Horizontal Gaze Palsy in Two Brothers with Compound Heterozygous ROBO3 Gene Mutations

Horizontal gaze palsy with progressive scoliosis (HGPPS; MIM#607313) is a rare autosomal recessive axon guidance disorder caused by mutations of the ROBO3 gene.[1] Main symptoms are congenital bilateral absence of voluntary horizontal eye movements and early onset progressive debilitating scoliosis. The oculomotor disorder might be mistaken as bilateral abduction palsy since strabism may occur and convergence is often preserved. Nystagmus, vertical smooth pursuit defects and delays in motor development have also been reported.[2] Decussation failure of the corticospinal and dorsal column tracts leads to the pathognomonic hindbrain malformation with pontine hypoplasia and ventral/dorsal cleft of the medulla, resulting in a butterfly configuration.[3]

The older brother presented at the age of 7 months with horizontal gaze palsy, esotropia, and anisocoria. Magnetic resonance imaging (MRI) at the age of 1 year is shown in [Fig. 1A] to [C]. As early as 15 months of age, thoracic scoliosis was found ([Fig. 2]). Sequencing of the ROBO3 gene confirmed two compound heterozygous mutations: c.416G > T (p.Gly139Val), novel; c.2108G > C (p.Arg703Pro).[1] The younger brother suffered from neonatal seizures caused by right temporal hemorrhage, unlikely to be related to the ROBO3 mutations. MRI revealed the same hindbrain malformation as in his brother ([Fig. 1D]). On follow-up, horizontal gaze palsy was diagnosed ([Video 1]).

Video 1

Horizontal gaze palsy in two brothers. Younger brother, aged 5 months. Object moving first to the right side and then to the left side: note horizontal gaze palsy with consecutive turning of the head. Object moving upward and downward: normal vertical pursuit.

Older brother, aged 4 years. Object on the right side: adverse reaction to having his head held straight due to horizontal gaze palsy, strabism. Object moving to the left side: horizontal gaze palsy. Online content including video sequences viewable at: www.thieme-connect.com/products/ejournals/html/10.1055/s-0036-1597610.

Fig. 1 (A) Sagittal T1 magnetic resonance imaging (MRI) with pontine hypoplasia (white arrow) and concave floor of the fourth ventricle. (B) Axial T2 MRI with butterfly configuration of the medulla (black arrow). (C) DTI tractography with ipsilateral descending corticospinal tracts. (D) Axial T2 MRI with split pons sign (arrowhead) and temporal hemorrhage (asterisk).

Fig. 2 X-ray of the spine demonstrating scoliosis.

HGPPS should be considered in horizontal gaze limitation and/or early onset scoliosis.

• References

• 1 Jen JC, Chan WM, Bosley TM , et al. Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science 2004; 304 (5676): 1509-1513
• 2 Bosley TM, Salih MA, Jen JC , et al. Neurologic features of horizontal gaze palsy and progressive scoliosis with mutations in ROBO3. Neurology 2005; 64 (7) 1196-1203
• 3 Nugent AA, Kolpak AL, Engle EC. Human disorders of axon guidance. Curr Opin Neurobiol 2012; 22 (5) 837-843