ESPE Abstracts

Background: 80–95% of congenital adrenal hyperplasia (CAH) cases are due to mutations in the CYP21A2 gene encoding 21 hydroxylase. The residual activity of the gene defines the clinical form. Routine mutational screening of CYP21A2 defects is shown to effectively support the complex diagnostic and treatment procedure of newborns with CAH.

Objective: We aimed to characterise the phenotype of a girl with compound heterozygosity of CYP21A2 in order to derive a methodological approach for molecular diagnostics for patients with severe CAH.

Methods: Clinical evaluation, Newborn screening by 17-OHP (Delfia), Biochemistry, G-banding (46XX) and MLPA (multiplex ligation-dependent probe amplification). Additional, direct sequencing of CYP21A2 were conducted.

Clinical case: We report a girl born at term, BW 3340 g, BL 50 cm, after first pregnancy, with severe asphyxia (Apgar 3), ambiguous genitalia (Prader 3–4), who developed aspiration pneumonia, gastroesophageal reflux. At first 17OHP screening -d7, extreme high levels were evident – 675.7 mnol/l (ISNS <20 nmol/l), the clinical diagnosis classical CAH – SW form was established and treatment introduced at d11. Genetic tests confirmed classical type of CAH due to 21-hydroxylase deficiency with compound heterozygosity (c.113G>A, Pro31Leu, Del8 E3-inherited from the mother; Q118X inherited from the father). SW phenotype is determined by Del8 E3 (frameshift) and Q118X, both of them affecting the hem binding site and leading to <1% enzyme activity. Persistent abnormal electrolytes were present until hydrocortisone and fludrocortisone dosages were several times adjusted to the high initial needs.

Conclusions: The patient underlines once more the importance of complex screening, contemporary diagnostic and treatment procedures in the sense of personalized medicine for a most favourable outcome. Such multiple CYP21A2 mutations represent a unique opportunity for genotype-phenotype correlations. Further methodological approaches for revealing the underlying cause of patients who require higher doses of mineralocorticosteroids could be set up.

Funding: Financial support by Medical University Sofia 30/2013, 42Д/2013.