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

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 appr...

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Published in:European journal of endocrinology 2005-07, Vol.153 (1), p.99-106
Main Authors: Dolž, an, V, Sólyom, J, Fekete, G, Kovács, J, Rakosnikova, V, Votava, F, Lebl, J, Pribilincova, Z, Baumgartner-Parzer, SM, Riedl, S, Waldhauser, F, Frisch, H, Stopar-Obreza, M, Krž, išnik, C, Battelino, T
Format: Article
Language:English
Subjects:
Adrenal Hyperplasia, Congenital - diagnosis
Adrenal Hyperplasia, Congenital - ethnology
Adrenal Hyperplasia, Congenital - genetics
Adrenals. Adrenal axis. Renin-angiotensin system (diseases)
Biological and medical sciences
Child
Clinical Studies
Endocrinopathies
Europe, Eastern - epidemiology
Female
Fundamental and applied biological sciences. Psychology
Gene Deletion
Gene Frequency
Genetic Counseling
Genetic Testing - methods
Genotype
Humans
Male
Medical sciences
Non tumoral diseases. Target tissue resistance. Benign neoplasms
Phenotype
Point Mutation
Steroid 21-Hydroxylase - genetics
Vertebrates: endocrinology
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Summary: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.
ISSN:0804-4643
1479-683X
DOI:10.1530/eje.1.01944