The neuroradiology of Kallmann's syndrome: a genotypic and phenotypic analysis.

A detailed neurological investigation of patients with Kallmann's syndrome (KS) has been performed in an attempt to relate phenotypic characterization with genotype. Twenty-seven subjects with KS were studied (including 12 males with X-linked disease and 3 females). Six male and 2 female normosmics with isolated GnRH deficiency, 1 male with KS variant, and 1 obligate female carrier were also imaged. Evidence for X-linked disease was derived both from analysis of pedigree and by mutation analysis at the KAL locus. The female carrier and all 8 normosmics had normal olfactory bulbs and sulci, as did 3 male KS. The study, therefore, confirms the value of magnetic resonance imaging in the diagnosis of KS, but suggests that the technique is not sufficiently sensitive to differentiate KS from the normosmic form of GnRH deficiency in all cases. Phenotypic characterization of KS was more effectively achieved by accurate estimation of olfactory status. Three new mutations at the KAL locus were identified, 2 single exon deletions and 1 point mutation. In 2 pedigrees with clear X-linked inheritance, no coding sequence mutations were detected; it may be that these harbor mutations of pKAL, the recently characterized 5'-promoter region. No clear relationship could be established between specific phenotypic anomalies and particular KAL mutations. Involuntary, mirror movements of the upper limbs were present in 10 of 12 cases of X-linked KS, but in none of the other subjects. Although this phenomenon has been ascribed to an abnormality of the corpus callosum, in the present study magnetic resonance imaging demonstrated no quantitative or qualitative morphological anomalies of this structure.