4H syndrome: a rare cause of leukodystrophy

Abstract

A 24-year-old woman suffered from gait unsteadiness and tetraparesis since childhood. Her medical history was characterized by a normal delivery of non-consanguineous parents. Walking with support was acquired at 10 months. Childhood development was characterized by occurrence of a progressive cerebellar ataxia, short stature, mental development retardation (IQ = 46), and hypodontia (i.e., absence of deciduous teeth eruption and short tooth roots). Walking without support was never acquired. At the age of 14, a partial growth hormone (GH) deficit (insufficient peak of GH in standard condition and with stimulation tests) and an hypogonadotropic hypogonadism [absence of luteinizing hormone (LH) and follicle stimulating hormone (FSH), lack of response to LH-releasing hormone (LH-RH) injection with LH peak at 0.6 UI/l and FSH peak at 1.4 UI/l] were found. Dental panoramic radiographs showed short tooth roots and absence of dental pulp chamber (Fig. 1). At the age of 24, neurological examination observed a severe static and kinetic cerebellar syndrome, spastic tetraparesis, multidirectional nystagmus, vertical down and up-gaze palsy, and mental retardation. Walking perimeter was 10 m with human assistance. Neuro-ophthalmologic examination confirmed vertical gaze palsy, and revealed amblyopia (with visual acuity of 4/10 on both sides), severe myopia, and bilateral temporal papillary atrophy. Nerve conduction studies and electromyography were normal. Neuroimaging performed at 3 Tesla (Philips, Best, The Netherlands) showed marked atrophy of the corpus callosum (reflecting the global white matter (WM) volume) and the cerebellum. In addition, spinal cord atrophy was moderate (data not shown). Myelinated areas including the pyramidal tracts, the internal capsule, the deep cerebellum, and the brainstem were hyperintense relative to cortical grey matter (CGM) on T1-WI and hypomyelinated areas (=rest of the white matter) were diffusely hypointense relative to CGM on T1-W1 (Fig. 2a–c). On T2-FLAIR images, the myelinated area appeared iso/hypointense relative to CGM and the hypomyelinated area appeared diffusively hyperintense relative to CGM (Fig. 2d–f). The pons appeared small with widening of the prepontine cystern, which was probably due to hypomyelinated corticopontine tracts as well as atrophy of crossing cerebellar tracts (Fig. 2a, c, d, f). Single voxel proton-magnetic resonance spectroscopy (HMRS) spectra showed low choline/creatine and N-acetylaspartate/creatine ratios within the left semi-ovale WM, left basal ganglia and pons. A prominent myo-inositol peak was also found within the pons (Fig. 2g). Tractography obtained from a Diffusion O. Outteryck (&) D. Devos L. Hopes P. Vermersch Department of Neurology, Salengro Hospital, Universite Lille Nord de France, CHRU Lille, Rue Emile Laine, 59037 Lille Cedex, France e-mail: Olivier_outteryck@hotmail.com