CLINICAL CHARACTERISTICS: POLR3-related leukodystrophy, a hypomyelinating 
leukodystrophy with specific features on brain MRI, is characterized by varying 
combinations of four major clinical findings: Neurologic dysfunction, typically 
predominated by motor dysfunction (progressive cerebellar dysfunction, and to a 
lesser extent extrapyramidal [i.e., dystonia], pyramidal [i.e., spasticity] and 
cognitive dysfunctions). Abnormal dentition (delayed dentition, hypodontia, 
oligodontia, and abnormally placed or shaped teeth). Endocrine abnormalities 
such as short stature (in ~50% of individuals) with or without growth hormone 
deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as 
delayed, arrested, or absent puberty. Ocular abnormality in the form of myopia, 
typically progressing over several years and becoming severe. POLR3-related 
leukodystrophy and 4H leukodystrophy are the two recognized terms for five 
previously described overlapping clinical phenotypes (initially described as 
distinct entities before their molecular basis was known). These include: 
Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); 
Ataxia, delayed dentition, and hypomyelination (ADDH); Tremor-ataxia with 
central hypomyelination (TACH); Leukodystrophy with oligodontia (LO); 
Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum 
(HCAHC). Age of onset is typically in early childhood but later-onset cases have 
also been reported. An infant with Wiedemann-Rautenstrauch syndrome (neonatal 
progeroid syndrome) was recently reported to have pathogenic variants in POLR3A 
on exome sequencing. Confirmation of this as a very severe form of POLR3-related 
leukodystrophy awaits replication in other individuals with a clinical diagnosis 
of Wiedemann-Rautenstrauch syndrome.
DIAGNOSIS/TESTING: POLR3-related leukodystrophy is diagnosed by the combination 
of classic clinical findings, typical brain MRI features, and the presence of 
biallelic pathogenic variants in POLR3A, POLR3B, or POLR1C.
MANAGEMENT: Treatment of manifestations: Individualized care by a 
multidisciplinary team including a pediatric neurologist, clinical geneticist, 
physiotherapist, occupational therapist, speech and language pathologist, 
neuropsychologist, rehabilitation physician, dentist, endocrinologist, 
ophthalmologist, ear-nose-and-throat specialist, and primary care physician is 
recommended. Special caution needs to be taken when managing dysphagia in this 
disorder as it is known to vary widely, even in a single day. Swallowing 
difficulties will progress over time and dystonia should be monitored and 
treated to prevent complications and improve the quality of life.
GENETIC COUNSELING: POLR3-related leukodystrophy is inherited in an autosomal 
recessive manner. At conception, each sib of an affected individual has a 25% 
chance of being affected, a 50% chance of being an asymptomatic carrier, and a 
25% chance of being unaffected and not a carrier. Carrier testing for at-risk 
relatives and prenatal diagnosis for pregnancies at increased risk are possible 
if both pathogenic variants in the family are known.