scholarly journals The spectrum of CYP21A2 gene mutations in patients with 2l-hydroxylase deficiency -induced congenital adrenal hyperplasia in a Chinese cohort

2020 ◽  
Author(s):  
Yang Liu ◽  
Jie Zheng ◽  
Xiaowei Xu ◽  
Xinjie Zhang ◽  
Ying Zhang ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Gene Mutations ◽  
Autosomal Recessive Disorder ◽  
Northern China ◽  
Molecular Data ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Cyp21a2 Gene ◽  
Large Gene ◽  
21 Hydroxylase Deficiency

Abstract Background 21-hydroxylase deficiency (21-OHD) caused by the CYP21A2 gene mutations is the most popular form of congenital adrenal hyperplasia. It is an autosomal recessive disorder results in the defective synthesis of cortisol and aldosterone. The incidences of various CYP21A2 gene mutations and the genotype-phenotype correlations vary among different populations. Therefore, the aim of current study was to identify the spectrum of CYP21A2 gene mutations of patients from northern China and analyze the genotype-phenotype correlation.Methods The clinical and molecular data of 22 patients were analyzed in this study. Locus-specific polymerasechain reaction and Sanger sequencing were applied to identify gene micro-conversions, and multiplex ligation-dependent probe amplification as an alternative to Southern blotting was used to detect large fragment deletions/conversions. Then the genotypes were categorized in to Null, A, B, C and D groups to analyze the relationships between genotypes and phenotypes.Results Molecular defects were detected in 44 alleles (100%). Micro-conversion mutation IVS2-13A/C> G (70.5%) is most common in our cohort, followed by large gene deletions and conversions (22.7%). The other mutations present were p.R357W (4.5%) and E6 Cluster (2.3%). Genotypes of 22 patients (100%) were consistent with the predictive phenotypes.Conclusions In this study, we collected 22 21-OHD patients’ clinical and mutations data in Chinese population, especially in northern China. Micro-conversions were the most popular mutations and the frequencies were consistent with other cohorts. Moreover, thegenotypes and phenotypes in 21-OHDwere well correlated. This studyidentifiedthe mutation spectrum of CYP21A2gene and conduced to genetic counseling and prenatal diagnosis.

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.

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 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 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.

scholarly journals So, and if it is not congenital adrenal hyperplasia? Addressing an undiagnosed case of genital ambiguity

2021 ◽  
Author(s):  
Reinaldo Luna de Omena Filho ◽  
Reginaldo José Petroli ◽  
Fernanda Caroline Soardi ◽  
Débora de Paula Michelatto ◽  
Taís Nitsch Mazzola ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Treatment Options ◽  
External Genitalia ◽  
Autosomal Recessive Disorder ◽  
Missense Variant ◽  
Ambiguous Genitalia ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Genital Ambiguity ◽  
21 Hydroxylase Deficiency

Abstract The Congenital Adrenal Hyperplasia due to 21 hydroxylase deficiency is the most common cause of genital ambiguity in persons with XX sexual chromosomes. Genital ambiguity among persons with XY sexual chromosomes comprises diverse and rare etiologies. The deficiency of 17-beta-hydroxysteroid dehydrogenase type 3 enzyme (HSD17B3) is a rare autosomal recessive disorder due to functionally altered variants of the HSD17B3 gene. In this disorder/difference of sex development, the conversion of androstenedione into testosterone is impaired. The appearance of external genitalia of 46,XY individuals varies from typically male to almost female. We report on a child presenting severe ambiguous genitalia. Due to access constraints, specialized care did not start until the child was 10 months old. Parents are consanguineous and were born in an area of high isonymy that is a cluster for rare recessive diseases. A new homozygous missense variant c.785G > T was found in exon 10 of the HSD17B3 gene. Researchers-clinicians and researchers-researchers collaborative efforts to elucidate the genetic basis of this disease were critical since this etiologic investigation is not available through the public health system. This case exemplifies the families’ pilgrimage in cases of genital ambiguity due to a rare genetic condition. Recognizing the etiology was the baseline to provide information on prognosis and treatment options, and to shelter family and child doubts and hopes in order to better support their decisions.

scholarly journals Congenital adrenal hyperplasia: focus on the molecular basis of 21-hydroxylase deficiency

2007 ◽  
Vol 9 (11) ◽  
pp. 1-23 ◽  
Author(s):  
João Gonçalves ◽  
Ana Friães ◽  
Luís Moura
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Autosomal Recessive ◽  
Clinical Symptoms ◽  
Genetic Recombination ◽  
Autosomal Recessive Disorder ◽  
Gene Duplications ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Recent Developments ◽  
21 Hydroxylase Deficiency

AbstractCongenital adrenal hyperplasia (CAH) is an autosomal recessive disorder caused by defects in one of several steroidogenic enzymes involved in the synthesis of cortisol from cholesterol in the adrenal glands. More than 90% of cases are caused by 21-hydroxylase deficiency, and the severity of the resulting clinical symptoms varies according to the level of 21-hydroxylase activity. 21-Hydroxylase deficiency is usually caused by mutations in theCYP21A2gene, which is located on the RCCX module, a chromosomal region highly prone to genetic recombination events that can result in a wide variety of complex rearrangements, such as gene duplications, gross deletions and gene conversions of variable extensions. Molecular genotyping ofCYP21A2and the RCCX module has proved useful for a more accurate diagnosis of the disease, and prenatal diagnosis. This article summarises the clinical features of 21-hydroxylase deficiency, explains current understanding of the disease at the molecular level, and highlights recent developments, particularly in diagnosis.

scholarly journals Case Report: Infant With Congenital Adrenal Hyperplasia and 47,XXY

2022 ◽  
Vol 12 ◽  
Author(s):  
Sophia Q. Song ◽  
Andrea Gropman ◽  
Robert W. Benjamin ◽  
Francie Mitchell ◽  
Michaela R. Brooks ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Genetic Disorders ◽  
Gene Mutations ◽  
Tall Stature ◽  
Clinical Report ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Autosomal Recessive Disorders ◽  
21 Hydroxylase Deficiency ◽  
Recessive Disorders

Congenital adrenal hyperplasia is a group of autosomal recessive disorders in which enzymes in the cortisol biosynthesis pathways are disrupted by gene mutations. The most common form of congenital adrenal hyperplasia, caused by 21-hydroxylase deficiency, is characterized by decreased cortisol and aldosterone synthesis and excessive androgen production. Adult height is often compromised in affected patients. Intellectual capability remains intact in patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency, based on previous studies. 47,XXY (KS) is a sex chromosomal aneuploidy that manifests with hypergonadotropic hypogonadism, tall stature, and variable intellectual and behavioral dysfunction. This clinical report describes an infant with 21-hydroxylase deficiency congenital adrenal hyperplasia and 47,XXY. The results of his neurodevelopmental, endocrine, neurological, and physical therapy evaluations during his first 22 months are included and were normal. This is the first published case investigating the neurodevelopmental profile of a patient with the combination of these two genetic disorders.

The Spectrum of Genetic Defects in Congenital Adrenal Hyperplasia in the Population of Cyprus: A Retrospective Analysis

2019 ◽  
Vol 51 (09) ◽  
pp. 586-594 ◽  
Author(s):  
Vassos Neocleous ◽  
Pavlos Fanis ◽  
Meropi Toumba ◽  
Charilaos Stylianou ◽  
Michalis Picolos ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Cyp21a2 Gene ◽  
Salt Wasting ◽  
Greek Cypriot ◽  
Frequent Mutations ◽  
Simple Virilizing ◽  
21 Hydroxylase Deficiency ◽  
Greek Cypriots

AbstractCongenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is caused by mutations in the CYP21A2 gene. The study refers to CAH patients of Greek-Cypriot ancestry between years 2007 and 2018. One hundred and twenty patients with various degrees of CAH were categorized and genotyped. The patients were categorized in 4 mutation groups based on their clinical and biochemical findings. The majority of patients (85.0%) belonged to the non-classic (NC)-CAH form and the disorder was more often diagnosed in females (71.7%). The most severe classic salt-wasting (SW) form was identified in 11 neonates (9.2%). Seven (5.8%) children were also identified with the simple virilizing (SV) form and a median presentation age of 5 years [interquartile range (IQR) 3.2–6.5]. In the 240 nonrelated alleles, the most frequent mutation was p.Val281Leu (60.0%) followed by c.655 A/C>G (IVS2–13A/C>G) (8.8%), p.Pro453Ser (5.8%), DelEx1–3 (4.6%), p.Val304Met (4.6%), and p.Gln318stop (4.2%). Other less frequent mutations including rare deletions were also identified. Following our recent report that the true carrier frequency of CYP21A2 in Greek-Cypriots is 1:10, this study reports that the CAH prevalence is predicted around 1.7 cases per 10 000 people. Therefore, the up-to-date 120 CAH patients identified by our group make only the 6.9% of the ones estimated (approximately 1750) to exist in the Greek Cypriot population. The compiled data from a coherent population such as the Greek-Cypriot could be valuable for the antenatal diagnosis, management and genetic counselling of the existing and prospect families with CAH.

scholarly journals Four Novel Missense Mutations in the CYP21A2 Gene Detected in Russian Patients Suffering from the Classical Form of Congenital Adrenal Hyperplasia: Identification, Functional Characterization, and Structural Analysis

2006 ◽  
Vol 91 (12) ◽  
pp. 4976-4980 ◽  
Author(s):  
Yulia Grischuk ◽  
Petr Rubtsov ◽  
Felix G. Riepe ◽  
Joachim Grötzinger ◽  
Svetlana Beljelarskaia ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Enzyme Analysis ◽  
Missense Mutations ◽  
Adrenal Hyperplasia ◽  
Inherited Disorders ◽  
Hydroxylase Deficiency ◽  
Cyp21a2 Gene ◽  
Functional Relationships ◽  
21 Hydroxylase Deficiency

Abstract Context: Congenital adrenal hyperplasia is a group of autosomal recessive inherited disorders of steroidogenesis. The most frequent cause is the deficiency of steroid 21-hydroxylase (CYP21) due to mutations in the CYP21A2 gene. Objective: We analyzed the functional and structural consequences of the four CYP21A2 missense mutations (C169R, G178R, W302R, and R426C) to prove their clinical relevance and study their impact on CYP21 function. Results: Analyzing the mutations in vitro revealed an almost absent or negligible CYP21 activity for the conversion of 17-hydroxyprogesterone to 11-deoxycortisol and progesterone to deoxycorticosterone. Protein translation and intracellular localization were not affected by the mutants, as could be demonstrated by Western blotting and immunofluorescence studies. Analysis of these mutants in a three-dimensional model structure of the CYP21 protein explained the observed in vitro effects because all the mutations severely interfere either directly or indirectly with important structures of the 21-hydroxylase protein. Conclusion: The in vitro expression analysis of residual enzyme function is a complementary method to genotyping and an important tool for improving the understanding of the clinical phenotype of 21-hydroxylase deficiency. This forms the foundation for accurate clinical and genetic counseling and for prenatal diagnosis and treatment. Moreover, this report demonstrates that the combination of in vitro enzyme analysis and molecular modeling can yield novel insights into CYP450 structure-functional relationships.

Sign in / Sign up

Export Citation Format

Share Document