Kallmann's syndrome: a comparison of the reproductive phenotypes in men carrying KAL1 and FGFR1/KAL2 mutations.

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.