Genotype-phenotype correlation in 153 adult patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: analysis of the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) cohort

Abstract

Context: In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a strong genotype-phenotype correlation exists in childhood. However, similar data in adults are lacking.

Objective: The objective of the study was to test whether the severity of disease-causing CYP21A2 mutations influences the treatment and health status in adults with CAH.

Research design and methods: We analyzed the genotype in correlation with treatment and health status in 153 adults with CAH from the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive cohort.

Results: CYP21A2 mutations were distributed similarly to previously reported case series. In 7 patients a mutation was identified on only 1 allele. Novel mutations were detected on 1.7% of alleles (5 of 306). Rare mutations were found on 2.3% of alleles (7 of 306). For further analysis, patients were categorized into CYP21A2 mutation groups according to predicted residual enzyme function: null (n = 34), A (n = 42), B (n = 36), C (n = 34), and D (n = 7). Daily glucocorticoid dose was highest in group null and lowest in group C. Fludrocortisone was used more frequently in patients with more severe genotypes. Except for lower female height in group B, no statistically significant associations between genotype and clinical parameters were found. Androgens, blood pressure, lipids, blood glucose, and homeostasis model assessment of insulin resistance were not different between groups. Subjective health status was similarly impaired across groups.

Conclusions: In adults with classic CAH and women with nonclassic CAH, there was a weak association between genotype and treatment, but health outcomes were not associated with genotype. The underrepresentation of males with nonclassic CAH may reflect that milder genotypes result in a milder condition that is neither diagnosed nor followed up in adulthood. Overall, our results suggest that the impaired health status of adults with CAH coming to medical attention is acquired rather than genetically determined and therefore could potentially be improved through modification of treatment.

Trial registration: ClinicalTrials.gov NCT00749593.

Figure 1.

Definition of mutation groups and their distribution in the cohort. A, Genotype-phenotype correlations in CAH due to 21-hydroxylase deficiency based on in vitro CYP21A2 activity. Mutation groups null and A are associated with the SW form of 21OHD, group B with the SV form, and group C with the nonclassic (NC) form. E6 cluster refers to the p.Ile236Asn, p.Val237Glu, and p.Met239Leu mutation cluster at exon 6; intron splice refers to the c.293–13A/C>G mutation (other names: i2G, I2G, IVS2–13A/C>G); Δ8bp refers to the p.Gly110ValfsX21 mutation. B, Patient cohort according to CYP21A2 mutation group and gender.

Figure 2.

Subjective health status according to SF-36 dimension scores for different mutation groups (panel A): null [n = 27; 13 females (f), 14 males (m)]; A (n = 35; 20 f, 15 m); B (n = 34; 22 f, 12 m); C (n = 27; 25 f, 2 m). Panels B and C depict the same analysis for males (B) and females (C) in a separate fashion. Results for the males in mutation group C are not shown due to the small sample size (n = 5). #, Significant difference (P < .05) between patients and normal controls; *, difference between mutation groups at a significance level of P < .05. SF-36 dimensions: BP, bodily pain; GH, general health; MH, mental health; PF, physical functioning; RE, role limitations due to emotional problems; RP, role limitations due to physical problems; SF, social functioning; VT, vitality.