A Novel PLOD1 Gene Mutation causing Kyphoscoliotic Ehlers-Danlos Syndrome in Chinese patient

Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is a rare autosomal recessive connective tissue disorder characterized by progressive kyphoscoliosis, congenital muscular hypotonia, marked joint hypermobility, and severe skin hyperextensibility and fragility. Deficiency of lysyl hydroxylase 1 (LH1) due to mutations of PLOD1 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1) gene has been identified as the pathogenic cause of kEDS (kEDS-PLOD1). Up to now, kEDS-PLOD1 has not been reported among Chinese population. We reported a 17-year-old Chinese male patient presenting with hypotonia, joint hypermobility and scoliosis was referred to our hospital. After birth, he was found to have severe hypotonia leading to delayed motor development. Subsequently, joint hypermobility, kyphoscoliosis and amblyopia were found. Inguinal hernia was found at age 5 years and closed by surgery. At the same time, he presented with hyperextensible and bruisable velvety skin with widened atrophic scarring after minor trauma. Dislocation of elbow joint was noted at age of 6 years. Orthopedic surgery for correction of kyphoscoliosis was performed at age 10 years. His family history was unremarkable. Physical examination revealed elevated blood pressure. Slight facial dysmorphologies including high palate, epicanthal folds, and down-slanting palpebral fissures were found. He also had blue sclerae with normal hearing. X-rays revealed severe degree of scoliosis and osteopenia. The Echocardiography findings were normal. Laboratory examination revealed a slightly elevated bone turnover. Based on the clinical manifestations presented by our patient, kEDS was suspected. Genetic analysis revealed a novel homozygous missense mutation of PLOD1 (c.1697 G>A, p.C566Y) (NM_000302.4), confirming the diagnosis of kEDS-PLOD1. Corresponding heterozygous mutation was detected in his parents. This variant is possibly causative for kEDS because it was predicted to be “PROBABLY DAMAGING” with a score 0.999 by Polyphen‐2, “AFFECT PROTEIN FUNCTION” with a score 0.00 by SIFT, and “disease causing” by Mutation Taster.脊柱后侧凸型埃勒斯-当洛综合征（kyphoscoliotic Ehlers-Danlos syndrome, kEDS）是一种罕见的常染色体隐性结缔组织疾病，以进行性脊柱侧后凸、先天性肌张力低下、显著关节过度活动，以及严重皮肤过度伸展与脆性增加为特征。由PLOD1基因（procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1）突变引发的赖氨酰羟化酶1（lysyl hydroxylase 1, LH1）缺乏，已被确定为kEDS（kEDS-PLOD1）的致病原因。截至目前，中国人群中尚未见kEDS-PLOD1的相关报道。本研究报告1例因肌张力低下、关节过度活动及脊柱侧凸就诊于我院的17岁中国男性患者。患者出生后即出现严重肌张力低下，导致运动发育迟缓；后续相继出现关节过度活动、脊柱侧后凸及弱视。5岁时确诊腹股沟疝并接受手术修补。同期患者皮肤表现为过度伸展、易挫伤的天鹅绒样外观，轻微外伤后可出现宽大萎缩性瘢痕。6岁时出现肘关节脱位，10岁时接受脊柱侧后凸矫形手术。患者家族史无异常。体格检查显示血压升高，存在轻度面部畸形，包括高腭弓、内眦赘皮及下斜型睑裂；巩膜发蓝，听力正常。X线检查提示严重脊柱侧凸及骨量减少。超声心动图结果正常。实验室检查显示骨转换标志物轻度升高。基于患者的临床表现，临床疑似kEDS。基因分析发现PLOD1基因（NM_000302.4）存在新型纯合错义突变c.1697 G>A, p.C566Y，从而确诊kEDS-PLOD1。其父母均携带该杂合突变。该变异可能为kEDS的致病变异：Polyphen-2预测其为"PROBABLY DAMAGING"（得分0.999），SIFT预测其为"AFFECT PROTEIN FUNCTION"（得分0.00），Mutation Taster则预测其为"disease causing"。