A novel PLOD1 gene mutation

yphoscoliotic 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.

脊柱后凸侧凸型埃勒斯-当洛斯综合征（kyphoscoliotic Ehlers-Danlos syndrome, kEDS）是一种罕见的常染色体隐性遗传性结缔组织疾病，以进行性脊柱后凸侧凸、先天性肌张力减退、显著的关节过度活动，以及严重的皮肤过度伸展与脆性增加为主要特征。由PLOD1（前胶原-赖氨酸，2-氧戊二酸5-双加氧酶1，procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1）基因突变导致的赖氨酸羟化酶1（lysyl hydroxylase 1, LH1）缺乏，已被确定为kEDS（kEDS-PLOD1）的致病原因。截至目前，中国人群中尚无kEDS-PLOD1的相关报道。本文报告1例因肌张力减退、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。患儿出生后即出现重度肌张力减退，导致运动发育迟缓；后续相继出现关节过度活动、脊柱后凸侧凸及弱视。5岁时确诊腹股沟疝，并行手术修补；同时患儿皮肤呈天鹅绒样质地，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岁时接受脊柱后凸侧凸矫正骨科手术。患儿家族史无特殊。体格检查示血压升高，可见轻度面部畸形，包括高腭弓、内眦赘皮及下斜型睑裂；同时存在蓝色巩膜，听力正常。X线检查提示重度脊柱侧凸及骨质减少，超声心动图检查结果正常。实验室检查示骨转换标志物轻度升高。结合患儿的临床表现，临床怀疑为kEDS。基因检测发现PLOD1基因存在1个新的纯合错义突变（c.1697 G>A, p.C566Y）（NM_000302.4），据此确诊为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：经Polyphen-2预测得分为0.999，判定为"PROBABLY DAMAGING"；经SIFT预测得分为0.00，判定为"AFFECT PROTEIN FUNCTION"；经Mutation Taster判定为"disease causing"。