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4H syndrome

Hypomyelination, hypogonadotropic hypogonadism and hypodontia

Introduction

4H syndrome is a novel white matter disorder. 4H is short for hypomyelination, hypogonadotropic hypogonadism and hypodontia. Hypomyelination means that there is lack of myelin in the central nervous system. In hypogonadotropic hypogonadism, normal puberty development is absent because the central nervous system is not able to initiate it properly. Hypodontia means that not all teeth are present. Other names of 4H syndrome include "Ataxia, hypodontia and hypomyelination (AHH)" and "Ataxia, delayed dentition and hypomyelination (ADDH)".

Clinical symptoms

At birth and during the first year of life, a child with 4H syndrome appears normal. Symptoms usually start during the second year of life, but patients with normal early childhood and symptoms only from the second decade have been described.
Neurological symptoms include:
" Late walking
" Early-onset ataxia (problems with balance and fine motor skills)
" Deterioration of ataxia with infections with complete or partial recovery
" Slow progression of ataxia over time
" Dysarthria (speech is difficult to understand)
" Later, development of spasticity (abnormally stiff muscles and restricted movements)
" Seizures (these are rare)

Other symptoms:
" Some teeth may be already present at birth (natal teeth)
" Dentition (eruption of teeth) is delayed, and the first teeth to erupt are the deciduous molars, not the incisors as usual. Upper medial incisors erupt late, often after the age of 6 years. Some of the teeth, especially of the permanent teeth, may be missing (hypodontia) or are have an unusual shape.
" Normal puberty development is absent.
" Short stature may develop during childhood.
" Myopia (shortsightedness) is common.
 

Diagnosis - MRI

The diagnosis of 4H syndrome is based on clinical findings (ataxia, dental abnormalities and later absence of normal puberty development) and on the MRI findings. MRI shows hypomyelination and cerebellar atrophy (volume loss of the cerebellum which is a part of the brain). Myelin is the isolation material of the nerve fibres in the brain and forms together with these nerve fibers the white matter of the brain. Normally, myelination (the process in which myelin sheaths are formed to surround nerve fibers) of these nerve fibers takes place during the first two years of life. Hypomyelination means that there is a permanent significant deficit of myelin in the brain. The signal intensity ("colour") of the unmyelinated white matter is different of the normally myelinated white matter in the brain. See also http://www.vumc.com/afdelingen/Children-White-Matter-Disorders/419542/419569/
 


Figure A and B are from a 4-year-old child with 4H syndrome, B and C are from a healthy child the same age. (A) and (C) are transversal T2-weighted images. Normally, the white matter has a dark signal as in (C). In (A), the white matter signal is diffusely abnormal and seems almost white. This means that there is not enough normal myelin present. (B) and (D) are sagittal T1-weighted images. The cerebellum looks smaller than normal in (B).

Genetics

4H syndrome is a genetic disease. As in some families, several children - boys and girls - are affected, we think that it is inherited in an autosomal recessive manner. This means that parents are healthy, but carry each one defective copy of the responsible gene (http://www.vumc.com/afdelingen/Children-White-Matter-Disorders/419542/419571/). If a child inherits two defective copies of this gene, it will be affected. The gene causing 4H syndrome is not yet found. Prenatal diagnosis is therefore not possible yet.

References

1. Wolf NI, Harting I, Boltshauser E, Wiegand G, Koch MJ, Schmitt-Mechelke T, Martin E, Zschocke J, Uhlenberg B, Hoffmann GF, Weber L, Ebinger F, Rating D. Leukoencephalopathy with ataxia, hypodontia, and hypomyelination. Neurology 2005; 64: 1461-1464.
2. Timmons M, Tsokos M, Asab MA, Seminara SB, Zirzow GC, Kaneski CR, Heiss JD, van der Knaap MS, Vanier MT, Schiffmann R, Wong K. Peripheral and central hypomyelination with hypogonadotropic hypogonadism and hypodontia. Neurology 2006; 67: 2066-2069.
3. Wolf NI, Harting I, Innes AM, Patzer S, Zeitler P, Schneider A, Wolff A, Baier K, Zschocke J, Ebinger F, Boltshauser E, Rating D. Ataxia, delayed dentition and hypomyelination: a novel leukoencephalopathy. Neuropediatrics 2007; 38: 64-70.
4. Vazquez-Lopez M, Ruiz-Martin Y, de Castro-Castro P, Garzo-Fernandez C, Martin-del Valle F, Marquez-de la Plata L. [Central hypomyelination, hypogonadotrophic hypogonadism and hypodontia: a new leukodystrophy]. Revista de neurologia 2008; 47: 204-208.
5. Wolff A, Koch MJ, Benzinger S, van Waes H, Wolf NI, Boltshauser E, Luder HU. Rare dental peculiarities associated with the hypomyelinating leukoencephalopathy 4H syndrome/ADDH. Pediatr Dent 2010; 32: 386-392.

 


 

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