https://doi.org/10.1177/1120672120977343 European Journal of Ophthalmology 1–6 © The Author(s) 2020 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/1120672120977343 journals.sagepub.com/home/ejo EJO European Journal of Ophthalmology Introduction Knobloch syndrome is a rare autosomal recessive disease, first described by Knobloch as the association between encephalocele and retinal detachment (RD) in a single family. 1 Since the first description in 1971, a few publica- tions have described additional ocular manifestations and different severity of this syndrome. The ocular phenotype can be variable and includes both posterior and anterior segment manifestations such as high myopia, lens sublux- ation and early-onset cataracts, vitreoretinal degeneration, RD, and smooth irides. 2–4 Retinal degeneration with severe cone-rod dystrophy (CRD) confirmed by electroretino- gram (ERG) is another recently described manifestation among patients with Knobloch syndrome. 4 Non ophthalmic manifestations are typical as well and include occipital changes (cutis aplasia, encephalocele, bone defects), brain defects (Dandy-Walker Malformation Variable phenotype of Knobloch syndrome due to biallelic COL18A1 mutations in children Nadav Levinger 1 , Karen Hendler 1 , Eyal Banin 1 , Mor Hanany 1 , Adva Kimchi 1,2 , Hadas Mechoulam 1 , Vardiella Meiner 2 , Yoav Parag 3 , Dror Sharon 1 , Michal Macarov 1,2 and Claudia Yahalom 1 Abstract Purpose: Knobloch syndrome is a rare, recessively inherited disorder classically characterized by high myopia, retinal detachment, and occipital encephalocele. Our aim is to report the clinical and genetic findings of four Israeli children affected by Knobloch syndrome. Methods: Retrospective study of four patients diagnosed with Knobloch syndrome, who underwent full ophthalmic examination, electroretinography, and neuroradiologic imaging. Genetic analysis included whole exome sequencing (WES) and Sanger sequencing. Results: The four patients included in this study had high myopia and nystagmus at presentation. Ocular findings included vitreous syneresis, macular atrophy, macular coloboma, and retinal detachment. One child had iris transillumination defects and an albinotic fundus, initially leading to an erroneous clinical diagnosis of albinism. Electroretinography revealed a marked cone-rod pattern of dysfunction in all four children. Brain imaging demonstrated none to severe occipital pathology. Cutaneous scalp changes were present in three patients. WES analysis, confirmed by Sanger sequencing revealed COL18A1 biallelic null mutations in all affected individuals, consistent with autosomal recessive inheritance. Conclusions: This report describes variable features in patients with Knobloch syndrome, including marked lack of eye pigment similar to albinism in one child, macular coloboma in two children as well as advanced cone-rod dysfunction in all children. One patient had normal neuroradiologic findings, emphasizing that some affected individuals have isolated ocular disease. Awareness of this syndrome, with its variable phenotype may aid early diagnosis, monitoring for potential complications, and providing appropriate genetic counseling. Keywords Genetics, retinal degenerations associated with systemic disease, retina, inner retinal/vitreoretinal dystrophies, genetic disease/congenital abnormalities, pediatric ophthalmology, molecular 1 Department of Ophthalmology, Hadassah University Medical Center, Faculty of Medicine, Hebrew University, Jerusalem, Israel 2 Department of Genetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 3 Department of Diagnostic Radiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Corresponding author: Claudia Yahalom, Department of Ophthalmology, Hadassah Hebrew University Medical Center, Kiryat Hadassah POB 12000 Hadassah University Hospital, Jerusalem 9112001, Israel. Email: kloudia@hadassah.org.il 977343EJO 0 0 10.1177/1120672120977343European Journal of OphthalmologyLevinger et al. research-article 2020 Original research article