DGH - Posters/abstracts em congressos internacionais
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Browsing DGH - Posters/abstracts em congressos internacionais by Subject "21-Hydroxylase"
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- Molecular characterization of a new CYP21A2 allele and classification of its pathogenicityPublication . Gomes, Susana; Saraiva, Jorge; Gonçalves, JoãoBackground: The CYP21A2 gene, coding for 21-Hydroxylase (21-OH), is located on 6p21.3 within the major histocompatibility complex, and integrated in a cluster of genes (RP1, C4A, C4B, TNXB) and pseudogenes (RP2, CYP21A1P, TNXA). This genomic region is variable in size and gene copy number. Due to the high homology between genes and their pseudogenes, recombination is common, deletions, insertions and duplications are frequent. The great diversity of this cluster and rare alleles contributes to additional difficulties on molecular analysis and pathogenicity classification. Methods: The CYP21A cluster was characterized using genomic DNA obtained from four healthy brothers (parents not available). Two long-PCR products, specific for each CYP21A2 copy of a trimodular allele (with two CYP21A2 copies), and for a normal/bimodular allele present in this family, were characterized by Sanger cycling sequencing and MLPA (MRC-Holland, P050-C1 kit). Results: The molecular studies revealed that one sister, who asked for genetic counselling, has a very rare trimodular allele, with two CYP21A2 genes. One of these genes has a deletion covering exons 4 to 7 and an insertion of exons 4 to 7 of the pseudogene (CYP21A1P) which has the pathogenic variants c.518T>A, c.710T>A, c.713T>A, c.719T>A, c.844G>T and c.923dupT, all in phase. This alteration can be described as: CYP21A2ex4_7delinsCYP21A1Pex4_7. Conclusion: The developed molecular approach, which was specifically designed for this family and included segregation analysis of all brothers, allowed the characterization of a new CYP21A2 trimodular allele that, even containing six pathogenic variants, is non-pathogenic as it also has (in phase) a normal CYP21A2 copy.
- Nonclassic Congenital Adrenal Hyperplasia (NCCAH) Due to 21-Hydroxylase Deficiency: Clinical Management and Genetic Counseling of Two Portuguese FamiliesPublication . Lurdes de Matos, Maria; Antunes, Diana; Gonçalves, João; Lopes, Lurdes; Kay, TeresaIntroduction: Congenital adrenal hyperplasia (CAH) due to 21-Hydroxylase deficiency occurs in 90-95% of cases, being a common autosomal recessive condition that can present with a wide range of hyperandrogenemic signs in childhood or adulthood. Severity of this disease is correlated with the enzymatic blockade of 21-Hydroxylase which depends of the mutation in gene CYP21A2. Two clinical forms are possible: classic, subdivided in salt-wasting and simple virilizing form (severe) and nonclassic or late onset (less severe). Aims: We studied two portuguese families with NCCAH due to 21-Hidroxilase deficiency in order to improve clinical management and genetic counseling of their members. Methods: Clinical presentation and hormonal assays (including test of tetracosactide) were performed in index cases (IC) . Genomic DNA of each family member was sequenced for the 9 most frequent mutations in CYP21A2. Total deletion of CYP21A , conversion in non functioning CYP21A1P or CYP21A1P_ CYP21A2 quimeras were also analyzed by enzymatic restriction. Results: Family 1- IC: Female, 31 years old with NCCAH diagnosed at age 6 , after investigation of precocious pubarche and with test of tetracosactide positive (17-alpha hydroxyprogesterone levels > 10-15 ng/ml) . Molecular study of CYP21A2 showed a mutation g.1683G> T , homozygous , in CYP21A2 and a non functioning allele of CYP21A2 , heterozygous (non severe 21-Hidroxilase deficiency). Mother was carrying a non functioning allele of CYP21A2 , heterozygous (severe); Father, Brother and Partner were heterozygous for mutation g.1683G> T (non severe). Family 2- IC: Female, 45 years old presenting hirsutism and oligoamenorrhea at age 35 and with test of tetracosactide positive confirming NCCAH Genetic study identified mutation g.1683G> T (less severe) in a copy and g.655A/C>G in another copy (splicing mutation severe). Familial genetic study identified two sisters (age 36 and age 40), asymptomatic but with pathologic genotype confirming NCCAH.