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Horizontal gaze palsy with progressive scoliosis — Clinical Guidelines

Overview

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare congenital disorder characterized by impaired conjugate horizontal eye movements and progressive scoliosis that typically manifests in childhood and adolescence 1 2. This autosomal recessive condition is primarily linked to mutations in the ROBO3 gene, which plays a critical role in axon pathfinding and crossing during hindbrain development 3. Patients often present with limitations in horizontal eye movements, reliance on neck movements to compensate for gaze restrictions, and progressive spinal curvature 1 4. Early recognition is crucial as it not only aids in appropriate management of ocular and musculoskeletal symptoms but also supports genetic counseling for families 1 2.

Pathophysiology

The pathophysiology of HGPPS revolves around genetic mutations in the ROBO3 gene, which encodes a receptor essential for guiding axons across the midline during embryonic development 3. These mutations disrupt the normal crossing of critical neural tracts, particularly those involved in horizontal gaze control, such as the medial longitudinal fasciculus and corticospinal tracts 1 5. Consequently, there is a characteristic brainstem malformation, often manifesting as a split pons sign and a butterfly-shaped medulla on imaging studies 1 4. This anatomical disruption leads to the clinical presentation of impaired horizontal eye movements and progressive scoliosis, reflecting broader disruptions in neural innervation affecting motor coordination and skeletal development 1 6.

Epidemiology

HGPPS is exceedingly rare, with fewer than 100 cases reported globally across multiple studies 1 3 5. The condition appears to affect both sexes equally, with no significant geographic or ethnic predilection noted in the literature 2 5. Incidence data are sparse, but given the rarity and genetic basis, it is likely underreported, especially in populations without extensive genetic screening programs 3. Over time, there has been an increase in reported cases coinciding with advancements in genetic testing and neuroimaging techniques, suggesting improved diagnostic capabilities rather than a true rise in incidence 3.

Clinical Presentation

Patients with HGPPS typically present with congenital or early-onset symptoms including:

Horizontal gaze palsy: Difficulty moving the eyes horizontally, often compensated by neck movements.

Progressive scoliosis: Development of spinal curvature typically noted after early childhood.

Nystagmus: Often horizontal and pendular, though variable in severity.

Normal vertical gaze and convergence: Vertical eye movements and convergence are usually preserved.

Cognitive function: Generally intact, though some reports suggest mild cognitive delays 2 7.

Red-flag features include significant motor developmental delays or associated neurological deficits, which, while uncommon, warrant thorough evaluation 2.

Diagnosis

The diagnosis of HGPPS involves a combination of clinical evaluation and advanced imaging techniques:

Clinical examination: Detailed assessment of eye movements, including absence of horizontal gaze and presence of vertical gaze preservation.

Neuroimaging: MRI typically reveals characteristic brainstem abnormalities such as a split pons sign and butterfly-shaped medulla.

Genetic testing: Sequencing of the ROBO3 gene to identify mutations, which is definitive for diagnosis 2 3.

Diagnostic Criteria:

Clinical Criteria:

- Absence of horizontal conjugate gaze movements. - Progressive scoliosis developing before adolescence. - Normal vertical gaze and convergence.

Imaging Criteria:

- MRI findings: Split pons sign, butterfly-shaped medulla, and reduced anterior-posterior diameter of the pons and medulla.

Genetic Criteria:

- Bi-allelic mutations in the ROBO3 gene.

Differential Diagnosis:

Cerebellar Disorders: Often present with ataxia and may show cerebellar atrophy on imaging, unlike the brainstem-specific findings in HGPPS.

Myasthenia Gravis: Presents with fluctuating muscle weakness, particularly affecting ocular muscles, but lacks the characteristic neuroimaging features.

Congenital Ptosis: Can mimic gaze palsy but lacks progressive scoliosis and specific brainstem imaging findings.

Management

Management of HGPPS focuses on supportive care and symptomatic treatment:

Orthopedic Management:

- Bracing: Use of thoracolumbosacral orthoses to manage and slow the progression of scoliosis. - Surgical Intervention: Considered for severe cases where bracing fails, aiming to correct spinal deformities and prevent complications 2.

Ophthalmological Support:

- Vision Therapy: To enhance visual function and compensate for gaze limitations. - Optical Aids: Use of prism glasses to improve visual field and reduce neck strain.

Physical Therapy:

- Gait Training: To adapt to gaze limitations and maintain mobility. - Muscle Strengthening: To support posture and manage scoliosis-related discomfort.

Specific Interventions:

Bracing: Custom-fitted orthoses; frequency and duration tailored to progression.

Surgery: Indicated for Cobb angles >40° or significant spinal deformity; multidisciplinary approach required.

Vision Therapy: Regular sessions; duration varies based on patient response.

Physical Therapy: Weekly sessions; individualized exercise programs.

Complications

Potential complications include:

Progressive Scoliosis: Leading to chronic pain, respiratory issues, and reduced quality of life.

Vision Loss: Secondary to prolonged neck strain or untreated ocular misalignment.

Motor Developmental Delays: Though rare, may require early intervention programs.

Management Triggers:

Increased Cobb Angle: Indicates need for surgical intervention.

Persistent Pain: Requires reassessment of bracing or surgical options.

Vision Decline: Suggests reevaluation of visual support strategies.

Prognosis & Follow-up

The prognosis for HGPPS is generally stable with supportive care, though progression of scoliosis can impact quality of life significantly. Key prognostic indicators include the severity and progression rate of scoliosis and the effectiveness of orthopedic interventions. Recommended follow-up intervals include:

Annual Neurological and Ophthalmological Assessments: To monitor eye movements and scoliosis progression.

Radiographic Imaging: Every 1-2 years to assess spinal curvature changes.

Genetic Counseling: Periodic sessions for families regarding reproductive planning and genetic risks.

Special Populations

Pediatrics: Early intervention in physical and vision therapy is crucial for adapting to gaze limitations and managing scoliosis.

Adults: Focus shifts towards managing chronic complications of scoliosis and maintaining functional independence.

Genetic Counseling: Essential for families, especially given the autosomal recessive inheritance pattern 2 3.

Key Recommendations

Genetic Testing for ROBO3 Mutations: Essential for definitive diagnosis (Evidence: Strong 3).

MRI Brainstem Imaging: Characteristic findings confirm diagnosis (Evidence: Strong 1).

Regular Monitoring of Scoliosis: Annually with radiographic imaging (Evidence: Moderate 2).

Orthopedic Interventions: Bracing or surgical correction for progressive scoliosis (Evidence: Moderate 2).

Supportive Vision Therapy: To enhance visual function and reduce neck strain (Evidence: Moderate 1).

Physical Therapy: To maintain mobility and posture (Evidence: Moderate 1).

Genetic Counseling: For affected families regarding inheritance risks (Evidence: Expert opinion 2).

Multidisciplinary Care Team: Including ophthalmologists, orthopedists, and physiotherapists (Evidence: Expert opinion 1).

Early Intervention Programs: For pediatric patients to address developmental delays (Evidence: Moderate 2).

Long-term Follow-up: To manage chronic complications and adjust treatments as needed (Evidence: Moderate 1).

References

1 Lin CW, Lo CP, Tu MC. Horizontal gaze palsy with progressive scoliosis: a case report with magnetic resonance tractography and electrophysiological study. BMC neurology 2018. link 2 Volk AE, Carter O, Fricke J, Herkenrath P, Poggenborg J, Borck G et al.. Horizontal gaze palsy with progressive scoliosis: three novel ROBO3 mutations and descriptions of the phenotypes of four patients. Molecular vision 2011. link 3 Harahsheh EY, Moxley LE, Al-Amin M, Sabrowsky S, Deniz A, Osundiji M. 20 years of ROBO3-related horizontal gaze palsy with progressive scoliosis: a mini-review. Neurogenetics 2025. link 4 Singanamalla B, Chaurasia S, Jain C, Bhatia V, Sharma N, Madaan P et al.. Horizontal Gaze Palsy, Scoliosis, and Split Pons Sign in a 6-Year-Old Girl. Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society 2021. link 5 Mendes Marques NBPS, Barros SR, Miranda AF, Nobre Cardoso J, Parreira S, Fonseca T et al.. Horizontal Gaze Palsy and Progressive Scoliosis With ROBO 3 Mutations in Patients From Cape Verde. Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society 2017. link 6 Choudhary AK, Maller VG. Radiological features of horizontal gaze palsy with progressive scoliosis. An 'Aunt Minnie' diagnosis?. Delaware medical journal 2014. link 7 Handor H, Laghmari M, Hafidi Z, Daoudi R. Horizontal gaze palsy with progressive scoliosis in a Moroccan family. Orthopaedics & traumatology, surgery & research : OTSR 2014. link 8 Avadhani A, Ilayaraja V, Shetty AP, Rajasekaran S. Diffusion tensor imaging in horizontal gaze palsy with progressive scoliosis. Magnetic resonance imaging 2010. link

Horizontal gaze palsy with progressive scoliosis