Brain Advance Access originally published online on June 30, 2006
Brain 2006 129(9):2363-2374; doi:10.1093/brain/awl161
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Neurological features of congenital fibrosis of the extraocular muscles type 2 with mutations in PHOX2A
1 Neuro-ophthalmology Division, King Khaled Eye Specialist Hospital (KKESH) Riyadh, Saudi Arabia 2 Pediatric Ophthalmology Division, King Khaled Eye Specialist Hospital (KKESH) Riyadh, Saudi Arabia 3 Department of Genetics, King Faisal Specialist Hospital and Research Centre Riyadh, Saudi Arabia 4 Department of Radiology, Children's Hospital Boston Boston, MA, USA 5 Program in Genomics, Children's Hospital Boston Boston, MA, USA 6 Department of Neurology, Children's Hospital Boston Boston, MA, USA 7 Program in Neuroscience, Division of Medical Sciences, Harvard Medical School Boston, MA, USA
Correspondence to: Thomas M. Bosley, Division of Neurology, Suite 320, 3 Cooper Plaza, Cooper University Hospital, Camden, NJ, 08103, USA and Elizabeth C. Engle, Program in Genomics and Department of Neurology, Enders 560.2, Children's Hospital Boston, 300 Longwood Ave, Boston, MA 02115, USA E-mail: Thomas{at}CooperHealth.edu and elizabeth.engle{at}childrens.harvard.edu
Congenital fibrosis of the extraocular muscles type 2 (CFEOM2) is a complex strabismus syndrome that results from mutations in the homeodomain transcription factor PHOX2A. To define the clinical and neuroimaging features of patients with this autosomal recessive syndrome, we studied 15 patients with genetically defined CFEOM2. All patients underwent full neurological, neuro-ophthalmological and orthoptic assessments. Twelve patients had pupillary pharmacological testing and nine had 3.0 tesla MRI of the brain, brainstem and orbits. Patients were born with severe bilateral ptosis and exotropia with almost complete bilateral absence of adduction, elevation, depression and intorsion. Variable abduction was present prior to strabismus surgery in 14 patients, and central ocular motility reflexes (smooth pursuit, saccades, vestibulo-ocular reflex and optokinetic reflex) were intact except for convergence. Pupillary light and near reflexes were not present, but irises were anatomically normal and responded to pupillary pharmacology. Neuroimaging of brain and brainstem was remarkable for the anatomical absence of cranial nerve (CN) 3 and probably CN 4 bilaterally. Therefore, the CFEOM2 phenotype and neuroimaging are both consistent with the congenital absence of CNs 3 and 4. Additional features included presence of most central ocular motility reflexes, a central lack of pupillary responsiveness of uncertain aetiology and modest phenotypic variability that does not correlate with specific PHOX2A mutations. Clinical presentation, neuroimaging and Phox2a–/– animal models all support the concept that CFEOM2 is a primary neurogenic abnormality with secondary myopathic changes.
Key Words: brain imaging; brain development; ocular motor nerve; congenital ophthalmoplegia
Abbreviations: CCDDs, congenital cranial dysinnervation disorders; CFEOM2, congenital fibrosis of the extraocular muscles type 2; CN, cranial nerve; EOM, extraocular muscle
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Received March 17, 2006. Revised May 16, 2006. Accepted May 20, 2006.
Dr Bosley is now in the Neurology Division, Cooper University Hospital, Camden, NJ, USA.
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