Horizontal Gaze Palsy and Rapidly Progressive Scoliosis: Typical Findings in ROBO3 Mutations

Background: Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare autosomal recessive disorder characterized by the absence of conjugate horizontal eye movements and early onset rapidly progressive scoliosis. The disorder is caused by mutations in the ROBO3 gene, which has an important role in axonal guidance and neuronal migration during embryonic development of brain stem and rhombencephalon. Cerebral magnetic resonance imaging (MRI) shows a typical pattern with butterfly configuration of the medulla, a deep midline pontine cleft, and pontine hypoplasia. Diffusion tensor imaging maps can show the absence of decussating pontocerebellar fibers and superior cerebellar peduncles. Motor development is delayed in many patients whereas cognitive function does not seem to be grossly impaired.

Case Report: The girl was born at term as the first child of nonconsanguineous Austrian parents. Birth weight was normal, postnatal adaptation was uncomplicated. At the age 4 months, she was presented to orthopedics because of abnormal head posture, at age 6 months to ophthalmology due to strabismus. When she was 8 months old, horizontal gaze palsy was diagnosed and incomplete Moebius syndrome was suggested. The girl was supported by orthoptist therapy and received physiotherapy for abnormal head posture. She was first presented to our neuropediatric department at the age of 1 year at which point she did not show scoliosis and motor and cognitive development were normal. We recommended an MRI scan at 18 months and the continuation of supportive therapy. Over the following months, our patient developed a rapidly progressive scoliosis and the MRI showed a deep midline cleft of pons and brain stem. Clinical symptoms and MRI findings were highly suggestive of a ROBO3 mutation. Therefore, we initiated molecular genetic testing and could confirm a homozygous frameshift mutation (c.2576del) in ROBO3.

Conclusion: Clinical findings of horizontal gaze palsy in an infant or child together with scoliosis are highly suggestive of a mutation in ROBO3. MRI findings are very characteristic. Early diagnosis is important with respect to genetic counseling of HGPPS families. A main focus of treatment is physiotherapy to control progressive scoliosis. Three-dimensional correction using thermoplastic braces and corrective spine surgery may be necessary.