Virilized external genitalia in young girls: clinical characteristics and management challenges in a low-resource setting.

OBJECTIVE: Virilization of the external genitalia in young girls (VEG) manifests mostly as ambiguity of the genitalia and elicits concerns and uncertainties especially in settings with poor awareness. This study evaluates the profile and challenges of VEG in southeast Nigeria. METHODS: We analyzed 23 children with VEG managed in 2 referral centers in southeast Nigeria from June 2005 to January 2013. RESULTS: They presented at median age of 13.3 months (interquartile range [IQR] 3 months-3 years). The cases included 3 (13%) of Prader type 1, 6 (26%) of type 2, 11 (48%) of type 3, and 3 (13%) of type 4. Five of the Prader type 3 and all 3 cases of Prader type 4 were reared as male prior to presentation. Following evaluation, all the cases were assigned female gender at a mean age of 2.7 years (range 2 months-10.5 years). Appropriate feminizing genitoplasty was undertaken in all the cases and after a follow-up period of 3 months to 5 years (mean 2 years), 2 patients developed vaginal stenosis, and 3 cases had surgical wound infection. Poor awareness, delayed presentation, inadequate facilities, and lack of trained manpower were the challenges in the management of the cases. CONCLUSION: VEG in our setting is associated with delayed management. Focused health education and public awareness programs, and improved healthcare funding may improve outcome and minimize the need for gender reassignment.

Anti-Mullerian hormone confirms the novel classification of female functional androgenization including polycystic ovary syndrome.

OBJECTIVE: Functional androgenization (FA) can be divided into five groups corresponding to the predominant organ pathology as recently shown by our group: functional cutaneous androgenization (FCA, skin) and FA syndrome (FAS) I (ovary, lean individual), II (adrenal gland), III (ovary, fat tissue, pancreas, and hyperinsulinemia), and IV (residual FA dysfunctions). Group-specific clusters are based on primary variables such as LH, testosterone, DHEAS, sex hormone-binding globulin (SHBG), body mass index (BMI), glucose, insulin, and enlarged polyfollicular ovaries. Because anti-Müllerian hormone (AMH) positively correlates with the antral follicle count, its relevance as an additional primary variable for classifying FA was investigated. DESIGN: In this study, 178 patients with FA were consecutively enrolled and classified into the five FA groups as described earlier and 30 women with regular menstrual cycles served as control. METHODS: Primary variables and serum AMH were analyzed in the early follicular phase. RESULTS: FA patients showed significantly elevated AMH levels (11.1±6.7 ng/ml) versus control (3.0±2.0 ng/ml; P<.0001). AMH was significantly increased in groups FAS I (15.6±5.8 ng/ml) and FAS III (11.6±6.6 ng/ml) compared with groups FCA (7.0±3.8 ng/ml), FAS II (5.05±3.0 ng/ml), and FAS IV (6.9±4.6 ng/ml) and correlated positively (P<.0001) with LH (r=0.538) and testosterone (r=0.368). In regression and multivariate analyses, AMH was not dependent on SHBG, DHEAS, BMI, glucose, or insulin. In receiver operating characteristic analysis, 9.21 ng/ml AMH showed 90% specificity with 71.2% sensitivity for the diagnosis of the two ovarian FA groups, FAS I and III. CONCLUSION: AMH confirms the novel stratification system and constitutes a useful primary variable in the algorithm of FA classification.

No correlation between androgen receptor CAG and GGN repeat length and the degree of genital virilization in females with 21-hydroxylase deficiency.

CONTEXT: In 21-hydroxylase (CYP21A2) deficiency (21OHD), the level of in vitro enzymatic function allows for classification of mutation groups (null, A, B, C) and prediction of disease severity. However, genital virilization in affected females correlates only weakly with CYP21A2 mutation groups, suggesting the influence of genetic modifiers. OBJECTIVE: The objective of the study was to investigate the influence of the polymorphic CAG and GGn repeats of the androgen receptor (AR) gene on the degree of genital virilization in 21OHD females. DESIGN AND PATIENTS: Design of the study was the determination of CYP21A2 genotype, degree of genital virilization (Prader stage), and X-weighted biallelic mean of AR CAG and GGn repeat length in 205 females with 21OHD. OUTCOME MEASUREMENTS: Correlation of AR CAG and GGn repeat lengths with Prader stages using nested stepwise logistic regression analysis was measured. RESULTS: CYP21A2 mutation groups null and A showed significantly higher levels of genital virilization than groups B and C (P < 0.01). However, Prader stages varied considerably within mutation groups: null, Prader I-V (median IV); A, Prader I-V (median IV); B, Prader I-V (median III); C, 0-III (median I). Mean GGn repeat length of patients was not significantly associated with Prader stages, classified as low (0-I), intermediate (II-III), or severe (IV-V) (odds ratio per repeat: 0.98, 95% confidence interval 0.71-1.35). In contrast, patients with Prader 0-I showed a trend toward longer CAG repeats without reaching statistical significance (P = 0.07, odds ratio per repeat: 0.82, 95% confidence interval 0.65-1.02). CONCLUSION: Neither CAG nor GGn repeat lengths are statistically significant modifiers of genital virilization in females with 21OHD.

Virilising adrenocortical tumours in children.

UNLABELLED: Adrenocortical tumours (ACT) are a rare but important cause of virilisation in infancy and childhood. Four cases of virilising ACT are presented. Two girls (age 0.9 years and 3.9 years) and two boys (age 6.2 years and 6.4 years) had symptoms and signs of virilisation before the age of 6 years. Diagnosis of a virilising adrenal tumour was confirmed by laboratory tests, diagnostic imaging and histology. However, one female patient was misdiagnosed and treated for 3 months as atypical congenital adrenal hyperplasia. Ultrasonography of the adrenal region could not visualise the tumour in three out of four cases. The most sensitive method of diagnostic imaging was MRI. In all cases, treatment consisted of complete surgical resection of the adrenal tumour by open abdominal surgery. Immunohistochemistry was performed in all patients and in two patients there was an overexpression of p53, indicating p53 mutation and in three cases the ki67 proliferation index was greater than 5%. The classification of ACT in childhood is extremely difficult. Histology scores adapted from adrenal tumours in adults and molecular markers are under investigation, but there is still not enough clinical experience since ACT are so rare. CONCLUSION: Long-term follow-up is mandatory not only because of the uncertainty in classification of adrenocortical tumours, but also for observation of growth and pubertal development.

Hirsutism and virilization. A systematic approach to benign and potentially serious causes.

A woman with excessive body hair may visit a physician with concerns about fertility and general health as well as appearance. Fortunately, the cause is usually benign, most often polycystic ovarian syndrome. However, life-threatening causes must be quickly ruled out. Hirsutism secondary to endocrinopathies and tumors can typically be recognized by the rapid progression of hair growth; patients should be referred for prompt evaluation and treatment. Benign causes can usually be treated effectively with medical and mechanical methods.

Genetic differences between the salt-wasting, simple virilizing, and nonclassical types of congenital adrenal hyperplasia.

Human leukocyte antigen (HLA) alleles and plasma 17-hydroxyprogesterone levels after ACTH stimulation were studied in 134 German families of patients with the salt-wasting (SW), simple virilizing (SV), or nonclassical (NC) late-onset form of congenital adrenal hyperplasia (CAH). Unexpected hormonal evidence for CAH was found in 6 otherwise healthy members of the relatives' group, who, therefore, were considered to be NC cryptic cases. HLA typing revealed a genetic difference between the 2 classical disease forms; SW CAH was strongly associated with Bw47, whereas SV CAH was closely linked to B5(w51). It also confirmed the nearly complete connection of NC CAH with B14. These alleles, especially Bw47 and B14, are mostly components of normally rare haplotypes: A3,Bw47,DR7 and Aw33,B14,DR1, respectively. They do not occur in the families' disease-unaffected haplotypes. Thus, it may be that all or almost all individuals from the general population bearing 1 of them are in fact CAH heterozygotes. Moreover, it seems possible to predict the severity of an infant's disease from his genomic type. The HLA linkage data were consistent with those obtained from ACTH testing, which showed significantly higher 17-hydroxyprogesterone increases in the genetically defined heterozygous relatives of SW patients than in the respective members of SV families. Of the families, 2 were also informative for mapping of the CAH disease gene(s) within the HLA-B to Glo interval.

[Biological parameters of virilism in women]. / Paramètres biologiques du virilisme féminin.

Comparative results of the suppression-stimulation test by dexamethasone and chorionic gonadotropin, chromatographic separation of 17-ketosteroids, and plasma testosterone levels in the ovarian and adrenal veins, in cases of virilism in women. Thirteen patients with hirsutism and virilization were investigated as follows: 1. measurement of plasma testosterone (T) levels by radioimmunoassay (RIA) during suppression-stimulation tests by the administration of Dexamethasone (DXM) and chorionic Gonadotropin (HCG). 2. chromatographic determination of urinary 17-ketosteroids, pregnanediol (P2), and pregnanetriol (P3). An attempt was made to classify virilism as "ovarian" or "adrenal" based on the results of 1. and 2. 3. bilateral ovarian and adrenal venous catheterization through the femoral vein to measure T (RIA) levels. 4. laparotomy with bilateral wedge resections of the ovaries for therapeutic and biopsy purposes. Surgical catheterization of the ovarian veins was carried out during the operation. The results of these tests show that: a) the dynamic DXM-HCG test can be used to separate those cases in which the ovary is not involved in T formation from those in which, apparently, it is involved. b) chromatographic determination of urinary steroids has no aetiological value, as the variations in the different fractions are not significant. c) in all patients, the principal source of T is the adrenals and not the ovaries, even when there is an increase in T in the ovarian efferent blood vessels.