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

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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.

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Funding

This study was funded by Italian Ministry of Health (Young Investigators funds: GR-2016-02362389) and IRCCS Istituto Auxologico Italiano (Ricerca Corrente funds: O5C202_2012).

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Author notes

  1. B. Cangiano and R. Indirli equally contributed to this work and they appear in the alphabetical order.

Authors and Affiliations

  1. Laboratorio di Ricerche Endocrino-Metaboliche, Dipartimento di Medicina Endocrino-Metabolica, IRCCS Istituto Auxologico Italiano, Piazzale Brescia 20, 20149, Milan, Italy

    Biagio Cangiano, Giovanni Goggi, Valeria Vezzoli, Luca Persani & Marco Bonomi

  2. Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

    Biagio Cangiano, Rita Indirli, Eriselda Profka, Giovanni Goggi, Giovanna Mantovani, Maura Arosio, Luca Persani & Marco Bonomi

  3. Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Via F. Sforza 35, 20122, Milan, Italy

    Rita Indirli, Giovanna Mantovani, Maura Arosio & Emanuele Ferrante

  4. S.C. di Endocrinologia, Diabetologia E Metabolismo, Dipartimento di Medicina Interna, A. O. Santa Croce E Carle-Ospedale S.Croce, Cuneo, Italy

    Elena Castellano & Giorgio Borretta

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  1. Biagio Cangiano
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  2. Rita Indirli
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  3. Eriselda Profka
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  4. Elena Castellano
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  6. Valeria Vezzoli
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  11. Emanuele Ferrante
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  12. Marco Bonomi
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Contributions

BC and RI conducted the literature review, collected clinical data and prepared the manuscript. EP, EC, GG, GB, EF and MB performed patient follow-up, clinical diagnosis and treatment. MB, LP, BC and VV were responsible for genetic analyses. GM, MA, LP, GB, EF and MB performed the critical revision of the manuscript. All authors read and approved the submitted version.

Corresponding authors

Correspondence to Emanuele Ferrante or Marco Bonomi.

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This article does not contain any studies with animals performed by any of the authors.

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This study was exempt from ethical approval procedures being a case report study that describes the clinical course and outcome of two patients who were referred to our outpatient clinic. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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Cangiano, B., Indirli, R., Profka, E. et al. Central hypogonadism in Klinefelter syndrome: report of two cases and review of the literature. J Endocrinol Invest 44, 459–470 (2021). https://doi.org/10.1007/s40618-020-01324-3

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