儿童Kearns-Sayre综合征8例临床分析

Clinical characteristics of eight cases with Kearns-Sayre syndrome in children

目的分析儿童Kearns-Sayre综合征(KSS)的临床特点及诊断方法。方法对8例临床诊断为KSS患儿的临床症状体征、头颅影像学特点、实验室检查、常见线粒体基因(mtDNA)点突变筛查、肌肉病理和随访等资料进行回顾性分析。结果男6例,女2例;发病年龄5岁3个月至13岁1个月,平均9岁5个月;病程1个月至3年,平均1年6个月。8例就诊时均出现眼睑下垂,5例以眼睑下垂为首发症状,双眼同时发病4例;2例以共济失调为首发,1例以智力倒退为首发,这3例在发病后1个月至2年半均出现双眼睑下垂。2例合并糖尿病,1例既往患Person综合征。8例均有眼球活动受限和身材矮小体征,身高和体重均在正常同龄儿的P10以下;6例眼底检查发现视网膜色素变性,1例入院时无视网膜色素变性,5年随访时出现视网膜色素变性。8例均未见视神经萎缩。小脑共济失调6例。心脏传导阻滞5例,其中3例入院时即发现完全或不完全右束支传导阻滞,分别于1年7个月至4年后发展为Ⅲ度房室传导阻滞,随访均死亡;2例入院时ECG未见传导阻滞,随访4～5年时出现Ⅰ度房室传导阻滞。6例CSF蛋白均>1000mg·L-1。7例行尿有机酸分析,其中4例正常,3例提示酮尿症。常见mtDNA的A3243G、A8344G、T8993G、T8993C、A1555G、G11778A点突变筛查,均未发现突变。8例均行头颅MRI检查,均表现为双侧对称性白质长T1长T2信号,Flair像高信号,以额、顶叶皮质下白质及小脑白质为主,2例累及胼胝体压部,1例内囊后肢受累;6例脑干受累,以中脑和桥脑背盖部为主,丘脑和基底节区受累分别为4例和3例。肌肉病理6例组织化学检查可见破碎红肌纤维,8例电镜下均观察到肌膜下线粒体堆积和形态异常的线粒体。1例应用Southern印迹方法发现肌肉组织中存在大片段mtDNA缺失约6kb。6例随访2～5年,其中3例死亡,3例病情进行性加重。结论儿童KSS罕见,双眼睑下垂、眼肌麻痹、视网膜色素变性、小脑共济失调和心脏传导阻滞为主要表现。根据临床及肌肉活检可进行临床诊断,肌肉样本中发现mtDNA大片段缺失可确诊。

Objective To analyze the clinical characteristics and the diagnostic methods of Kearns-Sayre syndrome（KSS） in children. Methods The clinical features including clinical manifestations, neurologic signs, cranial MRI, laboratory tests, common point mutations of the mtDNA and muscular pathology in 8 patients with KSS were retrospectively analyzed and the cases were followed-up. Results There were six males and two females in this study. The ages of onset ranged from 5 years 3 months to 13 years with the average age being 9 years 5 months. The disease course was from 1 month to 3 years with an average age of 1.5 years. Eight cases had ptosis in whom five had ptosis as the first symptom and four had both eyes affected at the same time. Two cases had ataxia as the first symptom, one of which had intelligence retrogression as the first symptom and three cases had double eyelid ptosis 1 month to 2.5 years after the onset. Two cases had diabetes mellitus and one case had Person syndrome before. All of 8 cases had ocular motor abnormalities and short stature in whom the height and weight were the tenth centile below the normal children of the same age. Six cases were found retinal pigmentary by ocular fundus examination. One case had no retinal pigmentary degeneration until 5 years in follow-up visit. All the cases had no optic atrophy. Six cases had cerebellar ataxia. Five cases had cardiac conduction block. Three cases were with complete or incomplete right bundle branch block at admission and developed to third-degree atrioventricular block from 1 year 7 months to 4 years respectively and died in follow-up visit. Two cases without cardiac conduction block when hospitalized were found to have first-degree atrioventricular block in 4 or 5 years follow-up. Six cases were found cerebrospinal fluid protein increased（ 1 000 mg·L-1）. In seven cases with urine amino acid/organic acid analysis,four were normal, three were with ketonuria. No mutation was found in mtDNA A3243G,A8344G,T8993G,T8993C,A1555G,G11778A screening. Eight cases with MRI examination showed a bilaterally symmetrical hypointense on T1 weighted image,hyperintense on T2 and high flair signal in white matter, mainly in the subcortical white-matter of frontal and parietal lobe and cerebellum white-matter. In two cases, splenium of corpus callosum was affected. In one case, posterior limb of internal capsule was affected. In six cases, brain stem was affected, mainly in deutocerebrum and dorsal part of pontine tegmentum. Thalamus was affected in three cases and basal ganglia was affected in four cases. Six cases of muscle pathology who accepted histochemical examination revealed RRFs. Eight cases were observed under the electronmicroscope subsarcolemmal accumulation of mitochondria and morphologic abnormalities of mitochondria. By using southern blot analysis, in the samples of muscle large fragment mtDNA deletion of 6 kb was existed in one case. In 6 cases followed-up from 2 to 5 years, three patients died and three patients′ course was slowly aggravatin. Conclusions KSS is rare in children. Clinical findings consist of bilateral ptosis, ophthalmoplegia, pigmentary retinopathy, cerebellar ataxia and cardiac conduction block. Clinical diagnosis can be made according to the clinical manifestation and muscle biopsy, and mtDNA deletion in muscle samples can confirm the diagnosis.