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

Abstract

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

The effect of fetal androgen metabolism‐related gene variants on external genitalia virilization in congenital adrenal hyperplasia

“…In the Brazilian patients included in this study, except for the gene founder effect of some mutations (28,29), the mutation distribution was similar to that of other ethnic groups and we also observed a strong correlation between genotype and phenotype. However, three studies (6,8,9) as well as our previous report comprising 85 CAH females from a single center (33) have indicated some controversies in the correlation between genotype and degree of external genitalia virilization.…”

“…The SW form was characterized by external genital virilization as well as weight loss, vomiting and volume depletion starting from the neonatal period. Basal serum hormone levels are presented as the median value (IQR = interquartile range) as follows: 17OHP, 151 (89-251) ng/ml; testosterone and androstenedione levels in prepubertal patients, 133 (95-297) ng/dl and 8.5 (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) ng/ml, respectively. The mean (±SD) age at diagnosis was 24 (±30) days after birth for SW patients and 4.4 (±4.4) years for SV patients.…”

A Single Nucleotide Variant in the Promoter Region of 17β-HSD Type 5 Gene Influences External Genitalia Virilization in Females with 21-Hydroxylase Deficiency

“…In CAH, it is well known that there is a strong correlation between impairments of enzymatic activity predicted by genotype, clinical form, and basal 17-OH-progesterone level [2,23,24]; regarding the correlation between genotype and degree of external genitalia virilization, some studies have indicated disagreement [9,10]. However, two recent multicenter studies with large patient cohorts demonstrated an association between genotype and severity of genital virilization [6,7].…”

“…However, in our cohort, as well as in other studies, Prader stages that reflect the severity of external genitalia virilization are quite variable among females carrying similar genotypes. These stages range from mild clitoral enlargement to complete fusion of the labioscrotal folds with a phallic urethra [7,8,9,10]. These findings suggest that other genetic factors act on the genital phenotype [7,11].…”

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

“…3,4 Elevation of 17-OHP in CAH leads to increased androgen levels, but the relationship between 17-OHP and virilization phenotype has not been consistent as seen in previous studies. 2,5 The incidence of CAH in the general population is approximately 1 in 16,000 on screened newborns worldwide, and carriers are present in 1:60. 6,7 Data from our center from 2004 to 2016 show that there are 84 patients with CAH, consisting of a wide age range of 3 days to 44 years old.…”