scholarly journals Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

2017 ◽  
Vol 114 (10) ◽  
pp. E1933-E1940 ◽  
Author(s):  
Ahmed Khattab ◽  
Shozeb Haider ◽  
Ameet Kumar ◽  
Samarth Dhawan ◽  
Dauood Alam ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Severe Disease ◽  
Gene Mutations ◽  
Structural Basis ◽  
Missense Mutations ◽  
Adrenal Hyperplasia ◽  
Clinical Genetic ◽  
Hydroxylase Deficiency ◽  
Gene Encoding ◽  
21 Hydroxylase Deficiency

Congenital adrenal hyperplasia (CAH), resulting from mutations inCYP11B1, a gene encoding 11β-hydroxylase, represents a rare autosomal recessive Mendelian disorder of aberrant sex steroid production. Unlike CAH caused by 21-hydroxylase deficiency, the disease is far more common in the Middle East and North Africa, where consanguinity is common often resulting in identical mutations. Clinically, affected female newborns are profoundly virilized (Prader score of 4/5), and both genders display significantly advanced bone ages and are oftentimes hypertensive. We find that 11-deoxycortisol, not frequently measured, is the most robust biochemical marker for diagnosing 11β-hydroxylase deficiency. Finally, computational modeling of 25 missense mutations ofCYP11B1revealed that specific modifications in the heme-binding (R374W and R448C) or substrate-binding (W116C) site of 11β-hydroxylase, or alterations in its stability (L299P and G267S), may predict severe disease. Thus, we report clinical, genetic, hormonal, and structural effects ofCYP11B1gene mutations in the largest international cohort of 108 patients with steroid 11β-hydroxylase deficiency CAH.

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.

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.

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.

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 Cystic fibrosis and congenital adrenal hyperplasia: A rare occurrence with diagnostic dilemmas, similarities and contradictions

2020 ◽  
Vol 4 (1) ◽  
pp. 018-020
Author(s):  
Nabavi Mohammad ◽  
Rezaeifar Parisa ◽  
Fallahpour Morteza ◽  
Arshi Saba ◽  
Bemanian Mohammad Hassan ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Congenital Adrenal Hyperplasia ◽  
Respiratory Infections ◽  
Pancreatic Enzyme ◽  
Gene Mutations ◽  
Failure To Thrive ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Multiple Systems ◽  
21 Hydroxylase Deficiency

Cystic fibrosis (CF) is a hereditary syndrome composed of exocrine gland dysfunction involving multiple systems which if untreated may result in chronic respiratory infections, pancreatic enzyme deficiency and failure to thrive. The association between CF and other inherited diseases or congenital anomalies is rare. We describe a rare case of CF with concomitant congenital adrenal hyperplasia (CAH). 21- Hydroxylase deficiency accounts for most CAH cases. Varity in clinical phenotypes depends on the amount of enzymatic activity which in turn depends on different combination of gene mutations. The genes of CAH and CF are located in different locations. The chance of these diseases coexisting in our patient would be a rare combination. However, such a case will be more frequent in our population than others because of consanguineous marriage and common ancestors. There are diagnostic difficulties, similarities and contradictions between two diseases and they are pointed out.

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