Clinical and Biochemical Phenotype Across the Genotypic Spectrum of 21-hydroxylase Deficiency in 457 Individuals
Authors' 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.
Study context
- Population
- Individuals with 21-hydroxylase deficiency (21OHD) enrolled in a Natural History Study at the National Institutes of Health Clinical Center
- Participants
- 457 individuals
- Outcome
- Clinical and biochemical phenotype across the genotypic spectrum of 21OHD
Methodological detailsNatural History Study, single-centre
- Natural History Study
- Single-centre
Main finding
As reported in the abstract
Genotype distribution
- Compound heterozygous
- 79%
- Chimeric alleles/30-kb deletions
- 46%
- Attenuated chimeras
- 2.6%
- CAH-X
- 10.1%
- Cardiac defects among CAH-X
- 33%
- Genotype-phenotype discordance
- 3.7%
- Rare or novel mutations (alleles)
- 4.3%
- Arose de novo
- 0.33%
Observational data: associations, not effects.
Further findings
17OHP at diagnosis by genotype group
- Varied by genotype group (Null > In2G > simple-virilizing genotypes > P30L > Other nonclassic (NC))
- P < 0.001
- Maximum values during clinical care over time similar among all classic and among all NC genotypes
P30L vs other NC genotypes · at diagnosis
- Higher 17OHP and lower cortisol with P30L vs other NC genotypes
- P < 0.001
- More likely basal 17OHP >1000 ng/dL with P30L
- P < 0.001
17OHP after cosyntropin stimulation, cryptic vs symptomatic NC CAH
- Lower with cryptic NC CAH vs symptomatic NC CAH
- P = 0.02
Original publication
Clinical and Biochemical Phenotype Across the Genotypic Spectrum of 21-hydroxylase Deficiency in 457 Individuals. J Clin Endocrinol Metab. Published 6 October 2025. doi:10.
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