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

Abstract

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 2015-2016. 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 three predominant centers. Patients 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-1, prolactin, ACTH, cortisol, TSH, and T4), 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 under-investigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.

Defective myelination in an RNA polymerase III mutant leukodystrophic mouse

“…The existence of a growth rate phenotype in a Pol III hypomorph that is restricted to the Olig2 lineage is intriguing and suggests a cell non-autonomous effect. Interestingly, the short stature of many Pol IIIleukodystrophy patients correlates with a growth hormone deficiency among a number of tested patients (8,45). How this reduction in growth hormone is achieved is not known.…”

Case Report: Severe Osteoporosis and Preventive Therapy in RNA Polymerase III-Related Leukodystrophy

“…A major clinical problem, in this case, was recurrent pathological fractures that occurred during attacks of generalized tonic seizures. Epilepsy is reported in 19-27.9% of POLR3related leukodystrophy and, when it is present, is typically easy to control (5,7). In a minority of cases, several antiepileptic drugs are required to achieve seizure control (8).…”

“…In POLR3-related leukodystrophy, endocrine abnormalities are underestimated (5), and we should also be aware that early-adult onset osteoporosis could occur, and resulting pathological fractures could be a serious complication that limits patient's activities of daily living. Early evaluation and prophylactic intervention for osteoporosis, including sufficient nutrition, weight-bearing (standing board), and anti-osteoporosis medications, including vitamin D and calcium, should be considered immediately after the diagnosis of POLR3related leukodystrophy (21).…”

“…Cognitive decline is also common, and tooth agenesis, including hypodontia (lacking one to five permanent teeth) or oligodontia (lacking six or more permanent teeth), is a characteristic manifestation (4). A majority of female patients lack secondary sex characteristics and menstruation caused by hypogonadotropic hypogonadism (5). However, severe osteoporosis has not been emphasized in patients with POLR3-related leukodystrophy.…”

RNA Polymerase III Subunit Mutations in Genetic Diseases

“…hypodontia, oligodontia, delayed or abnormal pattern of tooth eruption, natal tooth/teeth, etc.) (Wolff et al, 2010) and endocrine abnormalities, typically but not exclusively, hypogonadotropic hypogonadism leading to arrested or absence of puberty (Potic et al, 2012(Potic et al, , 2015Pelletier et al, 2021). The MRI of patients with a typical POLR3-HLD is characterized by a specific and recognizable pattern of hypomyelination (Schiffmann and van der Knaap, 2009;Steenweg et al, 2010), with relative preservation of the myelination of certain structures (i.e.…”