Cockayne综合征并肾病综合征一家系的临床特征及遗传学分析

Clinical and molecular genetic study of Cockayne syndrome accompanied with nephrotic syndrome in a family

目的分析确诊Cockayne综合征同卵双生姐妹的临床特征及遗传学特点。方法患儿为2016年9月于首都儿科研究所附属儿童医院神经内科确诊为Cockayne综合征的双胞胎姐妹，对其临床表现、诊疗经过、血液生化、代谢检查和全外显子基因检测结果等进行分析。结果2例患儿初诊时4岁5个月，因＂生长发育落后4年余＂就诊。双胎之小，初诊时体质量14.0 kg，身高97 cm，头围43 cm；双胎之大，体质量15.5 kg，身高98 cm，头围43 cm。2例患儿新生儿期体健，8月龄会抬头，10月龄会坐，1岁可扶站，就诊时4岁5个月仍独走不稳。2岁时可喊爸妈，目前仅能发单音。患儿均有小头畸形，高鼻梁，眼窝凹陷，短下颌，日光敏感性皮疹，听力损害，意向性震颤，双下肢肌张力高。4.5岁时先后被确诊为肾病综合征，病理为肾小球微小病变，泼尼松治疗效果欠佳。头颅磁共振成像均提示大脑及小脑脑萎缩征象。2例患儿ERCC8基因分析均为复合杂合突变，分别来自父母，受检者父亲携带ERCC8基因c.394_398delTTACA杂合移码突变，受检者母亲存在ERCC8基因第4外显子大片段杂合缺失。结论Cockayne综合征为常染色体隐性遗传，以发育落后、小头畸形、眼球内陷、皮肤日光过敏、听力受损为主要表现，还可累及肾脏等器官，存在ERCC8基因移码突变和杂合缺失以复合杂合形式致病。

Objective To analyze the clinical and genetics characteristics in twin sisters with Cockayne syndrome. Methods The identical twin sisters visited the Affiliated Children＇s Hospital of Capital Institute of Pediatrics in December 2016. The clinical presentations ,course of treatment,blood biochemistry ,metabolic screening and whole exon sanger sequencing were analyzed. Results These two patients were referred at 4 years and 5 months of age for growth failure and developmental delay. The younger sister manifested short stature （ only 97 cm） ,low weight （ 14.0 kg） and little head circumference （43 cm）, and the elder sister manifested short stature （only 98 cm） ,low weight （15.5 kg） and little head circumference （43 cm）. They were born with out adverse event, and then they kept the head up at 8 months of age. They could sit at 10 months of age, but they had not acquired independent walking ability up till now. They spoke their first words at 2 year of age, and made little progress after that. They had a variety of abnormal clinical features including cognitive deficits, microcephaly, thin pointy nose, sunken eyes, small chin, photosensitive rash, hearing impairment, volitional tremor and hypermyotonia. They had been diagnosed as nephrotic syndrome at 4.5 years old, with little response to prednisone. The renal biopsy revealed minimal change nephropathy. Cerebrum and cerebellum atrophy was detected by magnetic resonance image scanning. Two heterozygous ERCC8 mutations in both patients, c. 394_ 398delTFACA and large fragment deletion,were identified in the patient. The c. 394_398delTTACA mutation originated from his father. The exon 4 deletion from his mother caused the defection of the protein. Conclusions Cockayne syndrome is a rare autosomal recessive disease. It is not only characterized by developmental delay, microcephaly, sunken eyes, photosensitive rash and auditory abnormalities, but also can be involved in nephrotic syndrome. Cockayne syndrome can be caused by compound heterozygous mutation, including c. 394_398delTTACA and a large fragment deletion of exon 4 in ERCC8.