背景

先天性脊柱侧凸（congenital scoliosis, CS）是胚胎早期由于体节形成过程异常导致的脊椎畸形。CS特点为发病早且进展快，畸形较重且并发症较多，手术治疗为主要治疗方式。CS患者常常还伴发先天性心脏病、泌尿系及消化道畸形等多种先天发育障碍，给治疗带来了困难。国际上已有相关研究就CS的自然史及治疗进行报道，但目前尚缺乏对汉族人群CS伴发畸形的临床特点及手术治疗的效果和趋势的大样本研究以阐明CS伴发畸形的临床特点及手术治疗的效果和趋势，因而总结汉族人群CS大样本队列并对其临床特征及手术治疗进行全面系统的研究和分析有重大意义。

CS病因复杂，具体发病机制不明。目前学界普遍认同CS是遗传及环境因素导致的多因素疾病。既往研究揭示了TBX6罕见无效突变联合常见亚效等位基因共同致病的全新遗传模式，并在多中心、多人种队列中得到验证，可以解释世界范围内约10%的散发CS患者病因。这类CS被称为TBX6相关性先天性脊柱侧凸（TBX6-associated congenital scoliosis, TACS）。TACS患者具有一些相似的临床特征：CS分型大多为形成不良型（半椎体或蝴蝶椎），畸形位置大多为脊柱下段,畸形累及节段较少，肋骨发育正常或仅有轻微畸形，合并髓内畸形发生率较低；有研究还通过基因组-表型关联分析，建立了TACScore预测系统来评估临床TACS的患病风险。然而，既往研究集中于报道TACS患者的临床表型特征，尚未有相关文献报道TACS患者的手术治疗效果，因此评估TACS的手术预后，进而探索TBX6相关遗传学研究成果对CS的临床转化应用有其重要意义。

目的

第一部分：报道迄今中国人群最大先天性脊柱侧凸队列伴发畸形的发生率，并分析先天性脊柱侧凸分型及其伴发畸形间的相互关系。

第二部分：分析近十年单中心大型先天性脊柱侧凸队列手术治疗的变化趋势，探索恰当的、可推广的CS手术策略。

第三部分：首次评估TBX6相关性先天性脊柱侧凸患者的手术预后特征，探索基因研究成果的临床转化应用。

方法

第一部分：回顾并提取了2010年1月至2019年12月在我院接受住院治疗的1289名CS患者的病历资料，记录并统计各个患者全脊柱X线、CT、MRI、超声心动图、腹部超声、泌尿系超声检查和全身体格检查的结果，分析人口信息学、CS分型、畸形累及部位和伴发畸形之间的关系。

第二部分：回顾2010年1月至2019年12月在我院接受手术治疗的1207名CS患者的病历，收集其人口信息学和手术相关结果，描述融合手术年龄、融合节段数量、截骨和钛笼的使用率、住院时间（LOS）、术中失血（EBL）、并发症及再入院率随时间的变化趋势，分析手术年龄和融合节段及住院费用的关系。

第三部分：对2017年至2019年就诊于我院的473例汉族散发CS患者的外周血DNA样本进行遗传检测，共筛选出48例TACS患者。按性别、年龄、主弯度数、CS分型、畸形节段、术式、融合节段和数量等进行倾向性匹配，共28对患者成功配对。对术前、术后和末次随访时评估冠、矢状面影像参数和手术信息（术式、融合节段、出血量、并发症等）进行测量并比较分析

结果

第一部分：共纳入1289例CS患者，其中633例（49.1%）为形成不良型，251例（19.5%）为分节不良型，405例（31.4%）为混合型。相较于形成不良型，在分节不良和混合型CS患者中伴发椎管内畸形（16.0%：FS 45.4%：MD 40.5%）和肌肉骨骼畸形（10.3%：19.9%：23.7%）的发生比例较高。最常见的伴发畸形是椎管内畸形，占379例（29.4%），接着为心血管系统畸形177例（13.7%），泌尿生殖系统畸形75例（5.8%），胃肠道畸形46例（3.6%），骨骼系统畸形211例（16.4%）。在CS椎体畸形的累及节段上，颈椎和胸椎累及患者伴发椎管内和肌肉骨骼畸形的发生率高于腰椎累及患者（伴发椎管内畸形占比分别为33.8%：33.4%：20.7%；肌肉骨骼畸形为28.4%：19.1%：9.0%）。心脏、泌尿生殖系统和胃肠道缺陷之间有很强的相关系，椎管内畸形和肌肉骨骼畸形之间也存在显著相关性。

第二部分：该研究纳入了2010年至2019年在我院接受单纯后路融合手术的1207例CS患者。在过去的十年中，年龄小于5岁的患者比例从15.5％增加到了25％以上。平均融合节段从9.24±4.29减少到7.48±4.02，使用短节段融合治疗的患者比例从13.4％增加到30.3％。截骨和钛笼植入的患者比例分别从55.65％和12％分别增加到76.5％和40％以上。平均住院时间和平均失血从16.5±5.6天和801.1±663.9ml分别降至13.5±4.1天和510.1±472.3ml。在这十年中，并发症和再入院率也有所下降。融合年龄与长节段融合（OR=1.213；P<0.001）及较高医疗费用（OR=1.091；P<0.001）呈明显正相关关系。

第三部分：匹配的TACS组和NTACS组的术前参数：性别、年龄、CS分型、畸形节段、术式、主弯度数、头侧代偿弯、尾侧代偿弯、胸后凸、胸腰段后凸、腰前凸、冠状面平衡、矢状面平衡、融合节段和数量等参数结果相似(P＞0.05）。TACS组的头侧代偿弯矫形率（63.0±18.8% vs. 51.2±24.0%，P=0.046）、尾侧代偿弯矫形率（76.2±11.6% vs. 65.0±24.1%，P=0.031）均显著高于NTACS组，且TACS组的头侧代偿弯矫形丢失率（4.7±19.2% vs. 28.8±50.8，P=0.023）显著低于NTACS组。TACS组总并发症发生率（7.2% vs. 14.3%）、总矫形丢失相关发生率（3.6% vs. 10.7%）和附加现象发生率（0 vs. 7.1%）低于NTACS组。但两组在出血量、翻修情况、随访时长、平衡参数（冠状面平衡、矢状面平衡、胸后凸、胸腰段后凸、腰前凸）及并发症等方面无显著统计学差异。

结论

第一部分：椎管内和肌肉骨骼畸形的发生率在分节不良和混合型CS患者中比例较高。椎管内和肌肉骨骼畸形之间以及心血管、泌尿生殖系统和胃肠道畸形间有很强的相关性。女性、畸形累及颈段、分节不良和混合型CS可能是CS患者伴发更多其他系统畸形的危险因素。

第二部分：在过去十年期间，我院CS手术治疗显示出融合手术年龄趋于年轻、融合节段数量减少、截骨手术和钛笼植入率更高、失血量减少、住院时间缩短和并发症发生率和再入院率减少的趋势。在较早的年龄进行截骨短节段手术可以实现良好的矫形效果、减少融合节段、医疗费用和并发症，这是CS治疗经济、安全、有效的手术策略。

第三部分：尽管人口信息学和部分脊柱侧凸参数及手术参数相匹配，但与NTACS患者相比，TACS患者术后代偿弯的矫形率更高，矫形丢失率和并发症发生率更低，而在其他矫形参数及平衡参数方面两组间没有显著统计学差异。

Background

Congenital scoliosis (CS) is the developmental deformity of vertebrae caused by abnormal somitogenesis in the early stage of embryo development. CS features early onset, rapid progression, severe deformity and more comorbidities and needs to be surgically treated. Many patients with CS have associated anomalies of cardiac, urogenital and gastrointestinal systems, which lead to more challenging surgeries for surgeons, and higher economic and mental burden for patients and their families. However, there is still a lack of large-sample studies on the Han population to clarify the clinical characteristics of CS associated anomalies and the effects and trends of surgical treatment. Therefore, we believe that comprehensive and systematic analysis of the large-sample CS cohort in the Han population and its clinical features and surgical treatment is of great significance.

The etiology of CS is complex, and the specific pathogenic mechanism is unknown. At present, most scholars believe that CS is a complex disease that combines genetic and environmental factors. Previous studies have revealed a new genetic model caused by the combination of rare null mutations in TBX6 and common hypomorphic alleles, and it has been verified in a multi-center and multi-ethnic cohort, explaining about 10% of the causes of sporadic CS patients worldwide. This type of CS is called TBX6-associated congenital scoliosis (TBX6-associated congenital scoliosis, TACS). TACS patients have certain common clinical features: most TACS patients have failure of formation (hemivertebrae or butterfly vertebrae), the deformities located in the lower spine and involved fewer segments, and ribs with normal form or minor deformities. The incidence of intramedullary malformations is low in TACS patients; some studies have also established a TACScore prediction system through genome-phenotype association analysis to assess the risk of clinical TACS. However, previous studies focused on reporting the clinical phenotypic characteristics of TACS patients, and there is no relevant literature that reports the prognosis of surgical treatment of TACS patients. Therefore, to evaluate the effect of surgical treatment of TACS, and to explore the results of TBX6 related genetic research have important meanings for clinical translation.

Purposes

First part: To report associated anomaly incidences of the largest Chinese CS cohort and analyze interrelationships among vertebral anomaly types and associated abnormalities.

Second part: To report and analyze the changes in CS surgical treatment of a large CS cohort during recent 10 years in a single center.

Third part: To evaluate the prognostic characteristics of patients with TBX6-related CS for the first time, and to explore the clinical application of genetic research results.

Methods

First part: We retrospectively searched and extracted medical records of 1,289 CS inpatients surgically treated in our institute from January 2010 - December 2019. All patients have taken spine X-ray, CT, MRI, echocardiogram, urogenital ultrasound and systemic physical examination. We analyzed information on demographics, CS types and associated anomalies.

Second part: We retrospectively searched and extracted medical records of 1,207 CS inpatients surgically treated in our institute from January 2010 - December 2019.Patients who did not undertake posterior instrumented fusion surgeries were excluded. We compiled and analyzed information on demographics and extracted surgical information included surgery approach, fusion segments, osteotomy methods, titanium cage appliance, length of stay, blood loss during surgery, complication and readmission details.

Third part: We performed genetic tests on the peripheral blood DNA samples of 473 cases of CS patients of Han nationality in our hospital from January 2017 to December 2019. A total of 48 cases of TBX6-associated congenital scoliosis were enrolled. With the method of propensity score matching, twenty-eight TACS patients were enrolled, and were matched with 28 NTACS patients according to gender, age, main curvature, CS classification, deformity segment, surgical procedure, fusion segment and number. All patients underwent posterior-only osteotomy and fusion. We also evaluated the coronal and sagittal X-ray parameters and surgical information (surgical method, fusion segment, blood loss, complications, etc.) before surgery, immediately after surgery, and at the final follow-up. The results of the assessment were compared and analyzed, and the prognostic characteristics of TACS were summarized.

Results

First part:  CS type was found to be 49.1% for failure of formation (FF), 19.5% for failure of segmentation (FS) and 31.4% for mixed defects (MD). Intraspinal defects were found in 29.4% patients (16.0% for FF, 45.4% for FS, 40.5% for MD), cardiac in 13.7% (12.3% for FF, 14.3% for FS, 15.6% for MD), genitourinary in 5.8% (4.1% for FF, 6.0% for FS, 8.4% for MD), gastrointestinal in 3.6% (4.7% for FF, 1.6% for FS, 3.0% for MD) and musculoskeletal in 16.4% (10.3% for FF, 19.9% for FS, 23.7% for MD) . The intraspinal and musculoskeletal defect incidences were significantly higher in patients with failure of segmentation and mixed defects. We also observed a decreasing trend for intraspinal and musculoskeletal defect incidences as well as a tendency for more failure of formation and less failure of segmentation from 2010-2019.

Second part: 1,207 inpatients were included in this study from 2010 to 2019. In the past decade, patients younger than 5 years old increased from 15.5% to more than 25%; The average fusion segments decreased from 9.24±4.29 segments to 7.48±4.02 segments and proportion of short-segment fusion increased from 13.4% to 30.3%; Osteotomy and titanium cage ratios increased from 55.65% and 12% to 76.5% and more than 40%, respectively; The average length of stay and average blood loss decreased from 16.5±5.6 days and 801.1±663.9ml to 13.5±4.1 days and 510.1±472.3ml. Complication and readmission rates also decreased during these ten years.

Third part: Preoperative parameters like Gender, age, CS classification, deformity segment, surgical method, main curvature, cranial compensatory curve, caudal compensatory curve, thoracic kyphosis, thoracolumbar kyphosis, lumbar lordosis, coronal plane balance, sagittal plane balance, fusion segment and number of matched pairs between TACS group and NTACS group were similar. In the TACS group, the correction rate of cranial compensatory curve (63.0±18.8% vs. 51.2±24.0%, P=0.046) and the correction rate of caudal compensatory curve (76.2±11.6% vs. 65.0±24.1%, P=0.031) were significantly higher than the NTACS group, and the loss of correction of cranial compensatory curve in the TACS group (4.7±19.2% vs. 28.8±50.8, P=0.023) was significantly lower than the NTACS group. The total complication rate (7.2% vs. 14.3%), total loss of correction incidence (3.6% vs.10.7%) and the incidence of adding-on (0 vs. 7.1%) in the TACS group were lower than those in the NTACS group. However, there were no significant differences between the two groups in terms of blood loss, revision, other correction parameters, balance parameters (coronal balance, sagittal balance, thoracic kyphosis, thoracolumbar kyphosis, lumbar lordosis) and the incidence of complications.

Conclusions

First part: The intraspinal and musculoskeletal defect incidences were higher in patients with failure of segmentation and mixed defects. Strong interrelationships were found between intraspinal and musculoskeletal defects and among cardiovascular, genitourinary and gastrointestinal defects. From 2010-2019, the proportion of patients with failure of formation increased significantly, causing a decrease in the intraspinal and musculoskeletal defect incidences over time. Female sex, failure of segmentation and mixed defects could be considered risk factors for more associated anomalies in CS individuals, which would help surgeons in medical management and prenatal consultation.

Second part: This study found that during recent ten years, the trends of CS surgical treatment in our institute included younger fusion age, shorter fusion segments, more osteotomies and titanium cages, less blood loss, shorter length of stay and lower rates of complications and readmissions. Our results suggested osteotomies at an earlier age can achieve good correction, shorter fusion, less medical cost with less complications, which suggest to be an economic, safe and effective surgical strategy.

Third part: Although demographics, some scoliosis parameters and surgical parameters are similar, compared with NTACS patients, TACS patients have a higher postoperative correction rate of compensatory curves, less correction loss and a lower incidence of complications. There were no significant differences between the two groups in terms of correction parameters and balance parameters.