Complete virilization in congenital adrenal hyperplasia: clinical course, medical management and disease-related complications.

OBJECTIVE: In girls with congenital adrenal hyperplasia (CAH), genital ambiguity usually leads to a rapid neonatal diagnosis. Rarely, CAH causes complete virilization and male sex assignment with a delayed diagnosis. After being confronted with very specific problems in two of such patients, we collected data of patients with CAH and complete virilization in a nationwide study to delineate specific problems of these rare patients in order to improve their management. DESIGN AND PATIENTS: Through the German Working Group of Paediatric Endocrinology (Arbeitsgemeinschaft Pädiatrische Endokrinologie, APE), questionnaires were sent to all members caring for patients with CAH and complete virilization in their endocrine clinics. Data from 16 patients from 10 paediatric endocrine centres were assessed by questionnaire. RESULTS: The following problems have been encountered. (1) Sex assignment/gender identity: initially all patients had a male sex assignment. Six patients were diagnosed during the first month of life. Five were reassigned to female sex immediately, one at the age of 19 months. Except in one girl demonstrating some tomboyish behaviour, gender role behaviour in these patients did not differ from unaffected girls. Ten patients were diagnosed late at 3.4--7 years of age. In seven patients with a late diagnosis, male sex assignment was maintained; one of them expressed some concerns about living as a male. In three patients late sex reversal was performed, gender identity is very poor in one and new sex assignment is currently under consideration. (2) SURGERY: irrespective of the sex assigned, all patients had between one and three surgical procedures, including clitoris reduction and (repeated) vaginoplasties in patients with female sex assignment. Hysterectomy and ovarectomy were performed in patients with male sex assignment. (3) Short stature: patients with a late diagnosis of CAH had extremely advanced bone ages of +6.3 to +9.5 years, leading to severely reduced final height of 137 to 150 cm in adult patients. Patients tended to follow height percentiles of genetic females. One pubertal patient was suicidal due to short stature. (4) Central precocious puberty (CPP): prolonged exposition to adrenal androgens led to CPP in one patient. He was treated with GnRH analogues until gonadectomy. CONCLUSIONS: Patients with CAH and complete virilization have a high risk of being diagnosed late. There are major problems and uncertainties of the patients' families and the treating physicians concerning gender assignment. Gender identity is disturbed in some patients. In addition, multiple surgical procedures are necessary and short stature as well as central precocious puberty might be important to avoid late sequelae. While some surgical interventions are probably unavoidable, most of these issues could be resolved with an early diagnosis. Thus, especially for these patients, a neonatal screening programme for CAH would be of paramount importance.

Basal inhibin B and the testosterone response to human chorionic gonadotropin correlate in prepubertal boys.

During childhood, the quiescent phase of testicular activity, the hCG stimulation test is widely used to evaluate testicular function. Inhibin B, a gonadal peptide regulating FSH secretion, is an established marker of Sertoli cell function and spermatogenesis in adults. In contrast to the other hormones of the hypothalamo-pituitary-gonadal axis, inhibin B is also secreted in detectable amounts during childhood. The aim of this study was to determine whether basal inhibin B levels are able to predict prepubertal testicular function, so as to avoid a stimulation test. Inhibin B and testosterone before and after hCG stimulation were measured in 54 male children with various testicular disorders by an immunoassay specific for inhibin B. Basal inhibin B was compared to the testosterone increase after hCG. Inhibin B and the hCG-induced testosterone increment correlated strongly (r = 0.84; P<0.0001). Patients with anorchia were clearly distinguishable from those with abdominal testes, having undetectable (inhibin B, <15 pg/mL) respective normal inhibin B levels for age. Inhibin B and the testosterone response to hCG were low in boys with testicular damage (delayed diagnosis of cryptorchidism; after testicular torsion) and in patients with gonadal dysgenesis, but were normal or increased in children with androgen insensitivity syndrome. We conclude that basal inhibin B predicts the testosterone response to hCG in boys and therefore gives reliable information about both the presence and function of the testes. The diagnostic procedure in cryptorchidism may be reduced to a single inhibin B measurement. Furthermore, inhibin B levels show specific alterations in patients with sexual ambiguity, adding a valuable diagnostic tool to the complex differential diagnosis of male pseudohermaphroditism.

15 beta-hydroxylated steroids may be diagnostically misleading in confirming congenital adrenal hyperplasia suspected by a newborn screening programme.

UNLABELLED: In a Swiss screening programme for detection of congenital adrenal hyperplasia (CAH), 27 of over 120,000 newborns examined from 1992 to 1994 were further studied because of persistingly high 17 alpha hydroxyprogesterone (17OHP). Out of 27, 11 were later confirmed to have CAH by specific gas chromatography of urinary steroids and ACTH test at age 3-4 months. Of 27, 11 were born at term (7 confirmed 21-hydroxylase deficiency, one 11 beta-hydroxylase deficiency). Out of 27, 16 were preterm newborns. Of them, only 2 were confirmed to have CAH (one 21-, one 11 beta-hydroxylase deficiency). In 3 cases with high 17OHP, but later not confirmed CAH, what appeared to be a pregnanetriolone peak in the gas chromatograms was shown to be 3 beta, 15 beta, 17 alpha-pregnenetriol. This compound may be misleading in confirming the diagnosis of CAH. 15 beta-Hydroxylated compounds occur in fetuses, neonates, and amniotic fluid. Since human tissues do not have 15 beta-hydroxylating capacity, their origin is unclear. However, since some bacteria (Bacillus megatherium) and mycelial fungi (fusaria) are known to hydroxylate steroids in position 15 beta, it is likely that this compound is formed by micro-organisms in the enterohepatic circulation of newborns or their mothers. CONCLUSION: For the confirmation of the diagnosis of CAH in cases suspected by screening, later ACTH stimulation and specific steroid analysis are necessary.