4H-Syndrome: A Common Cause for Hypomyelination

Background: Hypomyelination with hypodontia and hypogonadotropic hypogonadism (HHHH) is an inherited autosomal recessive disease, which was first recorded in four children¹ and four adults². The patients all demonstrated a progressive ataxia as well as cerebellar atrophy. Mutations in POLR3A or POLR3B gene have been identified as the cause. It is now known from a larger collective that not only a genetic but also a clinical heterogeneity exists. Hypodontia and hypogonadism are not always present. This report describes a 16-month-old patient.

Case Report: The child was evaluated because of ataxia and increased “tremors” of his whole body and head. At the time of birth, six teeth were already broken (in the meantime four had already fallen out, no new tooth has broken). When the child was 10 months’ old, his mother first noticed the intermittent shaking which increased during infection but was followed by partial improvement. In the neurological examination, the patient demonstrated both hypotonia focused around the torso also ataxia of the extremities and torso. He was able to pull himself into a standing position and to stand with his knees extended. Even when the head was turned to the left, his gaze was to the right. In the cerebral magnetic resonance imaging (MRI), there was a clear global myelin deficit. The ventrolateral thalamus had a relatively T2-hypointense signal. The posterior limb of the internal capsule and part of the optic radiation were myelinated and the cerebellum was mildly atrophied. The combination of “hypomyelination” (still of young age), “dentes natales” and cerebellar atrophy prompted us to genetically test for 4H syndrome. Through our attempts, we were able to detect the two heterozygous mutations in the compound POLR3B gene (c.1568T> A; p.Val523Glu and c.2570 +1 G> A). A study of the hormonal status has not yet been undertaken.

Conclusion: When hypomyelination appears on an MRI with cerebellar atrophy and progressive ataxia one should always look at dental development and if abnormal one should test for mutations in the POLR3A and POLR3B gene.

Reference

References

1 Wolf NI, Harting I, Boltshauser E, et al. Leukoencephalopathy with ataxia, hypodontia, and hypomyelination. Neurology 2005;64(8):1461–1464

2 Timmons M, Tsokos M, Asab MA, et al. Peripheral and central hypomyelination with hypogonadotropic hypogonadism and hypodontia. Neurology 2006;67(11):2066–2069