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.

Background: RNA polymerase III-related or 4H leukodystrophy (POLR3-HLD) is an autosomal recessive hypomyelinating leukodystrophy characterized by neurological dysfunction, hypodontia and hypogonadotropic hypogonadism. The disease is caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C or POLR3K. Craniofacial abnormalities reminiscent of Treacher Collins syndrome have been originally described in patients with POLR3-HLD caused by biallelic pathogenic variants in POLR1C. To date, no published studies have appraised in detail the craniofacial features of patients with POLR3-HLD. In this work, the specific craniofacial characteristics of patients with POLR3-HLD associated with biallelic pathogenic variants in POLR3A, POLR3B and POLR1C are described. Methods: The craniofacial features of 31 patients with POLR3-HLD were evaluated, and potential genotype–phenotype associations were evaluated. Results: Various craniofacial abnormalities were recognized in this patient cohort, with each individual presenting at least one craniofacial abnormality. The most frequently identified features included a flat midface (61.3%), a smooth philtrum (58.0%) and a pointed chin (51.6%). In patients with POLR3B biallelic variants, a thin upper lip was frequent. Craniofacial anomalies involving the forehead were most commonly associated with biallelic variants in POLR3A and POLR3B while a higher proportion of patients with POLR1C biallelic variants demonstrated bitemporal narrowing. Conclusion: Through this study, we demonstrated that craniofacial abnormalities are common in patients with POLR3-HLD. This report describes in detail the dysmorphic features of POLR3-HLD associated with biallelic variants in POLR3A, POLR3B and POLR1C.

Hereditary sensory and autonomic neuropathies (HSAN) are rare, genetically inherited disorders characterized by impaired unmyelinated nerve fiber function. Here we report a patient with self-mutilation behavior and decreased response to pain, suggestive of an underlying small fiber neuropathy. Nerve conduction studies were normal but sympathetic skin response was absent at the left arm. Intradermal histamine challenge test was performed to evaluate the function of small unmyelinated nerve fibers and revealed absence of a flare response. Using whole genome sequencing, a novel variant in the neurotrophic tyrosine kinase type 1 gene was identified, expanding the known disease-causing variants associated with HSAN type 4. Through this case, we demonstrate the role of the histamine challenge test in patients suspected to have a small fiber neuropathy where electrophysiological testing may be normal and who may present with non-specific symptoms including hypotonia and failure to thrive. The information gained can guide genetic testing and contribute to interpretation of new variants identified.

Recognition of radiologic lag, the presence of clinical symptoms despite absence of a visible corresponding lesion on MRI, is essential when evaluating a patient suspected to have a demyelinating disease. In this report, we present the case of a 16-year-old girl with bilateral internuclear ophthalmoplegias (INO), in whom initial high-resolution 3T MRI failed to reveal an abnormality within the brainstem. Repeat MRI performed 2 months later demonstrated a lesion in the paramedian midbrain tegmentum, corresponding to the anatomical localization of her clinical symptoms. This case aims to raise awareness that radiologic lag can occur in pediatric-onset multiple sclerosis, similarly to what has been described in other demyelinating conditions such as myelin oligodendrocyte glycoprotein antibody-associated disease. The absence of a visible lesion on imaging in the context of an acute INO does not exclude the possibility of underlying demyelination, and short-interval follow-up imaging should be considered in these patients to establish the correct diagnosis and guide additional investigations and treatment.