POLR3 related leukodystrophy

Hypomyelination, Hypogonadotropic Hypogonadism and Hypodontia (4H Syndrome)


Autosomal recessive

Inheritance from both parents will result in the disease

Age range at onset:

Between age 1-2, or 10-20

Specialists you may see:


Intellectual disability is common in those with 4H syndrome, and worsens over time. Ataxia begins in childhood and also worsens over time, with the ability to walk delayed. Characteristically, those with 4H syndrome walk with their feet wide apart for balance. Tremor of the hands occurs in some cases, either while moving, while at rest, or both.

Development of teeth is abnormal, resulting in hypodontia. Teeth may be unusually shaped and will develop in an unusual order, with development of permanent teeth delayed. Dysarthria and swallowing difficulties may occur. Abnormalities in eye movement such as vertical gaze palsy, nearsightedness, cataracts and optic atrophy are common.

Normal puberty development is absent in 4H syndrome, as the nervous system cannot initiate it. In adolescence, the function of a man’s testes or a woman’s ovaries will be affected and signs such as the growth of pubic hair will be delayed.

Patients do not always have full blown 4H; and may indeed have hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum or leukodystrophy with oligodontia.


Mutations in the POLR3A or POLR3B gene cause 4H syndrome. These genes both contribute to production of an enzyme which produces RNA (ribonucleic acid). This binds to DNA. Mutations impair the ability of the enzyme to make RNA, or the ability of the RNA to bind to the DNA. This seems to affect the development and function of the nervous system and other parts of the body, but it is not fully understood how this causes the symptoms of 4H syndrome.