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

Abstract

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.

A Novel Mutation of the KAL1 Gene in Kallmann Syndrome.

“…Since the patient's unaffected mother was heterozygous for the mutation and we did not find the mutation in the patient's aunt or grandmother, we determined this mutation to be a germline mutation starting de novo from the patient's mother. Small deletions and point mutations in the KALI gene have been reported previously [15,16,17] (Fig. Fig.…”

“…This is the same patient in which we found the point mutation in the KAL1 gene. Previously reported point mutation cases have been associated with unilateral renal aplasia [15,16]. Thus, the KALI gene may play a part in renal development.…”

“…However, this particular patient lacked the other symptoms of Kallmann syndrome associated with the KALI gene mutations such as pes cavus deformity and mirror movement. Moreover, in the one family reported with X-linked Kallmann syndrome, one case was accompanied by unilateral renal aplasia and the other was not [16]. This suggests that the gene associated with the accompanying symptoms such as pes cavus deformity, mirror movement or unilateral renal aplasia may be caused not only by the KAL1 gene but by other cooperative genes or factors.…”

“…Since the KAL1 gene structure was clarified, some mutations of the KAL1 gene have been reported in many X-linked Kallmann syndrome patients [12][13][14][15][16][17]. To date, large deletions, including the entire KALI gene, have been reported in four families, a translocation in one family, a 3300-bp deletion in one family, small deletions in four families and point mutations in 13 families.…”

Invertebrate Models of Kallmann Syndrome: Molecular Pathogenesis and New Disease Genes

“…Post mortem anatomical analysis of a human foetus [9], studies in chicken embryos [10, 48] and more recently the use of in vivo neuroimaging techniques in humans [12, 13] have helped define the embryonic developmental defects that underlie KS main symptoms. Anosmia is the result of an impaired migration and targeting of olfactory sensory axons to the olfactory bulbs [14].…”