RESUMO
Abstract Objective: The classic triad, which defines IFAP syndrome, is ichthyosis follicularis, alopecia, and photophobia. It is a rare X-linked genetic disorder characterized by multiple congenital anomalies with variable severity, caused by pathogenic variants in the MBTPS2 gene, which encodes a zinc metalloprotease that is essential for normal development. This study aimed to report a case of a Brazilian patient with IFAP syndrome presenting skeletal anomalies, which is a rare finding among patients from different families. Case description: We describe a male proband with IFAP syndrome showing severe ichthyosis congenita, cryptorchidism, limb malformation, and comprising the BRESHECK syndrome features. Using whole-exome sequencing, we identified a rare missense variant in hemizygosity in the MBTPS2 gene, which had not been identified in other family members. Comments: This is the first diagnosis of IFAP syndrome in Brazil with a molecular investigation. The present case study thus expands our knowledge on the mutational spectrum of MBPTS2 associated with IFAP syndrome.
RESUMO Objetivo: A clássica tríade de ictiose folicular, alopecia e fotofobia dá nome a uma síndrome rara de origem genética com herança ligada ao cromossomo X (síndrome IFAP, do inglês Ichthyosis Follicularis, Alopecia, and Photophobia). Esta é uma síndrome caracterizada por múltiplas anomalias congênitas de expressividade variável, causada por variantes patogênicas no gene MBTPS2, que codifica uma zinco-metaloprotease essencial para o desenvolvimento normal humano. O objetivo deste estudo é apresentar o relato de caso de um paciente brasileiro com síndrome IFAP que apresentou anomalias esqueléticas, um achado raro entre os pacientes de diferentes famílias. Descrição do caso: Apresentamos um probando do sexo masculino com síndrome IFAP, com ictiose congênita grave, criptorquidia, malformação de membros e as características da síndrome de BRESHECK. Por meio do sequenciamento do exoma completo, identificamos uma variante rara do tipo missense, em hemizigose, no gene MBTPS2, não identificada em outros membros da família. Comentários: Este é o primeiro diagnóstico de síndrome IFAP no Brasil com investigação molecular. A análise molecular e a descrição de uma variante rara no gene MBPTS2 expandem nosso conhecimento sobre o espectro mutacional desse gene associado à síndrome IFAP.
RESUMO
Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20) and delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic density protein PSD-95. We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics.
Assuntos
Proteínas ADAM , Encefalopatias , Epilepsia Resistente a Medicamentos , Proteínas do Tecido Nervoso , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Atrofia , Encefalopatias/genética , Proteína 4 Homóloga a Disks-Large , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismoRESUMO
ABSTRACT Objective: For every 100 random children diagnosed with autism, at least 20 have morphological abnormalities, often associated with syndromes. Brazil does not have a standardized and validated instrument for morphological physical examination. This study aimed to translate into Brazilian Portuguese and culturally adapt the clinical signs described in the Autism Dysmorphology Measure, as well as validate the instrument in a sample of children with autism. Methods: The original instrument was translated, culturally adapted, and published in full, following traditional procedures for translation, back-translation, and terminology adaptation according to the Nomina Anatomica. The sample included 62 children from a published multicenter study, with intelligence quotient between 50-69, of both genders, with chronological age between 3-6 years. Two clinical geneticists performed the morphological physical examination, which consisted of investigating 82 characteristics assessing 12 body areas. We used Cohen's Kappa coefficient to evaluate the agreement between the two observers. Results: The final version of the instrument - translated into Brazilian Portuguese and culturally adapted - showed high agreement between the two observers. Conclusions: The translated instrument meets all international criteria, and minor anomalies and their clinical descriptions were standardized and are recognizable for physicians not specialized in genetics.
RESUMO Objetivo: Entre 100 crianças, não selecionadas, com diagnóstico de autismo, pelo menos 20 apresentam anomalias morfológicas, quase sempre associadas a síndromes. Não há no Brasil instrumento de exame físico morfológico padronizado e validado. O objetivo foi traduzir para o português do Brasil e adaptar culturalmente os sinais clínicos descritos no Autism Dysmorphology Measure, assim como procurar evidências de validade quando aplicado a uma amostra de crianças com autismo. Métodos: Foram feitas a tradução e a adaptação cultural do instrumento original, publicado na íntegra. Foram adotados os procedimentos tradicionais de tradução, retrotradução e adaptação da terminologia segundo a Nomina Anatomica. Foram incluídas na amostra 62 crianças com quociente de inteligência entre 50 e 69, de ambos os sexos, com idade cronológica entre três e seis anos, provenientes de estudo multicêntrico com os procedimentos metodológicos já publicados. O exame físico morfológico foi realizado por dois médicos geneticistas e consistiu na pesquisa de 82 características que avaliam 12 áreas corporais. Para avaliar a concordância entre os dois observadores foi utilizado o coeficiente Kappa de Cohen. Resultados: A versão final do instrumento traduzido e adaptado culturalmente ao português do Brasil mostrou alta concordância entre os dois observadores. Conclusões: O instrumento traduzido preenche todos os critérios propostos internacionalmente e o reconhecimento das anomalias menores e sua descrição clínica estão padronizados e são de fácil reconhecimento aos médicos não especialistas em genética.
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Humanos , Masculino , Feminino , Pré-Escolar , Criança , Exame Físico/métodos , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/genética , Adaptação Psicológica/fisiologia , Transtorno do Espectro Autista/psicologia , Traduções , Brasil/epidemiologia , Inquéritos e Questionários , Reprodutibilidade dos Testes , Características Culturais , Transtornos Dismórficos Corporais/psicologia , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/genéticaRESUMO
Abstract Objective: To establish the frequency of 82 morphological features in a sample of Brazilian children (between 3 and 13 years old), to understand the influence of age, gender, and ethnicity. Methods: This was a cross-sectional study that evaluated 239 children with typical development (between 3 and 13 years old) regarding the presence of 82 morphological characteristics. A previously described protocol, based on the London Dysmorphology Database, was applied to evaluate the sample. This protocol was culturally adapted to Brazilian Portuguese. Results: The frequency of 82 morphological characteristics was established in the sample; of 82 characteristics, 50% were considered morphological anomalies (frequency less than 4%). At least 25% of the sample presented more than one minor morphological anomaly. Age was shown to influence the frequency of the following morphological characteristics: widow's peak, prominent antihelix, prominent upper lip, irregular or crowded teeth, and clinodactyly, but had no influence on the frequency of minor morphological anomalies. Gender influenced dysplastic ears and attached earlobe, but had no influence on the frequency of minor morphological anomalies; ethnicity showed influence on camptodactyly and prominent antihelix. A statistically significant divergence was observed regarding 43 of the 73 morphological characteristics that could be compared with literature data (58.9%). Conclusions: The study determined the frequency of 82 morphological characteristics in 239 children with typical development. Age was the variable that showed more influence on the frequency of morphological characteristics, and comparison with literature data showed that the frequency depends on variables such as age and ethnicity.
Resumo Objetivo: Estabelecer a frequência de 82 características morfológicas em uma amostra de crianças brasileiras (entre três e 13 anos), para entender a influência da idade, do sexo e da etnia. Métodos: Estudo transversal. Avaliamos 239 crianças com desenvolvimento típico (entre três e 13 anos), em relação à presença de 82 características morfológicas. Aplicamos um protocolo descrito anteriormente, baseado no London Dysmorphology Database, para avaliar nossa amostra. Esse protocolo foi culturalmente adaptado ao português do Brasil. Resultados: A frequência de 82 características morfológicas foi estabelecida em nossa amostra; de 82 características, 50% foram consideradas anomalias morfológicas (frequência inferior a 4%). Pelo menos 25% da nossa amostra apresentaram mais de uma anomalia morfológica menor. A idade mostrou influência na frequência das seguintes características morfológicas: "bico de viúva", "anti-hélice proeminente", "lábio superior proeminente", "dentes irregulares ou encavalados" e "clinodactilia", mas não teve influência na frequência de anomalias morfológicas menores. O sexo mostrou influência nas seguintes características: "orelhas displásicas" e "lóbulo da orelha aderente", mas não teve influência na frequência de anomalias morfológicas menores; a etnia mostrou influência na "camptodactilia" e "anti-hélice proeminente". Houve divergência (estatisticamente significativa) em 43 características morfológicas de 73 que pudemos comparar com os dados da literatura (58,9%). Conclusões: Estabelecemos a frequência de 82 características morfológicas em 239 crianças com desenvolvimento típico. A idade foi a variável que mostrou maior influência na frequência de características morfológicas e a comparação com dados da literatura mostrou que a frequência depende de variáveis como idade e etnia.
Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Variação Anatômica , Brasil , Fatores Sexuais , Estudos TransversaisRESUMO
OBJECTIVE: To establish the frequency of 82 morphological features in a sample of Brazilian children (between 3 and 13 years old), to understand the influence of age, gender, and ethnicity. METHODS: This was a cross-sectional study that evaluated 239 children with typical development (between 3 and 13 years old) regarding the presence of 82 morphological characteristics. A previously described protocol, based on the London Dysmorphology Database, was applied to evaluate the sample. This protocol was culturally adapted to Brazilian Portuguese. RESULTS: The frequency of 82 morphological characteristics was established in the sample; of 82 characteristics, 50% were considered morphological anomalies (frequency less than 4%). At least 25% of the sample presented more than one minor morphological anomaly. Age was shown to influence the frequency of the following morphological characteristics: widow's peak, prominent antihelix, prominent upper lip, irregular or crowded teeth, and clinodactyly, but had no influence on the frequency of minor morphological anomalies. Gender influenced dysplastic ears and attached earlobe, but had no influence on the frequency of minor morphological anomalies; ethnicity showed influence on camptodactyly and prominent antihelix. A statistically significant divergence was observed regarding 43 of the 73 morphological characteristics that could be compared with literature data (58.9%). CONCLUSIONS: The study determined the frequency of 82 morphological characteristics in 239 children with typical development. Age was the variable that showed more influence on the frequency of morphological characteristics, and comparison with literature data showed that the frequency depends on variables such as age and ethnicity.
Assuntos
Variação Anatômica , Adolescente , Brasil , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Masculino , Fatores SexuaisRESUMO
BACKGROUND: Pycnodysostosis is an autosomal recessive skeletal dysplasia, the prevalence of which is estimated to be low (1 per million). Nevertheless, in recent years we have found 27 affected individuals from 22 families in Ceará State, a region of the Brazilian Northeast, giving a local prevalence of 3 per million. This local prevalence associated with a high parental consanguinity, suggesting a possible founder effect, prompted us to perform a molecular investigation of these families to test this hypothesis. METHODS: The CTSK gene was sequenced by the Sanger method in the patients and their parents. In addition to 18 families from Ceará, this study also included 15 families from other Brazilian regions. We also investigated the origin of each family from the birthplace of the parents and/or grandparents. RESULTS: We have studied 39 patients, including 33 probands and 6 sibs, from 33 families with pycnodysostosis and identified six mutations, five previously described (c.436G>C, c.580G>A, c.721C>T, c.830C>T and c.953G>A) and one novel frameshift (c.83dupT). This frameshift variant seems to have a single origin in Ceará State, since the haplotype study using the polymorphic markers D1S2344, D1S442, D1S498 and D1S2715 suggested a common origin. Most of the mutations were found in homozygosity in the patients from Ceará (83.3 %) while in other states the mutations were found in homozygosity in half of patients. We have also shown that most of the families currently living outside of Ceará have northeastern ancestors, suggesting a dispersion of these mutations from the Brazilian Northeast. CONCLUSIONS: The high frequency of pycnodysostosis in Ceará State is the consequence of the high inbreeding in that region. Several mutations, probably introduced a long time ago in Ceará, must have spread due to consanguineous marriages and internal population migration. However, the novel mutation seems to have a single origin in Ceará, suggestive of a founder effect.