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.
Highlights
Klinefelter syndrome (47,XXY or Klinefelter’s syndrome (KS)) is the commonest aneuploidy
We analysed the literature for the published cases of testicular tumors in aneuploidies, over nearly 4000 patients with KS and its variants, we identified only 34 patients with gonadal and extra gonadal tumors. 20 patients had Leydig cell tumors, only two were malignant; teratomas were the second most common tumors described (Table 2)
We present a case of 49,XXXXY sex polysomy, who shares a number of characteristics of the other 176 patients cases described in the literature, namely, hypogonadism with cryptorchidism, facial dysmorphism, musculoskeletal and cardiac malformations, and mental retardation seriously affecting language skills
Summary
Klinefelter syndrome (47,XXY or KS) is the commonest aneuploidy. It affects 1/650 male births (0.2 % of general population). More severe, rare, aneuploidies are described; these include: 48,XXXY, 48,XXYY and 49,XXXXY. 48,XXYY affects 1/8000-1/ 40,000 male deliveries, while 48,XXXY affects 1/50,000. Pentasomy 49,XXXXY incidence is around 1/85000 male births [1, 2]. A 49,XXXXY karyotype is thought to arise from maternal non-disjunction during both stages of meiosis, retaining all the X chromosomes within the oocyte. The major endocrine issues of aneuploidies are hyper gonadotropic hypogonadism, testicular degenerative changes and the risk of testicular tumorigenesis. Leydig cell tumors or Leydigioma are occasionally described in cases of KS, but never in the Klinefelter variants
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