关键词: 水平注视麻痹伴进行性脊柱侧弯, 磁共振成像, 全外显子组测序

Abstract: Objective To investigate the clinical features, neuroimaging findings, and genetic etiology of horizontal gaze palsy with progressive scoliosis (HGPPS), and to enrich the spectrum of pathogenic mutations in the Chinese population. Design Retrospective case series study. Participants Seven HGPPS patients (from 6 non-consanguineous families) who presented between January 2013 and May 2025. Methods All patients underwent detailed ophthalmological examination, comprehensive physical examination, and spinal assessment. Four patients received magnetic resonance imaging (MRI) and spinal computed tomography (CT) of the brain and spine. Peripheral blood samples were collected from the patients and their core family members. Genomic DNA was extracted and subjected to whole-exome sequencing. Bioinformatic analysis was performed to identify causative genetic variants. Main Outcome Measures Primary position, ocular motility, brain MRI findings, and systemic developmental abnormalities, whole exome sequencing results. Results The cohort included 3 males and 4 females, with a mean age of (7.4±3.3) years. All patients exhibited complete or severe congenital limitation (-4 grade) of horizontal conjugate eye movements, with vertical movements remaining intact. Primary position was orthotropic in 4 cases, with esotropia in 2 cases and exotropia in 1 case. Refractive errors were present in all patients, and one case was accompanied by nystagmus. Scoliosis onset occurred in early childhood, with a mean age of (2.2±2.0) years. Brain MRI revealed characteristic "butterfly-shaped" medulla and "split pons" signs in all examined patients. Whole-exome sequencing identified pathogenic variants in the ROBO3 gene (NM_022370.3) in 4 patients. These included three previously reported pathogenic/likely pathogenic variants (c.1447C>T/p.R483X, c.2462G>C/p.R821P, c.C3412T/p.R1138X) and one variant of uncertain significance in a splice region (c.2594-4A>T). The inheritance patterns comprised both compound heterozygous and homozygous mutations. Conclusion HGPPS is characterized by congenital horizontal gaze palsy and progressive scoliosis, with typical brainstem malformations on neuroimaging. This study identified ROBO3 mutations in four patients, expanding the mutational spectrum of the disease. For children with congenital ocular motility disorders, even those with orthotropic primary position, HGPPS should be considered. Early multidisciplinary evaluation and ROBO3 genetic testing are crucial for diagnosis and management.

Key words:  HGPPS, Magnetic resonance imaging, Whole exome sequencing