ESPE Abstracts (2014) 82 P-D-3-1-624

Genotype-Phenotype Correlations in Bulgarian Patients with c.293-13A/C[gt]G Splice Mutation of 21CYPA2 Picked up by Neonatal Screening (NS)

Iva Stoevaa, Ganka Dinevaa, Andrey Kirovb,c, Antoaneta Kostovaa, Tihomir Todorovc, Ani Aroyoa, Albena Todorovab,c & Vanio Mitevb


aUniversity Pediatric Hospital Sofia/Medical University Sofia, Screening and Functional Endocrine Diagnostics, Sofia, Bulgaria; bDepartment of Medical Chemistry and Biochemistry, Medical University Sofia, Sofia, Bulgaria; cGenetic Medico-Diagnostic Laboratory Genica, Sofia, Bulgaria


Background: Congenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive disorders caused by defects in one of the several adrenal steroidogenic enzymes. 80–95% of CAH are due to mutations in CYP21A2 gene encoding 21 hydroxylase. Its residual activity defines the clinical form. Except deletions and large gene conversions, nine pseudogene-derived mutations are responsible for 95% of all CAH alleles. The mutational distribution varies between different populations. c.293-13A/C>G may give either salt wasting (SW) or simple virilizing (SV) forms due to enzyme residual activity.

Objective and hypotheses: To study genotype–phenotype correlations in Bulgarian patients with homozygous c.293-13A/C>G CYP21A2 mutations.

Method: Newborns and siblings with elevated 17-OHP picked up by NS; 17-OHP (Delfia), clinical evaluation, electrolytes; MLPA (multiplex ligation-dependent probe amplification) – first step genetic screening strategy, second direct sequencing of CYP21A2.

Results: 222 827 screened newborns (coverage 82.5%); 22 patients with CYP21A2 mutations were characterized (two of them previously undiagnosed older brothers); c.293-13A/C>G is the most common mutation found in this study (59% frequency, one of the highest reported). Ten patients are homozygous for c.293-13A/C>G (seven male and three female). The SW form was clear in nine patients; CAH was late diagnosed in an older brother with history of failure to thrive, frequent vomiting, hospital admissions until early childhood, no regular corticosteroid treatment; at 6 years of age he developed pseudoprecocious puberty. The clinical form, despite the genotype, is difficult to be classified. Virilisation (Prader 2–4) was evident in all of the diagnosed girls. The 17-OHP screening levels were elevated: average 398.2 nmol/l (S.D.±224), but varied widely (median 414, range 69.9–703).

Conclusions: c.293-13A/C>G homozygous patients showed variability at manifestation and evolution, even within a family; the c.293-13A/C>G splice mutation is the most common in Bulgaria; our mutational screening strategy needs adaptation.

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