Three Novel Mutations in CYP21 Gene in Brazilian Patients with the Classical Form of 21-Hydroxylase Deficiency Due to a Founder Effect

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is one of the most common autosomal recessive disorders. The aim of this study was to assess the frequencies of CYP21 mutations and to study genotype-phenotype correlation in a large population of Dutch 21-hydroxylase deficient patients. From 198 patients with 21-hydroxylase deficiency, 370 unrelated alleles were studied. Gene deletion/conversion was present in 118 of the 370 alleles (31.9%). The most frequent point mutations were I2G (28.1%) and I172N (12.4%). Clustering of pseudogene-derived mutations in exons 7 and 8 (V281L-F306 + 1nt-Q318X-R356W) on a single allele was found in seven unrelated alleles (1.9%). This cluster had been reported before in two other Dutch patients and in two patients in a study from New York, but not in other series worldwide. Six novel mutations were found: 995–996insA, 1123delC, G291R, S301Y, Y376X, and R483Q. Genotype-phenotype correlation (in 87 well documented patients) showed that 28 of 29 (97%) patients with two null mutations and 23 of 24 (96%) patients with mutation I2G (homozygous or heterozygous with a null mutation) had classic salt wasting. Patients with mutation I172N (homozygous or heterozygous with a null or I2G mutation) had salt wasting (2 of 17, 12%), simple virilizing (10 of 17, 59%), or nonclassic CAH (5 of 17, 29%). All six patients with mutation P30L, V281L, or P453S (homozygous or compound heterozygous) had nonclassic CAH. The frequency of CYP21 mutations and the genotype-phenotype correlation in 21-hydroxylase deficient patients in The Netherlands show in general high concordance with previous reports from other Western European countries. However, a cluster of four pseudogene-derived point mutations on exons 7 and 8 on a single allele, observed in almost 2% of the unrelated alleles, seems to be particular for the Dutch population and six novel CYP21 gene mutations were found.

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Hyperandrogenic Phenotypes Cannot Differentiate Non-Classical Form of 21-Hydroxylase Deficiency and Classic PCOS

10.1210/endo-meetings.2011.part2.p32.p2-222 ◽

2011 ◽

pp. P2-222-P2-222

Author(s):

Vivian O Moura ◽

Larissa G Gomes ◽

Gustavo AR Maciel ◽

Jose AM Marcondes ◽

Sylvia AY Yamashita ◽

...

Keyword(s):

Hydroxylase Deficiency ◽

Classical Form ◽

21 Hydroxylase Deficiency

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Low-dose ACTH test for the diagnosis of non-classical form of congenital adrenocortical dysfunction

Problems of Endocrinology ◽

10.14341/probl201056210-14 ◽

2010 ◽

Vol 56 (2) ◽

pp. 10-14

Author(s):

N B Chagaĭ ◽

V V Fadeev ◽

E G Bakulina

Keyword(s):

Low Dose ◽

Stimulation Test ◽

Acth Test ◽

Acth Stimulation Test ◽

Acth Stimulation ◽

Hydroxylase Deficiency ◽

Classical Form ◽

21 Hydroxylase Deficiency

The possibilities to diagnose the non-classical form of 21-hydroxylase deficiency using the low-dose (5 mcg) 1-24 ACTH stimulation test are considered.

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Screening of CYP21 gene mutations in 129 French patients affected by steroid 21-hydroxylase deficiency

Human Mutation ◽

10.1002/humu.1380050205 ◽

1995 ◽

Vol 5 (2) ◽

pp. 126-130 ◽

Cited By ~ 35

Author(s):

Benoit Barbat ◽

Any Bogyo ◽

Marie-Charles Raux-Demay ◽

Frédéarique Kuttenn ◽

Joelle Boué ◽

...

Keyword(s):

Gene Mutations ◽

Hydroxylase Deficiency ◽

Cyp21 Gene ◽

21 Hydroxylase Deficiency

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Nonisotopic Identification of Two Point Mutations in the CYP21 Gene Responsible for Nonclassic 21-Hydroxylase Deficiency

Biochemical Medicine and Metabolic Biology ◽

10.1006/bmmb.1994.1037 ◽

1994 ◽

Vol 52 (2) ◽

pp. 85-88

Author(s):

S.P. Shevtsov ◽

S. Rechitsky ◽

O. Verlinsky ◽

E.I. Schwartz

Keyword(s):

Point Mutations ◽

Hydroxylase Deficiency ◽

Cyp21 Gene ◽

21 Hydroxylase Deficiency

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The prevalence of the non-classical form of congenital adrenal hyperplasia as exemplified (by the population of the Moscow region)

Problems of Endocrinology ◽

10.14341/probl201359418-22 ◽

2013 ◽

Vol 59 (4) ◽

pp. 18-22

Author(s):

T A Ionova ◽

A N Tiul'pakov ◽

S G Kalinenkova

Keyword(s):

Neonatal Screening ◽

Moscow Region ◽

Hydroxylase Deficiency ◽

Classical Form ◽

True Incidence ◽

Monogenic Diseases ◽

Frequent Mutations ◽

17 Hydroxyprogesterone ◽

21 Hydroxylase Deficiency ◽

Autosomal Recessive Pattern

The non-classical form of 21-hydroxylase deficiency (NC21OH) is one of the most common monogenic diseases inherited in the autosomal-recessive pattern. The incidence of this condition in the Russian population, unlike that of its classical variant, remains to be elucidated. Aim. The objective of the present study was to estimate the true incidence of NC21OH based on the prevalence of the two most frequent mutations associated with this disease. A total of 998 randomly selected blood spots were obtained in the course of neonatal screening of the children born within one calendar year at the territory of the Moscow region. The incidence of the disease was calculated with the use of Hardi-Weinberg equation. The minimal prevalence rate of NC21OH in the population of the Moscow region was estimated to be 1:2206. The level of 17-hydroxyprogesterone (17-OHP) calculated based on the results of the screening studies can not be used to identify the carriers of the pathology of interest whereas neonatal screening allows to diagnose no more than 90% of the cases of NC21OH.

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Potential advantage of N363S glucocorticoid receptor polymorphism in 21-hydroxylase deficiency

Acta Endocrinologica ◽

10.1530/eje.1.02162 ◽

2006 ◽

Vol 154 (6) ◽

pp. 859-864 ◽

Cited By ~ 13

Author(s):

A Luczay ◽

D Török ◽

A Ferenczi ◽

J Majnik ◽

J Sólyom ◽

...

Keyword(s):

Glucocorticoid Receptor ◽

Plasma Renin ◽

Hydroxylase Deficiency ◽

Laboratory Findings ◽

Specific Pcr ◽

Cyp21 Gene ◽

Significant Difference ◽

Allele Specific ◽

21 Hydroxylase Deficiency

Objective: Congenital adrenal hyperplasia (CAH) shows a range of severity which is explained in part by the different mutations of the CYP21 gene. To better understand the incomplete concordance between genotype and phenotype in CAH the role of the sensitizing N363S polymorphism of the glucocorticoid receptor (GR) was examined in CAH patients. Design: CAH patients were screened for N363S. Laboratory findings and clinical characteristics of carriers and non-carriers were analyzed retrospectively. Methods: The CYP21 gene of 200 CAH patients was analyzed by allele-specific PCR. The GR gene was tested for N363S by PCR followed by restriction fragment length polymorphism. Antropometric data (height, weight), degree of intrauterine virilization, hormone concentrations (17-OH-progesterone, dehydroepiandrosterone (DHEA), aldosterone, testosterone, plasma renin activity), substitution doses and clinical course were analyzed. Results: The carrier frequency of N363S in CAH patients was equivalent to that of the general Hungarian population (6% vs 7.8%). Interestingly, none of the non-classical CAH (NC-CAH) patients were carriers of the polymorphism. Carrier girls had milder genital virilization than mutation-matched non-carrier controls. There was no significant difference between the carriers and non-carriers in either the substitution doses, the hormonal, or the auxiological parameters. Conclusions: The association of sensitizing the GR variant with impaired cortisol production in CAH might be compensatory in mild NC-CAH and may prevent severe intrauterine virilization in classical form. Although the exact role of N363S in extrauterine life should be further investigated, the consideration of certain genetic polymorphisms of CAH patients may lead to better, individualized therapeutic regimes.

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