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

Abstract

Objective: To analyze the mutational spectrum of steroid 21-hydroxylase (CYP21) and the genotypephenotype 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.European Journal of Endocrinology 153 99-106

Identification of CYP21A2 mutant alleles in Czech patients with 21-hydroxylase deficiency

“…Point mutations and copy number variations, such as deletions and duplications, have been described in many populations (20)(21)(22)(23)(24). Using the analysis of the CYP21A2 gene, we confirmed the referral diagnosis in 241 Czech unrelated patients suspected of 21OHD.…”

Clinical Role of CYP2C19 Polymorphisms in Patients with Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency

“…The results of molecular analyses of 24 out of 28 patients were previously reported. 6,15 Legend: The step that can be augmented by extraadrenal hydoxylation via hepatic cytochrome P450 CYP2C19 is bolded. CYP11A1 -cholesterol side-chain cleavage enzyme; CYP17 -17-alpha-hydroxylase / 17,20-lyase; HSD3B2 -3β-hydroxysteroid dehydrogenase; CYP21A2 -steroid 21-hydroxylase; CYP11B1-steroid 11-β-hydroxylase; CYP11B2 -aldosterone synthase; 17β-HSD -17-beta-hydroxysteroid dehydrogenase.…”

“…4,5 However, some patients with absent or functionally inactive 21-hydroxylase do not clinically present with the expected salt-wasting (SW) form of 21OHD. 6,7 Further-more, some patients may regain their ability to retain salt over time, possibly also by increased activity of other 21-hydroxylating enzymes. It has been shown that hepatic cytochrome P450 drug-metabolizing enzyme CYP2C19 can 21-hydroxylate progesterone but not 17-hydroxyprogesterone, possibly ameliorating mineralocorticoid deficiency, but not glucocorticoid deficiency.…”

Congenital Adrenal Hyperplasia, the Origin of Combined Infertility: A Case Report and a Review of Literature

“…However, the correlation between the genotype and the virilization phenotype assessed by Prader genital stages is less pronounced [6]. In addition, this association is weaker in cases of compound heterozygotes for two different mutations or those carrying mutations of intermediate severity and as a result prediction of phenotype from genotype tends to become more difficult [25][26][27][28][29][30][31].…”