Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency: An Update on Genetic Analysis of CYP21A2 Gene

2020 ◽  
Author(s):  
Berta Carvalho ◽  
C.Joana Marques ◽  
Rita Santos-Silva ◽  
Manuel Fontoura ◽  
Davide Carvalho ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Congenital Adrenal Hyperplasia ◽  
Late Onset ◽  
Molecular Genetic Analysis ◽  
Clinical Severity ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Cyp21a2 Gene ◽  
Pathogenic Variants ◽  
21 Hydroxylase Deficiency

AbstractCongenital Adrenal Hyperplasia is a group of genetic autosomal recessive disorders that affects adrenal steroidogenesis in the adrenal cortex. One of the most common defects associated with Congenital Adrenal Hyperplasia is the deficiency of 21-hydroxylase enzyme, responsible for the conversion of 17-hydroxyprogesterone to 11-deoxycortisol and progesterone to deoxycorticosterone. The impairment of cortisol and aldosterone production is directly related to the clinical form of the disease that ranges from classic or severe to non-classic or mild late onset. The deficiency of 21-hydroxylase enzyme results from pathogenic variants on CYP21A2 gene that, in the majority of the cases, compromise enzymatic activity and are strongly correlated with the clinical severity of the disease. Due to the exceptionally high homology and proximity between the gene and the pseudogene, more than 90% of pathogenic variants result from intergenic recombination. Around 75% are deleterious variants transferred from the pseudogene by gene conversion, during mitosis. About 20% are due to unequal crossing over during meiosis and lead to duplications or deletions on CYP21A2 gene. Molecular genetic analysis of CYP21A2 variants is of major importance for confirmation of clinical diagnosis, predicting prognosis and for an appropriate genetic counselling. In this review we will present an update on the genetic analysis of CYP21A2 gene variants in CAH patients performed in our department.

scholarly journals Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency*

2000 ◽  
Vol 21 (3) ◽  
pp. 245-291 ◽  
Author(s):  
Perrin C. White ◽  
Phyllis W. Speiser
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
External Genitalia ◽  
Clinical Severity ◽  
Sodium Balance ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Gene Encoding ◽  
Salt Wasting ◽  
Direct Mutation ◽  
21 Hydroxylase Deficiency

Abstract More than 90% of cases of congenital adrenal hyperplasia (CAH, the inherited inability to synthesize cortisol) are caused by 21-hydroxylase deficiency. Females with severe, classic 21-hydroxylase deficiency are exposed to excess androgens prenatally and are born with virilized external genitalia. Most patients cannot synthesize sufficient aldosterone to maintain sodium balance and may develop potentially fatal “salt wasting” crises if not treated. The disease is caused by mutations in the CYP21 gene encoding the steroid 21-hydroxylase enzyme. More than 90% of these mutations result from intergenic recombinations between CYP21 and the closely linked CYP21P pseudogene. Approximately 20% are gene deletions due to unequal crossing over during meiosis, whereas the remainder are gene conversions—transfers to CYP21 of deleterious mutations normally present in CYP21P. The degree to which each mutation compromises enzymatic activity is strongly correlated with the clinical severity of the disease in patients carrying it. Prenatal diagnosis by direct mutation detection permits prenatal treatment of affected females to minimize genital virilization. Neonatal screening by hormonal methods identifies affected children before salt wasting crises develop, reducing mortality from this condition. Glucocorticoid and mineralocorticoid replacement are the mainstays of treatment, but more rational dosing and additional therapies are being developed.

scholarly journals Molecular Analysis of CYP21A2 Gene Mutations among Iraqi Patients with Congenital Adrenal Hyperplasia

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Ruqayah G. Y. Al-Obaidi ◽  
Bassam M. S. Al-Musawi ◽  
Munib Ahmed K. Al-Zubaidi ◽  
Christian Oberkanins ◽  
Stefan Németh ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Molecular Analysis ◽  
Point Mutations ◽  
Gene Mutations ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Cyp21a2 Gene ◽  
Gene Deletions ◽  
Large Gene ◽  
21 Hydroxylase Deficiency

Congenital adrenal hyperplasia is a group of autosomal recessive disorders. The most frequent one is 21-hydroxylase deficiency. Analyzing CYP21A2 gene mutations was so far not reported in Iraq. This work aims to analyze the spectrum and frequency of CYP21A2 mutations among Iraqi CAH patients. Sixty-two children were recruited from the Pediatric Endocrine Consultation Clinic, Children Welfare Teaching Hospital, Baghdad, Iraq, from September 2014 till June 2015. Their ages ranged between one day and 15 years. They presented with salt wasting, simple virilization, or pseudoprecocious puberty. Cytogenetic study was performed for cases with ambiguous genitalia. Molecular analysis of CYP21A2 gene was done using the CAH StripAssay (ViennaLab Diagnostics) for detection of 11 point mutations and >50% of large gene deletions/conversions. Mutations were found in 42 (67.7%) patients; 31 (50%) patients were homozygotes, 9 (14.5%) were heterozygotes, and 2 (3.2%) were compound heterozygotes with 3 mutations, while 20 (32.3%) patients had none of the tested mutations. The most frequently detected mutations were large gene deletions/conversions found in 12 (19.4%) patients, followed by I2Splice and Q318X in 8 (12.9%) patients each, I172N in 5 (8.1%) patients, and V281L in 4 (6.5%) patients. Del 8 bp, P453S, and R483P were each found in one (1.6%) and complex alleles were found in 2 (3.2%). Four point mutations (P30L, Cluster E6, L307 frameshift, and R356W) were not identified in any patient. In conclusion, gene deletions/conversions and 7 point mutations were recorded in varying proportions, the former being the commonest, generally similar to what was reported in regional countries.

Late-Onset Steroid 21-Hydroxylase Deficiency: A Variant of Classical Congenital Adrenal Hyperplasia*

1982 ◽  
Vol 55 (5) ◽  
pp. 817-827 ◽  
Author(s):  
BRENDA KOHN ◽  
LENORE S. LEVINE ◽  
MARILYN S. POLLACK ◽  
SONGYA PANG ◽  
FRANZISKA LORENZEN ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Late Onset ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
21 Hydroxylase Deficiency

scholarly journals Fertility recovery in patients with non-classical congenital adrenal hyperplasia caused by 21-hydroxylase deficiency

2018 ◽  
Vol 64 (2) ◽  
pp. 79-84
Author(s):  
Elena L. Soboleva ◽  
Natalia S. Osinovskaya ◽  
Natalia N. Tkachenko ◽  
Vladislav S. Baranov ◽  
Marina A. Tarasova
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Fertility Restoration ◽  
Glucocorticoid Therapy ◽  
Total Testosterone ◽  
Adrenal Hyperplasia ◽  
Miscarriage Rate ◽  
Hydroxylase Deficiency ◽  
Cyp21a2 Gene ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency

Background. Very little research has been devoted to the studying fertility problem in nonclassical congenital adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency. It is difficult to draw definitive conclusions regarding the need for glucocorticoid therapy in NCAH women based on limited data. Therefore, evaluating fertility in patients with NCAH and exploring the possibility of correcting its disturbances seemed to us to be a matter of importance. Aims — to evaluate the reproductive function of patients with NCAH and explore potential treatments for this disorder. Materials and methods. The study group included 60 patients with NCAH aged between 18 and 33 years old. NCAH was diagnosed based on early-morning serum 17-hydroxyprogesterone (17-OHP) levels above 30 nmol/l or 17-hydroxyprogesterone levels after ACTH stimulation above 26 nmol/l and/or characterized by molecular analysis of the CYP21A2 gene. Ultrasonography of the uterus and ovaries were performed in the cycle’s follicular phase. Total testosterone, dehydroepiandrosterone sulfate (DHEAS), Androstenedione, 17-OHP and Progesterone was measured. Results. Overall, the patients complained of menstrual cycle disorders (60%), infertility — (28%), hirsutism — (63%). Prior to being diagnosed with NCAH, Thirty-four women sought care because of infertility or recurrent miscarriages. Seventeen women (50%) had miscarriages; later on, five of them developed secondary infertility. Two patients became pregnant without treatment being already diagnosed and progressed to delivery. Once the diagnosis of NCAH was made, 58 women started receiving glucocorticoid therapy, Thirty nine (67%) women became pregnant while on glucocorticoid therapy. Thus glucocorticoid therapy reduced the miscarriage rate from 50 to 10.3%; р<0.001. There was no difference in the miscarriage rate between patients who received or quit glucocorticoid therapy during pregnancy. Conclusions. Glucocorticoid therapy is a highly efficacious method of fertility restoration in NCAH patients. Use of glucocorticoids during pregnancy planning significantly reduced the miscarriage rate. No difference in pregnancy outcome between the patients who received glucocorticoid therapy during pregnancy as opposed to those who did not indicates the advisability of treatment discontinuation once pregnancy is determined.

scholarly journals Molecular genetic analysis of CYP21A2 gene in patients with congenital adrenal hyperplasia

2012 ◽  
Vol 16 (3) ◽  
pp. 384 ◽  
Author(s):  
AriacheryC Ammini ◽  
Arundhati Sharma ◽  
Rajesh Khadgawat ◽  
Eunice Marumudi ◽  
Bindu Kulshreshtha ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Congenital Adrenal Hyperplasia ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Adrenal Hyperplasia ◽  
Cyp21a2 Gene

scholarly journals Genotype-Phenotype Correlation in Patients with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency in Cuba

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Tania Mayvel Espinosa Reyes ◽  
Teresa Collazo Mesa ◽  
Paulina Arasely Lantigua Cruz ◽  
Adriana Agramonte Machado ◽  
Emma Domínguez Alonso ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Point Mutations ◽  
Clinical Manifestations ◽  
Adrenal Hyperplasia ◽  
Phenotype Correlation ◽  
Hydroxylase Deficiency ◽  
Cyp21a2 Gene ◽  
Genotype Phenotype Correlation ◽  
21 Hydroxylase Deficiency ◽  
Cuban Population

Background. There are several studies that show a good genotype-phenotype correlation in congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD). However, there is well-documented evidence of inconsistency in some cases. Objectives. To determine if there is a correlation between the identified mutations and the clinical manifestations of 21OHD in the Cuban population. Methods. A cross-sectional descriptive study of all patients referred for a molecular diagnosis of 21OHD in Cuba from January 2000 to December 2018. The clinical manifestations of each patient were identified and classified according to the phenotype. The CYP21A2 gene was analyzed for the presence of 5 point mutations involved in the pathogenesis of 21OHD (intron 2, deletion of 8bp, I172N, P30L, and Q318X); correlation was sought between the phenotypic characteristics and the frequencies of point mutations in the patients using the Spearman test. Results. A total of 55 patients underwent direct analysis of the CYP21A2 gene in order to determine the presence of the 5 point mutations. Point mutations were identified in 31 patients, which corresponded to 56%. A statistically significant genotype-phenotype correlation was found. Conclusions. The correlation between the detected molecular defect and the clinical expression of 21OHD was reasonable in the Cuban population, which could allow phenotypic predictions to be made from the genotype.

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