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.

• MeSH
• Biological Variation, Population MeSH
• Hereditary Central Nervous System Demyelinating Diseases complications   epidemiology   genetics   MeSH
• Child MeSH
• DNA-Directed RNA Polymerases genetics   MeSH
• Adult MeSH
• Genetic Heterogeneity MeSH
• Hypogonadism epidemiology   etiology   MeSH
• Cohort Studies MeSH
• Infant MeSH
• Humans MeSH
• Mitochondrial Diseases complications   epidemiology   genetics   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Mutation MeSH
• Endocrine System Diseases epidemiology   etiology   genetics   MeSH
• Infant, Newborn MeSH
• Growth Disorders epidemiology   etiology   genetics   MeSH
• Child, Preschool MeSH
• Cross-Sectional Studies MeSH
• Retrospective Studies MeSH
• RNA Polymerase III genetics   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

We present a case of megalencephalic leukoencephalopathy with subcortical cysts without macrocephaly and who initially presented with severe psychiatric symptoms. The patient presented with presented with late-onset secondary generalized focal motor seizures, gait ataxia and mild spasticity with hyperreflexia. MRI showed diffuse white matter hyperintensities and bilateral anterotemporal cysts. Genetic analysis confirmed the causal MLC1 mutation and Turner's syndrome. Surprisingly, our patient had no macrocephaly, which is a typical finding in MCL1 mutations; we emphasize that comorbid unrelated Turner's syndrome could explain the absence of macrocephaly: although short stature is typical, microcephaly is not associated with Turner's syndrome. Our observation thus argues for detailed investigations in cases presenting with an atypical clinical picture.

• MeSH
• Cysts complications   diagnostic imaging   MeSH
• Hereditary Central Nervous System Demyelinating Diseases complications   diagnostic imaging   MeSH
• Adult MeSH
• Humans MeSH
• Megalencephaly * MeSH
• Turner Syndrome complications   diagnostic imaging   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH