A woman in her 30s with intellectual disability, primary amenorrhoea, and focal seizures (Figure, A) described 2 years of progressive balance difficulties. On examination, she had short stature (1.45 m), cerebellar ataxia, and a visual acuity of 6/60 OU. T2-weighted magnetic resonance imaging showed severe cerebellar atrophy, an atrophic corpus callosum, and patchy signal change in the corona radiata suggestive of hypomyelination (Figure, B).

Given the clinical features, a diagnosis of 4H syndrome (hypomyelination, hypodontia, and hypogonadotrophic hypogonadism) was considered. Genetic sequencing of POLR3B identified compound heterozygous mutations that segregated with parents. Detailed endocrine assessment confirmed hypogonadotropic hypogonadism (leutenising hormone/follicle stimulating hormone ratio <0.5 u/L and low estradiol [<16.34 pg/mL; to convert to picomoles per liter, multiply by 3.671]) but not growth hormone deficiency (insulinlike growth factor I, 99.24 ng/mL [normal range, 45.80-221.37; to convert to nanomoles per liter, multiply by .131]). Contact with the patient’s dentist established the presence of hypodontia (Figure, C).