the father was crucial to suggest the diagnosis of AOI in the newborn, since she died early and there were no biological samples available.

A atelosteogênese tipo I (AOI) é uma displasia esquelética autossômica dominante causada por mutações no gene filamina B (FLNB) com achados clínicos clássicos e bem reconhecíveis. No entanto, pais afetados com um fenótipo mais leve, provavelmente com mosaicismo somático, podem gerar uma prole com um fenótipo muito mais grave de AOI. No presente relato, descrevemos um recém-nascido do sexo feminino com AOI clássica, que levou à morte neonatal precoce, e cujo diagnóstico foi baseado em achados radiológicos pré-natais e no exame físico de seu genitor. Como o genitor apresentava deformidades em membros e assimetria corporal, que sugeriam mosaicismo somático, suas amostras biológicas foram analisadas por meio de um painel de genes para displasias esqueléticas. Uma mutação missense, não descrita anteriormente na literatura, foi detectada no gene FLNB, afetando ∼ 20% das células avaliadas, e, portanto, confirmando o diagnóstico de AOI em mosaico no genitor. A análise molecular realizada no genitor foi fundamental para sugerir o diagnóstico de AOI na recém-nascida, uma vez que esta morreu precocemente, e não havia amostras biológicas disponíveis.