In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency a genotype-phenotype correlation exists for paediatric cohorts, helping to predict the severity of disease expression. Data on the correlation in adults is lacking. Here we report the genetic analysis of the UK CaHASE cohort, comprising CAH adults seen at 17 endocrine tertiary care centres. CYP21A2 mutation analysis was performed in 153 patients (median age 35 (range 1869) yrs; 103 f, 50 m) by multiplex ligation-dependent probe amplification to screen for deletions, multiplex-minisequencing to screen for common mutations and DNA sequencing for mutation confirmation and rare mutation detection. 135 patients (88%) carried a common CYP21A2 mutation on both alleles. In addition, 6 rare known (H62L, L308F, R426 h, R426C, R435C, R483P) and 5 novel mutations (R124C, Q141X, fsV334X28, IVS9+1G>C, fsex10) were identified. Patients were classified into established CYP21A2 mutation groups Null (n=34), A (n=42), B (n=36), C (n=34) and D (n=7). Patterns of prescribed glucocorticoid were similar across groups. Glucocorticoid daily dose was highest in group Null and lowest in group C. Fludrocortisone was used most frequently in patients with the more severe genotypes. Except for lower female height in group B no statistically significant associations between genotype and height or other clinical parameters were found. Blood pressure, lipid profiles, blood glucose concentrations and HOMA-IR were statistically not different between groups. Quality of hormonal control defined by 17OHP and androstenedione concentrations was similar. Subjective health status (SF-36) was similarly impaired across mutation groups. The majority of females had never been pregnant; most male patients never fathered a child. In conclusion, unsatisfactory outcomes in adults with CAH are not explained by differences in underlying genotype and are more likely related to factors shared by all patients. Future studies will determine whether a therapeutic approach tailored to distinct mutation groups could help to optimize management.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: Declaration of Funding: The CaHASE Study Group is grateful to the Society for Endocrinology for the management of the project and The Clinical Endocrinology Trust for their financial support.