Rita Santos-Silva1, Rita Cardoso2, Lurdes Lopes3, Marcelo Fonseca4, Filipa Espada4, Lurdes Sampaio5, Carla Brandão6, Ana Antunes7, Graciete Bragança8, Raquel Coelho8, Teresa Bernardo9, Paula Vieira10, Rita Morais10, Ana Luísa Leite11, Luís Ribeiro12, Berta Carvalho13, Ana Grangeia14, Renata Oliveira14, Maria João Oliveira15, Vicente Rey16, Joana Rosmaninho-Salgado17, Bernardo Marques18, Ana Margarida Garcia19, Andreia Meireles20, Joana Carvalho20, Ana Sequeira21, Alice Mirante2, Teresa Borges15. 1. Department of Pediatric Endocrinology,<bold></bold> Centro Hospitalar Universitário de S. João, Porto, Portugal, ritasantossilva@gmail.com. 2. Department of Pediatric Endocrinology, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal. 3. Department of Pediatric Endocrinology, Hospital D. Estefânia, Lisboa, Portugal. 4. Department of Pediatric Endocrinology, Unidade Local de Saúde de Matosinhos, Matosinhos, Portugal. 5. Department of Pediatric Endocrinology, Centro Hospitalar de Lisboa Norte, Lisboa, Portugal. 6. Department of Pediatrics, Centro Hospitalar do Tâmega e Vouga, Penafiel, Portugal. 7. Department of Pediatric Endocrinology, Hospital de Braga, Braga, Portugal. 8. Department of Pediatric Endocrinology, Hospital Fernando Fonseca, Lisboa, Portugal. 9. Department of Pediatrics, Unidade Local de Saúde do Alto Minho, Viana do Castelo, Portugal. 10. Department of Pediatrics, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal. 11. Department of Pediatric Endocrinology, Centro Hospitalar de Vila Nova Gaia e Espinho, Vila Nova de Gaia, Portugal. 12. Department of Pediatrics, Unidade Local de Saúde do Nordeste, Bragança, Portugal. 13. Genetics Unit, Department of Pathology, Oporto Medical School, Porto, Portugal. 14. Department of Medical Genetics, Centro Hospitalar Universitário de S. João, Porto, Portugal. 15. Department of Pediatric Endocrinology, Centro Materno-infantil do Norte, Porto, Portugal. 16. Department of Pediatrics,<bold></bold> Centro Hospitalar Universitário de S. João, Porto, Portugal. 17. Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal. 18. Department of Endocrinology, Instituto Português de Oncologia de Coimbra Francisco Gentil, Coimbra, Portugal. 19. Department of Pediatrics, Hospital D. Estefânia, Lisboa, Portugal. 20. Department of Pediatrics, Unidade Local de Saúde de Matosinhos, Matosinhos, Portugal. 21. Department of Pediatrics, Centro Hospitalar de Lisboa Norte, Lisboa, Portugal.
Abstract
BACKGROUND: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder characterized by 3 overlapping phenotypes: salt-wasting (SW), simple virilizing (SV), and non-classic (NC). We aimed at conducting a nationwide genotype description of the CAH pediatric patients and to establish their genotype-phenotype correlation. METHODS: CAH patients were recruited from Portuguese pediatric endocrinology centers and classified as SW, SV, or NC. Genetic analysis was performed by polymerase chain reaction (sequence specific primer, restriction fragment length polymorphism) or direct Sanger sequencing. Genotypes were categorized into 4 groups (0, A, B, and C), according to their predicted enzymatic activity. In each group, the expected phenotype was compared to the observed phenotype to assess the genotype-phenotype correlation. RESULTS: Our cohort comprises 212 unrelated pediatric CAH patients (29% SW, 11% SV, 60% NC). The most common pathogenic variant was p.(Val282Leu; 41.3% of the 424 alleles analyzed). The p.(Val282Leu) variant, together with c.293-13A/C>G, p.(Ile173Asn), p.(Leu308Thr), p.(Gln319*), and large deletions/conversions were responsible for 86.4% of the mutated alleles. Patients' stratification by disease subtype revealed that the most frequent pathogenic variants were c.293-13A/C>G in SW (31.1%), p.(Ile173Asn) in SV (46.9%), and p.(Val282Leu) in NC (69.5%). The most common genotype was homozygosity for p.(Val282Leu; 33.0%). Moreover, we found 2 novel variants: p.(Ile161Thr) and p.(Trp202Arg), in exons 4 and 5, respectively. The global genotype-phenotype correlation was 92.4%. Group B (associated with the SV form) showed the lowest genotype-phenotype correlation (80%). CONCLUSION: Our cohort has one of the largest NC CAH pediatric populations described. We emphasize the high frequency of the p.(Val282Leu) variant and the very high genotype-phenotype correlation observed.
BACKGROUND:Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder characterized by 3 overlapping phenotypes: salt-wasting (SW), simple virilizing (SV), and non-classic (NC). We aimed at conducting a nationwide genotype description of the CAH pediatric patients and to establish their genotype-phenotype correlation. METHODS: CAH patients were recruited from Portuguese pediatric endocrinology centers and classified as SW, SV, or NC. Genetic analysis was performed by polymerase chain reaction (sequence specific primer, restriction fragment length polymorphism) or direct Sanger sequencing. Genotypes were categorized into 4 groups (0, A, B, and C), according to their predicted enzymatic activity. In each group, the expected phenotype was compared to the observed phenotype to assess the genotype-phenotype correlation. RESULTS: Our cohort comprises 212 unrelated pediatric CAH patients (29% SW, 11% SV, 60% NC). The most common pathogenic variant was p.(Val282Leu; 41.3% of the 424 alleles analyzed). The p.(Val282Leu) variant, together with c.293-13A/C>G, p.(Ile173Asn), p.(Leu308Thr), p.(Gln319*), and large deletions/conversions were responsible for 86.4% of the mutated alleles. Patients' stratification by disease subtype revealed that the most frequent pathogenic variants were c.293-13A/C>G in SW (31.1%), p.(Ile173Asn) in SV (46.9%), and p.(Val282Leu) in NC (69.5%). The most common genotype was homozygosity for p.(Val282Leu; 33.0%). Moreover, we found 2 novel variants: p.(Ile161Thr) and p.(Trp202Arg), in exons 4 and 5, respectively. The global genotype-phenotype correlation was 92.4%. Group B (associated with the SV form) showed the lowest genotype-phenotype correlation (80%). CONCLUSION: Our cohort has one of the largest NC CAH pediatric populations described. We emphasize the high frequency of the p.(Val282Leu) variant and the very high genotype-phenotype correlation observed.