The 4H syndrome (hypomyelination, hypodontia, hypogonadotropic hypogonadism) is 
a newly recognized leukodystrophy. The classical form is characterized by the 
association of hypomyelination, abnormal dentition, and hypogonadotropic 
hypogonadism, but the recent identification of 2 genes responsible for the 
syndrome demonstrates that these 3 main characteristics can be variably combined 
among "Pol-III (polymerase III)-related leukodystrophies." The pathophysiology 
of this group of diseases is still to be elucidated, and there are no 
neuropathologic descriptions of brain tissue. We report the clinical, 
neuroradiologic, and neuropathologic findings of a patient affected by 4H 
syndrome with confirmed POLR3A mutations. We found a marked loss of 
oligodendrocytes, varying in severity in different brain regions, and 
accompanied by severe loss of myelin, moderately severe loss of axons, and 
patchy perivascular regions of better preserved white matter. There was 
relatively mild white matter astrogliosis and microgliosis. A macrophage 
reaction involving viable normal-appearing oligodendroglia suggests the 
possibility of an immunologic process in this disorder. Cortical laminar 
astrogliosis and mineralization of Layers I and II in particular were present. 
Thus, despite the uniformly hypomyelinating pattern seen on magnetic resonance 
imaging, neuropathologic examination reveals a complex heterogeneous 
leukodystrophy with prominent neuroaxonal and glial involvement in this 
disorder.