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Mutational spectrum of steroid 21-hydroxylase and the genotype-phenotype association in Middle European patients with congenital adrenal hyperplasia

V Dol;an¹, J Sólyom³, G Fekete³, J Kovács⁴, V Rakosnikova⁵, F Votava⁵, J Lebl⁵, Z Pribilincova⁶, SM Baumgartner-Parzer⁷, S Riedl⁸, F Waldhauser⁸, H Frisch⁸, M Stopar-Obreza², C Kr;inik² and T Battelino²

¹ Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia, ² University Children’s Hospital, Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, Vrazov trg 1 SI-1000, Ljubljana, Slovenia, ³ 2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary, ⁴ Department of Paediatrics, University of Szeged, Szeged, Hungary, ⁵ Department of Paediatrics, 3rd Faculty of Medicine, Charles University, Prague, Czech Republic, ⁶ Department of Paediatrics, Comenius University, Bratislava, Slovakia, ⁷ Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University, Vienna, Austria and ⁸ Department of Paediatrics, Medical University, Vienna, Austria

(Correspondence should be addressed to T Battelino; Email: tadej.battelino{at}mf.uni-lj.si)

Objective: To analyze the mutational spectrum of steroid 21-hydroxylase (CYP21) and the genotype– phenotype correlation in patients with congenital adrenal hyperplasia (CAH) registered in the Middle European Society for Pediatric Endocrinology CAH database, and to design a reliable and rational approach for CYP21 mutation detection in Middle European populations.

Design and methods: Molecular analysis of the CYP21 gene was performed in 432 CAH patients and 298 family members. Low-resolution genotyping was performed to detect the eight most common point mutations. High-resolution genotyping, including Southern blotting and sequencing was performed to detect CYP21 gene deletions, conversions, point mutations or other sequence changes.

Results: CYP21 gene deletion and In2 and Ile172Asn mutation accounted for 72.7% of the affected alleles in the whole study group. A good genotype–phenotype correlation was observed, with the exception of Ile172Asn and Pro30Leu mutations. In 37% of patients low resolution genotyping could not identify the causative mutation or distinguish homozygosity from hemizygosity. Using high-resolution genotyping, the causative mutations could be identified in 341 out of 348 analyzed patients. A novel mutation Gln315Stop was found in one simple virilising CAH (SV-CAH) patient from Austria. In the remaining seven patients polymorphisms were identified as the leading sequence alteration. The presence of elevated basal and ACTH-stimulated 17-hydroxyprogesterone, premature pubarche, advanced bone age and clitoral hypertrophy directly implicated Asn493Ser polymorphism in the manifestation of nonclassical- (NC) and even SV-CAH.

Conclusions: By genotyping for the most common point mutations, CYP21 gene deletion/conversion and the 8 bp deletion in exon 3, it should be possible to identify the mutation in 94–99% of the diseased alleles in any investigated Middle European population. In patients with a mild form of the disease and no detectable mutation CYP21 gene polymorphisms should be considered as a plausible disease-causing mutation.

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