Influence of different genotypes on 17-hydroxyprogesterone levels in patients with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
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.


METHODS
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.
Bachega
T A
TA
Unidade de Endocrinologia do Desenvolvimento e Laboratório de Hormônios e Genética Molecular-LIM/42, Disciplina de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
Billerbeck
A E
AE
Marcondes
J A
JA
Madureira
G
G
Arnhold
I J
IJ
Mendonca
B B
BB
D019326:17-alpha-Hydroxyprogesterone / Q000097:blood*; D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D000324:Adrenocorticotropic Hormone; D000328:Adult; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018709:Statistics, Nonparametric; D013255:Steroid 21-Hydroxylase / Q000235:genetics*
D019326:17-alpha-Hydroxyprogesterone; D000324:Adrenocorticotropic Hormone; D013255:Steroid 21-Hydroxylase; D006854:Hydrocortisone