The tale of two siblings with gaze palsy: More than meets the eye

Rajat Kapoor; Surabhi Dubay; Virender Sachdeva; Ravi Varma; Pratik Chougule; Preeti Patil-Chhablani

doi:10.4103/ijo.IJO_1663_20

CASE REPORT

Year : 2021 | Volume : 1 | Issue : 2 | Page : 357-359

The tale of two siblings with gaze palsy: More than meets the eye

Rajat Kapoor¹, Surabhi Dubay², Virender Sachdeva¹, Ravi Varma³, Pratik Chougule⁴, Preeti Patil-Chhablani⁵
¹ Department of Pediatric Ophthalmology, Strabismus, and Neuro-ophthalmology, Child Sight Institute, Nimmagada Prasad Children's Eye Care Centre, L V Prasad Eye Institute, GMRV Campus, Visakhapatnam, Andhra Pradesh, India
² Academy of Eye Care Education, Department of Pediatric Ophthalmology, Strabismus, and Neuro-ophthalmology, Child Sight Institute, Nimmagada Prasad Children's Eye Care Centre, Visakhapatnam, Andhra Pradesh, India
³ Citi Neuro Center, Hyderabad, Telangana, India
⁴ Department of Pediatric Ophthalmology, Strabismus, and Neuro-ophthalmology, Child Sight Institute, David Brown Children's Eye Care Centre, L V Prasad Eye Institute, KVC Campus, Vijaywada, Andhra Pradesh, India
⁵ Consultant in Pediatric and Neuro-ophthalmology at LV Prasad Eye Institute, Child Sight Institute, Jasti V Ramanamma Children's Eye Care Centre, KAR Campus, Hyderabad, Telangana, India; UPMC Children's Hospital, Pittsburgh, PA 15224, USA

Date of Submission	26-May-2020
Date of Acceptance	07-Oct-2020
Date of Web Publication	01-Apr-2021

Correspondence Address:
Dr. Preeti Patil-Chhablani
Consultant in Pediatric and Neuro-ophthalmology at UPMC Children's Hospital, Pittsburgh, PA 15224

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijo.IJO_1663_20

Abstract

Horizontal gaze palsy and progressive scoliosis (HGPPS) is an autosomal recessive disease with a mutation in the ROBO3 gene. Features include horizontal gaze palsy, preserved vertical eye movements, and convergence. Progressive scoliosis is present in all patients. On MRI, HGPPS is characterized by brainstem hypoplasia, bifid medulla, split pons sign, and absence of facial colliculi. We report two siblings who presented with characteristic ocular and neuroimaging features of HGPPS but no scoliosis. The diagnosis was confirmed by neuroimaging and genetic analysis. This case report highlights the role of suspecting HGPPS in children with gaze palsy and characteristic neuroimaging findings even when there is an absence of clinical manifestation of scoliosis. Subsequent referral should be made to the orthopedician to rule out scoliosis both clinically and radiologically.

Keywords: Brainstem lesions, gaze palsy, ROBO3 gene, scoliosis

How to cite this article:
Kapoor R, Dubay S, Sachdeva V, Varma R, Chougule P, Patil-Chhablani P. The tale of two siblings with gaze palsy: More than meets the eye. Indian J Ophthalmol Case Rep 2021;1:357-9

How to cite this URL:
Kapoor R, Dubay S, Sachdeva V, Varma R, Chougule P, Patil-Chhablani P. The tale of two siblings with gaze palsy: More than meets the eye. Indian J Ophthalmol Case Rep [serial online] 2021 [cited 2022 Dec 5];1:357-9. Available from: https://www.ijoreports.in/text.asp?2021/1/2/357/312336

Horizontal gaze palsy and progressive scoliosis (HGPPS) is a rare autosomal recessive disease associated with a biallelic mutation in the roundabout homolog of the Drosophila 3 (ROBO 3) gene.^[1],[2],[3] It is characterized by the congenital absence of horizontal gaze under conjugate conditions, with preserved vertical eye movements and convergence. Scoliosis is present invariably in all patients of HGPPS and usually occurs during early childhood and progresses thereafter.^[2],[4] Radiographically, HGPPS is characterized by hypoplasia of the brainstem, the butterfly-like bifid appearance of the medulla, a deep midline cleft of pons (split pons sign), and the absence of facial colliculi.^[1],[2],[5]

HGPPS is a rare disorder, with a few cases being reported from Indian, African, Chinese, and middle eastern population.^[1],[2] Herein, w describe two siblings from India, a sister and brother with HGPPS.

Case Report

A 9-year-old girl presented to our clinic with a diminution of vision and abnormal eye movements. She had a history of parental consanguinity and was born full term without any adverse antenatal and postnatal events. Her best-corrected visual acuity was 20/100 with -3.00DS/[email protected] degree and 20/80 with -3.00DS/[email protected] degree in the right and left eye, respectively. Her stereopsis was poor at 400 s of arc. On extraocular motility testing, she could not adduct and abduct either eye though her vertical eye movements and convergence was grossly normal [Figure 1]. There was no ocular misalignment in the primary position of gaze. She had horizontal pendular nystagmus in all gazes since birth. On detailed family history, her 6-year-old brother also had a very similar presentation [Figure 2]. Both children had ocular dysmotility since birth, this was confirmed using old pictures from the time of early childhood until the present day. Detailed retinal evaluation along with ocular coherence tomography of the macula and fundus auto-fluorescence exam was done to rule out the presence of macular dystrophies.

Figure 1: Nine gaze pictures of the 9-year-old girl shows the diffuse limitation of adduction (black star) and abduction (black arrow) in both eyes in horizontal gaze

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Figure 2: Nine gaze pictures of a 6-year-old boy showing diffuse limitation of adduction (black star) and abduction (black arrow) in both eyes in horizontal gaze

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We diagnosed both patients as having horizontal gaze palsy with pendular nystagmus, compound myopic astigmatism, and ammetropic amblyopia in both eyes. On further workup, the magnetic resonance imaging (MRI) brain with contrast revealed hypoplasia of the brainstem with depression of the floor of the fourth ventricle in both children [Figure 3]a. There was a midline cleft, extending into the dorsal pons from the floor of the fourth ventricle causing a “tent-shaped fourth ventricle” and “split pons” appearance [Figure 3]b. Facial colliculi were absent on the floor of the fourth ventricle. The medulla had a “butterfly-like configuration”with a ventral midline cleft and flattening of the medullary pyramids on either side of the cleft [Figure 3]c. The supratentorial parenchyma was normal. Fig. 3 represents the MRI findings in the girl (Patient 1).

Figure 3: (Patient 1): (a) Sagittal midline T2-weighted image showing hypoplasia of the brainstem with depression of the floor of the fourth ventricle (white arrow), (b) Axial T1-weighted image at the level of the pons showing the midline cleft on the pons (split pons sign,) and tent-shaped fourth ventricle (white arrow) and (c) Axial T1-weighted image at the level of the medulla showing a butterfly-like configuration with a ventral midline cleft and flattened pyramids (white arrow)

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Based on the phenotypic and radiographic findings, we suspected both cases as HGPPS. Since the general examination of both the patients did not reveal scoliosis, we advised the parents to undergo genetic testing for themselves and their children to confirm the diagnosis. Full exome sequencing was performed using the next-generation sequencing using Illumina chemistry. The genetic testing revealed the deletion of both copies of ROBO3 on chromosome 11:2 in both children. The parents did not undergo the test.

Parents were informed about the progressive nature of this disease, especially about the development of scoliosis subsequently in late childhood or adolescence and its rapid progression. They were referred to an orthopedician for further screening and management.

Discussion

HGPPS was first described in 1975 by Sharpe et al.^[6] in four siblings of a Chinese family. Thirty years later, Jen et al. mapped the disease locus to a 30-cM (centiMogran) interval on chromosome 11q23-25 and in 2004 established the association of this syndrome with the ROBO3 gene.^[7] This gene produces an axon pathfinding protein, the absence of which results in uncrossing of the corticospinal and dorsal column medial lemniscus pathways in the brainstem.^[8] Even though there are many different described mutations in different populations across the world, the phenotypic and radiographic findings of HGPPS appear similar.^[4]

This report described siblings with HGPPS with characteristic ocular motility, neuroimaging, and genetic findings but without scoliosis. Our patients had a congenital absence of a smooth horizontal gaze under conjugate conditions. Physiologically, this is controlled by two populations of neurons of abducens nuclei: one directly innervating the lateral rectus of the ipsilateral eye and the other consisting of internuclear neurons that project through the medial longitudinal fasciculus (MLF) to the contralateral oculomotor nucleus, to innervate medial rectus of the other eye.^[9] The abducens nuclei are located in the lower part of the pontine tegmentum at the level of the fourth ventricular floor, where they are surrounded by the axons of the motor nuclei of the facial nerve which along with the abducens nuclei form the facial colliculi appears as paired prominences of the fourth ventricular floor in sagittal MRI of the healthy individuals.^[9] The absence of such prominence in our patients in [Figure 3]c, suggests selective agenesis of the abducens nuclei, thereby explaining the congenital horizontal gaze palsy. Besides, due to the agenesis, there is a persistence of an abnormally deep fourth ventricular furrow, resulting in the “tent-shaped fourth ventricle” and “split pons sign” [Figure 3]b. Facial (seventh cranial) nerve function was normal in our patients suggesting that in HGPPS there is a normal development of facial nerve despite the agenesis of the abducens nuclei. Our patients also had pendular nystagmus in all gazes. This has been reported before in literature, even though no cause has been identified for it.^[4] Other ocular abnormalities reported in association with HGPPS includes asynchronous blinking and saccadic vertical smooth pursuits.^[4] Patients with HGPPS are often neurologically unaffected, but a few can show delayed motor and cognitive development.^[4]

Children affected with HGPPS, universally develop progressive scoliosis that becomes clinically evident after the age of 2 years.^[9],[10] The diagnosis is usually made, if at all, when scoliosis becomes severe, often by the early teenage years which subsequently requires treatment.^[10] The cause of scoliosis remains unclear. Possibly, it is due to maldevelopment of extrapyramidal projections in the reticular formation of patients with HGPPS, leading to alterations in muscle tone.^[8] The clinical findings of scoliosis appear to require atrophy of the medulla (”butterfly” configuration on MRI).^[11]

Conclusion

The diagnosis of HGPPS can be made on routine ocular examination, neuroimaging findings, and later confirmed by genetic studies even in the absence of clinical manifestation of scoliosis. This helps us to prognosticate these patients, explain to the parents, and advise early referral to the orthopedician for spine screening and treatment which avoids significant physical morbidity in these children. A multidisciplinary approach involving the ophthalmologist, pediatrician, radiologist, and orthopedician is required to diagnose and manage these cases.

Acknowledgments

We thank our diagnostic and photographic teams of L V Prasad Eye Institute, GMRV Campus, for their support in patient management and documentation of the clinical pictures and investigations.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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