The degree of external genitalia virilization in girls with 21‐hydroxylase deficiency appears to be influenced by the CAG repeats in the androgen receptor gene

Rocha, Rachel de Oliveira; Billerbeck, Ana Elisa C.; Pinto, Emília M.; Melo, Karla Fabiana Santana de; Lin, Chin Jia; Longui, Carlos Alberto; Mendonca, Berenice B.; Bachega, Tânia A. S. S.

doi:10.1111/j.1365-2265.2007.03023.x

Cited by 31 publications

(34 citation statements)

References 39 publications

(104 reference statements)

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“…The 17-OHP levels were weakly correlated with phallus length (r=0.19). However, there was no clear relationship between 17-OHP levels and virilization of external genitalia, similar to findings by Rocha et al 20 Genetic counseling for families and patients is advised to explain the clinical manifestations, mode of inheritance, recurrence risk and consequences of CAH. Some challenges to our work include varied cultural beliefs within families, patient discrimination and taboos pertaining to their masculinized condition, and the unavailability of a genetic counselor.…”

Section: Discussionsupporting

confidence: 56%

Phenotypic Variation of 46,XX Late Identified Congenital Adrenal Hyperplasia among Indonesians

Juniarto

Ulfah

Ariani

et al. 2018

JAFES

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Objectives. To describe the phenotype variation in Indonesian 46,XX late-identified congenital adrenal hyperplasia (CAH) and the correlation between 17-hydroxyprogesterone (17-OHP) and genital virilization.Methodology. Retrospective study of 39 cases with five salt-wasting (SW) and 34 simple virilizing (SV) types.Results. The median age of the patients was 9.83 years (range, 0.58 to 44 years) with Prader score 2 to 5. Clitoromegaly (100%) and skin hyperpigmentation (87%) were the most common features. Lack of breast development (Tanner 1 to 2) and menstrual disorders occurred in 9 patients (teenagers and adults). Short stature (6), low voice (14), prominent Adam's apple (9) and hirsutism (4) were found only in SV types. Rapid growth (7) and precocious puberty (8) were identified in children. Male gender on admission was found in 13 patients. The mean of 17-OHP level was 304.23 nmol/L [standard deviation (SD) 125.03 nmol/L]. There was no correlation between 17-OHP levels and virilization (r=0.19, p>0.05).Conclusion. Late-identified CAH showed severe virilization and irreversible sequelae, with clitoromegaly and skin hyperpigmentation as the most commonly seen features. Masculinization of CAH females created uncertainty with regard to sex assignment at birth, resulting in female, male and undecided genders. There is no significant correlation between 17-OHP levels with the degree of virilization in CAH females.

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Section: Discussionsupporting

confidence: 56%

Phenotypic Variation of 46,XX Late Identified Congenital Adrenal Hyperplasia among Indonesians

Juniarto

Ulfah

Ariani

et al. 2018

JAFES

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“…Moreover, aside from a relatively strong genotype-phenotype correlation concerning the impairment of mineralocorticoid synthesis in classical CAH, there is a high variability in the degree of external genitalia virilization in affected females (5,6). Background genetic factors such as individual androgen receptor (AR) sensitivity due to nCAG length polymorphisms within the AR gene have been suggested to explain parts of the phenotypical variability (7). Interestingly, genetically determined increased glucocorticoid receptor (GR) sensitivity in 363S-carriers of the GR N363S variant has recently been found to be associated with less severe virilization and lower 17-OHP levels in females at the time CAH was diagnosed clinically (8).…”

Section: Introductionmentioning

confidence: 99%

Functional glucocorticoid receptor gene variants do not underlie the high variability of 17-hydroxyprogesterone screening values in healthy newborns

Schreiner

Tozakidou²,

Maslak³

et al. 2009

European Journal of Endocrinology

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Objective: 17-Hydroxyprogesterone (17-OHP) screening for classical congenital adrenal hyperplasia (CAH) is part of many newborn screening programs worldwide. Cut-off values are relatively high, and screening sensitivity does not reach 100%. Recently, the glucocorticoid receptor (GR) N363S-variant has been linked to relatively low degree of virilization and comparatively lower 17-OHP serum concentrations in clinically diagnosed female CAH patients. We sought to determine whether functional GR gene variants, either increasing (N363S, BclI) or decreasing GR sensitivity (R23K), underlie the variable 17-OHP screening levels in healthy newborns. Design: GR genotypes were compared with 17-OHP screening values in 1000 random samples from routine screening. 17-OHP was measured by conventional immunoassay (TRFIA) and a liquid chromatography-tandem mass spectrometry method (LC-MS/MS), which has been shown to increase screening specificity by steroid profiling and avoiding cross-reactions of the 17-OHP-antibody. Results: There was no significant association of 17-OHP with GR genotypes, even after inclusion of gestational and postnatal age as covariates. However, among LC-MS/MS steroid measurements, we observed some unexpected trends, including lower 11-deoxycortisol concentrations in both 363S-and 23K-carriers. For carriers of the frequent BclI variant, linear regression analysis revealed a significant increase of 4-androstenedione levels with every mutant allele inherited. Conclusions: Functional GR variants do not underlie the variation of 17-OHP values observed in healthy individuals. However, whether and to which extent genetically determined differences in individual GR sensitivity influence 17-OHP screening levels in conditions of a pathological hypothalamus-pituitary-adrenal gland-axis stimulation and thus may explain false-negative screening results in those affected by CAH remains to be investigated.

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“…Bachega et al (1998) observed a good correlation of genotype with testosterone and androstenedione levels and concluded that the intensity of hyperandrogenism was correlated with the severity of neonatal genitalia virilization found in Groups N and A. In contrast, Rocha et al (2008) did not observe a correlation between basal testosterone levels and the degree of external genitalia virilization. Although basal androgen levels were available in only six out of thirteen patients, our data did not show a clear relationship between the severity of external genitalia virilization and androgens.…”

Section: Discussionmentioning

confidence: 84%

“…Several previous manuscripts have described correlations between genotype and phenotype, which includes Prader stages, in all type of 21OHD patients (Jaaskelainen et al 1997;Krone et al 2000;Rocha et al 2008). Jaaskelainen et al agreed with previous results in that the genotypephenotype correlation in 21OHD is generally rather good.…”

Section: Discussionmentioning

confidence: 99%

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Severity of Virilization of External Genitalia in Japanese Patients with Salt-wasting 21-hydroxylase Deficiency

Sugiyama

Mizuno

Hayashi

et al. 2008

Tohoku J. Exp. Med.

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Females with salt-wasting (SW) 21-hydroxylase deficiency (21OHD) may present with mild external genitalia virilization, despite complete or almost complete enzyme inactivation. We therefore analyzed genotype/phenotype correlation in 13 Japanese female patients with SW 21OHD. Criteria for classification into the SW phenotype included history of a salt-losing crisis with documented hyponatremia, hyperkalemia, and markedly elevated plasma renin activity. Urologists and pediatricians determined the Prader genital stage and classified the location of the vaginal entrance into the common urogenital sinus as low, moderate, or high. CYP21A2 gene, coding for 21-hydroxylase, was analyzed with Southern blotting and direct sequencing. Genotypes were categorized into four mutation groups, based on the degree of enzymatic activity (N, complete enzyme inactivation; groups A, < 2%, B, 3-7%, and C > 30%). Basal androgen levels were available from only six out of thirteen patients, so we could not relate androgen levels with the severity of external genitalia virilization. We compared the degree of external genitalia virilization with genotype. The severity of external genitalia virilization varied from Prader stage 1 to 4. One patient who presented with Prader 1 had a genotype consistent with Group B. In addition, discordance between Prader classification and the location of the vaginal entrance was noted; one patient classified as Prader 4 showed low vaginal entrance, while another patient classified as Prader 3 showed high vaginal entrance. The degree of the impairment of 21-hydroxylase activity does not correlate with the severity of virilization of the external genitalia in female patients with the SW type of 21OHD.congenital adrenal hyperplasia; 21-hydroxylase deficiency; CYP21A2 genotype; genital virilization; Prader classification. Tohoku

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The degree of external genitalia virilization in girls with 21‐hydroxylase deficiency appears to be influenced by the CAG repeats in the androgen receptor gene

Abstract: We observed great variability in the degree of external genitalia virilization in both CYP21A2 genotypes, and we showed that the CAG repeats of the androgen receptor gene influences this phenotypic variability.

Cited by 31 publications

References 39 publications

Phenotypic Variation of 46,XX Late Identified Congenital Adrenal Hyperplasia among Indonesians

Phenotypic Variation of 46,XX Late Identified Congenital Adrenal Hyperplasia among Indonesians

Functional glucocorticoid receptor gene variants do not underlie the high variability of 17-hydroxyprogesterone screening values in healthy newborns

Severity of Virilization of External Genitalia in Japanese Patients with Salt-wasting 21-hydroxylase Deficiency

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