Central hypogonadism in Klinefelter syndrome: report of two cases and review of the literature

Abstract

Purpose: Klinefelter syndrome (KS) is characterized by late adolescence/young adulthood onset of primary hypogonadism. Hypogonadotropic hypogonadism (HH), when congenital, is usually associated with absent/incomplete puberty and low/normal gonadotropins. We report the clinical and genetic features of two subjects with KS and an unexpected HH hormone profile.Methods: Magnetic resonance imaging (MRI) of hypothalamus-pituitary region and next generation sequencing (NGS) of congenital HH-associated genes were obtained. A narrative review of the literature was conducted.Results: Patients were diagnosed with Klinefelter syndrome following karyotype analysis. Nevertheless, they showed unusual features: both had incomplete puberty, low gonadotropins and testosterone levels, and the first one was anosmic. Sellar lesions were excluded by MRI, and NGS was negative in both subjects. Our data add to those of the only fourteen similar cases reported so far. Unexplained HH rarely occurs in KS and is variably associated with anosmia, other pituitary hormones deficiencies and heterogeneous karyotypes. However, most cases show an early, prepubertal onset of hypogonadism. If the causes behind this gonadotropins defect are largely unknown, hereby we provide the first review of the literature on this topic and propose some pathogenetic hypotheses, including the coexistence of KS and congenital HH as suggested by overlapping clinical features in some of these patients. Conclusion:HH is an exceptional occurrence in Klinefelter syndrome and is associated with heterogeneous phenotypes and, probably, aetiologies. Moreover, KS could underlie HH nonresponsive to gonadotropins. An exhaustive diagnostic workup and a tailored clinical management are advisable in these rare forms.

Mixed hypogonadism: a neglected combined form of hypogonadism

“…Patient 2 and patient 3 were diagnosed as Kallmann syndrome and Klinefelter syndrome, based on anosmia, absence of puberty, and bilateral olfactory dysplasia on COFT, SROS, MR and the karyotype. A combination of Klinefelter syndrome and hypogonadotropic hypogonadism had rarely been described [4,[19][20][21][22][23][24][25][26][27] (summarized in Supplementary Table 2). According to these cases, patients always present with hypogonadotropic hypogonadism despite of Klinefelter syndrome.…”

“…Low gonadotropin levels in Klinefelter syndrome and high gonadotropin levels in Kallmann syndrome during treatment are very rare clinical situations [4] . This paper reports three Klinefelter syndrome patients with low gonadotropin levels, and one Kallmann syndrome patient with history of cryptorchidism with mixed gonadotropin levels.…”

Occurrence of Klinefelter Syndrome Mosaic 45,X/46,XY/47,XXY/48,XXYY/48,XXXY and Primary Hyperparathyroidism

“…Unelevated serum gonadotropin levels in nonmosaic KS have been reported before. 13 It has been associated with different grades of mosaicism, 14 homogenous 47,XXY, 13 and trisomy Xq, 15 which indicate no obvious association between cytogenetic compositions and phenotypes. Typically, testosterone levels start to decline in late adolescence, and by early adulthood, overt hypergonadotropic hypogonadism ensues.…”

Giftedness and atypical sexual differentiation: enhanced perceptual functioning through estrogen deficiency instead of androgen excess

“…Prenatal androgen production rate is diverse, as manifested in the micropenis manifestation in 10–25% of diagnosed cases ( 16 ). Hypogonadotropic hypogonadism cases are included in such a phenotype, and the percentage is as low as two in 160 KS individuals ( 167 ). Decrease in bone mineral density is observed in <40% individuals, indicating lower estrogen function ( 16 ).…”