4H Syndrome: Hypomyelination with Hypogonadotropic Hypogonadism and Hypodontia

What is 4H syndrome?

4H syndrome 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. This condition affects the function of the testes in males and the ovaries in females. Hypodontia means that not all teeth are present.


4H syndrome is inherited in an autosomal recessive manner. This means that parents are healthy, but each carries one defective copy of the responsible gene. If a child inherits two defective copies of this gene, one from each parent, it will be affected. The parents are both considered “carriers” of the condition, meaning that they carry a change in their genes, but that change does not affect their own health. A couple that has a child with 4H syndrome has one-in- four chance (25%) to have another child with 4H syndrome. Genetic counselling can help families with a history of 4H syndrome determine which members are at risk to have the disease or an affected child.

What causes 4H syndrome?

4H syndrome is a rare genetic disorder. It is caused by a mutation in the POLR3A or POLR3B gene. This means that the set of instructions for the body to make the proteins to complete their creative function are unable to do so. Hence the symptoms that our children have.

How do we diagnose?

4H syndrome is diagnosed on the basis of the clinical symptoms, especially ataxia and delayed dentition or Hypodontia, in combination with the results of an MRI also which shows Hypomyelination (lack of myelin in the brain) and cerebellar atrophy (volume loss of the cerebellum which is a part of the brain). The diagnosis is based on these symptoms and the results of MRI, a medical imaging technique, which can show a specific pattern of the brain tissue. Genetic testing, using a blood sample, can identify changes in the POLR3A or POLR3B gene.

What are the symptoms of 4H syndrome?

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 (short sightedness) is common.

Treatments for:

There is no cure for 4H syndrome; treatment is supportive.


It is believed to be very rare with a small number of people diagnosed but a significant number people with an unspecified hypomyelinating Leukodystrophy could have this disorder.

Other names for 4H syndrome:

  • Ataxia, Hypodontia and Hypomyelination (AHH)
  • Ataxia, delayed dentition and Hypomyelination (ADD)
  • Pol III – related Leukodystrophy

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