Hypomyelination, hypogonadotropic hypogonadism and hypodontia
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)".
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)
- 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.
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 (https://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.
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