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Horizontal gaze palsy — Clinical Guidelines

Overview

Horizontal gaze palsy with progressive scoliosis (HGPPS; OMIM 607313) is a rare autosomal recessive disorder characterized by congenital absence or severe restriction of horizontal eye movements and progressive scoliosis that typically manifests in early childhood 1 2. This condition primarily affects motor coordination related to horizontal gaze, leaving vertical eye movements intact, while progressive scoliosis can significantly impact posture and quality of life. Given its rarity, early recognition and management are crucial for mitigating the impact of scoliosis on patients' daily activities and long-term health. Understanding HGPPS is essential for clinicians to provide appropriate referrals and interventions, particularly focusing on spinal management to prevent complications associated with severe spinal deformities 4 5.

Pathophysiology

HGPPS arises from mutations in the ROBO3 gene located on chromosome 11q23–25, which encodes a critical axon guidance receptor expressed exclusively by commissural (C-) neurons in the developing spinal cord 7 8. These C-neurons play a pivotal role in integrating sensory information from both sides of the body, essential for functions such as binocular vision and sound localization. The ROBO3 protein facilitates axon guidance and midline crossing in the hindbrain, crucial for proper neural circuit formation 9 10. Mutations in ROBO3 disrupt these processes, leading to non-crossing motor and sensory pathways as evidenced by neuroimaging and neurophysiological studies 6 7. Specifically, defects in the abducens nuclei (CN VI) and supranuclear control regions like the paramedian pontine reticular formation (PPRF) contribute to the horizontal gaze palsy observed clinically 7. Despite these neurological alterations, patients often maintain intact neurological functioning and sensorimotor integration, highlighting the complexity of the underlying pathophysiology 13.

Epidemiology

The incidence of HGPPS is exceedingly rare, with limited population-based studies providing precise figures. Cases predominantly arise in consanguineous populations, suggesting a genetic predisposition linked to inherited mutations 1 4. Reports indicate a higher prevalence in certain geographic regions where consanguinity is more common, though global distribution remains sparse. Over time, there has been an increase in reported cases likely due to enhanced genetic testing capabilities rather than a true rise in incidence 1 7. Age of onset typically occurs in early childhood, with symptoms becoming apparent by mid-childhood, often initially presenting with progressive scoliosis 2 3.

Clinical Presentation

Patients with HGPPS present with characteristic horizontal gaze palsy, manifesting as an inability or severe difficulty in abducting and adducting the eyes, while vertical eye movements remain unaffected 1 2. Progressive scoliosis, often severe and requiring surgical intervention, typically becomes evident in early childhood and progresses throughout adolescence 4 5. Synergistic convergence, where the eyes turn inward during attempted horizontal movements, can be observed during routine eye examinations 2. Neurological examination may reveal normal cognitive function and intact vertical gaze, but subtle signs of brainstem involvement might be present 6. Red-flag features include rapid progression of spinal curvature and associated respiratory complications, necessitating prompt referral for specialized care 14.

Diagnosis

The diagnosis of HGPPS involves a combination of clinical evaluation and genetic testing. Clinicians should suspect HGPPS in patients presenting with congenital horizontal gaze palsy and progressive scoliosis, particularly in families with a history of consanguinity 1 2 4.

Clinical Criteria:

- Absence or severe restriction of horizontal eye movements. - Progressive scoliosis noted by early childhood. - Normal vertical eye movements. - Synergistic convergence during eye movement testing.

Diagnostic Tests:

- Genetic Testing: Sequencing of the ROBO3 gene to identify mutations 7 8. - Neuroimaging: MRI may show characteristic abnormalities such as pontine flattening, hypoplasia of the pontine tegmentum, and butterfly-shaped medulla 7 12. - Electrophysiological Studies: To assess non-crossed motor and sensory pathways 6.

Differential Diagnosis:

Duane Syndrome: Characterized by horizontal gaze limitation with globe retraction, often unilateral and associated with specific eye movement patterns 16.

Moebius Syndrome: Involves bilateral facial nerve palsy alongside horizontal gaze palsy, often with additional limb and oral-motor deficits 17.

Myasthenia Gravis: Can present with fluctuating muscle weakness affecting eye movements but typically involves other muscle groups and responds to acetylcholinesterase inhibitors 18.

Management

Management of HGPPS focuses primarily on addressing progressive scoliosis, given the functional and structural implications of spinal deformities.

First-Line Management

Regular Monitoring: Frequent orthopedic evaluations to monitor spinal curvature progression 4.

Physical Therapy: To maintain spinal flexibility and muscle strength, though evidence is limited 19.

Second-Line Management

Surgical Intervention: Early surgical correction of scoliosis is often necessary to prevent severe deformity and respiratory complications 4 5.

- Specifics: - Timing: Typically initiated in early to mid-childhood based on curve progression. - Techniques: Spinal fusion, growing rods, or other corrective surgeries as indicated 20. - Monitoring: Postoperative follow-up with imaging to assess fusion and spinal alignment 21.

Refractory / Specialist Escalation

Multidisciplinary Care: Involvement of orthopedic surgeons, neurologists, and physical therapists for comprehensive management 22.

Pain Management: Address any post-surgical pain or discomfort with appropriate analgesics 23.

Contraindications:

Surgical interventions should be carefully considered in patients with significant comorbidities that increase surgical risk 24.

Complications

Acute Complications:

- Respiratory issues due to severe spinal deformities. - Post-surgical complications such as infection, pseudarthrosis, or hardware failure 25.

Long-Term Complications:

- Chronic pain related to spinal fusion or surgical interventions. - Progressive spinal deformity leading to reduced quality of life and mobility issues 26.

Refer patients with rapid progression of scoliosis or signs of respiratory compromise to specialists promptly to manage these complications effectively 14.

Prognosis & Follow-Up

The prognosis for HGPPS is generally favorable in terms of neurological function, with most patients maintaining normal cognitive abilities and sensorimotor integration despite their motor deficits 13. However, the progression of scoliosis significantly impacts quality of life and necessitates vigilant monitoring.

Follow-Up Intervals:

- Orthopedic Monitoring: Every 6-12 months, depending on the rate of scoliosis progression 27. - Neurological Assessments: Annually to ensure no new neurological deficits develop 28.

Special Populations

Pediatrics: Early intervention for scoliosis is crucial to prevent severe deformities and associated complications 4 5.

Comorbidities: Patients with additional neurological or musculoskeletal conditions may require tailored management plans, emphasizing multidisciplinary care 29.

Ethnic Risk Groups: Higher prevalence in populations with higher rates of consanguinity underscores the importance of genetic counseling and prenatal screening in these communities 1 7.

Key Recommendations

Genetic Testing for ROBO3 Mutations: Confirm diagnosis through sequencing of the ROBO3 gene in patients with clinical suspicion [Evidence: Strong]

Early Orthopedic Evaluation: Initiate regular monitoring of spinal curvature in early childhood [Evidence: Moderate]

Surgical Intervention for Progressive Scoliosis: Consider early surgical correction to prevent severe spinal deformities and respiratory complications [Evidence: Moderate]

Multidisciplinary Care Approach: Involve orthopedic surgeons, neurologists, and physical therapists for comprehensive management [Evidence: Expert opinion]

Regular Follow-Up Monitoring: Schedule orthopedic assessments every 6-12 months and neurological evaluations annually [Evidence: Moderate]

Genetic Counseling: Offer genetic counseling to families with a history of consanguinity or recurrent cases [Evidence: Expert opinion]

Pain Management Post-Surgery: Address post-surgical pain with appropriate analgesic regimens [Evidence: Moderate]

Monitor for Respiratory Issues: Closely monitor patients for signs of respiratory compromise due to severe spinal deformities [Evidence: Moderate]

Physical Therapy for Spinal Flexibility: Incorporate physical therapy to maintain spinal flexibility and muscle strength [Evidence: Weak]

Refer for Specialist Care: Prompt referral to specialists for acute complications such as rapid scoliosis progression or respiratory issues [Evidence: Expert opinion]

References

1 Pinero-Pinto E, Pérez-Cabezas V, Tous-Rivera C, Sánchez-González JM, Ruiz-Molinero C, Jiménez-Rejano JJ et al.. Mutation in . International journal of environmental research and public health 2020. link 2 Dhiman R, Gandepalli L, Rathod A, Badkhane S, Phuljhele S, Saxena R. Horizontal gaze palsy with progressive scoliosis. Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus 2024. link 3 Xavier C, Vieira M, Duarte AF, Xavier A, Silva ED. Horizontal Gaze Palsy and Progressive Scoliosis in Dizygotic Twins. Journal of binocular vision and ocular motility 2022. link 4 Rousan LA, Qased ABL, Audat ZA, Ababneh LT, Jaradat SA. Horizontal gaze palsy and progressive scoliosis with two novel ROBO3 gene mutations in two Jordanian families. Ophthalmic genetics 2019. link

Horizontal gaze palsy