Biagio Cangiano1,2, Rita Indirli2,3, Eriselda Profka2, Elena Castellano4, Giovanni Goggi1,2, Valeria Vezzoli1, Giovanna Mantovani2,3, Maura Arosio2,3, Luca Persani1,2, Giorgio Borretta4, Emanuele Ferrante5, Marco Bonomi6,7. 1. Laboratorio di Ricerche Endocrino-Metaboliche, Dipartimento di Medicina Endocrino-Metabolica, IRCCS Istituto Auxologico Italiano, Piazzale Brescia 20, 20149, Milan, Italy. 2. Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. 3. Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Via F. Sforza 35, 20122, Milan, Italy. 4. S.C. di Endocrinologia, Diabetologia E Metabolismo, Dipartimento di Medicina Interna, A. O. Santa Croce E Carle-Ospedale S.Croce, Cuneo, Italy. 5. Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Via F. Sforza 35, 20122, Milan, Italy. emanuele.ferrante@policlinico.mi.it. 6. Laboratorio di Ricerche Endocrino-Metaboliche, Dipartimento di Medicina Endocrino-Metabolica, IRCCS Istituto Auxologico Italiano, Piazzale Brescia 20, 20149, Milan, Italy. m.bonomi@auxologico.it. 7. Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. m.bonomi@auxologico.it.
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 14 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, pre-pubertal 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.
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 14 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, pre-pubertal 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.