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

A case with central and peripheral hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome) plus cataract

“…Alternatively, ADDH patients reported may be too young to present pubertal delay. There are now 16 patients with 4H syndrome/ADDH published [1,[6][7][8][9][10][11]. Future genetic analysis will make this issue clear.…”

Endocrine Aspects of 4H Leukodystrophy: A Case Report and Review of the Literature

“…Cerebellar dysfunction is the most frequent neurological abnormality [7, 10–13, 21], and the majority of patients also have cognitive dysfunction [1, 6, 7, 9, 12, 18, 22]. Progressive neurological deterioration is a characteristic feature of patients with 4H leukodystrophy and other Pol III-related leukodystrophies, with many patients becoming wheelchair-bound and exhibiting significant cognitive impairment by the time they reach young adulthood [1, 7, 10, 13, 18, 21, 23].…”

“…The majority of females with 4H leukodystrophy lack spontaneous pubertal development, suggesting that hypogonadotropic hypogonadism is usually established prior to adolescence in this disorder [12, 13]. Although hypogonadism has not been recognized until early adulthood in some male patients, normal initial pubertal development followed by progressive hypogonadism has not been described [9, 10].…”

“…Although hypogonadism has not been recognized until early adulthood in some male patients, normal initial pubertal development followed by progressive hypogonadism has not been described [9, 10]. Some patients also have growth hormone deficiency, which was shown to be progressive in one individual [9, 12]. The other pituitary hormones do not appear to be affected.…”

Advances in MR Imaging of Leukodystrophies

“…In addition, one patient had an increase in MI concentration, pointing to gliosis and astrocytic proliferation (50). The MR spectra of patients with 4H-Syndrome, a rare form of hypomyelinating leukodystrophy, reveals low Cho/Cr and NAA/Cr, while a prominent MI peak can be observed (51,52). Low Cho levels are indicative of hypomyelination due to decreased membrane synthesis and turnover.…”