Adrenal Hypoplasia Congenita and Hypogonadotropic Hypogonadism: Studies in Three Generations

Two brothers presenting with vomiting and dehydration in the neonatal period, recovered with rehydration only to develop overt adrenal insufficiency later in childhood, With steroid replacement therapy they enjoyed good health, but failed to enter puberty because of gonadotropin deficiency, A nephew, the older son of their sister, presented in a similar fashion 25 years later with adrenal insufficiency confirmed at age 2 years. Like his uncles, the nephew was thought to have adrenal hypoplasia, but the presence or absence of hypogonadotropic hypogonadism could not be ascertained. The observation recently that mutations in the dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X-chromosome gene 1 (DAX-1) may be responsible for both adrenal hypoplasia con genita and hypogonadotropic hypogonadism has facilitated diagnosis of this and other similar cases. Histopathology of a testicular biopsy and orchiectomy specimen in the younger brother revealed progressive loss of germinal epithelium with vacuolization of postpubertal Sertoli cells suggesting an additional role for DAX-1 in testicular maturation and spermatogenesis, Application of genomic DNA analysis to both affected and nonaffected family members has enabled accurate diagnosis, significantly reduced anxiety, and allowed for appropriate counseling and improved patient care.