Salt-Losing 21-Hydroxylase Deficiency Caused by Double Homozygosity for Two "mild" Mutations

Abstract

Context: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency presents with different severities that correlate with the genotype. The salt-losing phenotype requires 2 alleles with "severe"mutations. Case Description: We present a case of salt-losing 21-hydroxylase deficiency that was found to be homozygous for 2 "mild"pathogenic variants: V281L and S301Y. Both in silico and heterologous expression functional analysis demonstrated that co-occurrence of these 2 mutations in cis severely impairs the function of the 21-hydroxylase enzyme. Conclusions: This case has important implications for genetic counseling. Regarding this combination of 2 "mild"variants as having mild phenotypic effects could lead to inappropriate counseling of heterozygote carriers.