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.