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  • Kallmann syndrome is an inherited disorder characterized by the association of hypogonadotropic hypogonadism, due to gonadotropin-releasing hormone (GnRH) deficiency, with inability to smell (anosmia). These symptoms are the result of a defect in migration and targeting of two specific neuronal subpopulations, the GnRH producing neurons and the olfactory neurons.

  • Autosomal dominant (MIM 147950), autosomal recessive (MIM 244200), and X-linked recessive inheritance patterns have been described in Kallmann syndrome, indicating the presence of genetic heterogeneity. Deletion mapping and positional cloning efforts in the distal short arm of the X chromosome (Xp22.3) led to the isolation of the gene involved in the X-linked type of Kallmann syndrome (Kallmann syndrome protein or gene symbol, respectively (KAL)) (MIM 308700). Patients with Kallmann syndrome who carry deletions in the Xp22.3 region may have contiguous gene syndromes and may, therefore, display the phenotype of several X-linked disorders associated with Kallmann syndrome.

  • In addition to deletions, several point mutations in the KAL gene have been identified in patients with isolated Kallmann syndrome.

  • The KAL gene encodes a secreted protein of 680 amino acids that shares significant similarities with protease inhibitors and neural-cell adhesion molecules (cDNA GenBank M97252).

  • The characterization of KAL spatiotemporal expression pattern in human and chick embryos has provided important clues to the understanding of Kallmann syndrome pathogenesis. Within the olfactory system, the gene is expressed by the olfactory bulb, which represents the target of the olfactory axons.

  • It appears likely that the primary defect in Kallmann syndrome is an abnormality of olfactory system development affecting axonal targeting and/or synaptogenesis.


In 1856, Maestre de San Juan observed the association of hypogonadism with olfactory system abnormalities.1 Later de Morsier described, under the term olfactogenital dysplasia, a series of patients with hypogonadism and anosmia who had various abnormalities of the olfactory system associated with multiple malformations.2,3 Kallmann first identified the inherited nature of this condition in 1944.4 Subsequently, the term Kallmann syndrome (KS) came to designate an inherited disorder characterized by the association of hypogonadotropic hypogonadism and anosmia.

The hypogonadism in KS is due to a reduced secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus.5 The degree of GnRH deficiency in KS patients is variable, ranging from complete deficiency, in which both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels are low and there is no evidence of sexual maturation, to partial deficiency, in which FSH secretion predominates, allowing a certain degree of germinal-cell maturation in the testis but resulting in incomplete sexual development.6 Typical patients with KS have an eunuchoid habitus. Gynecomastia, micropenis, and cryptorchidism have been reported in some cases.7

The other cardinal feature of patients with KS is the presence of nonselective anosmia or hyposmia. Therefore, a precise determination of the olfactory threshold in patients with hypogonadotropic hypogonadism is of fundamental importance in confirming the diagnosis of KS.


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