Endocrine Abstracts

Introduction: Klinefelter syndrome (KS) is generally characterized by late adolescence/young adulthood onset of primary hypergonadotropic hypogonadism. Fourteen cases have been previously reported on apparently unexplained isolated hypogonadotropic hypogonadism (IHH) in KS. Gonadotropins defect was variably associated with anosmia or other pituitary hormones deficiencies, but no cause could be clearly identified to explain the central defect. We describe the clinical and genetic features of two additional cases followed up at two clinics in Northern Italy.

Case 1: A 60-year-old Caucasian man was referred for genital infantilism and smell defect, for which he had never sought medical attention before. He had a family history of infertility and anosmia; his parents were unrelated. His past medical history included recurrent respiratory infections resulting in restrictive ventilatory defect. The patient reported he had not gone through puberty during adolescence, and eunuchoid body proportions and infantile penis were observed at physical examination. Scrotal ultrasound revealed testes hypotrophy (volume <1 ml). Cytogenetic analysis documented 47,XXY karyotype. Nevertheless, IHH was found on hormonal assessment (total testosterone 1.0 nmol/l, LH 0.1 mIU/ml, FSH 0.1 mIU/ml), while other pituitary hormones were normal.

Case 2: A Caucasian boy with prenatal diagnosis of mosaic KS (47,XXY)(46,XY) confirmed after birth,presented at 17 years of age with small and firm testes (right 6 ml, left 8 ml) and first grade obesity. As a child, he had suffered from dyslexia and incomplete pubertal development. At 20 years of age hormonal exams were obtained and unexpected results consistent with IHHwere found (total testosterone 3.7 nmol/l, LH 3.5 mIU/ml, FSH 2.3 mIU/ml), while other pituitary hormones were preserved. Smell identification test was normal and the patient had no family history of anosmia or infertility.

Diagnostic work-up: Iron overload was excluded in both patients. Sellar region was normal on magnetic resonance scans. Finally, genetic analysis performed by next generation sequencing of IHH associated genes was negative in both patients.

Conclusion: Unexplained central hypogonadism rarely occurs in KS. The mechanism by which the gonadotropin defect is determined in these patients is unknown; coexistence of KS and normosmic isolated hypogonadotropic hypogonadism or Kallmann syndrome could be possible; alternatively,chronic metabolic or systemic comorbidities may suppress the hypothalamus-pituitary-testis axis in some KS subjects resulting in central hypogonadism; finally, these patients may represent a rare variant of KS with more extensive endocrine involvement besides the testicular defect.