Hagedorn Joshua, Avdic Armin, Schnieders Michael J, Roos Benjamin R, Kwon Young H, Drack Arlene V, Boese Erin A, Fingert John H
Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
BMC Ophthalmol. 2020 Oct 1;20(1):388. doi: 10.1186/s12886-020-01659-8.
Nanophthalmos has a significant genetic background and disease-causing mutations have been recently been reported in the myelin regulatory factor (MYRF) gene. We report clinical features in a patient with nanophthalmos and a Thr518Met MYRF mutation.
A three-year-old male was discovered to have nanophthalmos after first presenting to the emergency department for a frontal headache, eye pain, emesis, and lethargy. Imaging studies (CT and MRI) were negative except for increased posterior fossa cerebrospinal fluid. Subsequent examinations revealed nanophthalmos (short axial eye lengths 18.1 mm OD and 18.3 mm OS), microcornea, and a large crystalline lens. Peripheral chorioretinal pigment abnormalities were also observed. He experienced episodes of marked ocular hypertension (53 mmHg OD and 60 mmHg) likely due to intermittent angle closure precipitated by nanophthalmos. The ocular hypertension was responsive to topical medicines. Genetic analysis of known nanophthalmos genes MFRP and TMEM98 were negative, while a novel mutation, Thr518Met was detected in MYRF. The Thr518Met mutation was absent from 362 matched normal controls and was extremely rare in a large population database, allele frequency of 0.000024. The Thr518Met mutation altered a highly conserved amino acid in the MYRF protein and three of four algorithms suggested that this mutation is likely pathogenic. Finally, molecular modeling showed that the Thr518Met mutation is damaging to MYRF structure. Together these data suggest that the Thr518Met mutation causes nanophthalmos.
Nanophthalmos may present at an early age with features of angle closure glaucoma and a Thr518Met mutation in MYRF was detected in a patient with nanophthalmos. Prevalence data, homology data, mutation analysis data, and protein modeling data suggest that this variant is pathogenic and may expand the phenotypic range of syndromic nanophthalmos caused by MYRF mutations to include central nervous system abnormalities (increased posterior fossa cerebrospinal fluid).
小眼球症具有显著的遗传背景，最近已报道髓磷脂调节因子（MYRF）基因中存在致病突变。我们报告了一名患有小眼球症且携带MYRF基因Thr518Met突变患者的临床特征。
一名三岁男性因前额头痛、眼痛、呕吐和嗜睡首次就诊于急诊科，随后被发现患有小眼球症。影像学检查（CT和MRI）除后颅窝脑脊液增多外均为阴性。后续检查发现小眼球症（右眼眼轴短18.1毫米，左眼18.3毫米）、小角膜和一个大晶状体。还观察到周边脉络膜视网膜色素异常。他经历了明显的高眼压发作（右眼53毫米汞柱，左眼60毫米汞柱），可能是由于小眼球症引发的间歇性房角关闭所致。局部用药可控制高眼压。已知的小眼球症相关基因MFRP和TMEM98的基因分析为阴性，而在MYRF基因中检测到一个新的突变Thr518Met。362名匹配的正常对照中未发现Thr518Met突变，在一个大型人群数据库中该突变极为罕见，等位基因频率为0.000024。Thr518Met突变改变了MYRF蛋白中一个高度保守的氨基酸，四种算法中的三种表明该突变可能具有致病性。最后，分子模型显示Thr518Met突变对MYRF结构具有损害作用。这些数据共同表明Thr518Met突变导致了小眼球症。
小眼球症可能在幼年时出现闭角型青光眼的特征，在一名小眼球症患者中检测到MYRF基因的Thr518Met突变。患病率数据、同源性数据、突变分析数据和蛋白质模型数据表明该变异具有致病性，可能会将由MYRF突变引起的综合征性小眼球症的表型范围扩大到包括中枢神经系统异常（后颅窝脑脊液增多）。
