Clinical analyses of 81 infertile and 20 testicular tumor men with suspected X-chromosome-linked gene anomalies in Japan

A total of 101 cases of 81 infertile men and 20 men with testicular tumors were analyzed clinically for suspected X-chromosome-linked gene abnormalities. Among the 81 infertile men analyzed by testicular biopsy, 11 Klinefelter syndrome (KS) cases showed Leydig cell nodular hyperplasia with azoospermia. They had low levels of testosterone (131 ± 81 ng/dl) and high levels of luteinizing hormone (21 ± 7 mIU/ml) and follicle-stimulating hormone (36 ± 11 mIU/ml). From Leydig cell hyperplasia combined with atrophic tubules, X-linked androgen receptor dysfunctions in Sertoli and Leydig cells were judged in the KS cases. One azoospermia case of non-KS had primary yolk sac tumor of the mediastinum and liver. The removed yolk sac tumor showed complete necrosis after bleomycin, etoposide, and cisplatin (BEP) chemotherapy, which indicated cisplatin-sensitive apoptosis. X-linked inhibitor of apoptotic protein (XIAP) must exhibit an apoptosis-inducible mutation (XIAP-S87A) in the non-KS case. Subsequently, 20 testicular tumor cases were classified into ten with seminoma, eight with mixed germ cell tumors (MGCT), one with mature teratoma, and one with diffuse large B cell lymphoma. Although among the eight MGCT cases, six cases had high levels of α-fetoprotein (68–43647 ng/ml), their blood levels of human chorionic gonadotropin-β were <0.1 to 23 ng/ml with a good prognosis. Radiological examinations of the 20 cases showed nodular, hemorrhagic, or cystic changes in lung, liver, or periarterial lymph nodes, but no metastatic changes in bone or brain. Besides cisplatin-induced acute renal failure in one of the two seminoma cases treated with BEP chemotherapy, the two cases showed chronic renal failure (CRF) due to glomerular disturbance, but three treated MGCT cases did not. Their mutated humanin in spermatocytes, which located in X-chromosome and bound to podocytes, might have aggravated the CRF. Infertility and testis-related tumors were caused by X-chromosome-linked gene anomalies.