Horizontal gaze palsy with progressive scoliosis (HGPPS) is an autosomal recessive disorder characterized by absence of conjugate horizontal eye movements with preserved vertical gaze and progressive scoliosis, with onset at childhood or adolescence.1–5 Several mutations on the ROBO3 gene, either homozygous or compound heterozygous, have been identified as responsible for HGPPS. The ROBO3 protein belongs to a family of transmembrane receptors that are expressed in the growth cone of elongating axons, guiding them to contralaterally located target neurons during nervous system development. Imaging and neurophysiological studies have provided evidence for the presence of uncrossed motor and sensory pathways in patients with HGPPS.2,3,6
Keratoconus causes deterioration in vision as progressive thinning of the cornea induces myopia and irregular astigmatism. It requires sequential treatment including glasses, contact lenses, intrastromal corneal rings, and, in many cases, keratoplasty.7,8 Despite intensive investigation, its precise etiology is unknown. It is mostly an isolated disorder, although several reports describe systemic association with atopy and vernal keratoconjunctivitis, and also with some genetic syndromes such as Down syndrome, Leber’s congenital amaurosis, and connective tissue disorders.9 However, it has not been reported in association with HGPPS.
A 13-year-old girl was born at term to healthy, non-consanguineous parents and grandparents. At 2 years of age, she was diagnosed as having scoliosis with a left thoracic curve. Ocular motility alterations were noticed for the first time at 3 years of age (in 2003) when she was first observed in the Ophthalmology Department of a Lisbon hospital. Optical correction was implemented and she was lost to follow-up. Further optical corrections were done by optometrists. She continued to be observed at the Pediatric Orthopedic Department of another Lisbon hospital, with the diagnosis of severe juvenile idiopathic scoliosis, where she had various scoliosis corrective surgeries (Akbharnia Method). At 11 years of age, she was admitted at the ophthalmological emergency room of Hospital Prof. Dr. Fernando da Fonseca due to progressive visual acuity impairment, with severe deterioration during the previous year.
Further observation showed dorsal thoracolumbar scoliosis with torticollis over the left shoulder. An ocular examination showed orthotropic eye motility in the primary position without diplopia. The patient presented with complete horizontal gaze palsy, with preservation of vertical gaze and convergence, but convergence spasms when forcing abduction (Figure 1). Forced ductions were normal. No nystagmus or apparent defects by perimetry confrontation were observed. Pupillary reflexes and intraocular pressure were also normal. Occasional asynchronous eye closure was observed. Cycloplegic refraction by retinoscopy was impossible to quantify and autorefractor results were −23.50, −5.50 × 140º in the left eye. The right eye was impossible to assess. Best-corrected visual acuity was 20/80 in both eyes, with −16 diopters.
Photographs showing different postures and eye positions. The clinical profile of horizontal gaze palsy with progressive scoliosis was confirmed. Photographs demonstrating absent horizontal eye movement on attempted gaze to right (left) or left (right) but normal vertical gaze upward (upper) and downward (lower) from the primary position (central).
Biomicroscopy showed loss of normal corneal transparency in the right eye, outlining Vogt lines and inferior procidentia and thinning in both eyes. Both lenses were transparent (Figure 2). Funduscopy was unremarkable. Anterior segment tomography obtained by Pentacam HR (Oculus Optikgeräte, Wetzlar, Germany) confirmed the diagnosis of advanced bilateral keratoconus (Figure 3).
Biomicroscopy of the (A) right eye (OD) and left eye (OS) before surgery and (B) after penetranting keratoplasty in the right eye and after surgical implantation of intracorneal ring segments followed by corneal collagen cross-linking in the left eye.
Anterior segment tomography obtained by Pentacam HR (Oculus Optikgeräte, Wetzlar, Germany) confirmed the diagnosis of advanced bilateral keratoconus. (A) Preoperative assessment. In the right eye (OD): flat keratometry (K1) 67.9 diopters (D); steep keratometry (K2) = 71.8 D; corneal thickness = 348 μm thinner. Scheimpflug image shows significant corneal scarring and thinning in the central cornea. In the left eye (OS): K1 = 55.3 D; K2 = 56.9 D; corneal thickness = 424 μm thinner. Scheimpflug image shows corneal thinning in the central cornea. (B) Postoperative assessment. In the right eye, K1 = 43.4 D; K2 = 53.6 D; corneal thickness = 482 μm thinner. In the left eye: K1 = 51.9 D; K2 = 54.9 D; corneal thickness = 358 μm thinner.
Contrast-enhanced magnetic resonance imaging showed the typical brainstem hypoplasia of the medulla with a deep midline pontine cleft (butterfly configuration) and absence of facial colliculi. Orbital observation was normal, namely at the level of extraocular muscles.
Given these observations, a diagnosis of HGPPS was suspected and a blood sample was sent to Children’s Hospital in Boston for ROBO3 sequencing. ROBO3 analysis identified the child as a compound heterozygote with c.767-2_767-1delAG and c.767-776delAGCGTCCCTC mutations.
Due to intolerance to rigid gas permeable lenses, keratoconus approach in the left eye included surgical implantation of intracorneal ring segments (Intacs; Addition Technology, Inc., Lombard, IL) combined with corneal collagen cross-linking. The latter was made with hypotonic riboflavin (0.1% riboflavin in 0.9% saline instead of dextran) due to lower central corneal thickness values (< 400 μm after epithelial debridement). For the right eye, with significant central corneal scarring, penetrating keratoplasty was performed (Figures 2–3). Best-corrected visual acuity improved to 20/50 in both eyes.
HGPPS is a rare autosomal recessive disorder, considered a congenital cranial dysinnervation disorder, as a result of developmental errors in innervations10 due to mutations on the ROBO3 gene.
The ROBO3 gene encodes a receptor associated with axonal guidance during development. This protein plays a critical role in ensuring that motor and sensory nerve pathways cross over in the brainstem. In patients with HGPPS, these pathways do not cross over, but stay on the same side of the body.6,11,12 This is one of the hypotheses for the underlying cause of the horizontal ophthalmoplegia, the ocular hallmark of this condition. Another hypothesis that has been suggested and supported by imaging studies is hypoplasia or agenesis of the abducens nuclei associated with defects of supranuclear control regions such as the pontine paramedian reticular formation.4,5,12–14
The cause of progressive scoliosis in HGPPS is unclear. It is still uncertain why the effects of ROBO3 mutations appear to be limited to horizontal eye movement and scoliosis.
The early diagnosis of HGPPS is important to allow for adequate ocular follow-up, to apply supportive therapies to prevent rapid progression of scoliosis,4 and to lead to appropriate genetic counseling.
In our case, keratoconus management focused on visual acuity improvement and prevention of ectasia progression, which varies depending on the disease severity.1,5,8,11 Penetrating keratoplasty was performed in the right eye due to corneal hypotransparency with significant central scarring. This is the most commonly used surgical option for advanced cases of keratoconus such as those with corneal scarring.7 For the left eye, which was intolerant to rigid gas permeable lenses and had evidence of ectasia progression, keratoconus approach included surgical implantation of intracorneal ring segments (Addition Technology, Inc.) combined, in a second stage, with corneal collagen cross-linking. The intracorneal ring segments try to reshape the abnormal shape of the cornea in an attempt to improve visual acuity and contact lens tolerance, preventing, or at least delaying, the need for a corneal graft.7 The main goal of corneal cross-linking is to increase corneal rigidity and biomechanical stability, slowing the progression of the disease.7,8 Due to lower central corneal thickness values in our patient’s left eye, it was necessary to use hypotonic riboflavin during the cross-linking procedure because it has been shown to be effective in increasing intraoperative corneal stroma thickness due to its osmotic properties.15 Cross-linking may also increase the flattening effect of the intracorneal ring segments by altering the biomechanical properties of the cornea.15 Although we have a short follow-up time, we achieved good functional results with our approach, with visual acuity improvement in both eyes.
Association with corneal ectasia is not known and the occurrence of severe bilateral keratoconus with HGPPS has not been reported. Based on what is known of the ROBO3 gene function, there is no apparent pathogenic association between these two conditions. Nevertheless, there may be some hitherto unknown developmental genetic or physiologic association that warrants an ophthalmologic assessment in patients with HGPPS to detect early signs of keratoconus and, if necessary, adequately manage ophthalmological complications to improve prognosis.
- Bosley TM, Salih MA, Jen JC, et al. Neurologic features of horizontal gaze palsy and progressive scoliosis with mutations in ROBO3. Neurology. 2005;64:1196–1203. doi:10.1212/01.WNL.0000156349.01765.2B [CrossRef]
- MacDonald DB, Streletz LJ, Al-Zayed Z, Abdool S, Stigsby B. Intraoperative neurophysiologic discovery of uncrossed sensory and motor pathways in a patient with horizontal gaze palsy and scoliosis. Clin Neurophysiol. 2004;115:576–582. doi:10.1016/j.clinph.2003.10.029 [CrossRef]
- Avadhani A, Ilayaraja V, Shetty AP, Rajasekaran S. Diffusion tensor imaging in horizontal gaze palsy with progressive scoliosis. Magn Reson Imaging. 2010;28:212–216. doi:10.1016/j.mri.2009.10.004 [CrossRef]
- dos Santos AV, Matias S, Saraiva P, Goulao A. MR imaging features of brain stem hypoplasia in familial horizontal gaze palsy and scoliosis. AJNR Am J Neuroradiol. 2006;27:1382–1383.
- Bomfim RC, Tavora DG, Nakayama M, Gama RL. Horizontal gaze palsy with progressive scoliosis: CT and MR findings. Pediatr Radiol. 2009;39:184–187. doi:10.1007/s00247-008-1058-8 [CrossRef]
- Jen JC, Chan WM, Bosley TM, et al. Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science. 2004;304:1509–1513. doi:10.1126/science.1096437 [CrossRef]
- Romero-Jimenez M, Santodomingo-Rubido J, Wolffsohn JS. Keratoconus: a review. Cont Lens Anterior Eye. 2010;33:157–166. doi:10.1016/j.clae.2010.04.006 [CrossRef]
- Jhanji V, Sharma N, Vajpayee RB. Management of keratoconus: current scenario. Br J Ophthalmol. 2011;95:1044–1050. doi:10.1136/bjo.2010.185868 [CrossRef]
- Kok YO, Tan GF, Loon SC. Review: keratoconus in Asia. Cornea. 2012;31:581–593. doi:10.1097/ICO.0b013e31820cd61d [CrossRef]
- Engle EC. The genetic basis of complex strabismus. Pediatr Res. 2006;59:343–348. doi:10.1203/01.pdr.0000200797.91630.08 [CrossRef]
- Amoiridis G, Tzagournissakis M, Christodoulou P, et al. Patients with horizontal gaze palsy and progressive scoliosis due to ROBO3 E319K mutation have both uncrossed and crossed central nervous system pathways and perform normally on neuropsychological testing. J Neurol Neurosurg Psychiatry. 2006;77:1047–1053. doi:10.1136/jnnp.2006.088435 [CrossRef]
- Otaduy MC, Leite Cda C, Nagae LM, et al. Further diffusion tensor imaging contribution in horizontal gaze palsy and progressive scoliosis. Arq Neuropsiquiatr. 2009;67:1054–1056. doi:10.1590/S0004-282X2009000600017 [CrossRef]
- Lo B, Faiyaz-Ul-Haque M, Banwell B, et al. The locus responsible for horizontal gaze palsy/progressive scoliosis and brainstem hypoplasia is refined to a 9-cM region on chromosome 11q23. Clin Genet. 2004;65:137–142. doi:10.1111/j.0009-9163.2004.00201.x [CrossRef]
- Yee RD, Duffin RM, Baloh RW, Isenberg SJ. Familial, congenital paralysis of horizontal gaze. Arch Ophthalmol. 1982;100:1449–1452. doi:10.1001/archopht.1982.01030040427011 [CrossRef]
- Suri K, Hammersmith KM, Nagra PK. Corneal collagen cross-linking: ectasia and beyond. Curr Opin Ophthalmol. 2012;23:280–287. doi:10.1097/ICU.0b013e328354865e [CrossRef]