Horizontal gaze palsy with progressive scoliosis: Further expanding the ROBO3 spectrum

Objective Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare, autosomal recessive disorder resulting from axonal midline crossing defect due to variants in ROBO3. Methods We retrospectively evaluated demographics, clinical phenotype, course of spinal deformities, and neuroimaging findings of six Turkish patients with HGPPS. We performed targeted gene testing by next‐generation sequencing. Results The median age at symptom onset and diagnosis was 1.5 years (0.5–4), and 11 years (2–16), respectively. Oculomotor signs were the most common presenting symptom (n = 4), followed by scoliosis (n = 2). The course of scoliosis was progressive and accompanied by kyphosis, showed intrafamilial variability, and was corrected surgically in three of the patients. Intellectual disability (n = 4), hypergonadotropic hypogonadism (n = 2), hearing loss (n = 2), and tranisent movement disorders (n = 1) were additional features. Targeted gene sequencing revealed five distinct homozygous variants. Of the four novel variants, two of them were located in the acceptor site of the noncoding region of the gene, remaining two were missense and frameshift variants, located in immunoglobulin‐like domain‐2, and cytoplasmic signaling motif 2, respectively. Structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) showed the absence of decussation of superior cerebellar peduncle and dorsal transverse pontine fibers. Interpretation Spectrum of HGPPS is further expanded with novel variants in the ROBO3 with clinical and radiological fingerprints. Spinal deformities require close orthopedic screening and individualized approach. Intellectual disability and hearing loss emerge as additional features. Hypogonadism and transient subtle movement disorders require further attention and confirmation from other series.