scholarly journals Non-Classical Congenital Adrenal Hyperplasia-Causing Alleles in Adolescent Girls with PCOS and in Risk Group for PCOS Development

Diagnostics ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 980
Author(s):  
Lasma Lidaka ◽  
Laine Bekere ◽  
Gunta Lazdane ◽  
Iveta Dzivite-Krisane ◽  
Anda Kivite-Urtane ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Phenotypic Expression ◽  
Clinical Manifestations ◽  
Control Group ◽  
Compound Heterozygous ◽  
Heterozygous State ◽  
Adrenal Hyperplasia ◽  
Cyp21a2 Gene ◽  
Female Population ◽  
Increased Risk

Background: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women. Depending on the diagnostic criteria applied, it occurs in up to 16.6% of the general female population. Congenital adrenal hyperplasia includes a group of autosomal recessive disorders, the most common of which is non-classical congenital adrenal hyperplasia (NCAH) caused by mutations in the CYP21A2 gene. PCOS and NCAH have similar clinical manifestations (hyperandrogenemia, i.e., hirsutism, acne, alopecia, and increased androgen levels in the blood) and potential impact on long-term health (infertility, increased risk of type 2 diabetes, and cardiovascular disease. Consequently, it is thought that NCAH mutations in the heterozygous state may play a role in PCOS development and phenotypic expression. Objective: To determine the prevalence of the most common pathogenic alleles of the CYP21A2 gene in adolescents with PCOS and adolescents at risk of PCOS development, and to compare the results with healthy adolescents matched for gynecological age. Methods: A cross-sectional study was conducted with 55 PCOS patients, 23 risk patients (with hyperandrogenism but a normal menstrual cycle), and 49 healthy adolescents. Genetic variations in the CYP21A2 gene were analyzed using a standard Multiplex Ligation-dependent Probe Amplification test (SALSA MLPA Probemix P050-C1 CAH; MRC Holland). Results: No significant differences were found among the three groups regarding the frequency of carriers of NCAH variations in the heterozygous state. It was found that the I172N carrier in the PCOS group had a significantly higher Global Acne Grading Scale score than PCOS patients without this variation (p = 0.038). Within the control group of healthy adolescents, compound heterozygous carriers (IVS2-12A > G and -113G > A) had a significantly higher body mass index than non-carriers (p = 0.036). Conclusion: We found no differences in the incidence of NCAH-causing variations in the heterozygous state in adolescent PCOS patients, risk adolescents (with hirsutism but normal menstruation), and healthy adolescents. Future studies of larger cohorts and rarer pathogenic CYP21A2 gene variations are required.

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 Current Aspects of Genetic Diagnosis of 21-Hydroxylase Insufficiency

Doctor Ru ◽  
2021 ◽  
Vol 20 (6) ◽  
pp. 73-79
Author(s):  
N.S. Osinovskaya ◽  
◽  
Yu.A. Nasykhova ◽  
M.I. Yarmolinskaya ◽  
O.B. Glavnova ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Congenital Adrenal Hyperplasia ◽  
Genetic Counselling ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Clinical Manifestations ◽  
Adrenal Hyperplasia ◽  
Cyp21a2 Gene ◽  
Gene Sequence Analysis ◽  
Dideoxynucleotide Chain Termination Method

Objective of the Review: To discuss the current peculiarities of 21-hydroxylase insufficiency diagnostics. Key Points. Congenital adrenal hyperplasia (CAH) is a group of autosomal-recessive pathologies, associated with a defective enzyme or transport protein participating in cortisol biosynthesis. Currently, there is information on CAH genetics including information on 21-hydroxylase insufficiency. Neonatal screening, antenatal and postnatal methods to diagnose 21-hydroxylase deficit have been developed. Timely diagnosis and correct therapy have been found to facilitate normal physical and mental development of patients. Molecular genetic testing for CAH associated with 21-hydroxylase deficit is widely used both in Russia and globally and is of importance for differential diagnosis, identification of pathogenic CYP21A2 gene carriers and adequate genetic counselling. The best strategy to diagnose 21-hydroxylase insufficiency is 2-stage CYP21A2 gene analysis. The test should include both gene sequence analysis and identification of point replacements, minor deletions and duplication (e.g., dideoxynucleotide chain-termination method or Next Generation Sequencing), and identification of extended deletions and duplication (multiplex ligation dependent probe amplification, real-time polymerase chain reaction). Such a comprehensive approach can help finding a majority of types of possible changes. Conclusion. Correct genetic testing methods ensure detection of pathogen variants in CYP21A2 gene; evaluation of the possible rate of clinical manifestations of the disease, both during antenatal testing and if an unknown clinical CAH form is encountered; prescribing an adequate therapy; and ensuring genetic counselling in order to develop a management strategy, including when planning for pregnancy in a woman with confirmed CAH. Keywords: congenital adrenal hyperplasia, CYP21A2 gene, genetic counselling, 21-hydroxylase

scholarly journals A p.P30L Mutation at the CYP21A2 Gene in Macedonian Patients with Nonclassical Congenital Adrenal Hyperplasia

2010 ◽  
Vol 13 (1) ◽  
pp. 17-21 ◽  
Author(s):  
V Anastasovska ◽  
E Kocova ◽  
M Kocova
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Polymerase Chain Reaction Amplification ◽  
Restriction Enzymes ◽  
Heterozygous State ◽  
Adrenal Hyperplasia ◽  
Homozygous State ◽  
Adrenal Androgen ◽  
Androgen Excess ◽  
Cyp21a2 Gene ◽  
Reaction Amplification

A p.P30L Mutation at the CYP21A2 Gene in Macedonian Patients with Nonclassical Congenital Adrenal HyperplasiaNonclassical congenital adrenal hyperplasia (NCAH) is an autosomal recessive imbalance in cortisol synthesis with adrenal androgen excess. Although rarely recognized in infants, it may cause premature adrenarche and pubarche, virilization in young women and variable symptoms in young men. It is commonly caused by mutations in CYP21A2, the gene for steroid 21-hydroxylase. Patients with the p.P30L allele tend to have pronounced evidence of androgen excess but are categorized as nonclassical. We used direct molecular detection of the p.P30L mutation in CYP21A2 in 11 Macedonian NCAH patients and in 17 members of their families using polymerase chain reaction/amplification created restriction site (PCR/ACRS) analysis and digestion with restriction enzymes. The p.P30L mutation was found in a homozygous state in seven (63.6%) and in a heterozygous state in four (36.4%) patients. Of the latter, one was also heterozygous for the p.Q318X mutation. The p.P30L mutation was found in a heterozygous state in 10 (58.8%) and in a homozygous state in one (5.9%) of the family members. These findings support a role of the p.P30L mutation in NCAH.

scholarly journals A Case Report on Congenital Adrenal Hyperplasia, Varicella Zoster Infection, Varicella Encephalopathy & Cerebellitis

2021 ◽  
Vol 6 (2) ◽  
pp. 308-311
Author(s):  
Aswathy M Shaji ◽  
A. Priya ◽  
S Suwitha
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Neuronal Damage ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Cyp21a2 Gene ◽  
Varicella Zoster ◽  
Adrenal Steroidogenesis ◽  
Increased Risk ◽  
21 Hydroxylase Deficiency ◽  
Varicella Zoster Infection

Congenital adrenal hyperplasia (CAH) comprises a family of autosomal recessive disorder and it will disrupt adrenal steroidogenesis. The most common form of CAH is due to 21-hydroxylase deficiency associated with mutations in the cyp21a2 gene which is located at chromosome 6p21. The clinical features associated with this adrenal steroidogenesis represent a clinical spectrum reflecting to the consequences of the specific mutations. Treatment goals include normal linear growth velocity and “on-time” puberty in affected children. [1] Infection with Varicella zoster virus (vzv) causes chickenpox means Varicella that can be severe in immunocompromised individuals, infants and adults. The primary infection is followed by latency in ganglionic neurons. During this time, no virus particles will produce and no obvious neuronal damage occurs. Reactivation of virus leads to virus replication, which will causes zoster (shingles) in tissues innervated by the involved neurons, inflammation and cell death [2]. Potential complications of this infection are involved in the central nervous system causing encephalitis. An increased risk of this complication is associated with the immunocompromised patient. [3] Keywords: congenital adrenal hyperplasia, varicella zoster infection, varicella encephalopathy, cerebellitis.

Comparative analysis of polymorphic variants of IL-17A and MMP-1 genes with the risk of developing chronic periodontitis in petrochemical workers

2020 ◽  
Vol 60 (10) ◽  
pp. 687-693
Author(s):  
Iskander I. Zaidullin ◽  
Denis O. Karimov ◽  
Lilija K. Karimova ◽  
Milyausha F. Kabirova ◽  
Rasima R. Galimova ◽  
...  
Keyword(s):  
Ethylene Oxide ◽  
Chronic Periodontitis ◽  
Periodontal Diseases ◽  
Clinical Manifestations ◽  
Control Group ◽  
Periodontal Tissues ◽  
Dental Examination ◽  
Number Of Patients ◽  
Increased Risk ◽  
Harmful Substances

The susceptibility to the development and progression of inflammatory periodontal diseases, which depends on genetic and external factors (smoking, stress, oral hygiene), varies widely. In the development of these diseases, an important role is played not only by the presence of periodontal pathogenic microorganisms, but also by the presence of congenital or acquired immunodeficiency, immunoregulatory defects. The immune system plays a key role in the physiological and pathological processes of periodontal tissues. In this regard, IL17, produced by CD4+ Th cells, which has both Pro-inflammatory and protective activity, is of particular interest in the pathogenesis of periodontitis. The aim of study was to identify the relationship between polymorphic loci of the IL-17A (rs2275913) and MMP-1 (rs1799750) genes and clinical manifestations of chronic periodontitis in petrochemical workers. Dental examination was performed in 92 ethylene oxide production workers with chronic periodontitis and 74 patients with chronic periodontitis who did not come into contact with chemical factors (control group). Genotyping of polymorphisms rs2275913 of the IL17A gene and rs1799750 of the MMP1 gene was performed by allele-specific real-time polymerase chain reaction (PCR). Hygienic assessment of the degree of air pollution of the working area with harmful substances was carried out by gas chromatography according to the guidelines for the determination of harmful substances in the air № 5098-89, № 3119-84. When comparing the results of studies of both groups, there were no statistically significant differences in the frequency distributions of allelic variants and genotypes of the IL-17A and MMP-1 genes. The AA/AG genotypes of the IL-17A gene were associated with an increased risk of severe disease compared to the GG genotype in workers in the main group (OR=6.1; 95% CI 1.33-28.5; p=0.021) and in the control group (OR=7.26; 95% CI 1.34-39.25; p=0.016). Carriers of the A allele in the control group increased the risk of severe chronic periodontitis by 2.4 times compared to carriers of the G allele (OR=2.41; 95% CI 1.19-4.87; p=0.014). During the dental examination of employees of the ethylene oxide plant, the clinical course of periodontal diseases was more severe in comparison with the control group, and the number of patients with severe periodontitis was twice as high. It was found that the AA/AG genotypes of the IL-17A gene and the carrier of the A allele are associated with increased susceptibility to the development of severe chronic periodontitis. The association between the MMP-1 gene polymorphism and the risk of severe forms of chronic periodontitis has not been established. A risk factor for the development of inflammatory periodontal diseases in employees of the petrochemical complex is a complex of harmful production factors.

Congenital adrenal hyperplasia: molecular mechanisms resulting in 21-hydroxylase deficiency

1986 ◽  
Vol 113 (4_Suppl) ◽  
pp. S315-S320 ◽  
Author(s):  
Patricia A. Donohoue ◽  
Cornelis Van Dop ◽  
Nicholas Jospe ◽  
Claude J. Migeon
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Molecular Mechanisms ◽  
Sequence Data ◽  
Phenotypic Expression ◽  
Restriction Pattern ◽  
Class Iii ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Wide Range ◽  
21 Hydroxylase Deficiency

Abstract 21-Hydroxylase deficiency resulting in congenital adrenal hyperplasia (CAH) is a HLA-linked autosomal recessive disorder that has a wide range of phenotypic expression. Two homologous 21-hydroxylase genes (21-OHA and 21-OHB) occur within the Class III region of the major histocompatibility complex, but only one (21-OHB) appears to function in adrenal steroidogenesis. Our restriction maps, and initial sequence data from White et al. (Pediatr Res 20:274A (1986)) for the two human 21-OH genes reveal a high degree of homology between these genes and a reading frame shift mutation in the 21-OHA gene respectively. Among fourteen control subjects, the intragenic restriction patterns of the 21-OHA and 21-OHB genes are invariant. The few restriction fragment length polymorphisms (RFLPs) found in some controls result from polymorphic restriction sites outside the 21-OH genes. In patients with CAH, several different mechanisms for mutation of the 21-OHB gene have been described: 1) deletion of the unique sequences of the 21-OHB gene, 2) conversion of the unique sequences of the 21-OHB gene to those of 21-OHA, and 3) mutations of 21-OHB which do not result in a detectable alteration of restriction pattern (e.g., point mutations). Duplication of the 21-OHA gene has been found in some patients with attenuated CAH; however, the significance of this finding remains unclear.

scholarly journals ID: 1048 A novel nonsense mutation in the CYP21A2 gene of a Vietnamese patient with congenital adrenal hyperplasia

2017 ◽  
Vol 4 (S) ◽  
pp. 129
Author(s):  
Vu Chi Dung ◽  
Ngoc Lan Nguyen ◽  
Huy Hoang Nguyen ◽  
Thi Kim Lien Nguyen ◽  
Thinh Huy Tran ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Nonsense Mutation ◽  
Stop Codon ◽  
Large Deletion ◽  
Heterozygous Mutation ◽  
Normal Allele ◽  
Adrenal Hyperplasia ◽  
Steroid Synthesis ◽  
Cyp21a2 Gene ◽  
Exon 1

Inactivating mutations in the CYP21A2 gene which encodes the protein involved in steroid synthesis have been reported in the patients with congenital adrenal hyperplasia (CAH). An infant who diagnosed with the severe phenotype of CAH such as increasing testicular volume, elevating of 17-hydroxyprogesteron, testosterone and progesterone and his family were subjected for genetic studies. Initially, we used PCR and direct sequencing to screen mutations in the CYP21 gene in the proband and his family. We identified a novel nonsense mutation c.374C>G predicts a substitution of serine for a stop codon at codon 125 (p.S125*) within exon 3 in the proband. However, the inheritance pattern of the mutation was not consistent with disease causation because of a heterozygous mutation carrier in father and sibling, wild-type alleles in mother but mutant alleles in proband. This inspired us to find deletions of exon using multiplex ligation-dependent probe amplification (MLPA) assay. In the profiles of MLPA electropherogram, the proband had a large deletion in exon 3, but his mother did not have. It means that the proband inherited a normal allele from his mother and a mutant allele from his father, but the deletion of a normal allele occurred in the proband. Therefore, mutation c.374C>G (p.S125*) in exon 3 in the proband is considered as a heterozygous deletion mutation. In addition, a large deletion in exon 1 in the maternal allele in the proband is observed. Taking together, the proband carried a nonsense mutation accompanied with two deletions in exon 1 and exon 3 in the CYP21A2 gene affect the CAH phenotype severity. These mutations also expand the CYP21A2 mutation spectrum in CAH disorder. This case also highlights the need of caution when interpreting results of molecular genetics and biochemical testing during genetic counseling.

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