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X Chromosome-Linked Kallmann Syndrome: Clinical Heterogeneity in Three Siblings Carrying an Intragenic Deletion of the KAL-1 Gene

Department of Endocrinology and Reproductive Medicine (N.M., J.G., F.K., P.T.), Hôpital Necker, 75743 Paris Cedex 15, France; Department of Biochemistry and Molecular Genetics (C.P., C.D.), Hôpital Cochin, 75014 Paris, France; Department of Oto-Rhino-Laryngology (C.E.), Hôpital Lariboisière, 75010 Paris, France; Department of Radiology (J.-L.B.), Clinique Turin, 75008 Paris, France; and Unité de Génétique des Déficits Sensoriels (J.-P.H.), Institut Pasteur, 75724 Paris Cedex 15, France

Address all correspondence and requests for reprints to: Philippe Touraine, M.D., Ph.D., Department of Endocrinology and Reproductive Medicine, Hôpital Necker, 149 rue de Sèvres, 75743 Paris Cedex 15, France. E-mail: philippe.touraine{at}nck.ap-hop-paris.fr.

Kallmann syndrome (KS) is characterized by the association of hypogonadotropic hypogonadism and anosmia. The gene underlying the X chromosome-linked form of the disease, KAL-1, consists of 14 coding exons. It encodes a glycoprotein, anosmin-1, which is involved in the embryonic migration of GnRH-synthesizing neurons and the differentiation of the olfactory bulbs. We describe herein the clinical heterogeneity in three affected brothers who carry a large deletion (exons 3–13) in KAL-1. All three had a history of hypogonadotropic hypogonadism with delayed puberty. Although brain magnetic resonance imaging showed hypoplastic olfactory bulbs in the three siblings, variable degrees of anosmia/hyposmia were shown by olfactometry. In addition, these brothers had different phenotypic anomalies, i.e. unilateral renal aplasia (siblings B and C), high-arched palate (sibling A), brachymetacarpia (sibling A), mirror movements (siblings A and B), and abnormal eye movements (sibling C). Last but not least, sibling A suffered from a severe congenital hearing impairment, a feature that had been reported in KS but had not yet been ascribed unambiguously to the X-linked form of the disease. The variable phenotype, both qualitatively and quantitatively, in this family further emphasizes the role of putative modifier genes, and/or epigenetic factors, in the expressivity of the X-linked KS.

Abbreviations: KS, Kallmann syndrome; MRI, magnetic resonance imaging.

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