Leydig cell tumor in a patient with 49,XXXXY karyotype: a review of literature

Abstract

49,XXXXY pentasomy or Fraccaro's syndrome is the most severe variant of Klinefelter's syndrome (KS) affecting about 1/85000 male births. The classical presentation is the triad: mental retardation, hypergonadotropic hypogonadism and radio ulnar synostosis. Indeed, the reproductive function of Fraccaro's syndrome is distinguished from KS. Besides, Leydig cell tumors are described in cases of KS, but never documented in the Klinefelter variants.We describe a young adult of 22 years old who presented with hyper gonadotropic hypogonadism, delayed puberty and bilateral micro-cryptorchidism. Chromosomal pentasomy was confirmed since infancy. Bilateral orchidectomy revealed a unilateral well-circumscribed Leydig cell tumor associated with bilateral Leydig cell hyperplasia.Inspired from reporting the first case of Leydig cell tumor in a 49,XXXXY patient, we summarize the particularities of testicular function in 49,XXXXY from one side, and the risk and mechanisms of Leydig cell tumorigenesis in Klinefelter variants on the other side. The histological destructions in 49,XXXXY testes and hypogonadism are more profound than in Klinefelter patients, with early Sertoli, Leydig and germ cell destruction. Furthermore, the risk of Leydigioma development in KS and its variants remains a dilemma. We believe that the risk of Leydigioma is much higher in KS than the general population. By contrast, the risk could be lower in the Klinefelter variants with more than 3 supplementary X chromosomes, owing to an earlier and more profound destruction of Leydig cells rendering them irresponsive to chronic Luteinizing hormone (LH) stimulation.

Fig. 1

Identification of a Leydigioma in a patient with 49,XXXXY karyotype with bilateral testicular ectopia. a Identification of 1 and 1.5 cm diameter testes within the inguinal groin by computed tomography in adolescence. b Identification of a well circumscribed 2 mm diameter tumor in the testis. Tumor cells are hexagonal, with round uniform prominent nuclei. The cytoplasm is eosinophilic, or slightly pale due to lipid accumulation. Lipofuschine pigment is identified in steroid producing tumors. Some calcification and hyalinization of the stroma could be identified. Reinke crystals, pathognomonic for Leydigioma are present in only 40 % of the cases. They were absent in this case. c Immuno staining of the tumor by Calretinin, a specific marker of stroma cell tumors. d Ki67 immuno staining. the proliferative index is low in the benign tumors