Molecular pathology of 21‐hydroxylase deficiency

Summary Steroid 21‐hydroxylase deficiency is a recessively inherited disorder of adrenal steroidogenesis. Different clinical variants map to a single gene CYP21B , which maps within the HLA complex and is located about 30 kb proximal to a very closely related 21‐hydroxylase pseudogene, CYP21A . The two CYP21 genes are located on highly homologous tandemly repeated 30 kb units, facilitating interlocus sequence exchanges. One type of exchange, unequal crossover, can result in CYP21B gene deletion or replacement of a large segment of the CYP21B gene by the analogous segment of the CYP21A gene. Gene conversion‐like mechanisms can result in replacement of a very small segment of CYP21B by the analogous CYP21A sequence, thereby introducing a deleterious CYP21A ‐specific mutation. The vast majority of point mutation alleles seem to be accounted for by only a few of the mutations copied from CYP21A and can be assayed by ASO hybridization or allele‐specific amplification assays of selectively amplified CYP21B gene sequences. Genotype‐phenotype correlations are largely as expected: mutations resulting in no or severely curtailed gene expression are associated with severe clinical phenotypes; those resulting in significant residual enzyme activity are associated with milder clinical phenotypes.