simple virilizing
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Deficiency of 21-hydroxylase enzyme (CYP21A2) represents 90% of cases in congenital adrenal hyperplasia (CAH), an autosomal recessive disease caused by defects in cortisol biosynthesis. Computational prediction and functional studies are often the only way to classify variants to understand the links to disease-causing effects. Here we investigated the pathogenicity of uncharacterized variants in the CYP21A2 gene reported in Brazilian and Portuguese populations. Physicochemical alterations, residue conservation, and effect on protein structure were accessed by computational analysis. The enzymatic performance was obtained by functional assay with the wild-type and mutant CYP21A2 proteins expressed in HEK293 cells. Computational analysis showed that p.W202R, p.E352V, and p.R484L have severely impaired the protein structure, while p.P35L, p.L199P, and p.P433L have moderate effects. The p.W202R, p.E352V, p.P433L, and p.R484L variants showed residual 21OH activity consistent with the simple virilizing phenotype. The p.P35L and p.L199P variants showed partial 21OH efficiency associated with the non-classical phenotype. Additionally, p.W202R, p.E352V, and p.R484L also modified the protein expression level. We have determined how the selected CYP21A2 gene mutations affect the 21OH activity through structural and activity alteration contributing to the future diagnosis and management of CYP21A2 deficiency.

Deficiency of Cytochrome P450 Steroid 21-hydroxylase (CYP21A2) represents 90% of cases in congenital adrenal hyperplasia (CAH), an autosomal recessive disease caused by defects in cortisol biosynthesis. Computational prediction along with functional studies are often the only way to classify variants to understand the links to disease-causing effects. Here we investigated the pathogenicity of uncharacterized variants in the CYP21A2 gene reported in the Brazilian and Portuguese populations. Physicochemical alterations, residue conservation, and effect on protein structure were accessed by computational analysis. The enzymatic performance was obtained by functional assay with the wild-type and mutant CYP21A2 proteins expressed in HEK293 cells. Computational analysis showed that p.W202R, p.E352V, and p.R484L have severely impaired the protein structure, while p.P35L, p.L199P, and p.P433L have moderate effects. The p.W202R, p.E352V, p.P433L, and p.R484L variants showed residual 21OH activity consistent with the simple virilizing phenotype. The p.P35L and p.L199P variants showed partial 21OH efficiency associated with the non-classical phenotype. Additionally, p.W202R, p.E352V and p.R484L also modified the protein expression level. We have determined how the selected CYP21A2 gene mutations affect the 21OH activity through structural and activity alteration contributing to the future diagnosis and management of 21OH deficiency.

Objective: Treatment in classic congenital adrenal hyperplasia (CAH) is necessary to compensate for glucocorticoid/mineralocorticoid deficiencies and to suppress androgen excess. Hydrocortisone (HC) is preferred in growing children with classic CAH, but recommendations regarding dosage/administration are inconsistent. Aim of the study was to evaluate HC dosing in children with CAH in relation to chronological age, sex, and phenotype based on a multicentre CAH registry. Design: The CAH registry was initiated in 1997 by the AQUAPE in Germany. On December 31st 2018, data from 1571 patients were included. Methods: A custom-made electronic health record software is used at the participating centres. Pseudonymized data are transferred for central analysis. Parameters were selected based on current guidelines. Descriptive analyses and linear regression models were implemented with SAS 9.4. Results: We identified 1288 patients on exclusive treatment with hydrocortisone three times daily (604 boys; median age 7.2 years; 817 salt-wasting phenotype, 471 simple-virilizing phenotype). The mean [lower-upper quartiles] daily HC dose [mg/m² body surface area] was 19.4 [18.9-19.8] for patients <3 months (n=329), 15.0 [14.6-15.3] age ≥3-12 months (n=463), 14.0 [13.7-14.3] age 1-5.9 years (n=745), 14.2 [14.0-14.5] age 6 years-puberty entry (n=669), and 14.9 [14.6-15.2] during puberty-18 years (n=801). Fludrocortisone was administered in 74.1% of patients (median daily dosage 88.8 µg). Conclusion: Our analyses demonstrated still a high proportion of children with HC doses higher than recommended. This evaluation provides comprehensive information on nationwide hydrocortisone substitution dosages in children with CAH underlining the benefit of systematic data within a registry to assess daily practice.

Congenital adrenal hyperplasia is a disease in which a gene mutation, which is inherited in an autosomal recessive manner, causes a disorder in the synthesis of enzymes that create glucocorticoids, mineralocorticoids, or sex steroids from adrenal cholesterol. The incidence of the classic form of the disease ranges from 1:14000 to 1:18000 births. In the majority of cases, the disease is caused by mutations in the CYP21A2 gene that participates in the synthesis of the 21 Alpha-hydroxylase. Due to the lack of enzymes, the synthesis of cortisol is blocked with the accumulation of sex hormones. The classic form of the disease, or a simple virilizing form in which patients lose salt, is diagnosed in the infant period. In the non-classical or mild form of the disease, with late-onset, patients may be asymptomatic or with a milder form of virilization postnatally. The diagnosis is made based on 17-hydroxyprogesterone levels, in order to determine the deficiency of the 21 Alpha-hydroxylase enzyme. Common complications of the disease are adrenal crisis, hypoglycemia, infertility, and premature entry into puberty. Prenatal therapy is referred to as experimental treatment, while the basis of care is hydrocortisone replacement. In severe forms of the disease, patients are unable to produce enough cortisol in response to stress from gastroenteritis, surgery, trauma, or fever, requiring higher doses of hydrocortisone. In certain cases of genital uncertainty, surgical treatment is necessary. A multidisciplinary team of experts is necessary for adequate surveillance of the disease, in both childhood and adulthood.

Abstract Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a form of primary adrenal insufficiency characterized by impaired cortisol secretion and elevated androgen production, is the leading cause of atypical genitalia in the female newborn. Females with classic CAH, either salt-wasting or simple-virilizing form, usually present at birth with atypical genitalia ranging from clitoromegaly to male-appearing genitalia, due to in utero to elevated androgens (androstenedione and testosterone). Females with mild nonclassic CAH usually present with typical genitalia. Proving the importance of always keeping an open mind for exceptions to the rule, we report on 3 female newborns who presented with the nonvirilized genitalia, salt-wasting CAH phenotype and genotype most consistent with simple-virilizing CAH. It is only through a positive newborn screen identifying the females with CAH that they were diagnosed before developing adrenal and/or salt-wasting crisis.

21-hydroxylase deficiency is the cause of one of the most common hereditary diseases - congenital adrenal hyperplasia (CAH). The level of residual activity of 21-hydroxylase determines the clinical form and severity of the course of the disease. The article presents the clinical characteristics of two forms of CAH – salt-wasting and simple virilizing. Objective. To study the clinical aspects of CAH due to 21-hydroxylase deficiency in children. Material and methods. We analyzed 57 archived case histories and 58 extracts from case histories of children from 0 to 18 years old with an established diagnosis of CAH. In general, the sample comprised cases, of which 36 were boys (48%) and 39 (52%) girls. Results and discussion. Of the 75 children with CAH, 43 (57.3%) had a salt-wasting form, 32 (42.7%) had a simple virilizing form. In children with salt-wasting form, the leading clinical manifestation was salt loss syndrome, with simple virilizing - viril syndrome. The average age of diagnosis with salt-wasting form was 1.5 months (from 1 to 2.6 months), with simple virilizing - 3 years (from 1.4 to 4.4 years). Conclusions. According to our data, in Kazakhstan, the salt- wasting form of СAH is diagnosed more often than a simple virilizing form (57.3% / 42.7%). The problems of timely diagnosis of CAH and in the selection of the appropriate passport gender of the child were identified. Keywords: congenital adrenal hyperplasia, 21-hydroxylase deficiency, salt-wasting form, simple virilizing form.

Abstract Introduction: Congenital Adrenal Hyperplasia (CAH) is defined as a group of autosomal recessive disorders characterized by a deficiency of the enzyme required to synthesize cortisol by the adrenal cortex. Defects in the 21-hydroxylase enzyme make up of 90% of CAH. It is caused by several mutations in the CYP21A2 gene. These defects impaired cortisol synthesis leading to an ACTH increase resulting in androgen excess, either with salt-wasting or simple virilizing forms. Androgens play a crucial role in the human psychosexual development favoring male psychosexuality. This study was designed to evaluate the impact of androgens on psychosexuality of a cohort of individuals with CAH due 21-hydroxylase deficiency. Methods: This retrospective cohort is made up of 94 four individuals with proved molecular defect of the CYP21A2 gene. External genitalia virilization was scored using Prader scale. Clinical phenotype, age at diagnosis, sex assignment, gender reassignment and gender change were all assessed. The gender role at childhood was assessed through the playmates and favorite toys at childhood. Gender identity was assessed by a projective psychological test (HTP). Sexual orientation was assessed by self-report and sexual attractiveness. Compliance of glucocorticoid replacement was assessed by serum testosterone and 17OHP levels. Results: CAH was diagnosed at neonatal time in 67% (61 out 94). 51% (n=48) had the salt-wasting form (SW) and 49% (n=46) had the simple virilizing form (SV). While all cases of SW were diagnosed at neonatal time (0.12 ± 0.14 months), the mean age at diagnosis among SV was 6.03 ± 8.45 years (F 38.9; p=&lt;.001). A total of 84.5% were assigned as female at birth. The median of Prader score was 3 in both phenotypes. Male sex assignment was associated with more virilized external genitalia (Prader 4 and 5) while the opposite (Prader 1 and 2) was associated with female sex assignment (X2 16, p=.002, V=0.44). Gender change from female to male occurred in 7 cases (7.4%). All cases of gender change had SV form (p=.006). The mean age at diagnosis of those who changed gender was 7.92 yr and 2.67 yr for those who kept the assigned gender, p=.04). There was a strong association between male toys at childhood and male gender identity at adulthood (X2 28, p=.0001, V=0.59). A total of 11% defined themselves as homosexual. External genitalia virilization was associated with gynophilic sexual attractiveness (X2 82, p=0.001, V=0.59). Compliance issues were identified in 60% of individuals who changed their gender. Inappropriate hormonal control between 2 and 11 years of age was also associated with gender change (p=.04). Conclusion: Prenatal androgen exposure favors male psychosexuality in CAH. This influence is substantiated by post-natal androgen exposure since gender changed from female to male occurred in individuals with late diagnosis and bad compliance.