Genotype/phenotype correlations in 538 congenital adrenal hyperplasia patients from Germany and Austria: discordances in milder genotypes and in screened versus prescreening patients

Riedl, Stefan; Röhl, Friedrich-Wilhelm; Bonfig, Walter; Brämswig, Jürgen; Richter‐Unruh, Annette; Fricke-Otto, Susanne; Bettendorf, Markus; Riepe, Felix G.; Kriegshäuser, Gernot; Schönaü, Eckhard; Even, Gertrud; Hauffa, Berthold P.; Dörr, Helmuth-Günther; Holl, Reinhard W.; Mohnike, Klaus

doi:10.1530/ec-18-0281

Cited by 42 publications

(41 citation statements)

References 31 publications

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“…In our cohort, we found a high correlation between genotype and phenotype, similarly to a report on a large cohort from Brazil 18 . However, other authors reported higher percentages of discrepancy 17,33,37‐39 …”

Section: Discussionsupporting

confidence: 92%

Genetic characterization of a large cohort of Argentine 21‐hydroxylase Deficiency

Fernández

Taboas

Bruque

et al. 2020

Clinical Endocrinology

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Context 21‐hydroxylase deficiency is the most common cause of Congenital Adrenal Hyperplasia. It presents as severe or classical forms—salt wasting and simple virilizing—and a mild or nonclassical (NC). Several studies have reported the frequency of pathogenic variants in different populations, although few of them included a large number of NC patients. Objective To analyse the CYP21A2 gene defects in a large cohort of Argentine patients. Design Molecular characterization of 628 patients (168 classical, 460 nonclassical, representing 1203 nonrelated alleles), 398 relatives, 126 partners. Methods Genetic variants were assessed by allele‐specific PCR, PCR‐RFLP or direct sequencing. Deletions, duplications and large gene conversions (LGC) were studied by Southern blot/MLPA or long‐range PCR. Biological implications of novel variants were analysed by structure‐based in silico studies. Results The most frequent pathogenic variants were p.V282L (58%) in NC alleles and c.293‐13C>G (31.8%) and p.I173N (21.1%) in classical. Deletions and LGC were found at low frequency (6.2%), 57 alleles had rare pathogenic variants, and 3 had novel variants: p.(S166F); p.(P189R), p.(R436L). Genotype‐phenotype correlation was observed in 98.6% of the cases, 11 asymptomatic first‐degree relatives had pathogenic variants in both alleles, and 21/126 partners were carriers. Conclusions We conducted a comprehensive genetic characterization of the largest cohort of 21‐hydroxylase patients from the region. In particular, we add to the molecular characterization of a large number of NC patients and to the estimation of the disease carrier's frequency in our population.

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Section: Discussionsupporting

confidence: 92%

Genetic characterization of a large cohort of Argentine 21‐hydroxylase Deficiency

Fernández

Taboas

Bruque

et al. 2020

Clinical Endocrinology

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“…7 Medical Office, Endokrinologikum, Ulm, Germany. 8 Paediatric Endocrinology, University Children's Hospital, Munich, Germany. 9 Paediatric Endocrinology, University Children's Hospital, Freiburg, Germany.…”

Section: Acknowledgementsmentioning

confidence: 99%

“…The phenotype is influenced by the activity of the less affected allele, and the residual activity of 21-hydroxylase in the patients is around 20-50% [7]. However, the phenotypical degree of severity within a genotype can vary greatly and different phenotypes can be associated with the same mutation [8].…”

Section: Introductionmentioning

confidence: 99%

Genotype-phenotype correlations in children and adolescents with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency

et al. 2020

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Background: Nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency is caused by mutations in the active 21-hydroxylase gene (CYP21A2). The clinical symptoms can vary greatly. To date, no systematic studies have been undertaken in Germany. Aims: Description of the phenotype, evaluation of the diagnostics and genotype-phenotype correlation Patients and methodology: Retrospective analysis of the data of 134 patients (age range 0.1-18.6 years) in a multicentre study covering 10 paediatric endocrinology centres in Bavaria and Baden-Württemberg. The data was gathered on site from the medical records. Two hundred and thirty-three alleles with a mutation of the CYP21A2 gene were identified in 126 patients. A genotype-phenotype correlation of the mutation findings was undertaken (C1, severe/mild; C2, mild/mild). Individuals with a heterozygous mutation of the CYP21A2 were also included (C3). The data was collected with the approval of the ethics committee of the University Hospital of Erlangen during the period of 2014 and 2015. Results (MW ± SD): One hundred and seventeen out of 134 patients (115 f, 29 m) were symptomatic. The chronological age (CA) at diagnosis was 7.1 ± 4.4 years. The most frequent symptom (73.5%) was premature pubarche. The height-SDS on diagnosis was 0.8 ± 1.3 and the BMI-SDS was 0.8 ± 1.2. Bone age (BA) was ascertained in 82.9% of the symptomatic patients. The difference between BA and CA was 1.9 ± 1.4 years. Basal 17OHP concentrations were 14.5 ± 19.1 ng/ml (18 patients < 2 ng/ml). In total, 58.1% mild and 34.7% severe mutations were found. The most common mutation was p.Val281Leu (39.1%); 65.8% of the patients could be allocated to group C1. No phenotypical differences were found between the 3 mutation groups. The 17OHP levels (basal and after ACTH) in the standard ACTH stimulation test were highest in group C1 and also significantly higher in group C2 as in C3, the ACTH-stimulated cortisol levels (ng/ml) were significantly lower in groups C1 (192.1 ± 62.5) and C2 (218 ± 50) than in C3 (297.3 ± 98.7).

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“…Overall, the phenotype is extremely variable [63,64] since the majority (>65%) of CAH patients are compound heterozygotes with one or more mutations in both CYP21A2 alleles [64,65,66,67,68,69]. In these cases, the clinical phenotype depends on the less severely affected allele [53] (Figure 3B).…”

Section: 21-hydroxylase Deficiency (21-ohd)mentioning

confidence: 99%

46,XX DSD due to Androgen Excess in Monogenic Disorders of Steroidogenesis: Genetic, Biochemical, and Clinical Features

Baronio

Ortolano

Menabò

et al. 2019

IJMS

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The term ‘differences of sex development’ (DSD) refers to a group of congenital conditions that are associated with atypical development of chromosomal, gonadal, or anatomical sex. Disorders of steroidogenesis comprise autosomal recessive conditions that affect adrenal and gonadal enzymes and are responsible for some conditions of 46,XX DSD where hyperandrogenism interferes with chromosomal and gonadal sex development. Congenital adrenal hyperplasias (CAHs) are disorders of steroidogenesis that mainly involve the adrenals (21-hydroxylase and 11-hydroxylase deficiencies) and sometimes the gonads (3-beta-hydroxysteroidodehydrogenase and P450-oxidoreductase); in contrast, aromatase deficiency mainly involves the steroidogenetic activity of the gonads. This review describes the main genetic, biochemical, and clinical features that apply to the abovementioned conditions. The activities of the steroidogenetic enzymes are modulated by post-translational modifications and cofactors, particularly electron-donating redox partners. The incidences of the rare forms of CAH vary with ethnicity and geography. The elucidation of the precise roles of these enzymes and cofactors has been significantly facilitated by the identification of the genetic bases of rare disorders of steroidogenesis. Understanding steroidogenesis is important to our comprehension of differences in sexual development and other processes that are related to human reproduction and fertility, particularly those that involve androgen excess as consequence of their impairment.

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Genotype/phenotype correlations in 538 congenital adrenal hyperplasia patients from Germany and Austria: discordances in milder genotypes and in screened versus prescreening patients

Cited by 42 publications

References 31 publications

Genetic characterization of a large cohort of Argentine 21‐hydroxylase Deficiency

Genetic characterization of a large cohort of Argentine 21‐hydroxylase Deficiency

Genotype-phenotype correlations in children and adolescents with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency

46,XX DSD due to Androgen Excess in Monogenic Disorders of Steroidogenesis: Genetic, Biochemical, and Clinical Features

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