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 (β-hCG)-producing tumors also cause gonadotropin-independent PP by stimulating the production of testosterone in Leydig cells. Germ cell tumors and hepatoblastoma both produce β-hCG; however, there is limited evidence to show that gonadotropin-independent PP is caused by other β-hCG-producing tumors. We herein report the first case of β-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 hormone with an increased testosterone level were indicative of gonadotropin-independent PP. Since serum β-hCG was elevated, β-hCG-producing neuroblastoma was suspected. Histological findings of the resected tumor were compatible with neuroblastoma. An immunohistochemical analysis using serial sections revealed staining for β-hCG in synaptophysin-positive cells. Furthermore, immunofluorescence showed the co-staining of β-hCG with neuron-specific enolase. These results suggested that β-hCG was produced by tumor cells. Surgical removal of the tumor promptly normalized serum β-hCG and testosterone levels. In conclusion, we propose the addition of neuroblastoma to the list of differential diagnoses of gonadotropin-independent PP with β-hCG positivity in serum that includes germ cell tumors and hepatoblastoma.