Genetics of congenital adrenal hyperplasia and genotype-phenotype correlation

Narasimhan, Mithra L.; Khattab, Ahmed

doi:10.1016/j.fertnstert.2018.11.007

Cited by 35 publications

(27 citation statements)

References 16 publications

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“…P30L mutation in exon 1 of CYP21A2 gene is a mild missense single base pair mutation (g.89 C>T), which belongs to the pseudogene-derived mutations. It decreases 21-hydroxylase activity to 20-60% according different authors [1,38,52], frequently causing NC 21OHD. It is not associated with particular HLA antigens in contrast to V281L which is associated with the haplotype B14; DR1 [1].…”

Section: Molecular Structure Of P30l Mutation and Functional Analysismentioning

confidence: 99%

Clinical outcomes and characteristics of P30L mutations in congenital adrenal hyperplasia due to 21-hydroxylase deficiency

2020

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Despite numerous studies in the field of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, some clinical variability of the presentation and discrepancies in the genotype/phenotype correlation are still unexplained. Some, but not all, discordant phenotypes caused by mutations with known enzyme activity have been explained by in silico structural changes in the 21-hydroxylase protein. The incidence of P30L mutation varies in different populations and is most frequently found in several Central and Southeast European countries as well as Mexico. Patients carrying P30L mutation present predominantly as non-classical CAH; however, simple virilizing forms are found in up to 50% of patients. Taking into consideration the residual 21-hydroxulase activity present with P30L mutation this is unexpected. Different mechanisms for increased androgenization in patients carrying P30L mutation have been proposed including influence of different residues, accompanying promotor allele variability or mutations, and individual androgene sensitivity. Early diagnosis of patients who would present with SV is important in order to improve outcome. Outcome studies of CAH have confirmed the uniqueness of this mutation such as difficulties in phenotype classification, different fertility, growth, and psychologic issues in comparison with other genotypes. Additional studies of P30L mutation are warranted.

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Section: Molecular Structure Of P30l Mutation and Functional Analysismentioning

confidence: 99%

Clinical outcomes and characteristics of P30L mutations in congenital adrenal hyperplasia due to 21-hydroxylase deficiency

2020

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“…We deduced that an ampli cation allele dropout effect may occur due to the high similarity between the CYP21A1 and CYP21A2 genes. Additionally, the CYP21A2 gene promotor region and other intronic variants that have not been analysed in studies may also reduce transcriptional activity [4].…”

Section: Discussionmentioning

confidence: 99%

“…In clinical practice, the differential diagnosis and management of paediatric PAI are quite challenging [4]. Ori Eyal and colleagues reviewed the epidemiology and risk factors for adrenal crises in children with adrenal insu ciency (AI) between 1990 and 2017 at four Israeli paediatric endocrinology units and found that diagnosis and long-term management of paediatric patients remained a challenge [5].…”

Section: Introductionmentioning

confidence: 99%

Genetic Aetiology of Primary Adrenal Insufficiency in Chinese Children

Chang

Lü

Zhao

et al. 2020

Preprint

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Background Primary adrenal insufficiency (PAI) is a life-threatening condition, and a definitive aetiological diagnosis is essential for management and prognostication. We conducted this study to investigate the genetic aetiologies of PAI in South China and explore their clinical features. Results Among the 70 children, 84.29% (59/70) were diagnosed with congenital adrenal hyperplasia (CAH), and a diagnosis of 21-hydroxylase deficiency (21-OHD) was subsequently genetically confirmed in 91.53% of the cases. Salt wasting (SW), simple virilization (SV), and non-classic (NC) CAH accounted for 66.10% (39/59), 30.51% (18/59), and 3.39% (2/59) of the cases, respectively. Interestingly, 17-hydroxyprogesterone (17-OHP) and testosterone levels in females were significantly higher than those in males among both SW and SV CAH patients. Additionally, 15.71% (11/70) of the patients were diagnosed with PAI, 72.73% (8/11) of whom had positive genetic findings. Among all the cases, two novel variants in CYP21A2, c.833dupT (p. 279GfsX17) and c.651 + 2T > G, were harboured by CAH patients. A microdeletion (Xp21.2-21.3) and five novel variants, including 2 in the NR0B1 gene (p. 108S > X, p.L411Vfs*6, c.1231_1234delCTCA, p.L411Vfs*6), 2 in the AAAS gene (c.399 + 1G > A, p.V103Afs*8, c.250delT, p.W84Gfs*10) and 1 in the NNT gene (p.I758Mfs*10), were detected. The novel variant c.399 + 1G > A in the AAAS gene was further confirmed to lead to exon 4 deletion in mRNA transcription and produce a truncated ALADIN protein. Conclusions We found ethnic differences in the CYP21A2 gene variant spectrum among different study populations. Female 21-OHD patients tended to have higher 17-OHP and testosterone levels, which warrants caution in relation to the virilization effect both physically and psychologically. Novel gene variants detected in the CYP21A2, NR0B1, AAAS and NNT genes expanded the genetic spectrum of paediatric PAI; however, further improvement of genetic testing tools beyond our protocol is still needed to uncover the complete aetiology of PAI in children.

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“…Usually, a better correlation between phenotypegenotype is achieved on SW and NC forms, where genotype can predict the clinical severity of the disease [37]. Particular attention should be taken in SV form, where a large phenotypic variability is usually noted, and sometimes even in the supposed clearly correlated cases, the genotype-phenotype discordance exists [38,39]. In summary, the lack of a genotype-phenotype correlation in some cases reinforces the necessity to extend the analysis to less studied regions that may direct gene regulation.…”

Section: Cyp21a2 Genotype Interpretation and Reportingmentioning

confidence: 99%

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

Carvalho

Marques

Silva

et al. 2020

Exp Clin Endocrinol Diabetes

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Congenital 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.

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Genetics of congenital adrenal hyperplasia and genotype-phenotype correlation

Cited by 35 publications

References 16 publications

Clinical outcomes and characteristics of P30L mutations in congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Clinical outcomes and characteristics of P30L mutations in congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Genetic Aetiology of Primary Adrenal Insufficiency in Chinese Children

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

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