Browsing by Author "Ramos, Fabiana"
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- Congenital adrenal hyperplasia in paediatric age: molecular analysis of the CYP21A2 gene and implications for genetic counsellingPublication . Gomes, Susana; Silva, Júlia; Pereira-Caetano, Iris; Lopes, Lurdes; Limbert, Catarina; Amaral, Daniela; Pina, Rosa; Kay, Teresa; Sampaio, Lurdes; Pereira, Carla; Moldovan, Oana; Berta, Ana; Rebelo, Irene; Gaspar, Isabel; Cidade Rodrigues, José; Lina, Ramos; Ramos, Fabiana; Dinis, Isabel; Cardoso, Rita; Mirante, Alice; Gonçalves, JoãoIntroduction: 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.
- CYP21A2 gene mutations, its nature and frequency in a paediatric Portuguese cohort with congenital adrenal hyperplasiaPublication . Rosmaninho-Salgado, Joana; Caetano, Joana Serra; Gomes, Susana; Pereira-Caetano, Iris; Cardoso, Rita; Dinis, Isabel; Ramos, Lina; Ramos, Fabiana; Carvalho, Ana Luisa; Garabal, Ana; Sá, Joaquim; Maia, Sofia; Sousa, Sérgio; Saraiva, Jorge; Gonçalves, João; Mirante, AliceIntroduction: The most common cause of congenital adrenal hyperplasia (CAH) is 21-hydroxylase deficiency (21-OHD) caused by alterations in CYP21A2 gene. The clinical phenotypes of this autosomal recessive disease are classified as classic (saltwasting and simple virilizing) and non-classic forms of CAH. The severity of the disease is directly related with the impairment of the 21-OH enzymatic activity. Genetic testing can confirm the disease and is crucial for familial studies and genetic counseling. Aim: The aim of this work was to perform the clinical and molecular characterization of the patients observed at the Hospital Pediátrico de Coimbra (Portugal) with the clinical suspecion of CAH. Methods: Retrospective analysis of patient medical records of all cases observed in our hospital with suspicion of CAH and detailed literature comparison. CYP21A2 molecular analysis had been performed in 81 unrelated Portuguese patients (51 female, 30 males) with clinical and endocrine laboratorial findings suggestive of CAH, using mini-sequencing, restriction enzyme digestion, Sanger sequencing or/and multiplex ligation-dependent probe amplification (MLPA). Results: CYP21A2 variants were identified in 74/81 (91%) of the patients. Homozygosity for CYP21A2 was found in 39.2% (29/74) of the patients while 55.4% (41/74) were compound heterozygous and, in 5.4% of the cases (4/74), only one pathogenic variant was identified. The most frequent alterations were p.Val281Leu, g.655A/C>G (splicing variant) and p.Ile172Asn, that account for more than 50% of the alleles of this patient’s cohort. All variants were already described except a novel missense variant identified in a salt-wasting patient, g.1173T>C(p.Trp201Arg). The rare variant p.Gly424Ser which was detected in one patient had been previously associated with a possible founder effect in Brazil and the splicing variant g.391G>A, only described in the Portuguese population. Conclusion: Our study provides a detailed clinical and molecular characterization of a large cohort of CAH Portuguese patients. The overall concordance between the clinical phenotype and the inferred phenotype (based on genotype) was 90%.
- Espectro de alterações moleculares detetadas no gene CYP21A2 associadas a deficiência em 21 hidroxilasePublication . Gomes, Susana; Pereira-Caetano, Iris; Lopes, Maria Lurdes; Limbert, Catarina; Amaral, Daniela; Pina, Rosa; Antunes, Diana; Carvalho, Inês; Kay, Teresa; Sampaio, Lurdes; Pereira, Carla; Moldovan, Oana; Berta, Ana; Rebelo, Irene; Gaspar, Isabel; Cardoso, Helena; Rodrigues, José Cidade; Ramos, Lina; Ramos, Fabiana; Dinis, Isabel; Cardoso, Rita; Mirante, Alice; Gonçalves, JoãoA maioria dos doentes com hiperplasia suprarrenal congénita (HSC) apresenta alterações moleculares no gene CYP21A2, o qual codifica a enzima 21-hidroxilase (21-OH). Os doentes com a forma clássica de deficiência em 21-OH (21-OHD) apresentam a síntese de cortisol diminuída no córtex adrenal e, os casos mais graves, também apresentam deficiência de aldosterona. As mulheres com 21-OHD grave apresentam excesso de andrógenos desde a sua vida fetal conduzindo à virilização dos órgãos genitais externos. Tanto homens como mulheres com 21-OHD completa não sintetizam a aldosterona e, consequentemente, logo após o nascimento, podem desenvolver crises de perda de sal se não forem corretamente diagnosticados e tratados. A 21- OHD não clássica é devida à deficiência parcial em 21-OH, os fenótipos clínicos são menos graves, as mulheres não apresentam virilização dos genitais externos ao nascimento, e geralmente os sinais relativos a excesso de androgénios podem surgir durante a infância ou até mais tarde (durante ou após a puberdade). Neste trabalho descrevem-se as alterações e os genótipos mais frequentes encontrados em doentes portugueses não adultos com 21-OHD. As alterações mais frequentes encontradas na forma clássica da HSC são c.293-13C> G, diferentes deleções/quimeras/conversões génicas do gene CYP21A2 e c.518T> A, enquanto na 21-OHD não-clássica a variante c.844G> T é a mais frequente. Estes resultados contribuem para um diagnóstico correto e uma melhor gestão clínica dos doentes, para o seu aconselhamento genético e para oferecer o diagnóstico pré-natal a casais com risco de ter filhos afetados com a forma clássica de 21-OHD.
- Koolen-de Vries syndrome – National Case Series with clinical and molecular characterizationPublication . Soares, Marta P.; Rodrigues, Márcia; Dupont, Juliette; Medeira, Ana; Freixo, João; Nunes, Sofia; Cordeiro, Isabel; Travessa, André; Soares, Gabriela; Fortuna, Ana; Ramos, Fabiana; Sá, Joaquim; Rocha, Susana; Figueiredo, Cristina; Mendonça, Carla; Tapadinhas, Fernando; Silveira-Santos, Rosário; Custódio, Sónia; Barreta, Ana; Serafim, Sílvia; Correia, Hildeberto; Val, Mariana; Carreira, Isabel M.; Rendeiro, Paula; Sousa, Ana; Sousa, Ana BertaIntroduction: Koolen-de Vries Syndrome (KdVS) is a rare genetic condition, caused by a 17q21.31 microdeletion, or a pathogenic variant in KANSL1 gene. The clinical picture includes developmental delay (DD)/intellectual disability (ID) with expressive language particularly impaired, dysmorphisms, neonatal hypotonia, and friendly behaviour. Aim: To characterize at the molecular and clinical levels all patients in Portugal diagnosed with KdVS.