Bringing Kallmann syndrome into focus.

Three articles ( 1-3) in this issue of AJNR bring the power of magnetic resonance (MR) to bear on the problem of neuroimaging in Kallmann syndrome (KS). These investigators provide the most detailed views of KS olfactory pathology that can be obtained outside of the anatomy laboratory, opening a new window on the study of this disease. The principle phenotypic features of KS, anosmia and hypogonadism, were first reported at autopsy almost 150 years ago (4). When Franz Kallmann demonstrated the association in a living individual, he also showed that the disorder can be inherited in an X-linked fashion (5). Although a rare disorder, affecting about 1 in 1 0, 000 men and 1 in 50,000 women (6), evidence appeared that KS can be inherited as an autosomal recessive (7) or autosomal dominant (8) as well. The three patterns of inheritance imply that mutations in different genes can result in hypogonadism with anosmia. Many genes are known to have pleiotropic effects during development; therefore, it is not surprising that the two principle features of KS are associated with several other defects. Some of the defects are associated with a particular pattern of inheritance, probably reflecting the function of that gene in development. For example, renal abnormalities are seen in patients with the X-linked form (9), whereas midline defects, such as cleft lip and palate, are seen in autosomal recessive pedigrees (7). Some of the associated abnormalities reported in KS patients are likely to be chance associations unrelated to the underlying gene defect. For all of these reasons, correlating the genotype with the phenotype has been difficult in KS. Nevertheless , the basis of the central features of the disease was clear: anatomic studies showed that the olfactory disturbance was caused by hypoplasia or aplasia of the olfactory bulbs and tracts (10), and physiological studies showed that the hypogonadism was caused by gonadotropinreleasing hormone (GnRH) deficiency (11). The latter studies led to hormonal therapies that restore fertility (12). Neuroanatomic studies showed that the GnRHsecreting neurons of the hypothalamus originate in the olfactory placode and migrate into the brain along with olfactory, terminalis, and vomeronasal nerves (13, 14). A study of a fetus with X-linked KS showed that the cells and nerves of the olfactory placode develop normally, but fail to migrate to their proper position in the brain, instead stopping prematurely at the meninges (15) , suggesting that the X-linked KS gene product is involved in this movement. Despite these insights, little else was known about KS genes and how mutations in these genes related to the phenotype until recently. In 1991, the gene for X-linked KS (KAL) was isolated (16, 17). Using the cloned KAL gene, investigators have demonstrated mutations in KS patients ( 18, 19). The KAL-predicted protein sequence proved to have homology to a number of neural cell adhesion molecules involved in axonal pathfinding consistent with a migration defect. Therefore, it was surprising when in situ hybridization studies in the chick showed that KAL messenger RNA (mRNA) is expressed in the mitral cells of the olfactory bulb, the target of olfactory axons. No expression was found in the olfactory placode or its derivatives (20). These data suggest that the KAL protein may be involved in neural target recognition by mediating the interactions between olfactory axons and the mitral cells of the olfactory bulb. The KAL mRNA is found in other areas of the chick brain , providing a clue to the other neurodevelopmental abnormalities in KS. For the clinician, the availability of the cloned KAL gene will allow molecular diagnosis and, therefore , an unambiguous assignment of KS patients into those with a detectable mutation in