Beta-human chorionic gonadotropin-producing neuroblastoma: an unrecognized cause of gonadotropin-independent precocious puberty

The pathogenesis of gonadotropin-independent precocious puberty (PP) includes both congenital and acquired forms, the latter of which may be associated with neoplasms, such as sex-steroid hormone-producing tumors. Beta-human chorionic gonadotropin (beta-hCG)-producing tumors also cause gonadotropin-independent PP by stimulating the production of testosterone in Leydig cells. Germ cell tumors and hepatoblastoma both produce beta-hCO, however, there is limited evidence to show that gonadotropin-independent PP is caused by other beta-hCG-producing tumors. We herein report the first case of beta-hCG-producing neuroblastoma associated with the development of gonadotropin-independent PP. A 2-year-old boy presented with an increased penile length, enlargement of the testes, pigmentation of the external genitalia, and growth acceleration. Imaging, blood, and urinary examinations revealed the presence of neuroblastoma in the right adrenal region. Decreased levels of luteinizing hormone and follicle-stimulating honnone with an increased testosterone level were indicative of gonadotropin-independent PP. Since serum beta-hCG was elevated, beta-hCG-producing neuroblastoma was suspected. Histological findings of the resected tumor were compatible with neuroblastoma. An immunohistochemical analysis using serial sections revealed staining for beta-hCG in synaptophysin-positive cells. Furthermore, immunofluorescence showed the co-staining of beta-hCG with neuron-specific enolase. These results suggested that beta-hCG was produced by tumor cells. Surgical removal of the tumor promptly normalized serum beta-hCG and testosterone levels. In conclusion, we propose the addition of neuroblastoma to the list of differential diagnoses of gonadotropin-independent PP with beta-hCG positivity in serum that includes germ cell tumors and hepatoblastoma.