21-hydroxylase deficiency and klinefelter syndrome in an adult man: striking a balance between androgen excess and insufficiency.

Objective We describe the rare case of an adult man with normal virilization affected by both Klinefelter Syndrome (KS) and Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency, consulting for painful gynecomastia. A complete clinical workup included endocrinological, genetic, sexological evaluation and testis histology. Genetic analyses included karyotype, CYP21 sequencing and the CAG and GGC repeat polymorphism in the androgen receptor gene. Findings KS was diagnosed by karyotype analysis (47,XXY), the testis biopsy revealed Leydig cell hyperplasia. The CAH was diagnosed by the direct detection of a I2 homozygous mutation in the CYP21 gene. The hormonal analysis revealed a mild hypergonadotropic hypogonadism, serum levels of androstenedione and ACTH above the normal range and a slightly reduced cortisol response with exaggerated 17-OH progesterone increase to ACTH stimulation. Cortisone acetate treatment disclosed a clinically relevant pre-existent hypogonadism in the relatively short time of 6 months, thus suggesting that the reduction in adrenal steroids impaired the balance in the androgen status previously created by the two syndromes. Only the combined therapy with cortisone acetate and testosterone restored a normal androgenization and a male sexual behavior. Conclusions The simultaneous occurrence of KS and CAH is extremely rare. The clinical phenotype of our patient was characterized by mild symptoms of the two syndromes, probably because the high levels of adrenal androgens due to CAH counterbalanced the partial androgen deficiency due to KS.