ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2014) 36 P7 | DOI: 10.1530/endoabs.36.P7

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency in a regional cohort 1994-2004: characterisation and genotype-phenotype analysis

Bronwen Warner1, Rathi Prasad2, John Barton2, Christine Burren2, Jennifer Henchliffe3 & Liz Crowne2

1University of Bristol, Bristol, UK; 2Bristol Children’s Hospital, Bristol, UK; 3Manchester Centre for Genomic Medicine, Manchester, UK.

Congenital adrenal hyperplasia (CAH) has an estimated prevalence of one in 10 000–20 000 live births. Patients are described as salt wasting (SW), simple virilising (SV), or non-classical (NC). The CAH genotype is usually compound heterozygous.

Aims: To characterise the cohort of CAH patients presenting to a regional centre 1994–2014, to quantify the allelic frequency of CYP21A2 mutations and to examine genotype–phenotype associations.

Method: Retrospective notes review. Genotype according to mutational analyses performed at diagnosis using pyrosequencing, fluorescent PCR, and multiplex ligation-dependent probe amplification (MLPA). Phenotype determined by clinical presentation, age of presentation, 17-OHP levels, plasma renin, urinary steroid profile, and Synacthen tests.

Results: Using the regional endocrine database, 74 patients were identified (four had declined mutational analysis). Only four were non-Caucasian. 28 had a known family history. 48 presented within the first year of age. SW: total 47 (64%); 54% female; 85% presented <30 days. SV and NC: total 26 (36%); eight on glucocorticoid only and two on no long-term medication. The most common mutations in our cohort were the CYP21A2 chimeric deletion/conversion encompassing exons 1–3, c.290-13C>G, c.515T>A; p.Ile172Asn and c.841G>T; p.Val281Leu. Two SW patients were identified with the rarer mutations g.2578 C>T (p.Pro453Ser) and exon 6 cluster (p.Ile236Asn, pVal237Glu, and pMet239Lys). c.290-13C>G and c.515T>A; p.Ile172Asn were most common in SW patients, despite usually being associated with the SV form. c.841G>T; p.Val281Leu was associated with SV CAH, especially milder disease.

Conclusions: We characterise a cohort of CAH patients from a defined region of the UK with a relatively static population. Our work supports previous findings that a small number of mutations are commonly associated with CAH, while indicating a need to reconsider some established genotype–phenotype correlations. We report interesting rarer mutations. Improved understanding of genotype-phenotype correlation will have implications for management, genetic counselling, and prenatal diagnosis.

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