CS manifests early in life, is characterized by rigidity and rapid progression, and often necessitates surgical intervention [1]. CS is caused by both genetic and environmental factors [5]. The current genetic pathogenic framework explains only approximately 20% of CS cases, and half of these cases are explained by the TBX6 gene, making TBX6 the most significant genetic etiology [8]. A previous study revealed that common clinical features of TACS include vertebral formation failure (e.g., hemivertebrae or butterfly vertebrae), deformities in the lower spine (T8-S1), the involvement of fewer segments, ribs with normal shapes or only slight deformities, and a lower incidence of intraspinal malformations [9]. Based on this specific clinical phenotype, we speculated that certain surgical outcomes may prove more favorable for TACS patients than for other CS patients. The objective of this study was to investigate the long-term surgical outcomes of TACS patients by using a strict matching method. We found that TACS patients had superior outcomes compared with their NTACS counterparts. These findings highlight the potential for clinical translational application of genetic research achievements in the field of CS.

Wu et al. [8] first showed that the new compound genetic mechanism (rare CNV + common SNP) of the TBX6 gene accounted for 10.6% (17/161) of CS cases. Liu et al. [9] further verified this novel pathogenic model in three different races. In this study, 473 patients with CS who underwent genetic testing were included. Among these 473 CS patients, 48 patients with 16p11.2 duplication deletion and TBX6 nonsense mutations were identified (10.1%), consistent with the proportion reported in previous studies. Overall, 28 TACS patients were successfully matched. As Table 1 shown, the 16p11.2 deletion CNV was identified and verified in 21 patients, whereas the other 7 patients presented with TBX6 segmental alleles (frameshift mutation, stop-gain or splice region variations). The TBX6 risk haplotype of T-C-A (SNPs rs2289292, rs3809624, and rs3809627) was observed in all 28 patients, consistent with previous findings on the compound inheritance of TACS [8, 9, 14].

The rigorous 1:1 propensity score case matching procedure accounted for factors such as age, sex, main curve angle, CS clinical classification, segment of the deformity and the presence of intraspinal malformation in line with the specific clinical phenotype of TACS, as summarized in previous studies [9]. Furthermore, to reduce the impact of differences in surgical aspects, we also compared surgical parameters, including surgical method, fused segments, and number of fused segments, between the two groups. As shown in Table 2, there were no significant differences in preoperative matching parameters between the TACS and NTACS groups; in other words, these stringent matching parameters helped to minimize variation in preoperative and surgical conditions and improve the comparability of the two groups. Importantly, this process greatly mitigated the effects of confounding variables and enhanced the validity and robustness of our findings.

Compared with other types of spinal deformities, CS tends to have early onset and rapid progression. In severe cases, it can even cause progressive pulmonary dysfunction and neurological damage. Surgery is still the most common treatment method for CS [2]. In this series, all patients achieved satisfying sagittal balance and no difference between the two groups after surgery and at the last follow-up. This is similar with previous studies [15, 16] and reveals that posterior hemivertebra resection and segment fusion surgery is reliable and effective for CS. This study compared surgical outcomes after surgery and at the last follow-up. The correction rates of the main curve (76.0 ± 9.6% vs. 68.2 ± 21.1%), compensatory cranial curve (64.9 ± 18.6% vs. 51.2 ± 24.0%) and compensatory caudal curve (77.4 ± 12.5% vs. 65.4 ± 22.7%) were significantly higher in the TACS group than in the NTACS group. Moreover, the incidences of total complications (7.2% vs. 14.3%) and the adding-on phenomenon (0 vs. 7.1%) were lower in the TACS group than in the NTACS group. These results revealed that surgical outcomes were better in the TACS group than in the NTACS group. Figure 2 shows such a pair of typical matched cases. Both patients were 3-year-old male patients with a matching main curve, segmental kyphosis, normal ribs, no obvious intraspinal deformity, and hemivertebra in the thoracolumbar region who underwent hemivertebra resection and short-segment fixation. The top portion of the figure shows the TACS patient, and the postoperative(c, d) and 48-month follow-up (e, f) images indicate that the correction and balance were satisfactory. The lower portion of the figure shows an NTACS patient, and the postoperative (j, k) correction performed well; however, at the 50-month follow-up (l, m), he suffered from the distal adding-on phenomenon, thus showing worse surgical outcomes than the matching TACS patient.

The above part (a–f) of this figure refers to a 3-year-old male TACS patient. Genetic testing showed that 16p11.2 was deleted in combination with the TCA hypomorphic allele. (a–b) show a main curve of L1 butterfly vertebrae, L2 left segmented hemivertebrae, normal ribs, and no obvious intraspinal deformity. He underwent posterior L2 hemivertebral resection, short-segment fixation, and bone graft fusion (L1-3). The postoperative (c, d) and 48-month final follow-up (e, f) images showed that the correction and trunk balance were satisfactory. The lower part (g–m) of this figure refers to the matching NTACS patient. This was a 3-year-old male with a main curve of completely segmented T12/L1 hemivertebrae, normal ribs and no intraspinal deformity (g, i). He received posterior T12/L1 hemivertebra resection, short-segment fixation, and bone graft fusion (T11-L2). The immediate postoperative correction was good (j, k). However, at the 50-month final follow-up, the LIV moved to the distal end of the fused segment, and the adding-on phenomenon occurred (l, m)

We suggest that genetic pathologies underlie the poorer surgical outcomes in the NTACS group compared with the TACS group. We explored the biological processes associated with CS by searching the Gene Ontology database and discovered that the modulation of paravertebral tissues represented prominent pathways among the CS pathogenic genes. On the one hand, the TBX6 gene plays a major role in paraxial mesoderm differentiation and somite segmentation in early embryonic development [17, 18]. TBX6 can activate the transcription of Mesp2 and Ripply2 [19, 20], which promotes the development of somites and vertebral bodies [21]. The TBX6 gene is relatively ‘pure’ and is mainly involved in the formation of vertebral bodies rather than other paravertebral tissues, consistent with the relatively mild clinical phenotype of TACS. On the other hand, the current genetic pathogenic framework explains only approximately 20% of CS cases; NTACS patients have a complex and unclear pathogenesis that may affect both spine and paravertebral tissue development of cartilage, muscles and ligaments and other soft tissues, which will negatively affect surgical outcomes. For example, there are many subtypes of the human MYH gene, which encodes the basic unit of the myosin-myosin heavy chain (MyHC). The MYH gene plays an important role in ensuring normal muscle cell function, and a previous study reported associations between the MYH gene and pathological changes in the development and function of paraspinal muscles and CS [22]. Therefore, the TACS patients had better surgical outcomes than did the matched NTACS patients.

Diseases caused by gene mutations often have corresponding specific clinical manifestations, and a clear genetic diagnosis can guide clinical treatment. Clarifying the relationship between genotype and clinical outcomes is important for the treatment of CS. This study helps clarify and strengthen this relationship because it is the first to use a strict matching method to evaluate the long-term prognosis of a specific population of TACS patients in whom the TBX6 gene mutation is the clear cause. The current study revealed that genetic diagnosis of the TBX6 gene mutation in CS before surgery can help predict better surgical outcomes. This study is also the first to investigate the clinical translation of genetic research findings to CS surgical interventions. However, broader studies involving larger cohorts are required to fully elucidate the underlying mechanisms.