IMPORTANCE Knobloch syndrome is a rare, recessively inherited disorder classically characterized by highmyopia, retinal detachment, and occipital encephalocele, but it is now known to have an increasingly variable phenotype. There is a lack of reported electrophysiologic data, and some key clinical features have yet to be described. OBJECTIVE To expand on current clinical, electrophysiologic, and molecular genetic findings in Knobloch syndrome. DESIGN, SETTING, AND PARTICIPANTS Twelve patients from 7 families underwent full ophthalmic examination and retinal imaging. Further investigations included electroretinography and neuroradiologic imaging. Bidirectional Sanger sequencing of COL18A1 was performed with segregation on available relatives. The study was conducted from July 4, 2013, to October 5, 2015. Data analysis was performed from May 20, 2014, to November 3, 2015. MAIN OUTCOMES AND MEASURES Results of ophthalmic and neuroradiologic assessment and sequence analysis of COL18A1. RESULTS Of the 12 patients (6 males; mean age at last review, 16 years [range, 2-38 years]), all had highmyopia in at least 1 eye and severely reduced vision. A sibling pair had unilateral high myopia in their right eyes and near emmetropia in their left eyes from infancy. Anterior segment abnormalities included absent iris crypts, iris transillumination, lens subluxation, and cataract. Two patients with iris transillumination had glaucoma. Fundus characteristics included abnormal collapsed vitreous, macular atrophy, and a tesselated fundus. Five patients had previous retinal detachment. Electroretinography revealed a cone-rod pattern of dysfunction in 8 patients, was severely reduced or undetectable in 2 patients, and demonstrated cone-rod dysfunction in 1 eye with undetectable responses in the other eye in 2 patients. Radiologic imaging demonstrated occipital encephalocele or meningocele in 3 patients, occipital skull defects in 4 patients, minor occipital changes in 2 patients, and no abnormalities in 2 patients. Cutaneous scalp changes were present in 5 patients. Systemic associations were identified in 8 patients, including learning difficulties, epilepsy, and congenital renal abnormalities. Biallelic mutations including 2 likely novel mutations in COL18A1, were identified in 6 families that were consistent with autosomal recessive inheritance with a single mutation identified in a family with 2 affected children. CONCLUSIONS AND RELEVANCE This report describes new features in patients with Knobloch syndrome, including pigment dispersion syndrome and glaucoma as well as cone-rod dysfunction on electroretinography. Two patients had normal neuroradiologic findings, emphasizing that some affected individuals have isolated ocular disease. Awareness of the ocular phenotype may aid early diagnosis, appropriate genetic counseling, and monitoring for potential complications.
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