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Influence of different genotypes on 17‐hydroxyprogesterone levels in patients with nonclassical congenital adrenal hyperplasia due to 21‐hydroxylase deficiency
Author(s) -
Bachega Tânia A. S. S.,
Billerbeck Ana E. C.,
Marcondes José A. M.,
Madureira Guiomar,
Arnhold Ivo J. P.,
Mendonca Berenice B.
Publication year - 2000
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1046/j.1365-2265.2000.00995.x
Subject(s) - genotype , endocrinology , medicine , allele , congenital adrenal hyperplasia , 21 hydroxylase , biology , basal (medicine) , genetics , gene , insulin
OBJECTIVE The diagnosis of the nonclassical form of 21‐hydroxylase (NC‐21OH) deficiency, established before molecular studies, is based on basal 17OH‐progesterone (17OH‐P) values > 15 nmol/l or ACTH‐stimulated 17OH‐P values > 30 nmol/l. This disease is caused by mutations in the structural gene that can be grouped into three categories: A, B and C, according to the predicted level of enzymatic activity. So, the genotype of the nonclassical form is a combination of mutations that cause moderate impairment of enzymatic activity in one allele and mutations which cause total (A), severe (B: 3%) or moderate (C: 20–60%) impairment of enzymatic activity in the other allele. DESIGN We analysed the influence of the different genotypes on 17OH‐P levels in 58 patients with the nonclassical form of 21OH deficiency. RESULTS After screening for 18 mutations through Southern blotting, allele‐specific polymerase chain reaction (PCR) and enzyme restriction, mutations were identified in 73% of the alleles. Patients with mutations identified in both alleles were divided into groups A/C ( n = 18), B/C ( n = 3) and C/C ( n = 15). The basal and ACTH‐stimulated 17OH‐P levels in patients with A/C genotype ranged from 1.2 to 153 and 72–363 nmol/l, and in C/C genotype ranged from 0.9 to 72 and 51–363 nmol/l, respectively ( P < 0.05 for stimulated levels). The lowest value of ACTH‐stimulated 17OH‐P levels in fully genotyped patients was 51 nmol/l. Patients with the A/C genotype presented androgen excess symptoms earlier than patients with the C/C genotype. CONCLUSIONS These data suggest an influence of genotype on phenotype and on 17OH‐P levels. The high frequency of unidentified mutant alleles in nonclassical 21‐hydroxylase deficiency suggests that ACTH‐stimulated values of 17OH‐P between 30 and 51 nmol/l have overestimated this diagnosis. Genotyping more patients with nonclassical 21‐hydroxylase deficiency will help to redefine the cut‐off value for ACTH‐stimulated 17OH‐P for correct diagnosis of this disease.