Clinical and Biochemical Phenotype Across the Genotypic Spectrum of 21-Hydroxylase Deficiency in 457 Individuals

Authors

Qizong Lao, Department of Pediatrics, National Institutes of Health Clinical Center, Bethesda, MD 20892, USA.
Annie Schulman, Department of Pediatrics, National Institutes of Health Clinical Center, Bethesda, MD 20892, USA.
Sarah Kulkarni, Department of Pediatrics, National Institutes of Health Clinical Center, Bethesda, MD 20892, USA.
Sarah Kollender, Department of Pediatrics, National Institutes of Health Clinical Center, Bethesda, MD 20892, USA.
Daniella Bick, Department of Pediatrics, National Institutes of Health Clinical Center, Bethesda, MD 20892, USA.
Amy Moon, Department of Pediatrics, National Institutes of Health Clinical Center, Bethesda, MD 20892, USA.
Deepika Burkardt, Department of Pediatrics, National Institutes of Health Clinical Center, Bethesda, MD 20892, USA.
Deborah P. Merke, Department of Pediatrics, National Institutes of Health Clinical Center, Bethesda, MD 20892, USA.

Document Type

Journal Article

Publication Date

10-6-2025

Journal

The Journal of clinical endocrinology and metabolism

DOI

10.1210/clinem/dgaf546

Keywords

CYP21A2; 21-hydroxylase deficiency; CAH; CAH-X; congenital adrenal hyperplasia; genotype-phenotype

Abstract

CONTEXT: Genetic testing for 21-hydroxylase deficiency (21OHD) is advantageous when hormonal testing is equivocal, to molecularly confirm diagnosis, and for genetic counseling. OBJECTIVES: 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 NIH 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 (SW), simple-virilizing (SV), 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> SV genotypes > P30L > Other NC; P<0.001); 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<0.001) and were more likely to have basal 17OHP >1,000ng/dL (P<0.001). Individuals with cryptic NC had lower 17OHP post cosyntropin stimulation compared to those with symptomatic NC (P=0.02). 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.

APA Citation

Lao, Qizong; Schulman, Annie; Kulkarni, Sarah; Kollender, Sarah; Bick, Daniella; Moon, Amy; Burkardt, Deepika; and Merke, Deborah P., "Clinical and Biochemical Phenotype Across the Genotypic Spectrum of 21-Hydroxylase Deficiency in 457 Individuals" (2025). GW Authored Works. Paper 8311.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/8311

Department

Pediatrics