Peripheral and central hypomyelination with hypogonadotropic hypogonadism and hypodontia

Abstract

We identified four unrelated patients (three female, one male) aged 20 to 30 years with hypomyelination, pituitary hypogonadotropic hypogonadism, and hypodontia. Electron microscopy and myelin protein immunohistochemistry of sural nerves showed granular debris-lined clefts, expanded abaxonal space, outpocketing with vacuolar disruption, and loss of normal myelin periodicity. Reduced galactocerebroside, sphingomyelin, and GM1-N-acetylglucosamine and increased esterified cholesterol were found. This is a clinically homogeneous progressive hypomyelinating disorder. The term 4H syndrome is suggested.

Figure 1

Brain MRI of all four patients shows that the supratentorial white matter has a signal intensity close to that of the cortex on T1-weighted images, whereas the white-matter signal is hyperintense on T2 images, indicating hypomyelination. The cerebellum is atrophic and the corpus callosum is thin in all patients.

Figure 2

Sural nerve abnormalities observed on electron microscopy. (A) Electron microscopy of peripheral nerve myelin at low magnification in patient 3 shows an overview of peripheral nerve myelin sheaths with pools of granular material tapering to curvilinear deposits, circumferentially and diagonally across the thickness of the myelin sheath (arrowheads; original magnification 4100×). (B) Pools of granular material (arrowhead) tapering to acuminate curvilinear deposits appear to track the myelin sheath circumferentially, traversing the myelin sheath diagonally and, on occasion, perpendicularly traversing the myelin sheath (arrow). Granular deposits line a transverse cleft cutting across the myelin sheath (arrow), extending from an expansion of the abaxonal region within the innermost myelin layers to a collection of myelin, cell debris, and paracrystalline material forming an outpocketing (O) just within the outer myelin layers. The axonal membrane and inner and outer myelin layers appear intact (patient 3, original magnification 9750×). (C) A perpendicular, granular debris-lined cleft forms a disruption across the myelin sheath and in continuity with an abaxonal expanded space containing cell and myelin debris (arrow). The cleft does not transect the outer myelin leaflets. Several diagonal and perpendicular deposits of granular material traverse the myelin sheath (arrowheads, patient 1, original magnification 7400×). (D) Small foci and larger regional loss of the major and dense lines (L) are noted in many of the myelin sheaths of cross-sectioned peripheral nerve. Although tangential orientation of the myelin may be a possible cause for this morphologic appearance in this cross-sectional high-power view, transitions (arrowheads) between the areas where the major and dense lines are distinct and where they are not visible (L) are documented (patient 1, original magnification 71000×).