Human sex determination, sex differentiation, adrenal organogenesis and hypothalamic-pituitary gland development are complex developmental processes that are tightly regulated by a network of transcription factors including the orphan nuclear receptors DAX1 and SF-1.
We have investigated an infant with a novel disorder of adrenal, gonadal and hypothalamic/pituitary development. Pregnancy was complicated by low maternal estriol and high βhCG; a normal 46,XY karyotype was obtained at amniocentesis. At birth normal female external genitalia were noted. No gonads or internal genital structures were identified by ultrasound or MRI scan; genitogram revealed a blind-ending vagina. On day 8 the infant suffered a mild Addisonian episode (Na+ 125 mmol/L; K+ 6.0 mmol/L) and was found to be hypocortisolemic (cortisol < 1.0 mcg/dl). Endocrine studies obtained on days 4 - 9 of life (table) were consistent with absent gonadal steroidogenesis and adrenal hypoplasia congenita, with some residual function of the fetal adrenal. Despite absence of gonadal steroids the infant was hypogonadotropic: at 8 weeks of age peak LH was 0.87 IU/L and peak freeα-subunit was 1.0 ng/ml, following leuprolide 10 ug/kg. Testosterone, androstenedione, DHEA and 17-OHP showed no response to 3×1500 IU hCG every other day. Although there was no evidence of Leydig cell function, a normal infant male anti-Mullerian hormone level of 11.0 ng/ml (RR 7.8-121.5) indicated the presence of functioning Sertoli cells.
The infant's clinical and endocrine findings - male pseudohermaphroditism, congenital adrenal hypoplasia and hypogonadotropic hypogonadism - are consistent with defective function of a transcription factor involved in early fetal development of the gonads, adrenal glands and hypothalamic-pituitary axis. Although the clinical features of human DAX1 and murine SF-1 defects diverge from those of our patient, analysis of both genes is in progress and preliminary data reveal no abnormality of the coding sequence of DAX1. If no defect is found in either of these genes, we would postulate that this child has a defect of a previously undescribed transcription factor which could prove to be a vital link between development of the human adrenal, gonadal and hypothalamic-pituitary systems.
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Hofman, P., Quigley, C., McCabe, E. et al. A New Syndrome of Male Pseudohermaphroditism, Congenital Adrenal Hypoplasia and Hypogonadotropic Hypogonadism † 441. Pediatr Res 43, 78 (1998). https://doi.org/10.1203/00006450-199804001-00462