Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C

J Clin Endocrinol Metab. 2021 Jan 23;106(2):e660-e674. doi: 10.1210/clinem/dgaa700.


Context: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date.

Objective: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy.

Design: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated.

Setting: This was a multicenter retrospective study using information collected from 3 predominant centers.

Patients: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included.

Main outcome measures: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts.

Results: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients.

Conclusions: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.

Keywords: 4H leukodystrophy; POLR3-related leukodystrophy; hypogonadotropic hypogonadism; hypomyelination.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Biological Variation, Population
  • Child
  • Child, Preschool
  • Cohort Studies
  • Cross-Sectional Studies
  • DNA-Directed RNA Polymerases / genetics*
  • Endocrine System Diseases / epidemiology
  • Endocrine System Diseases / etiology
  • Endocrine System Diseases / genetics*
  • Female
  • Genetic Heterogeneity
  • Growth Disorders / epidemiology
  • Growth Disorders / etiology
  • Growth Disorders / genetics*
  • Hereditary Central Nervous System Demyelinating Diseases / complications
  • Hereditary Central Nervous System Demyelinating Diseases / epidemiology
  • Hereditary Central Nervous System Demyelinating Diseases / genetics*
  • Humans
  • Hypogonadism / epidemiology
  • Hypogonadism / etiology
  • Infant
  • Infant, Newborn
  • Male
  • Mitochondrial Diseases / complications
  • Mitochondrial Diseases / epidemiology
  • Mitochondrial Diseases / genetics*
  • Mutation
  • RNA Polymerase III / genetics
  • Retrospective Studies
  • Young Adult


  • DNA-Directed RNA Polymerases
  • POLR1C protein, human
  • POLR3A protein, human
  • POLR3B protein, human
  • RNA Polymerase III

Supplementary concepts

  • Leukodystrophy, Hypomyelinating, 4