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BackgroundKlippel-Feil syndrome (KFS) represents a rare anomaly characterized by congenital fusion of the cervical vertebrae. The underlying molecular etiology remains largely unknown because of the genetic and phenotypic heterogeneity.MethodsWe consecutively recruited a Chinese cohort of 37 patients with KFS. The clinical manifestations and radiological assessments were analyzed and whole-exome sequencing (WES) was performed. Additionally, rare variants in KFS cases and controls were compared using genetic burden analysis.ResultsWe primarily examined rare variants in five reported genes (GDF6,MEOX1, GDF3, MYO18BandRIPPLY2) associated with KFS and detected three variants of uncertain significance inMYO18B. Based on rare variant burden analysis of 96 candidate genes related to vertebral segmentation defects, we identifiedBAZ1Bas having the highest probability of association with KFS, followed byFREM2,SUFU,VANGL1andKMT2D. In addition, seven patients were proposed to show potential oligogenic inheritance involving more than one variants in candidate genes, the frequency of which was significantly higher than that in the in-house controls.ConclusionsOur study presents an exome-sequenced cohort and identifies five novel genes potentially associated with KFS, extending the spectrum of known mutations contributing to this syndrome. Furthermore, the genetic burden analysis provides further evidence for potential oligogenic inheritance of KFS.

Background There have been many reports on the treatment of congenital kyphoscoliosis. However, congenital deformities in the cervicothoracic spine (C7-T1) have not been well described because of the rarity of these conditions. Methods The medical records and imaging studies of 25 children who were treated with 360° osteotomy for congenital deformities in the cervicothoracic spine (C7-T1) at a mean age of 11.4 years were reviewed. Results All 25 children presented with torticollis; 4 presented with neck pain; 10, with facial asymmetry; and 3, with preoperative neurological deficits. Twenty-three patients had congenital deformities in other regions of the spine. Six patients had a total of 8 intraspinal deformities. On average, the cervicothoracic curve was corrected from 53° preoperatively to 14° at the latest follow-up, the segmental kyphosis was corrected from 25° to 12°, and the head tilt improved from 25° to 5°. Nineteen patients had a total of 28 complications, including 1 transient cord injury together with a permanent C8 nerve root injury, 11 transient nerve root injuries, 1 transient Horner syndrome, 9 cases of decompensation of a compensatory curve, 2 implant failures, 2 cases of hemothorax, 1 dural tear, and 1 case of delayed wound-healing. Conclusions Most congenital cervicothoracic deformities are fixed, and early surgical intervention may be needed. A 360° osteotomy is indicated for this type of rigid deformity and may provide satisfactory correction. However, 360° osteotomy in the cervicothoracic spine (C7-T1) is technically demanding with a higher risk of nerve root injuries, although most injuries tend to be transient. If the compensatory thoracic curve is severe and rigid, 1-stage or staged surgery in this region may be required. Level of evidence Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Background Klippel-Feil syndrome (KFS) represents the rare and complex deformity characterized by congenital defects in the formation or segmentation of the cervical vertebrae. There is a wide gap in understanding the detailed mechanisms of KFS because of its rarity, heterogeneity, small pedigrees, and the broad spectrum of anomalies. Methods We recruited eight patients of Chinese Han ethnicity with KFS, five patients with congenital scoliosis (CS) who presented with congenital fusion of the thoracic or lumbar spine and without known syndrome or cervical deformity, and seven healthy controls. Proteomic analysis by data-independent acquisition (DIA) was performed to identify the differential proteome among the three matched groups and the data were analyzed by bioinformatics tools including Gene Ontology (GO) categories and Ingenuity Pathway Analysis (IPA) database, to explore differentially abundant proteins (DAPs) and canonical pathways involved in the pathogenesis of KFS. Results A total of 49 DAPs were detected between KFS patients and the controls, and moreover, 192 DAPs were identified between patients with KFS and patients with CS. Fifteen DAPs that were common in both comparisons were considered as candidate biomarkers for KFS, including membrane primary amine oxidase, noelin, galectin-3-binding protein, cadherin-5, glyceraldehyde-3-phosphate dehydrogenase, peroxiredoxin-1, CD109 antigen, and eight immunoglobulins. Furthermore, the same significant canonical pathways of LXR/RXR activation and FXR/RXR activation were observed in both comparisons. Seven of DAPs were apolipoproteins related to these pathways that are involved in lipid metabolism. Conclusions This study provides the first proteomic profile for understanding the pathogenesis and identifying predictive biomarkers of KFS. We detected 15 DAPs that were common in both comparisons as candidate predictive biomarkers of KFS. The lipid metabolism-related canonical pathways of LXR/RXR and FXR/RXR activation together with seven differentially abundant apolipoproteins may play significant roles in the etiology of KFS and provide possible pathogenesis correlation between KFS and CS.