Horizontal gaze palsy with progressive scoliosis (HGPPS): expanding ROBO3 molecular spectrum and refining clinical–neuroimaging phenotypes

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare autosomal recessive disorder caused by biallelic ROBO3 variants, characterized by congenital horizontal gaze restriction, early-onset scoliosis, and distinctive hindbrain malformations. We report two pediatric Patients and integrate current evidence to expand the ROBO3 variant spectrum and refine phenotypic delineation. Detailed clinical evaluation was combined with whole-spine radiography and high-resolution brain MRI with diffusion tensor imaging. Trio-based exome sequencing identified three ROBO3 variants, interpreted according to ACMG/AMP criteria. A novel splice-region variant was evaluated using SpliceAI and Pangolin, while AlphaFold2 modeling and ThermoMPNN, DDMut, SIFT, PolyPhen-2, and ClinPred were used to assess a missense variant affecting the Ig-like domain. Both patients exhibited congenital horizontal gaze palsy, early-onset scoliosis, and the characteristic HGPPS hindbrain triad. Patient #1 carried compound heterozygous variants p.(Arg703Pro) and c.2073+4A > G, while Patient #2 harbored the homozygous p.(Arg245Trp) variant. Literature review confirmed a uniform neuroimaging signature despite variable clinical severity. These findings expand the molecular landscape of HGPPS and underscore the importance of early neuroimaging recognition and orthopedic surveillance in the absence of robust genotype-phenotype correlations.