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

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.

Automated summary

This case of salt-losing 21-hydroxylase deficiency is homozygous for two mild pathogenic variants: V281L and S301Y. Co-occurrence of these mutations severely impairs the function of the 21-hydroxylase enzyme, which has important implications for genetic counseling. Consideration of these mild variants as having mild phenotypic effects may lead to inappropriate counseling of heterozygote carriers.