The frequency of Kallmann syndrome (hypogonadotropic hypogonadism and anosmia, HHA) was estimated in patients presenting with hypogonadism and patients with anosmia.Of 791 hypogonadal males 19 had HHA.
The pathogenesis of the olfactory defect in the X-linked Kallmann syndrome is discussed in the light of the present results and the recent data reporting the immunohistochemical localisation of anosmin-1 during early embryonic development.
Linkage analysis using informative microsatellite markers predicts that a gene other than KAL1 (at Xp22.3) is implicated in the Kallmann's syndrome manifesting concurrently with ovarian dysgenesis found in this family.
As a consequence of this mutation, the function of the KAL1 protein consisting of 680 amino acids was severely truncated so as to be consistent with Kallmann syndrome.
A defective anosmin-1 molecule may also play a role in the development of synkinesia and renal agenesis, which are exclusively seen in the X-linked form of KS.
To date, 4 genes have been identified as causes of IHH in the human; KAL [the gene for X-linked Kallmann syndrome (IHH and anosmia)], DAX1 [the gene for X-linked adrenal hypoplasia congenita (IHH and adrenal insufficiency)], GNRHR (the GnRH receptor), and PC1 (the gene for prohormone convertase 1, causing a syndrome of IHH and defects in prohormone processing).
Mutations in a few genes have been identified in hypogonadotropic hypogonadism (HH): the gene KAL-1 is involved in X-linked Kallmann syndrome associated with anosmia and mutations in transcription factors, namely, DAX-1 and Prop-1 were also evidenced when associated with other pituitary or endocrine defects.
Based on the distribution of anosmin-1 in the early olfactory system, the pathogenesis of the olfactory loss and GnRH deficiency in X-linked Kallmann syndrome is discussed.
Genes currently recognized to be involved comprise KAL (associated with X-linked-KS), the GnRH receptor (associated with resistance to GnRH therapy), DAX 1 (associated with adrenohypoplasia congenita) and three loci also associated with obesity, leptin (OB), leptin receptor (DB) and prohormone convertase (PC1).