Molecular and Clinical Findings in Patients With Knobloch Syndrome.
Knobloch syndrome is a rare, recessively inherited disorder classically characterized by high myopia, 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.



To expand on current clinical, electrophysiologic, and molecular genetic findings in Knobloch syndrome.



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.



Results of ophthalmic and neuroradiologic assessment and sequence analysis of COL18A1.



Of the 12 patients (6 males; mean age at last review, 16 years [range, 2-38 years]), all had high myopia 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.



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.
University College London Institute of Ophthalmology, London, England2Moorfields Eye Hospital, London, England.
Sarah
S
Hull
University College London Institute of Ophthalmology, London, England2Moorfields Eye Hospital, London, England.
Gavin
G
Arno
Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland.
Cristy A
CA
Ku
Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
Zhongqi
Z
Ge
University College London Institute of Ophthalmology, London, England.
Naushin
N
Waseem
University College London Institute of Ophthalmology, London, England2Moorfields Eye Hospital, London, England.
Aman
A
Chandra
University College London Institute of Ophthalmology, London, England2Moorfields Eye Hospital, London, England.
Andrew R
AR
Webster
University College London Institute of Ophthalmology, London, England2Moorfields Eye Hospital, London, England.
Anthony G
AG
Robson
University College London Institute of Ophthalmology, London, England2Moorfields Eye Hospital, London, England.
Michel
M
Michaelides
Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland.
Richard G
RG
Weleber
Moorfields Eye Hospital, London, England5Brain Repair & Rehabilitation Department, University College of London Institute of Neurology, London, England.
Indran
I
Davagnanam
Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
Rui
R
Chen
University College London Institute of Ophthalmology, London, England2Moorfields Eye Hospital, London, England.
Graham E
GE
Holder
Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland.
Mark E
ME
Pennesi
University College London Institute of Ophthalmology, London, England2Moorfields Eye Hospital, London, England6Koret Vision Center, Department of Ophthalmology, University of California, San Francisco.
Anthony T
AT
Moore
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D024102:Collagen Type VIII / Q000235:genetics*; D043170:Collagen Type XVIII; D004252:DNA Mutational Analysis; D004596:Electroretinography; D004677:Encephalocele / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D017889:Exfoliation Syndrome / Q000175:diagnosis; D005091:Exons / Q000235:genetics; D005260:Female; D005902:Glaucoma, Open-Angle / Q000175:diagnosis; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008967:Molecular Biology; D009154:Mutation; D047728:Myopia, Degenerative / Q000175:diagnosis*; D010375:Pedigree; D020419:Photoreceptor Cells, Vertebrate / Q000502:physiology*; D016133:Polymerase Chain Reaction; D012162:Retinal Degeneration; D012163:Retinal Detachment / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D014786:Vision Disorders / Q000175:diagnosis*; D055815:Young Adult
C000612902:COL18A1 protein, human; D024102:Collagen Type VIII; D043170:Collagen Type XVIII