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

Objective: 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, 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 (14/21 vs 3/15; 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/L; 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/L; P < 0.01) and GnRH-stimulated LH plasma level (1.2 ± 1.0 vs 4.1 ± 3.5 IU/L; P < 0.01) were significantly lower in the subjects with KAL1 mutations. LH pulsatility was studied in 13 CHH subjects with KAL1 mutations and 7 subjects with FGFR1/KAL2 mutations : LH secretion was non pulsatile 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.