University College London Institute of Ophthalmology, London, England2Moorfields Eye Hospital, London, England.
Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland.
JAMA Ophthalmol. 2016 Jul 1;134(7):753-62. doi: 10.1001/jamaophthalmol.2016.1073.
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.
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.
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.
Knobloch 综合征是一种罕见的常染色体隐性遗传病，其特征为高度近视、视网膜脱离和枕骨脑膨出，但目前已知其具有越来越多样化的表型。目前缺乏有关电生理数据的报告，一些关键的临床特征尚未描述。
阐述 Knobloch 综合征的当前临床、电生理和分子遗传学发现。
设计、地点和参与者：7 个家庭的 12 名患者接受了全面的眼科检查和视网膜成像。进一步的研究包括视网膜电图和神经影像学检查。对 COL18A1 进行双向 Sanger 测序，并对可用的亲属进行分离。研究于 2013 年 7 月 4 日至 2015 年 10 月 5 日进行。数据分析于 2014 年 5 月 20 日至 2015 年 11 月 3 日进行。
眼科和神经影像学评估以及 COL18A1 序列分析的结果。
在 12 名患者（6 名男性；最后一次回顾时的平均年龄为 16 岁[范围，2-38 岁]）中，所有人的至少 1 只眼睛都有高度近视，视力严重下降。一对同胞兄弟在婴儿期右眼为单侧高度近视，左眼为近视力正常。前节异常包括虹膜隐窝缺失、虹膜透照、晶状体脱位和白内障。2 名有虹膜透照的患者患有青光眼。眼底特征包括异常塌陷的玻璃体、黄斑萎缩和棋盘状眼底。5 名患者曾有视网膜脱离。视网膜电图显示 8 名患者存在锥-杆功能障碍，2 名患者的功能严重降低或无法检测，2 名患者中 1 只眼为锥-杆功能障碍，另 1 只眼无法检测到反应，2 名患者中 2 只眼均无法检测到反应。3 名患者存在枕骨脑膨出或脑膜膨出，4 名患者存在枕骨颅骨缺损，2 名患者存在枕骨轻微改变，2 名患者无异常。5 名患者存在头皮皮肤变化。8 名患者存在全身合并症，包括学习困难、癫痫和先天性肾脏异常。在 6 个家庭中发现了 COL18A1 的 2 个可能的新突变，包括 2 个双等位基因突变，符合常染色体隐性遗传，1 个有 2 个受影响儿童的家庭中发现了 1 个突变。
本报告描述了 Knobloch 综合征患者的新特征，包括色素播散综合征和青光眼，以及视网膜电图上的锥-杆功能障碍。2 名患者的神经影像学检查结果正常，强调了一些受影响的个体存在孤立的眼部疾病。对眼部表型的认识可能有助于早期诊断、适当的遗传咨询和监测潜在并发症。
