Limbal Stem Cell Deficiency and Ocular Phenotype in Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome Caused by p63 Mutations
Limbal Stem Cell Deficiency and Ocular Phenotype in Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome Caused by p63 Mutations
复制标题
DOI：
10.1016/j.ophtha.2011.06.044
复制
发表时间：
2012-01-01
期刊：
影响因子：
13.7
通讯作者：
Willoughby, Colin E.
中科院分区：
文献类型：
--
作者：
Di Iorio, Enzo;Kaye, Stephen B.;Willoughby, Colin E.
目的：描述电趾-外胚层发育不良-裂（EEC）综合征（mim# 604292）患者的眼部表型，并确定视力发病的致病基础。设计：回顾性病例系列。参与者：来自英国、爱尔兰和意大利的EEC综合征的19个家庭（23名患者）。方法：通过常规医学检查，满足EEC综合征的诊断标准，确定表型严重程度。p63的突变分析采用基于聚合酶链反应的双向Sanger测序进行。所有的EEC综合征患者都进行了完整的眼科检查和眼表评估。角膜缘干细胞缺乏症（LSCD）的临床诊断是基于角膜结膜炎和Vogt角膜缘栅栏的解剖。使用免疫荧光抗体对1例患者进行印迹细胞学检查。对2例EEC患者的角膜扣和角膜膜进行了组织学和免疫组织化学分析。主要观察指标：EEC综合征表型严重程度（EEC评分）、最佳矫正Snellen视力（十进制分数）、裂隙灯生物显微镜、泪液功能指数、泪液破裂时间、LSCD、p63 DNA序列变异、印象细胞学和角膜组织病理学。结果：所有EEC综合征患者在p63 DNA结合域发现了11个杂合错义突变。所有患者均有眼部受累，最常见的是睑板腺异常和泪道引流系统缺陷。进行性LSCD是造成视力疾病的主要原因，占61%（14/23）。角膜缘干细胞缺乏与年龄的增长有关，并引起进行性角膜病变，导致血管密集的角膜膜，最终导致视力障碍。组织学分析和印象细胞学证实为LSCD。结论：p63杂合突变可引起EEC综合征，并导致进行性LSCD的视力损害。根据EEC评分分类，角膜缘干细胞衰竭与EEC综合征的严重程度或潜在的p63分子缺陷没有关系。财务披露：作者在本文中讨论的任何材料中没有专有或商业利益。眼科2012;119: 74-83 (C) 2012美国眼科学会。
Objective: To describe the ocular phenotype in patients with ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome (MIM#604292) and to determine the pathogenic basis of visual morbidity.Design: Retrospective case series.Participants: Nineteen families (23 patients) affected by EEC syndrome from the United Kingdom, Ireland, and Italy.Methods: General medical examination to fulfill the diagnostic criteria for EEC syndrome and determine the phenotypic severity. Mutational analysis of p63 was performed by polymerase chain reaction-based bidirectional Sanger sequencing. All patients with EEC syndrome underwent a complete ophthalmic examination and ocular surface assessment. Limbal stem cell deficiency (LSCD) was diagnosed clinically on the basis of corneal conjunctivalization and anatomy of the limbal palisades of Vogt. Impression cytology using immunofluorescent antibodies was performed in 1 individual. Histologic and immunohistochemical analyses were performed on a corneal button and corneal pannus from 2 EEC patients.Main Outcome Measures: The EEC syndrome phenotypic severity (EEC score), best-corrected Snellen visual acuity (decimal fraction), slit-lamp biomicroscopy, tear function index, tear breakup time, LSCD, p63 DNA sequence variants, impression cytology, and corneal histopathology.Results: Eleven heterozygous missense mutations in the DNA binding domain of p63 were identified in all patients with EEC syndrome. All patients had ocular involvement and the commonest was an anomaly of the meibomian glands and lacrimal drainage system defects. The major cause of visual morbidity was progressive LSCD, which was detected in 61% (14/23). Limbal stem cell deficiency was related to advancing age and caused a progressive keratopathy, resulting in a dense vascularized corneal pannus, and eventually leading to visual impairment. Histologic analysis and impression cytology confirmed LSCD.Conclusions: Heterozygous p63 mutations cause the EEC syndrome and result in visual impairment owing to progressive LSCD. There was no relationship of limbal stem cell failure with the severity of EEC syndrome, as classified by the EEC score, or the underlying molecular defect in p63.Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. Ophthalmology 2012; 119: 74-83 (C) 2012 by the American Academy of Ophthalmology.