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Kallmann’s Syndrome: A Comparison of the Reproductive Phenotypes in Men Carrying KAL1 and FGFR1/KAL2 Mutations

Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Service d’Endocrinologie et des Maladies de la Reproduction and Centre de Référence des Maladies Endocriniennes Rares de la Croissance (S.S., P.C., H.B., J.Y.) and Laboratoire de Génétique moléculaire, Pharmacogénétique et Hormonologie (S.B.); Univ Paris-Sud 11 (P.C., S.B., J.Y.); and INSERM U693 (P.C., S.B., J.Y.), F94275 Le Kremlin-Bicêtre, France; Hôpital Neurologique, Fédération d’Endocrinologie (M.P.), F69500 Bron, France; Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau, Laboratoire d’Exploration Fonctionnelles Endocriniennes (S.C.), F75012 Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, Service d’Endocrinologie Pédiatrique, and Centre de Référence des Maladies Endocriniennes Rares de la Croissance (J.C.C.), F75935 Paris, France; Centre Hospitalier Universitaire, Service d’Endocrinologie (A.M.), F44000 Nantes, France; Centre Hospitalier Universitaire, Service d’Endocrinologie (P.L.), F37044 Tours, France; Institut Pasteur, Unité de Génétique des Déficits Sensoriels (J.-P.H.), F75724 Paris, France; and Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Laboratoire de, Biochimie et de Génétique Moléculaire (C.D.), F75014 Paris, France

Address all correspondence and requests for reprints to: Jacques Young, Service d’Endocrinologie, Hôpital de Bicêtre, 94275 Le Kremlin-Bicêtre, France. E-mail: jacques.young{at}bct.aphp.fr.

Context: Kallmann’s syndrome (KS) is a genetically heterogeneous disorder consisting of congenital hypogonadotropic hypogonadism (CHH) with anosmia or hyposmia.

Objective: Our objective was to compare the reproductive phenotypes of men harboring KAL1 and FGFR1/KAL2 mutations.

Design and Patients: We studied the endocrine features reflecting gonadotropic-testicular axis function in 39 men; 21 had mutations in KAL1 and 18 in FGFR1/KAL2, but none had additional mutations in PROK-2 or PROKR-2 genes.

Results: Puberty failed to occur in the patients with KAL1 mutations, all of whom had complete CHH. Three patients with FGFR1/KAL2 mutations had normal puberty, were eugonadal, and had normal testosterone and gonadotropin levels. Cryptorchidism was more frequent (14 of 21 vs. 3 of 15; P < 00.1) and testicular volume (2.4 ± 1.1 vs. 5.4 ± 2.4 ml; P < 0.001) was smaller in CHH subjects with KAL1 mutations than in subjects with FGFR1/KAL2 mutations. The mean basal plasma FSH level (0.72 ± 0.47 vs. 1.48 ± 0.62 IU/liter; P < 0.05), serum inhibin B level (19.3 ± 10.6 vs. 39.5 ± 19.3 pg/ml; P < 0.005), basal LH plasma level (0.57 ± 0.54 vs. 1.0 ± 0.6 IU/liter; P < 0.01), and GnRH-stimulated LH plasma level (1.2 ± 1.0 vs. 4.1 ± 3.5 IU/liter; P < 0.01) were significantly lower in the subjects with KAL1 mutations. LH pulsatility was studied in 13 CHH subjects with KAL1 mutations and seven subjects with FGFR1/KAL2 mutations; LH secretion was nonpulsatile in all the subjects, but mean LH levels were lower in those with KAL1 mutations.

Conclusion: KAL1 mutations result in a more severe reproductive phenotype than FGFR1/KAL2 mutations. The latter are associated with a broader spectrum of pubertal development and with less severe impairment of gonadotropin secretion.