1 - Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge;
2 - Unidade de Endocrinologia Pediátrica; Hospital de D. Estefânia; Área da Mulher, Criança e Adolescente; Centro Hospitalar Universitário de Lisboa Central, EPE;
3 - Serviço de Genética Médica; Hospital de D. Estefânia; Área da Mulher, Criança e Adolescente; Centro Hospitalar Universitário de Lisboa Central, EPE;
4 - Unidade de Endocrinologia Pediátrica; Hospital de D. Estefânia; Área da Mulher, Criança e Adolescente; Centro Hospitalar Universitário de Lisboa Central, EPE;
5 - Serviço de Genética Médica, Departamento de Pediatria, Hospital de Santa Maria; Centro Hospitalar Universitário Lisboa Norte;
6 - Serviço de Pediatria, Hospital S. Francisco Xavier; Centro ;
7 - Serviço de Genética Médica, Hospital Egas Moniz, Lisboa;
8 - Serviço de Cirurgia Pediátrica, Hospital de Santo António, Porto;
9 - Serviço de Genética Médica,
10 - Serviço de Endocrinologia Pediátrica, Centro Hospitalar e Universitário de Coimbra, Coimbra;
11 - ToxOmics - Centro de Toxicogenómica e Saúde Humana; Nova Medical School; Lisboa; Portugal.
This work was partially funded by Project: UID/BIM/0009/2016 from Fundação para a Ciência e a Tecnologia, Lisboa, Portugal.
- 52nd European Human Genetics Conference.
Introduction: Congenital adrenal hyperplasia(CAH) is due to 21-hidroxilase deficiency(21-OHD) in about 95% of the cases. 21-OH is encoded by CYP21A2 gene, and most frequent mutations occurring in CYP21A2 are due to gene conversions originated from its pseudogene(CYP21A1P). The clinical severity of CAH is associated with the impairment of 21-OH activity, which is directly related with the molecular defect. CAH is classified as classic salt-wasting(SW) and simple virilising(SV) forms, and nonclassic(NC) form of the disease. SW and SV are usually diagnosed after birth or during the first years of life, respectively, while most cases of NC-CAH are diagnosed during infancy, puberty or until adult age. Here we present the molecular results performed in paediatric patients with CAH.
Methodology: molecular analysis (using genomic DNA) included mini-sequencing, restriction enzyme digestion, Sanger sequencing, Southern-blotting and/or multiplex ligation-dependent probe amplification(MLPA).
Results: We analysed 265 patients with CAH (65 with SW, 51 with SV and 149 with NC). In 211 patients (80%) the genotypes were in agreement with their phenotypes, while in the remaining 20%, only one pathogenic allele was identified or their genotype was normal. In the SW group the most frequent variant was the splicing mutation g.655A>G(28.5%), in the SV was g.999T>A(25.5%), and in NC was g.1683G>T(61%).
Conclusions: Knowing the molecular bases of CAH is essential for a correct genetic counselling; prenatal diagnosis and treatment during pregnancy can be offered to couples at risk of having a female child with SW or SV in order to avoid sexual ambiguity of the newborns.
Palavras Chave: Congenital adrenal hyperplasia; CYP21A2; molecular amalysis.