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.

kyphoscoliotic Ehlers-Danlos syndrome (kEDS)，又称埃勒斯-当洛斯综合症（kEDS），是一种罕见的常染色体隐性结缔组织疾病，其特征为进行性胸椎后凸畸形、先天性肌张力低下、显著关节过度活动性和严重皮肤过度伸展性和脆弱性。由于 PLOD1（前胶原蛋白赖氨酸，2-酮戊二酸5-脱氢酶1）基因突变导致的赖氨酸羟化酶1（LH1）缺乏已被确认为 kEDS 的致病原因（kEDS-PLOD1）。迄今为止，kEDS-PLOD1 在中国人群中尚未有报道。我们报道了一名17岁的中国男性患者，表现为肌张力低下、关节过度活动性和脊柱侧弯，被转诊至我院。出生后，他被发现存在严重的肌张力低下，导致运动发育迟缓。随后，发现了关节过度活动性、胸椎后凸畸形和弱视。5岁时发现腹股沟疝，经手术闭合。同时，他出现了轻微创伤后过度伸展且有瘀斑的细腻皮肤和扩张的萎缩性瘢痕。6岁时出现肘关节脱位。10岁时进行了胸椎后凸畸形矫正的骨科手术。他的家族史无特殊。体格检查发现血压升高。轻微的面部畸形，包括高穹窿、内眦皱褶和下斜的睑裂。他还伴有蓝巩膜和正常的听力。X光检查显示严重的脊柱侧弯和骨质疏松。超声心动图检查结果正常。实验室检查发现轻微升高的骨转换。根据我们的患者所呈现的临床表现，疑似诊断为 kEDS。遗传分析揭示了一个新的PLOD1同义突变（c.1697 G>A, p.C566Y）（NM_000302.4），确证了kEDS-PLOD1的诊断。在其父母中检测到了相应的杂合突变。这一变异可能为kEDS的致病因素，因为Polyphen-2预测其可能为“PROBABLY DAMAGING”，得分为0.999，SIFT预测其可能为“影响蛋白质功能”，得分为0.00，Mutation Taster预测其为“致病突变”。