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Original Investigation |

Molecular and Clinical Findings in Patients With Knobloch Syndrome

Sarah Hull, MA, FRCOphth, PhD1,2; Gavin Arno, PhD1,2; Cristy A. Ku, PhD3; Zhongqi Ge, PhD4; Naushin Waseem, PhD1; Aman Chandra, FRCOphth, PhD1,2; Andrew R. Webster, MD(Res), FRCOphth1,2; Anthony G. Robson, MSc, PhD1,2; Michel Michaelides, MD(Res), FRCOphth1,2; Richard G. Weleber, MD3; Indran Davagnanam, MD(Res), FRCR2,5; Rui Chen, PhD4; Graham E. Holder, MSc, PhD1,2; Mark E. Pennesi, MD, PhD3; Anthony T. Moore, MA, FRCOphth1,2,6
[+] Author Affiliations
1University College London Institute of Ophthalmology, London, England
2Moorfields Eye Hospital, London, England
3Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland
4Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
5Brain Repair & Rehabilitation Department, University College of London Institute of Neurology, London, England
6Koret Vision Center, Department of Ophthalmology, University of California, San Francisco
JAMA Ophthalmol. 2016;134(7):753-762. doi:10.1001/jamaophthalmol.2016.1073.
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Importance  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.

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 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.

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.

Figures in this Article


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Figure 1.
Pedigrees of Families Affected by Knobloch Syndrome With Segregation Analysis and First Report of the Mutation

M indicates mutation; WT, wild-type.

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Figure 2.
Anterior Segment and Retinal Imaging in Knobloch Syndrome

Patient 1.2 at age 21 years: left (L) anterior segment photograph (A), right (B) and left (C) color fundus photographs (Topcon Great Britain Ltd). Patient 2.2 at age 14 years: left anterior segment photograph (D), left Optos wide field color (E), and left Optos autofluorescence imaging (Optos plc) (F). Patient 3.2 at age 11 years: left anterior segment photograph (G), right wide field imaging (Optos plc) (H), and right (I) and left (J) optical coherence tomography (OCT) (Spectralis). Patient 5 at age 38 years: right anterior segment photograph (K), right fundus photograph (Topcon Great Britain Ltd) (L), right autofluorescence imaging (Spectralis) (M), and right OCT (N). Patient 6.2 at age 11 years: right anterior segment photograph (O) to demonstrate vitreous clumping, and right (P) and left (Q) fundus color photographs.

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Figure 3.
Electroretinogram (ERG) of 1 Eye of Patients 3.2, 6.1, 6.2, and 7

In patient 3.2 (A), rod-specific (dark-adapted [DA] 0.01) ERG is mildly subnormal; bright flash (DA 10.0) a-wave amplitude is subnormal; cone flicker (light-adapted [LA] 30 Hz) and single-flash (LA 3.0) ERGs are markedly subnormal and delayed (note the differences in calibration compared with the normal); pattern ERG (PERG) is undetectable. In patients 6.1 (B) and 6.2 (C), rod-specific and bright flash amplitudes are subnormal, cone flicker and single flash are markedly subnormal and delayed; abnormalities are more severe for patient 6.2, partly related to sedation required for the ERG. Patients 3.2, 6.1, and 6.2 show a cone-rod pattern of dysfunction; patient 7 (D) has severe loss of both rod and cone responses. Normal ERG (E) is shown for comparison. Div indicates division.

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Figure 4.
Neuroradiologic and Cutaneous Occipital Findings in Knobloch Syndrome

Patient 1.1: subgaleal fat pad (arrowheads) overlying occipital bone (A and B) and extensive bifrontal polymicrogyria (arrowheads) (C) on magnetic resonance imaging (MRI). Patient 1.2: small occipital bone defect (arrowhead) with atretic encephalocele/meningocele (D) and medial bifrontal polymicrogyria (arrowheads) (E) on MRI. Patient 2.1: no abnormalities on MRI (F) and occipital patch of white hair (G). Patient 2.2: aged 6 months, occipital encephalocele (arrowhead) on MRI (H), age 11 years, occipital scarring and retained retrocerebellar arachnoid cyst at site of previous surgery (arrowhead) (I), and age 11 years, bilateral inferior frontal polymicrogyria (arrowhead) (J) on MRI. Patient 3.2: small, well-corticated channel in the midline of the occipital lobe (arrowhead) (K) on computed tomographic scan. Patient 4.1: small bony occipital defect (arrowhead) with meningeal tissue communicating to subcutaneous tissue through the defect (L) on MRI. Patient 6.2: cutaneous alopecia overlying occiput (M). Patient 7: age 4 months, occipital encephalocele (arrowhead) (N and O) on MRI. The MRIs were intracranial sagittal and coronal T1-weighted and axial T2-weighted images.

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