Correlation Of The Phenotypic And Genotypic Characteristics Of Congenital Scoliosis And Surgical Treatment

Background:Our previous work elucidated a TBX6 compound inheritance model comprising one rare null mutation,often a deletion of 16p11.2 or nonsense mutation,in combination with one in trans hypomorphic risk allele.This specific genetic model accounts for approximately 7.9%-10.6%of CS in the Chinese population.The hypomorphic risk allele is a common TBX6 noncoding haplotype of 'T-C-A' defined by the co-occurrence of three common SNPs,namely,rs2289292,rs3809624 and rs3 809627.We defined congenital scoliosis caused by this TBX6 compound inheritance as TBX6-associated Congenital Scoliosis(TACS).We noticed that all TACS patients presented with one or more hemivertebrae or butterfly vertebrae and exhibited vertebral malformations involving the lower part of the spine(T8-S5).Simple rib anomalies were prevalent in the TACS patients,while intraspinal anomalies were uncommon.Literatures about Sacral Slanting in congenital scoliosis were rare despite of its high incidence.Great challenge remains in restoring coronal balance after hemivertebra resection with short fusion in cases with Sacral Slanting.Objects:First part:We aim to verify the relationship between the specific genetic model and its clinical characteristics.Second part:To clarify the definition,etiology and surgical strategy of Sacral Slanting.MethodsFirst part:We conducted genetic analyses in 108 sporadic CS patients in Chinese population using realtime-quantitative PCR,and DNA sequencing.Phenotypes were compared between the TBX6-associated CS and non-TBX6-associated CS.Second part:From July 2004 to December 2014,patients with early-onset congenital scoliosis were reviewed.Posterior hemivertebra resection with short fusion was performed.Coronal and sagittal parameters,as well as Sacral Slanted Angle and UIV-Pelvis Angle,were measured and calculated.Sacral Slanting was defined as the angle of more than 5° and severe Sacral Slanting was thought to be more than 10°.Statistical analyses were performed.ResultsFirst part:10 heterozygous TBX6 null mutations were identified in 108 sporadic CS,including copy-number variants(nine 16p11.2/TBX6 deletions)and single-nucleotide variants(one nonsense mutations).We identified a commonTBX6 haplotype as the second risk allele,which was shared by all 10 carriers of TBX6 null mutations.Notably,hemivertebra or butterfly vertebra,and less neutral tube deformity involved are the common clinical subtype of TBX6-associated CS.Second part:72 patients with congenital scoliosis were identified.It included 42 early-onset patients with lumbar hemivertebrae.The mean age was 4.0 years old with an average follow-up of 51.7 months.The mean segmental curve was corrected from 34.9° to 4.7°,and 8.7° at final follow-up.Trunk shift was 15.4mm preoperatively,16.9mm after surgery and 12.1mm at final follow-up.Sacral slanted angle was measured as 7.2° before surgery.It could be noticed in 26 patients with an incidence of 61.9%.Patients with hemivertebrae at or below L3 had higher incidence of Sacral Slanting than those with hemivertebrae above L3.Severe Sacral Slanting was noted in 11 patients with an incidence of 26.2%.Postoperative UIV-Pelvis Angle was 3.9°.Postoperative UIVT was correlated positively with postoperative TS.Two independent risk factors were identified for postoperative proximal adding-on:larger postoperative Sacral Slanted Angle and larger postoperative UIV-Pelvis Angle.ConclusionsTBX6-associated congenital scoliosis has its unique characteristics in clinical phenotype such as more simple deformity,less involved segments and less rib or intraspinal anomalies.These charateristics can provide great guidance for genetic consulting,prenatal diagnosis and optimzing clinical managements.Attentions must be paid to Sacral Slanting for its high incidence.The etiology may be congenital malformation.Segmental undercorrection and placing a more central and even UIV was a wise strategy for congenital EOS with severe Sacral Slanting.