Cho Soungmin, Traboulsi Elias I, Chiang John, Sierpina David
Loma Linda University Eye Institute, Loma Linda, CA, USA.
Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA.
Doc Ophthalmol. 2020 Aug;141(1):89-97. doi: 10.1007/s10633-020-09754-3. Epub 2020 Feb 11.
Cockayne syndrome is a rare autosomal recessive neurodegenerative disorder caused by mutations of either the ERCC6/CSB or ERCC8/CSA genes. Here, we describe two sisters with Cockayne syndrome caused by compound heterozygous mutations in the ERCC8 gene using multimodal imaging. Significant ophthalmic and systemic phenotypic variability is discussed.
Multimodal imaging was performed in two affected sisters and included electroretinography, optical coherence tomography, ultra-wide-field confocal scanning laser ophthalmoscopy, fundus autofluorescence and fluorescein angiography, and magnetic resonance imaging. Genetic analyses were performed on the affected sisters, both parents, and three unaffected siblings.
The older sister (Patient 1) had mental retardation, bilateral hearing loss, ataxia, and decreased visual acuity with retinal dystrophy. Radiographic studies revealed microcephaly, cerebral and cerebellar atrophy, ventriculomegaly, and a diffusely thickened skull. Full-field electroretinography waveforms were severely diminished with attenuation of cone and rod responses. The younger sister (Patient 2) had similar clinical features, including ataxia, bilateral hearing loss, and decreased visual acuity with retinal dystrophy. She also had paranoid schizophrenia. Wide-field fundus autofluorescence showed scattered areas of retinal pigment epithelium atrophy, which was different from her sister. Genetic analysis revealed two mutations in the ERCC8 gene shared by the sisters. These include an unreported missense point mutation: p.Thr328Ser:c.983C > G, and another previously reported pathogenic missense mutation: p.Ala205Pro:c.613G > C. Familial testing showed in trans segregation of these mutations with unaffected siblings inheriting one or neither mutation, but not both.
The clinical presentation and genetic studies confirmed a diagnosis of Cockayne syndrome in both sisters caused by compound heterozygous mutations in the ERCC8 gene on chromosome 10. Multimodal ocular imaging and systemic findings revealed wide phenotypic variability between the affected siblings.
科凯恩综合征是一种罕见的常染色体隐性神经退行性疾病，由ERCC6/CSB或ERCC8/CSA基因突变引起。在此，我们使用多模态成像描述了两名因ERCC8基因复合杂合突变导致科凯恩综合征的姐妹。讨论了显著的眼科和全身表型变异性。
对两名受影响的姐妹进行了多模态成像，包括视网膜电图、光学相干断层扫描、超广角共焦扫描激光眼底镜检查、眼底自发荧光和荧光素血管造影以及磁共振成像。对受影响的姐妹、父母和三名未受影响的兄弟姐妹进行了基因分析。
姐姐（患者1）有智力发育迟缓、双侧听力丧失、共济失调和视力下降伴视网膜营养不良。影像学研究显示小头畸形、大脑和小脑萎缩、脑室扩大以及颅骨弥漫性增厚。全视野视网膜电图波形严重减弱，伴有视锥和视杆反应衰减。妹妹（患者2）有类似的临床特征，包括共济失调、双侧听力丧失和视力下降伴视网膜营养不良。她还患有偏执型精神分裂症。超广角眼底自发荧光显示视网膜色素上皮萎缩的散在区域，这与她的姐姐不同。基因分析揭示了姐妹俩共有的ERCC8基因中的两个突变。其中包括一个未报告的错义点突变：p.Thr328Ser:c.983C＞G，以及另一个先前报道的致病性错义突变：p.Ala205Pro:c.613G＞C。家族检测显示这些突变以反式分离，未受影响的兄弟姐妹继承一个或不继承任何一个突变，但不会同时继承两个突变。
临床表现和基因研究证实两名姐妹均诊断为科凯恩综合征，由10号染色体上ERCC8基因的复合杂合突变引起。多模态眼部成像和全身检查结果显示受影响的兄弟姐妹之间存在广泛的表型变异性。
