Brain changes in Kallmann syndrome

Abstract

Background and purpose: Kallmann syndrome is a rare inherited disorder due to defective intrauterine migration of olfactory axons and gonadotropin-releasing hormone neurons, leading to rhinencephalon hypoplasia and hypogonadotropic hypogonadism. Concomitant brain developmental abnormalities have been described. Our aim was to investigate Kallmann syndrome-related brain changes with conventional and novel quantitative MR imaging analyses.

Materials and methods: Forty-five male patients with Kallmann syndrome (mean age, 30.7 years; range, 9-55 years) and 23 age-matched male controls underwent brain MR imaging. The MR imaging study protocol included 3D-T1, FLAIR, and diffusion tensor imaging (32 noncollinear gradient-encoding directions; b-value=800 s/mm2). Voxel-based morphometry, sulcation, curvature, and cortical thickness analyses and tract-based spatial statistics were performed by using Statistical Parametric Mapping 8, FreeSurfer, and the fMRI of the Brain Software Library.

Results: Corpus callosum partial agenesis, multiple sclerosis-like white matter abnormalities, and acoustic schwannoma were found in 1 patient each. The total amount of gray and white matter volume and tract-based spatial statistics measures (fractional anisotropy and mean, radial, and axial diffusivity) did not differ between patients with Kallmann syndrome and controls. By specific analyses, patients with Kallmann syndrome presented with symmetric clusters of gray matter volume increase and decrease and white matter volume decrease close to the olfactory sulci; reduced sulcal depth of the olfactory sulci and deeper medial orbital-frontal sulci; lesser curvature of the olfactory sulcus and sharper curvature close to the medial orbital-frontal sulcus; and increased cortical thickness within the olfactory sulcus.

Conclusions: This large MR imaging study on male patients with Kallmann syndrome featured significant morphologic and structural brain changes, likely driven by olfactory bulb hypo-/aplasia, selectively involving the basal forebrain cortex.

Fig 1.

Conventional brain MR imaging findings in 45 patients with Kallmann syndrome. A, Midsagittal T1-weighted image of a patient with agenesia of the posterior portion of the corpus callosum (white arrows). B, Axial FLAIR image of the patient disclosing several multiple sclerosis–like white matter signal abnormalities in the centrum semiovale bilaterally. C, Non-enhanced axial T1-weighted image at the level of the internal acoustic meatus showing a right intra/extrameatal dumbell-shaped mass consistent with an acoustic schwannoma.

Fig 2.

3D-T1-based whole-brain analyses on 42 patients with Kallmann syndrome versus 23 controls. A, Voxel-based morphometry findings. Clusters of significantly decreased white matter volume (colored areas in the multiplanar reconstructions in the first column) were detected exclusively and symmetrically in the posterior portion of the medial orbital-frontal gyrus close to the olfactory sulcus; no regions of increased white matter volume were detected in our sample. Clusters of significantly decreased (second column) and increased (third column) gray matter volume are shown as colored cortical areas in the volume-rendering technique images within or close to the olfactory sulci. B, Sulcation, curvature, and thickness findings. Colored areas represent increased (yellow-red) and decreased (blue) values in patients with KS. Almost all differences are clustered within the olfactory sulci and the neighboring cortex of the rectus and medial orbital-frontal gyri.