ESPE Abstracts

Background: Microtubules, polar polymers of αβ-tubulin heterodimers, constitute dynamic cytoskeletal structures implicated in the regulation of axonal activity along with neuronal proliferation and migration. Tubulinopathies, caused by pathogenic variants in genes encoding different isotypes of tubulin, lead to a wide and overlapping range of nervous system malformations and neurodevelopmental disorders. Namely, heterozygous missense and nonsense mutations in TUBB3 gene, encoding the neuron-specific β-tubulin isotype III, cause a rare syndrome termed ocular motility disorder termed congenital fibrosis of the extraocular muscles type 3 (CFEOM3), in addition to other clinical findings such as facial paralysis, intellectual and behavioral impairment, and axonal sensorimotor polyneuropathy. Recent studies have managed to delineate different subtypes of the TUBB3 syndrome, drawing on distinct phenotype-genotype correlations for reference, including the most recently defined TUBB3 R262H syndrome. Apart from core features, these patients present with Kallmann syndrome and joint contractures.

Case description: A 20-month-old boy with facial weakness, bilateral congenital ptosis, hypertelorism, left eye strabismus and nystagmus, poor right eye movements, low-set ears, psychomotor delay, sensorimotor polyneuropathy and hearing loss was referred to the endocrinologist because of suspected hypogonadism. On clinical examination, micropenis and bilateral cryptorchidism were observed. Low serum levels of inhibin B (26 pg/mL, normal range: 50 - 130) and anti-Müllerian hormone (14.2 ng/mL, normal range: 74.7 - 252.7) with normal gonadotropin raise in GnRH test were indicative of hypogonadotropic hypogonadism. MRI of the brain revealed hypoplasia of the corpus callosum and olfactory bulbs, deformation of the ventricular system, and moderate widening of the subarachnoid spaces. First-line genetic evaluation revealed a 46,XY karyotype and array comparative genomic hybridization did not report any microdeletions or microduplications. Whole exome sequencing identified a de novo heterozygous pathogenic variant c.785G>A (p.(Arg262His)) in the TUBB3 gene (NM_006086.4), which was absent from controls (not reported in the Genome Aggregation Database).

Discussion: Until now, there have been 22 different pathogenic variants in the TUBB3 gene reported along the protein with several hot spots. Phenotypic features of Kallmann syndrome have been associated with only two of them, R262H and E410K. It has been shown that TUBB3-R262 residue plays a critical role for mediating kinesin interactions, which in turn are required for normal growth of axons.

Conclusion: The newly described TUBB3 R262H syndrome constitutes the most severe form of syndromic CFEOM. Due to enhanced genetic testing and established phenotype-genotype correlation, more tailored multidisciplinary medical care and genetic counseling can be assured.