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

2007; Oxford University Press; Volume: 93; Issue: 3 Linguagem: Inglês

10.1210/jc.2007-1168

1945-7197

Sylvie Salenave, Philippe Chanson, H. Bry, Michel Pugeat, Sylvie Cabrol, Jean‐Claude Carel, Arnaud Murat, Pierre Lecomte, Sylvie Brailly, Jean‐Pierre Hardelin, Catherine Dodé, Jacques Young,

Plant Reproductive Biology

Kallmann's syndrome (KS) is a genetically heterogeneous disorder consisting of congenital hypogonadotropic hypogonadism (CHH) with anosmia or hyposmia.Our objective was to compare the reproductive phenotypes of men harboring KAL1 and FGFR1/KAL2 mutations.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.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.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.