THE NEUROBIOLOGY OF KALLMANNS-SYNDROME

Isolated hypogonadotrophic hypogonadism is a feature of several geneti c conditions, the commonest and best defined being Kallmann's syndrome , in which it is associated with anosmia. This condition results from a developmental failure of fascicles of the olfactory nerve complex to make synaptic contact with the forebrain. As a consequence, gonadotro phin-releasing hormone (GnRH)-secreting neurons are unable to migrate from their site of origin on the medial olfactory placode to the hypot halamus. However, the mechanisms underlying the GnRH deficiency found in other conditions, where there is no olfactory disturbance, remain t o be elucidated. Patients with Kallmann's syndrome are readily identif ied by olfactory testing, which reveals them to be completely anosmic to the Smell Identification Test(R). Magnetic resonance imaging (MRI) is helpful but does not invariably detect abnormal anatomy of the olfa ctory system. The genetics of X-linked Kallmann's syndrome is relative ly well understood, with the responsible gene, KAL, being located at X p22.3. However, the occurrence of affected females suggests that one o r more autosomal genes also exist, although these remain to be identif ied. Genotyping Kallmann's subjects is, moreover, complicated by the e xistence of well-defined X-linked pedigrees in which the KAL coding se quence is normal. Such families may harbour mutations of KALp, the rec ently identified promoter region. Phenotypically, patients with the X- linked condition can often be readily identified either by the presenc e of upper-limb mirror movements or the absence of one kidney. These c linical features correlate well with in-situ hybridization and reverse transcriptase polymerase chain reaction data showing KAL expression w ithin the embryonic spinal cord and developing kidneys as well as in t he olfactory bulbs. Early identification and treatment of hypogonadotr ophic patients is important, both for normal psychosocial development and for the attainment of peak bone mass. Despite advances in gonadotr ophin assay techniques, distinguishing children with delayed puberty f rom those who are truly hypogonadal is not always straightforward; but , in any case, initial treatment may be quite similar. However, a hist ory of cryptorchidism or of olfactory deficit suggest gonadotrophin de ficiency and MRI will usually show abnormal or absent olfactory bulbs and sulci in subjects with Kallmann's syndrome. Having first been take n through puberty with exogenous sex steroids, most patients respond w ell to fertility-induction regimes with either gonadotrophins or pulsa tile GnRH therapy. Nevertheless, a proportion of subjects do not respo nd and this may reflect prior absence of the neonatal gonadotrophin su rge, which may have a priming effect on subsequent gonadal development .