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遗传性结缔组织病，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，以及严重的皮肤过度伸展与脆性为主要特征。因PLOD1基因（前胶原-赖氨酸，2-氧戊二酸5-双加氧酶1）突变导致的赖氨酰羟化酶1（lysyl hydroxylase 1, LH1）缺乏，已被证实为kEDS的致病原因（kEDS-PLOD1）。截至目前，中国人群中尚未见kEDS-PLOD1的相关报道。本研究报道1例因出现肌张力低下、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。患儿出生后即因严重肌张力低下出现运动发育迟缓，后续陆续出现关节过度活动、脊柱侧后凸及弱视。5岁时发现腹股沟疝并接受手术修补。同期患者皮肤呈天鹅绒样外观，过度伸展且易出现瘀斑，轻微外伤后可形成宽大的萎缩性瘢痕。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。体格检查提示血压升高，同时存在轻度面部畸形，包括高腭、内眦赘皮及下斜睑裂；患者还存在蓝巩膜，听力正常。影像学检查显示重度脊柱侧凸及骨质减少。超声心动图结果正常。实验室检查提示骨转换指标轻度升高。结合患者的临床表现，临床怀疑为kEDS。基因检测发现其存在PLOD1基因的新型纯合错义突变（c.1697 G>A, p.C566Y）（NM_000302.4），从而确诊为kEDS-PLOD1。其父母均携带该杂合突变。经生物信息学工具预测，该变异可能为kEDS的致病突变：Polyphen-2预测其为“可能有害”（评分0.999），SIFT预测其为“影响蛋白质功能”（评分0.00），Mutation Taster预测其为“致病”。