The Natural History and Genotype-Phenotype Nonconcordance of HLA Identical Siblings with the Same Mutations of the 21-Hydroxylase Gene

Abstract

The correlation of genotype to phenotype in congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency has been investigated thoroughly since the mapping of the CYP21 gene to the short arm of chromosome 6. In most instances, it is possible to accurately predict the phenotype based on genoytpe; however, in a small number of patients, individuals with identical mutations demonstrate variable phenotypes. We report two HLA-identical brothers who represent a striking case of genotype-phenotype nonconcordance in CAH. Molecular genetic analysis showed both patients had mutations in intron 2 and exon 10 of CYP21. Both brothers underwent salt-deprivation tests at similar ages over three separate hospital admissions. Patient 1 was diagnosed with simple virilizing CAH and was able to maintain sodium balance during salt deprivation tests. Patient 2, 3 years younger, was diagnosed with salt-wasting CAH and was unable to maintain sodium balance but progressively increased his aldosterone secretion with age.