Genotype-Phenotype Correlation Study and Mutational Analysis in a Chinese Cohort with 21-Hydroxylase Deficiency

2018 ◽  
Author(s):  
Wenyu Jia ◽  
Zequn Li ◽  
Xiangdeng Cheng ◽  
Hui Ying ◽  
Fang Zhong ◽  
...  
Keyword(s):  
Mutational Analysis ◽  
Correlation Study ◽  
Phenotype Correlation ◽  
Hydroxylase Deficiency ◽  
Genotype Phenotype Correlation ◽  
Chinese Cohort ◽  
21 Hydroxylase Deficiency

scholarly journals Neonatal Screening and Genotype-Phenotype Correlation of 21-Hydroxylase Deficiency in the Chinese Population

2021 ◽  
Vol 11 ◽  
Author(s):  
Xin Wang ◽  
Yanyun Wang ◽  
Dingyuan Ma ◽  
Zhilei Zhang ◽  
Yahong Li ◽  
...  
Keyword(s):  
Neonatal Screening ◽  
Chinese Population ◽  
Eastern China ◽  
Laboratory Data ◽  
Adrenal Crisis ◽  
Molecular Characteristics ◽  
Phenotype Correlation ◽  
Hydroxylase Deficiency ◽  
Genotype Phenotype Correlation ◽  
21 Hydroxylase Deficiency

Background: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders encompassing enzyme deficiencies in the adrenal steroidogenesis pathway that leads to impaired cortisol biosynthesis. 21-hydroxylase deficiency (21-OHD) is the most common type of CAH. Severe cases of 21-OHD may result in death during the neonatal or infancy periods or sterility in later life. The early detection and timely treatment of 21-OHD are essential. This study aimed to summarize the clinical and genotype characteristics of 21-OHD patients detected by neonatal screening in Nanjing, Jiangsu province of China from 2000 to 2019.Methods: Through a retrospective analysis of medical records, the clinical presentations, laboratory data, and molecular characteristics of 21-OHD patients detected by neonatal screening were evaluated.Results: Of the 1,211,322 newborns who were screened, 62 cases were diagnosed with 21-OHD with an incidence of 1:19858. 58 patients were identified with the classical salt-wasting type (SW) 21-OHD and four patients were identified with simple virilizing type (SV) 21-OHD. Amongst these patients, 19 cases patients accepted genetic analysis, and another 40 cases were received from other cities in Eastern China. Eighteen different variants were found in the CYP21A2 gene. The most frequent variants was c.293-13A/C>G (36.29%). The most severe clinical manifestations were caused by large deletions or conversions of CYP21A2.Conclusions: This study suggested that neonatal screening effectively leads to the early diagnosis of 21-OHD and reduces fatal adrenal crisis. Our data provide additional information on the occurrence and genotype-phenotype correlation of 21-OHD in the Chinese population which can be used to better inform treatment and improve prognosis.

scholarly journals Pitfalls of Prenatal Diagnosis guiding Postnatal Management in Congenital Adrenal Hyperplasia(CAH)

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A150-A151
Author(s):  
Deepa Badrinath Murthy ◽  
Melissa Kaori Litao ◽  
Bina Cherryl Shah ◽  
Brenda Kohn ◽  
Emily Nicole Breidbart
Keyword(s):  
Prenatal Diagnosis ◽  
Genetic Analysis ◽  
Urogenital Sinus ◽  
High Dose ◽  
Phenotype Correlation ◽  
Hydroxylase Deficiency ◽  
Postnatal Management ◽  
Genotype Phenotype Correlation ◽  
Classic Cah ◽  
21 Hydroxylase Deficiency

Abstract Background: 21-hydroxylase deficiency is the most common form of CAH and is associated with a variety of clinical phenotypes (salt wasting SW, simple virilizing SV and non-classic NCCAH). Commonly, there is a strong genotype-phenotype correlation for SW and NCCAH, but this is less predictable with the SV forms. We present a case with prenatal diagnosis of classic CAH which demonstrated genotype-phenotype discordance. Clinical Case: Ex 39 weeker female born to non-consanguineous parents was prenatally diagnosed with CAH based on routine genetic screen. Mother was noted to be a carrier for Intron 2G and father was a carrier of p.I172N both known to be pathogenic variants on CYP21A2. At 23 weeks gestational age, DNA analysis revealed fetus was compound heterozygous for both mutations which is most commonly associated with either SV or SW phenotype. At birth, infant had mild edema of the labia majora which resolved; the clitoris was not enlarged. There was no genital virilization or urogenital sinus. Newborn screen sent at 15 hours of life:17 OHP 132 ng/ml, repeat on DOL 3:77 ng/ml and DOL 13:59.9 ng/ml. High dose cosyntropin stim test on DOL 3 at 0 min: Cortisol not done, 17 OHP 1279 ng/dl; 60 min: Cortisol 12.3mcg/dl, 17OHP 3394 ng/dl. DOL 5 at 0 min: Cortisol 2.7 mcg/dl, ACTH 164.5 pg/ml, 17OHP 803.7 ng/dl; 60 minute: Cortisol 7.6mcg/dl, 17OHP 5920 ng/dl. Using available 17OHP normograms, the infant’s stimulated 17 OHP levels were not consistent with classic CAH. Unstimulated testosterone on DOL 3: 25ng/dl, DOL 5: 14 ng/dl. Ultrasound showed adrenal gland thickness 4mm bilaterally (upper limit of normal). Hydrocortisone (HC) was started on DOL 5 at 35 mg/m2/day after the stim test. On DOL 7, HC was increased to 100 mg/m2/day; fludrocortisone 0.1 mg twice daily and NaCl 0.5 g/day were started (Na 131, K 6.5, plasma renin activity 80.2). Upon discharge (DOL 13), infant was on HC 35 mg/m2/day, Fludrocortisone 0.1mg twice daily and NaCl 2g/day. Doses were adjusted accordingly during outpatient follow up. Currently infant is 4 months of age, thriving and remains on HC 11.3 mg /m2/day, Fludrocortisone 0.05 mg twice daily and NaCl 750 mg daily. Postnatal genetic analysis confirmed prenatal genotype. Conclusion: In general, genotype-phenotype correlation has 80–90% concordance. However clinicians should be aware of genotype/phenotype discrepancies that exist in order to carefully guide postnatal management based on prenatal genetic analysis. Our patient’s 17-ohp was done by LC/MS, which is standard now for most specialized endocrine laboratories. However, the 17-ohp nomograms for CAH, which are frequently used for subtype categorization, are based on RIA levels. Further studies would be helpful in creating an updated normogram using LCMS specifically for the neonatal period, as confirmatory screening of CAH will become more common with the rise in parental prenatal carrier screening.

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 Genotype-Phenotype Correlation in 153 Adult Patients With Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency: Analysis of the United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive (CaHASE) Cohort

2013 ◽  
Vol 98 (2) ◽  
pp. E346-E354 ◽  
Author(s):  
Nils Krone ◽  
Ian T. Rose ◽  
Debbie S. Willis ◽  
James Hodson ◽  
Sarah H. Wild ◽  
...  
Keyword(s):  
United Kingdom ◽  
Health Status ◽  
Congenital Adrenal Hyperplasia ◽  
Adrenal Hyperplasia ◽  
Phenotype Correlation ◽  
Hydroxylase Deficiency ◽  
Adult Study ◽  
The United Kingdom ◽  
Genotype Phenotype Correlation ◽  
21 Hydroxylase Deficiency

Abstract Context: In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a strong genotype-phenotype correlation exists in childhood. However, similar data in adults are lacking. Objective: The objective of the study was to test whether the severity of disease-causing CYP21A2 mutations influences the treatment and health status in adults with CAH. Research Design and Methods: We analyzed the genotype in correlation with treatment and health status in 153 adults with CAH from the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive cohort. Results: CYP21A2 mutations were distributed similarly to previously reported case series. In 7 patients a mutation was identified on only 1 allele. Novel mutations were detected on 1.7% of alleles (5 of 306). Rare mutations were found on 2.3% of alleles (7 of 306). For further analysis, patients were categorized into CYP21A2 mutation groups according to predicted residual enzyme function: null (n = 34), A (n = 42), B (n = 36), C (n = 34), and D (n = 7). Daily glucocorticoid dose was highest in group null and lowest in group C. Fludrocortisone was used more frequently in patients with more severe genotypes. Except for lower female height in group B, no statistically significant associations between genotype and clinical parameters were found. Androgens, blood pressure, lipids, blood glucose, and homeostasis model assessment of insulin resistance were not different between groups. Subjective health status was similarly impaired across groups. Conclusions: In adults with classic CAH and women with nonclassic CAH, there was a weak association between genotype and treatment, but health outcomes were not associated with genotype. The underrepresentation of males with nonclassic CAH may reflect that milder genotypes result in a milder condition that is neither diagnosed nor followed up in adulthood. Overall, our results suggest that the impaired health status of adults with CAH coming to medical attention is acquired rather than genetically determined and therefore could potentially be improved through modification of treatment.

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