Endocrine Abstracts (2012) 28 P306

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

Nils Krone1, Ian Rose1, Debbie Willis2, Sarah Wild3, James Hodson4, Emma Doherty5, Stefanie Hahner6, Silvia Parajes1, Roland Stimson7, Thang Han8, Paul Carroll5, Gerard Conway8, Brian Walker7, Fiona Macdonald9, Richard Ross10, Wiebke Arlt1 & CaHASE The UK CAH Adult Study Executive2


1Centre for Endcrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, United Kingdom; 2Society for Endocrinology, Bristol, United Kingdom; 3Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom; 4Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom; 5Department of Endocrinology, Guy’s and St. Thomas’ National Health Service Foundation, London, United Kingdom; 6Endocrine and Diabetes Unit, Department of Medicine I, University of Wuerzburg, Wuerzburg, Germany; 7Endocrinology Unit, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom; 8Department of Endocrinology, University College London, London, United Kingdom; 9West Midlands Regional Genetics Laboratory, Birmingham Women's Hospital, Birmingham, United Kingdom; 10Academic Unit of Diabetes, Endocrinology and Metabolism, University of Sheffield, Sheffield, United Kingdom.


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 18–69) 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.

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