The Prevalence, Molecular Analysis and HLA Typing of Late-onset 21-Hydroxylase Deficiency in Turkish Woman with Hirsutism and Polycystic Ovary

OBJECTIVE: To study the incidence of 21-hydroxylase deficiency in Slovenian hyperandrogenic women, at the gene level. Previous endocrine studies indicated large differences in the incidence of 21-hydroxylase deficiency in hyperandrogenic women. The predictive values of the 17-hydroxyprogesterone (17-OHP) response to ACTH stimulation and of HLA typing in screening for carrier status were re-evaluated. DESIGN: Molecular analysis of CYP21 gene, ACTH stimulation and human leucocyte antigen (HLA) typing were performed in 83 consecutive Slovenian hyperandrogenic women. MEASUREMENTS: Cortisol and 17-OHP concentrations were measured at baseline and 60 min after ACTH stimulation. Basal adrenal androgen concentrations were also measured. RESULTS: None of 83 hyperandrogenic patients was affected with non-classical 21-hydroxylase deficiency, but 12 of 81 patients (14.8%) had high concentrations of 17-OHP after stimulation, indicative of carrier status. The increase in 17-OHP concentrations could be explained by a carrier status for CYP21 gene mutations in only three of 12 patients (25%), whereas seven of 69 patients (10. 1%) with normal concentrations of 17-OHP after stimulation were found to be carriers of CYP21 gene mutations, indicating low positive predictive values of ACTH stimulation as a screening test for carriers of 21-hydroxylase deficiency. In total, 11 carriers were identified among 83 patients: seven CYP21 gene deletions/conversions, two Gln(318)Stop and one Val(281)Leu mutation and one gene conversion extending from exon 4 to exon 7 were found. The association between Val(281)Leu mutation and HLA-B14 antigen was confirmed in this Slovenian population. CONCLUSIONS: Basal or ACTH-stimulated 17-OHP concentrations are not a good indicator of the carrier status for 21-hydroxylase deficiency among Slovenian hyperandrogenic patients. Reliable screening for carriers of 21-hydroxylase deficiency is possible only by molecular analysis of the CYP21 gene.

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Detection of heterozygous carriers for 21-hydroxylase deficiency by plasma 21-deoxycortisol measurement

Acta Endocrinologica ◽

10.1530/acta.0.1160507 ◽

1987 ◽

Vol 116 (4) ◽

pp. 507-512 ◽

Cited By ~ 20

Author(s):

M. Gourmelen ◽

B. Gueux ◽

M. T. Pham Huu Trung ◽

J. Fiet ◽

M. C. Raux-Demay ◽

...

Keyword(s):

Late Onset ◽

Hla Typing ◽

Biological Detection ◽

Normal Range ◽

Acth Stimulation ◽

Hydroxylase Deficiency ◽

Specific Radioimmunoassay ◽

Heterozygous Carriers ◽

17 Hydroxyprogesterone ◽

21 Hydroxylase Deficiency

Abstract. Using a highly specific radioimmunoassay recently described, plasma 21-deoxycortisol levels were measured in 55 heterozygous carriers of 21-hydroxylase deficiency (as demonstrated by HLA typing). Mean baseline 21-deoxycortisol levels were above the normal range, but there was a 38% overlap with control values. In contrast to 17-hydroxyprogesterone levels, which in 71% of the subjects remained within the normal range one hour after ACTH stimulation, 21-deoxycortisol levels increased over stimulated control levels in all but two heterozygous carriers. No differences as to the levels were observed between heterozygous carriers for the classic and the late-onset forms. Plasma 21-deoxycortisol measurement appears to be a valid tool in the biological detection of heterozygosity for 21-hydroxylase deficiency and its implications in genetic counselling.

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'Cryptic' form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency in the Yugoslav population

Acta Endocrinologica ◽

10.1530/acta.0.1090386 ◽

1985 ◽

Vol 109 (3) ◽

pp. 386-392 ◽

Cited By ~ 7

Author(s):

Miro Dumić ◽

Ljerka Brkljačić ◽

Duško Mardešić ◽

Vesna Plavšić ◽

Milica Lukenda ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Clinical Symptoms ◽

Index Case ◽

Late Onset ◽

Hla Typing ◽

Adrenal Hyperplasia ◽

Acth Stimulation ◽

Hydroxylase Deficiency ◽

Classical Form ◽

21 Hydroxylase Deficiency

Abstract. Five individuals with the asymptomatic, 'nonclassical', 'cryptic' form of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (21-OH) deficiency from 5 unrelated families were discovered during hormonal studies and HLA-typing performed in a series of 24 families with CAH due to 21-OH deficiency. Four of the 5 individuals with the 'cryptic' form of CAH belong to families where the index case was a patient with the classical form of CAH due to 21-OH deficiency. The fifth one originated from a family where the index case was a girl with the 'non-classical', 'late-onset' form of the disease. All the 5 individuals had no clinical symptoms in spite of clearcut biochemical signs of 21-OH deficiency: increased 17-OH-progesterone (17-OHP), dehydroepiandrosterone and androstenedione levels, particularly after ACTH-stimulation. The 17-OHP response upon ACTH stimulation of heterozygotes for this 'non-classical' form of 21-OH deficiency did not differ from the response of heterozygous individuals for the classical form of the disease. The results of this study confirm the hypothesis that individuals with the 'cryptic' form of CAH due to 21-OH deficiency are genetic compounds bearing one allele for the severe, classical form, and on the homologous locus, another one for the mild 'nonclassical' form of CAH due to 21-OH deficiency. Their genotype was 21-OHsevere/21-OHmild, The gene for 'cryptic' 21-OH deficiency, as well as the gene for the classical form of the disease is linked to the HLA system, but in our population apparently it is not in genetic disequilibrium with the antigens B 14 DR 1, as it was shown for other populations studied up to now.

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The frequency of late-onset 21-hydroxylase and 11 beta-hydroxylase deficiency in women with polycystic ovary syndrome

Acta Endocrinologica ◽

10.1530/eje.0.1370670 ◽

1997 ◽

pp. 670-674 ◽

Cited By ~ 31

Author(s):

Y Sahin ◽

F Kelestimur

Keyword(s):

Polycystic Ovary Syndrome ◽

Late Onset ◽

Polycystic Ovary ◽

Serum Testosterone ◽

Free Testosterone ◽

Sex Hormone Binding Globulin ◽

Acth Stimulation ◽

Hydroxylase Deficiency ◽

Ovary Syndrome ◽

Biochemical Features

OBJECTIVE: To determine the frequency of late-onset adrenal hyperplasia (LOCAH) due to 21-hydroxylase (21-OH) and 11 beta-hydroxylase (11 beta-OH) deficiency in women with clinical and biochemical features of polycystic ovary syndrome (PCOS). DESIGN: Eighty-three consecutively selected women with PCOS and eighteen normal women were included in the study. METHODS: Ultrasound, clinical and hormonal parameters were used to define PCOS. Basal FSH, LH, testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEA-S), sex hormone-binding globulin (SHBG) and cortisol levels were measured. Serum 17-hydroxyprogesterone (17-OHP) and 11-deoxycortisol (11-DOC) levels were also measured before, 30 and 60 min after a single bolus injection of 0.25 mg ACTH (1-24) at 0900 h during the mid-follicular phase of the cycle. ACTH-stimulated 17-OHP levels > 30 nmol/l were considered as the criteria of 21-OH deficiency. The diagnosis 11 beta-OH deficiency was made if the adrenal 11-DOC response to ACTH stimulation exceeded threefold the 95th percentile of controls. RESULTS: Basal serum testosterone, free testosterone, androstenedione, DHEA-S, cortisol and 11-DOC levels were significantly higher in PCOS than in control subjects. ACTH-stimulated 17-OHP (P < 0.05) and 11-DOC (P < 0.0005) levels were found to be significantly higher in patients with PCOS than in controls. Seven (8.4%) patients had an 11-DOC response to ACTH higher than threefold the 95th percentile of controls, while no patients showed evidence of 21-OH deficiency. CONCLUSIONS: We have found that 8.4% of the women with clinical and biochemical features of PCOS could be presumed to have 11 beta-OH deficiency. No patients among the women with PCOS showed evidence of 21-OH deficiency. 11 beta-OH deficiency is unexpectedly more common than 21-OH deficiency in women with PCOS.

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