Abstract
CONTEXT: Genetic testing for 21-hydroxylase deficiency (21OHD) is advantageous when hormonal testing is equivocal, to molecularly confirm diagnosis, and for genetic counseling. OBJECTIVE: To characterize the clinical and biochemical phenotype across the genotypic spectrum of 21OHD in a large cohort using updated genetic methodology. DESIGN: Retrospective study of 457 individuals with 21OHD enrolled in a Natural History Study at the National Institutes of Health Clinical Center. RESULTS: The majority (79%) were compound heterozygous, 46% with chimeric alleles/30-kb deletions including 2.6% with attenuated chimeras, 10.1% with CAH-X (33% with cardiac defects), and 3.7% with genotype-phenotype discordance. The most common mutations among individuals with salt-wasting, simple-virilizing, and nonclassic (NC) phenotypes were In2G, I172N, and V281L, respectively. Rare or novel mutations accounted for 4.3% alleles, 0.33% arose de novo. 17OHP levels at diagnosis varied by genotype group (Null > In2G > simple-virilizing genotypes > P30L > Other NC; P < .001); but maximum values obtained during clinical care over time were similar among all classic and among all NC genotypes. Individuals with P30L had higher 17OHP and lower cortisol at diagnosis compared to other NC genotypes (P < .001) and were more likely to have basal 17OHP >1000 ng/dL (P < .001). Individuals with cryptic NC CAH had lower 17OHP after cosyntropin stimulation compared to those with symptomatic NC CAH (P = .02). CONCLUSION: A continuum of disease phenotypes exists with biochemical overlap that increases with age. Improving genotype accuracy to include chimera subtyping to identify attenuated chimeras and CAH-X and consideration of P30L as a unique group are important to guide genetic counseling and provide anticipatory guidance in disease management.