Brain Changes in Kallmann Syndrome

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.

Kallmann syndrome (KS) is a rare inherited disorder (affecting about 1 in 10,000 males),¹ clinically characterized by the association of hypogonadotropic hypogonadism and hypo-/anosmia.² Both KS clinical hallmarks derive from a disturbed intrauterine migration process involving olfactory axons and gonadotropin-releasing hormone neurons from the olfactory placode to the hypothalamus.^3,4 The failure of the migration process results in hypo-/aplasia of the rhinencephalon (olfactory bulbs and tracts)^3–6 and in altered gonadotropic axis function with low levels of sex hormones. Besides rhinencephalon abnormalities, distinctive KS neuroradiologic changes have been detected in the brain and bone structures of the anterior cranial fossa by conventional MR imaging^7–14 and CT studies.¹⁵ The most known morphologic brain feature is the reduction in depth and length of the olfactory sulcus, which typically turns medially, opening anteriorly into the interhemispheric fissure.^7–13 This sulcal abnormality is thought to be driven by the absence/hypoplasia of the olfactory bulbs and represents an intriguing model of genetically driven developmental brain abnormalities. Furthermore, a few case reports postulated the strict relationship between KS and midline brain abnormalities, such as corpus callosum agenesis and holoprosencephaly,^6,16 though pathologic and neuroimaging data are relatively scarce and often contradictory.⁷In 2008, a pioneering study by voxel-based morphometry (VBM) MR imaging analysis revealed distinct regional gray and white matter volume changes in male patients with KS outside the frontal orbital regions.¹⁷ No study so far has replicated a larger sample of these findings, which would imply a much more profound effect of KS-related genes (KAL1, FGFR1, PROK2, PROKR2, FGF8, NELF, etc.)¹⁸ and/or sex hormone deficiency on brain morphogenesis and development. Moreover, no study has investigated regional white matter changes revealed by VBM by diffusion tensor imaging, a powerful quantitative technique able to investigate the structural nature of white matter involvement. Finally, novel MR imaging–based analyses have been developed that allow assessing precise curvature, sulcation, and cortical thickness quantitative evaluations,^19–21 thus providing further insights into cortex developmental abnormalities. Such analyses have not been applied to KS, though they might represent useful tools for investigating the structural underpinnings of neurologic and psychiatric disorders anecdotally reported in patients with KS.^22,23By conventional MR imaging and novel quantitative sulcation, curvature, cortical thickness, and tract-based spatial statistics (TBSS) analyses, we aimed to feature, more precisely and in a large sample of male patients, the morphologic and structural brain involvement in KS.