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


METHODS
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.


CONCLUSIONS
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.
Salenave
Sylvie
S
Assistance Publique-Hôpitaux de Paris, and Univ Paris-Sud, France.
Chanson
Philippe
P
Bry
Hélène
H
Pugeat
Michel
M
Cabrol
Sylvie
S
Carel
Jean Claude
JC
Murat
Arnaud
A
Lecomte
Pierre
P
Brailly
Sylvie
S
Hardelin
Jean-Pierre
JP
Dodé
Catherine
C
Young
Jacques
J
D000293:Adolescent; D000328:Adult; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D006801:Humans; D007006:Hypogonadism / Q000453:epidemiology / Q000235:genetics; D017436:Kallmann Syndrome / Q000235:genetics* / Q000503:physiopathology; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D012098:Reproduction; D013737:Testis / Q000378:metabolism / Q000473:pathology
C076266:ANOS1 protein, human; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D007986:Luteinizing Hormone; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1