Recapitulating the human segmentation clock with pluripotent stem cells.

Pluripotent stem cells are increasingly used to model different aspects of embryogenesis and organ formation1. Despite recent advances in in vitro induction of major mesodermal lineages and cell types2,3, experimental model systems that can recapitulate more complex features of human mesoderm development and patterning are largely missing. Here we used induced pluripotent stem cells for the stepwise in vitro induction of presomitic mesoderm and its derivatives to model distinct aspects of human somitogenesis. We focused initially on modelling the human segmentation clock, a major biological concept believed to underlie the rhythmic and controlled emergence of somites, which give rise to the segmental pattern of the vertebrate axial skeleton. We observed oscillatory expression of core segmentation clock genes, including HES7 and DKK1, determined the period of the human segmentation clock to be around five hours, and demonstrated the presence of dynamic travelling-wave-like gene expression in in vitro-induced human presomitic mesoderm. Furthermore, we identified and compared oscillatory genes in human and mouse presomitic mesoderm derived from pluripotent stem cells, which revealed species-specific and shared molecular components and pathways associated with the putative mouse and human segmentation clocks. Using CRISPR-Cas9-based genome editing technology, we then targeted genes for which mutations in patients with segmentation defects of the vertebrae, such as spondylocostal dysostosis, have been reported (HES7, LFNG, DLL3 and MESP2). Subsequent analysis of patient-like and patient-derived induced pluripotent stem cells revealed gene-specific alterations in oscillation, synchronization or differentiation properties. Our findings provide insights into the human segmentation clock as well as diseases associated with human axial skeletogenesis.

Instrumentation failure following pediatric spine deformity growth-sparing surgery using traditional growing rods or vertical expandable prosthetic titanium ribs.

BACKGROUND: Instrumentation failure (IF) is a major complication associated with growth-sparing surgery for pediatric spinal deformities; however, studies focusing on IF following each surgical procedure are lacking. We aimed to evaluate the incidence, timing, and rates of unplanned return to the operating room (UPROR) associated with IF following each surgical procedure in growth-sparing surgeries using traditional growing rods (TGRs) and vertical expandable prosthetic titanium ribs (VEPTRs). METHODS: We reviewed 1,139 surgical procedures documented in a Japanese multicenter database from 2015 to 2017. Of these, 544 TGR and 455 VEPTR procedures were included for evaluation on a per-surgery basis. IF was defined as the occurrence of an implant-related complication requiring revision surgery. RESULTS: The surgery-based incidences of IF requiring revision surgery in the TGR and VEPTR groups were 4.3% and 4.0%, respectively, with no significant intergroup difference. Remarkably, there was a negative correlation between IF incidence per surgical procedure and the number of lengthening surgeries in both groups. In addition, rod breakage in the TGR group and anchor-related complications in the VEPTR group tended to occur relatively early in the treatment course. The surgery-based rates of UPROR due to IF in the TGR and VEPTR groups were 2.0% and 1.5%, respectively, showing no statistically significant difference. CONCLUSIONS: We found that IF, such as anchor related-complications and rod breakage, occurs more frequently earlier in the course of lengthening surgeries. This finding may help in patient counseling and highlights the importance of close postoperative follow-up to detect IF and improve outcomes.

Relationship between lumbosacral transitional vertebra and postoperative outcomes of patients with Lenke 5C adolescent idiopathic scoliosis: a minimum 5-year follow-up study.

PURPOSE: To assess the incidence of lumbosacral transitional vertebra (LSTV) in Lenke 5C adolescent idiopathic scoliosis (AIS) and evaluate the relationship between postoperative outcomes and LSTV when the lowest instrumented vertebra (LIV) is fixed at L3. METHODS: The study included 61 patients with Lenke 5C AIS who underwent fusion surgery of L3 as the LIV who were followed-up for a minimum of 5 years. Patients were divided into two groups: LSTV + and LSTV-. Demographic, surgical, and radiographic data, including L4 tilt and thoracolumbar/lumbar (TL/L) Cobb angle, were obtained and analyzed. RESULTS: LSTV was observed in 15 patients (24.5%). The L4 tilt was not significantly different between the two groups preoperatively (P = 0.54); however, it was significantly greater in the LSTV group postoperatively (2 weeks: LSTV + = 11.7 ± 3.1, LSTV - = 8.8 ± 3.2, P = 0.013; 2 years: LSTV + = 11.5 ± 3.5, LSTV - = 7.9 ± 4.1, P = 0.006; 5 years: LSTV + = 9.8 ± 3.1, LSTV - = 7.3 ± 4.5, P= 0.042). The postoperative TL/L curve was greater in the LSTV + group, with significant differences at 2 weeks and 2 years postoperatively (preoperative: LSTV + = 53.5 ± 11.2, LSTV - = 51.7 ± 10.3,P = 0.675; 2 weeks: LSTV + = 16.1 ± 5.0, LSTV- = 12.2 ± 6.6, P = 0.027; 2 years: LSTV + = 21.7 ± 5.9, LSTV - = 17.6 ± 5.9, P = 0.035; 5 years: LSTV + = 18.7 ± 5.8, LSTV - = 17.0 ± 6.1, P = 0.205). CONCLUSION: The prevalence of LSTV in Lenke 5C AIS patients was 24.5%. Lenke 5C AIS patients with LSTV with the LIV at L3 had a significantly greater postoperative L4 tilt than those without LSTV and retained the TL/L curve.

Conditional inactivation of the L-type amino acid transporter LAT1 in chondrocytes models idiopathic scoliosis in mice.

Scoliosis, usually diagnosed in childhood and early adolescence, is an abnormal lateral curvature of the spine. L-type amino acid transporter 1 (LAT1), encoded by solute carrier transporter 7a5 (Slc7a5), plays a crucial role in amino acid sensing and signaling in specific cell types. We previously demonstrated the pivotal role of LAT1 on bone homeostasis in mice, and the expression of LAT1/SLC7A5 in vertebral cartilage of pediatric scoliosis patients; however, its role in chondrocytes on spinal homeostasis and implications regarding the underlying mechanisms during the onset and progression of scoliosis, remain unknown. Here, we identified LAT1 in mouse chondrocytes as an important regulator of postnatal spinal homeostasis. Conditional inactivation of LAT1 in chondrocytes resulted in a postnatal-onset severe thoracic scoliosis at the early adolescent stage with normal embryonic spinal development. Histological analyses revealed that Slc7a5 deletion in chondrocytes led to general disorganization of chondrocytes in the vertebral growth plate, along with an increase in apoptosis and a decrease in cell proliferation. Furthermore, loss of Slc7a5 in chondrocytes activated the general amino acid control (GAAC) pathway but inactivated the mechanistic target of rapamycin complex 1 (mTORC1) pathway in the vertebrae. The spinal deformity in Slc7a5-deficient mice was corrected by genetic inactivation of the GAAC pathway, but not by genetic activation of the mTORC1 pathway. These findings suggest that the LAT1-GAAC pathway in chondrocytes plays a critical role in the maintenance of proper spinal homeostasis by modulating cell proliferation and survivability.

A comparison of the inflammatory host response to particulate debris adjacent to unlocked and locked screws of a growth guidance system for early onset scoliosis.

PURPOSE: The SHILLA™ Growth Guidance system is a stainless-steel rod and screw system used for Early Onset Scoliosis which incorporates a unique flanged set screw designed to capture the rod, while allowing it to slide as the patient grows. Concomitant with this design is the potential for generation of wear debris and for an inflammatory host response. We hypothesized that the magnitude of the host response adjacent to the unlocked screws and rods would be greater than the host response to the locked rod/screws. METHODS: Seven tissue samples adjacent to locked (3) and unlocked screws (4) from three SHILLA patients (mean implantation time of 19 post-operative months) with infantile idiopathic scoliosis were obtained as part of an explant analysis protocol during a PMDA-approved clinical trial in Japan. Gross appearance, high-resolution radiographs, and histology were assessed. ISO Standard 10993 Part 6 was used to assess the host response. RESULTS: All three locked screw had no metallosis. In contrast, metallosis for unlocked screw tissue samples were rated as "ubiquitous" (2/4), "focal" (1/4), or "absent" (1/4). Microscopic metallic debris was found intracellularly and within interstices of fibrous connective tissues more frequently adjacent to unlocked screws compared to locked screws. Cell type and population scoring consistently showed a modestly larger inflammatory response (macrophages) in the unlocked tissue samples. CONCLUSIONS: The peri-prosthetic tissue response to the unlocked rods/screws had a higher reactivity grade (slight reaction, Δ = 4.0) per ISO 10993 Part 6 compared to the locked screws in three patients with the SHILLA™ Growth Guidance scoliosis system.

Bi-allelic loss of function variants of TBX6 causes a spectrum of malformation of spine and rib including congenital scoliosis and spondylocostal dysostosis.

BACKGROUND: Congenital scoliosis (CS) is a common vertebral malformation. Spondylocostal dysostosis (SCD) is a rare skeletal dysplasia characterised by multiple vertebral malformations and rib anomalies. In a previous study, a compound heterozygosity for a null mutation and a risk haplotype composed by three single-nucleotide polymorphisms in TBX6 have been reported as a disease-causing model of CS. Another study identified bi-allelic missense variants in a SCD patient. The purpose of our study is to identify TBX6 variants in CS and SCD and examine their pathogenicity. METHODS: We recruited 200 patients with CS or SCD and investigated TBX6 variants. We evaluated the pathogenicity of the variants by in silico prediction and in vitro experiments. RESULTS: We identified five 16p11.2 deletions, one splice-site variant and five missense variants in 10 patients. In vitro functional assays for missense variants identified in the previous and present studies demonstrated that most of the variants caused abnormal localisation of TBX6 proteins. We confirmed mislocalisation of TBX6 proteins in presomitic mesoderm cells induced from SCD patient-derived iPS cells. In induced cells, we found decreased mRNA expressions of TBX6 and its downstream genes were involved in somite formation. All CS patients with missense variants had the risk haplotype in the opposite allele, while a SCD patient with bi-allelic missense variants did not have the haplotype. CONCLUSIONS: Our study suggests that bi-allelic loss of function variants of TBX6 cause a spectrum of phenotypes including CS and SCD, depending on the severity of the loss of TBX6 function.

Preoperative 6-Minute Walk Performance in Children With Congenital Scoliosis.

BACKGROUND: The 6-minute walk test (6MWT) is used to assess the function of cardiopulmonary and neuromuscular conditions in adults and children. The primary research question was to determine the relationship between 6MWT distance and forced vital capacity (FVC) and the major curve among children with congenital scoliosis with rib anomalies. METHODS: The authors recorded 6MWT distance in meters, FVC as a percentage of predicted normal value using arm span for height (FVC%), and Cobb angle in 20 children (13 girls; average age, 6.7±1.3 y) with congenital scoliosis before outpatient surgical treatment. The 6MWT uses a standardized protocol and measures distance traveled in 6 minutes on a flat surface. The authors then determined the correlation between these measures using linear regression analysis. RESULTS: The Cobb angle of the major curvature was 55.4±20.5 degrees. The type of vertebral anomaly was mixed in 17 cases, formation failure in 2 cases, and segmentation failure in 1 case. The range of rib anomalies was 3.4±3.9 levels; 15 and 5 patients, respectively, had unilateral and bilateral rib anomalies. FVC and FVC% were 0.7±0.2 L and 60%±19%, respectively. The ratio of forced expiratory volume at 1 second to FVC (FEV1/FVC), which indicates obstructive lung disease, was normal at 93%±7%. The 6MWT distance was 386.3±59.4 m, which was ≤10% of the predicted distance for normal children. No child was able to walk the normal distance on the basis of published norms. 6MWT distance was significantly correlated with arm span (ρ=0.46, P=0.04) and major curve (ρ=-0.61, P=0.004), but not with FVC% (ρ=0.17, P=0.49). CONCLUSIONS: The 6MWT distance is a feasible measure of function and is substantially reduced before surgery in children with thoracic congenital scoliosis with rib anomalies. The 6MWT distance was significantly correlated with a major curve but not with FVC%. 6MWT distance is not affected by moderate lung function impairment. LEVEL OF EVIDENCE: Level IV-retrospective cohort study.

Nonanesthetized Alternatively Repetitive Cast and Brace Treatment for Early-onset Scoliosis.

BACKGROUND: Use of cast is a standard treatment (Tx) choice for early-onset scoliosis. Recently, toxicity from repetitive use of general anesthesia has received attention by the Food and Drug Administration (FDA). We introduce a nonanesthetized cast Tx protocol called alternatively-repetitive-cast-and-brace (ARCB) that we have used since 1995 and have conducted an extensive follow-up on these patients to verify the efficacy of this protocol. STUDY DESIGN: This is a retrospective cohort study. METHODS: Of a consecutive series of 155 patients who have undergone cast Tx at a single institution, 98 patients (male: 36, female: 62) have been identified under the following criteria: (1) Initial age before ARCB of ≤6; (2) Follow-up period of ≥2 years; (3) Initial scoliosis ≥35 degrees. Patients consisted of the following: congenital/structural: 45, idiopathic: 23, neuromuscular: 6, syndromic: 24. Precast, postfinal cast, minimum in-cast Cobb, as well as thoracic and T1-S1 heights were measured. Fifty-six of these patients had available pulse oximetry on days before and after initial cast, and these were also evaluated to assess cardiopulmonary effects that the cast have on the patients. RESULTS: Patients were casted 6.6 times, with a mean initial Cobb of 56.5 degrees and a final follow-up Cobb of 57.1 degrees. Follow-up period was 5.0 years. Mean curve progression per follow-up period was 0.5 degrees/y. Minimum in-cast Cobb was 25.6 degrees. Initially patients had a thoracic and T1-S1 height of 12.6 and 22.5 cm, respectively. At final cast, these were 15.3 and 27.2 cm, respectively. Of these patients, 39 had progression >1 degree/y, of which 83.1% had resulted in surgical correction, while this was true for only 37.3% of those that did not show such progression. Idiopathic patients had the greatest correction rate by cast (69%) and had shown an overall progression rate of -2.3 degrees/y. Pulse-oximetry results were not significant amongst patients before and after cast placement. CONCLUSIONS: ARCB is a versatile and practical Tx choice. It is an effective delaying method in sparing time until surgery with no apparent cardiopulmonary compromise. Curve control was most effective in Idiopathic patients while some curve control was achieved in other etiologies which may have spared time until their eventual surgery. SIGNIFICANCE: Cast Tx without the need of general anesthesia is an increasingly important topic since anesthesia toxicity from its repetitive use has become apparent. This study exemplifies safe and efficacious use of such cast with effective suppression on cast progression in different etiologies at various degrees.

Long-term Surgical Outcomes After Early Definitive Spinal Fusion for Early-onset Scoliosis With Neurofibromatosis Type 1 at Mean Follow-up of 14 Years.

BACKGROUND: Several authors mentioned surgical outcome for scoliosis associated with neurofibromatosis type 1 (NF-1). However, no studies have summarized long-term surgical outcomes after surgical treatment of early-onset scoliosis (EOS) with NF-1. The purpose of this study is to evaluate the long-term surgical outcome after early definitive spinal fusion for EOS in NF-1 patients. METHODS: We performed a retrospective review on a cohort of 11 patients diagnosed with EOS associated with NF-1 between 1990 and 2009 in our hospital. The study included 7 male and 4 female NF-1 patients with a mean age at fusion surgery of 8 years 4 months who underwent early definitive spinal fusion for EOS. We reviewed radiographs, computed tomography and magnetic resonance images for each patient. The data collected included type of NF-1, Cobb angles, kyphotic angle, spinal length (T1-S1), and pulmonary function. We also evaluated progression of the dystrophic change through radiographs and computed tomography during the follow-up period. RESULTS: The mean follow-up duration was 14 years (5 y 10 mo to 25 y). All patients underwent anterior and posterior fusion surgeries in either 1 or 2 stages. Seven cases had subtotal tumor resection from the concave side followed by rib strut grafting. The mean preoperative Cobb angle of the primary curve was corrected from 71.2 to 24.1 degrees and was maintained at the final follow-up at 23.5 degrees. Mean values for preoperative and final follow-up T1-S1 heights were 30.7 and 36.2 cm, respectively. Mean values for preoperative and final follow-up % forced vital capacity (the present/the predicted) were 75.0% and 74.4%, respectively. The dystrophic change progressed in all cases during the long-term follow-up. CONCLUSIONS: Our goals for NF-1 scoliosis are to obtain deformity correction, to achieve stable instrumentation by using longer fusion levels and to attain a solid fusion mass that can tolerate continual erosion during the long-term follow-up. We achieve this by using a circumferential approach for EOS associated with NF-1. LEVEL OF EVIDENCE: Level IV-case series.

Comparison of Early Definitive Fusion and Traditional Growing Rods in Early-onset Dystrophic Scoliosis in Neurofibromatosis Type 1: A Preliminary Report.

BACKGROUND: Early definitive spinal fusion (EF) has been widely recommended to avoid spinal deformity progression for early-onset scoliosis (EOS) with neurofibromatosis type 1 (NF-1). In contrast, growing rod (GR) procedure has recently been recommended for EOS associated with the dystrophic type NF-1. However, no studies have compared the surgical outcomes between EF and GR procedure for EOS with NF-1. The purpose of this study was to compare the surgical outcomes of EF versus GR for early onset and dystrophic scoliosis with NF-1. METHODS: This was a retrospective multicenter study; 26 EOS patients with dystrophic type of NF-1 who underwent EF (16 patients) or GR (10 patients) were investigated. We compared age at first surgery, fused levels, total number of surgeries, coronal major curve, complication rates, spinal height (T1-T12 and T1-S1 length), and forced vital capacity between the 2 groups. RESULTS: The mean age at first surgery was 7.3 years in the EF and 5.8 years in the GR (P<0.05). The mean follow-up period was 12.8 and 10.5 years, respectively. The 2 groups did not show significant differences in preoperative major Cobb angle (75.1 vs. 83.1 degrees), complication rate (53% vs. 60%), and increase rate of T1-T12 (20.0% vs. 30.4%). However, significant differences (P<0.05) were recognized in fusion segments (13.9 vs. 15.8), total numbers of surgery (2.6 vs. 10.1), correction rate of major curve (59.0% vs. 40.6%), increase rate of T1-S1 (19.0% vs. 33.9%), body height at final follow-up (151 vs. 142 cm), and forced vital capacity at final follow-up (2.23 vs. 1.46 L). CONCLUSIONS: Early fusion is still a viable option for progressive EOS with dystrophic type of NF-1 even in the growth-friendly era. Surgeons should consider the best procedure for each patient taking into account the severity of dystrophic change when treating EOS with NF-1. LEVEL OF EVIDENCE: Level IV.

Excessive correction impacts postoperative shoulder imbalance in lenke type 5C adolescent idiopathic scoliosis.

BACKGROUND: Postoperative shoulder imbalance (PSI) has a negative impact on the surgical outcomes of patients with adolescent idiopathic scoliosis. This study aimed to evaluate the risk factors of PSI in patients with Lenke type 5C curves. METHODS: This study included 100 patients who underwent posterior correction surgery using pedicle screw constructs for Lenke type 5C curves. The mean age of the patients at surgery was 15.5 ± 2.3 years, and the mean follow-up period was 36.6 ± 15.0 months. The subjects were classified into the following two groups: PSI and non-PSI. Radiographic parameters, including the preoperative and 2-year postoperative coronal and sagittal profiles, were compared between the two groups. RESULT: PSI was found in eight patients (8.0%). The preoperative Cobb angles were 47.3° ± 8.7° and 48.0° ± 3.9° in the non-PSI and PSI groups, respectively. The correction rate in the PSI group was significantly higher than that in the non-PSI group (81.0% ± 17.7% vs. 67.7% ± 14.7%; p = 0.018). The preoperative T1 tilt angle in the PSI group was significantly larger than that in the non-PSI group (6.1° ± 3.3° vs. 3.1° ± 2.8°; p = 0.005). Receiver operating characteristic (ROC) analysis showed that the area under the ROC curve was 0.769 (p = 0.012, 95% confidence interval [CI], 0.556-0.982) and 0.763 (p = 0.014, 95% CI, 0.598-0.928) for the correction rate and preoperative T1 tilt, respectively. The cut-off value was 73% and 4° for the correction rate and preoperative T1, respectively. CONCLUSION: PSI was found in 8.0% of Lenke type 5C curves. Excessive correction of the lumbar curve of >73% and preoperative T1 tilt of >4° can be risk factors for PSI in patients with Lenke type 5C curve.

A functional variant in MIR4300HG, the host gene of microRNA MIR4300 is associated with progression of adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is a common spinal deformity affecting millions of children. Since treatment and prognosis of AIS depend on curve progression, identifying factors related to AIS curve progression is important in its management. Although several genetic loci for AIS occurrence are reported, no locus for curve progression has been identified. To identify genes associated with AIS progression, we conducted a genome-wide association study followed by a replication study using a total of 2,543 AIS subjects who were evaluated for the curve progression. We identified a significantly associated locus on chromosome 11q14.1 (P = 1.98 × 10-9, odds ratio = 1.56). In silico and in vitro analyses identified a functional variant, rs35333564 in MIR4300HG, the host gene of a microRNA, MIR4300. The genomic region containing rs35333564 had enhancer activity, which was decreased in its risk allele. Our data suggest that decrease of MIR4300 is related to AIS progression.

A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis.

Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity. We previously conducted a genome-wide association study (GWAS) and detected two loci associated with AIS. To identify additional loci, we extended our GWAS by increasing the number of cohorts (2,109 affected subjects and 11,140 control subjects in total) and conducting a whole-genome imputation. Through the extended GWAS and replication studies using independent Japanese and Chinese populations, we identified a susceptibility locus on chromosome 9p22.2 (p = 2.46 × 10(-13); odds ratio = 1.21). The most significantly associated SNPs were in intron 3 of BNC2, which encodes a zinc finger transcription factor, basonuclin-2. Expression quantitative trait loci data suggested that the associated SNPs have the potential to regulate the BNC2 transcriptional activity and that the susceptibility alleles increase BNC2 expression. We identified a functional SNP, rs10738445 in BNC2, whose susceptibility allele showed both higher binding to a transcription factor, YY1 (yin and yang 1), and higher BNC2 enhancer activity than the non-susceptibility allele. BNC2 overexpression produced body curvature in developing zebrafish in a gene-dosage-dependent manner. Our results suggest that increased BNC2 expression is implicated in the etiology of AIS.

Evaluation of thoracic factors after scoliosis surgery in patients with both scoliosis and pectus excavatum.

PURPOSE: Pectus excavatum can negatively impact cardiac function during scoliosis surgery. Several authors reported severe hypotension associated with the prone position during scoliosis surgery in children that had both scoliosis and pectus excavatum. However, we could find no studies that evaluated the change in the thoracic factors, such as sternal tilt angle and Haller index after scoliosis surgery in patients with both scoliosis and pectus excavatum. The purpose of this study is to evaluate the change in thoracic factors after surgical treatment for scoliosis associated with pectus excavatum. METHODS: We performed a retrospective review on 20 patients (10 males and 10 females) who underwent surgical treatment for scoliosis associated with pectus excavatum from August 2004 to April 2014 in our hospital. We investigated the scoliosis diagnosis, preoperative and postoperative Cobb and thoracic kyphosis (TK) angles, the change in TK after surgery and thoracic factors, including the AP and transverse diameters of the chest, the sternal tilt angle, and Haller index. RESULTS: Patient mean age was 13.2 years old (4-27 years old) at surgery. Types of scoliosis were idiopathic in 8 patients, syndromic in 10, and neuromuscular in 2. The mean Cobb angles were 72.1° preoperatively and 19.0° postoperatively. Curve locations were thoracic in 13 patients, thoracolumbar in 4, and lumbar in 3. Surgical treatment of pectus excavatum was performed in 9 patients (45 %) before scoliosis treatment. Mean sternal tilt angles were 11.5° preoperatively and 11.1° postoperatively. Mean Haller indices were 4.8 preoperatively and 5.3 postoperatively. This was especially true for syndromic or neuromuscular scoliosis and thoracolumbar/lumbar curve type patients in which scoliosis surgery tended to worsen the Haller index. CONCLUSION: The Haller index increased postoperatively in 11 of 20 patients, which means sternal depression deteriorated after scoliosis surgery in about 50 % of patients. We suggest that surgeons fully assess the thoracic factors in patients with scoliosis and pectus excavatum prior to performing scoliosis surgery and carefully monitor their patient's general condition during surgery.

Three-Dimensional Analysis of Hemimetameric Segmental Shift in Congenital Scoliosis.

STUDY DESIGN: This is a retrospective cohort study. BACKGROUND: Hemimetameric segmental shift (HMMS) is defined as a hemivertebral deformation in which 2 or more hemivertebrae exist on both sides of the spine and are separated by at least 1 normal vertebra. Reports of HMMS are rare and based on simple anterior x-ray images. No reports have used 3-dimensional computed tomography (3D-CT) to analyze both the anterior and posterior elements. The objective of this study was to analyze the morphology and clinical features of HMMS 3 dimensionally. METHODS: HMMS was confirmed in 32 (6.6%, 16 males and 16 females) of 483 patients diagnosed with congenital scoliosis at the study institution between 1998 and 2013. The average age at the first visit was 6 years and 3 months. 3D-CT imaging was performed for 30 patients older than 2 years (average age: 9 y and 8 mo) and used to classify cases according to posterior elements. RESULTS: With regard to the number of hemivertebrae present, 21 patients had 2 hemivertebrae, 7 patients had 3 hemivertebrae, and 2 patients had 4 hemivertebrae. Patients with 2 hemivertebrae predominantly had hemivertebrae in the thoracolumbar spine. Patients were classified into 2 categories: malformation existing at an equal level in anterior and posterior sides (unison HMMS) and malformation existing at nonequal levels (discordant HMMS). Nine patients had unison HMMS and all of them had 2 hemivertebrae (average: 4.6 vertebrae). Twenty-one patients had discordant HMMS, with 12 having 2 hemivertebrae, 7 having 3 hemivertebrae, and 2 having 4 hemivertebrae. CONCLUSIONS: Through 3D-CT analysis, HMMS was categorized as unison or discordant. Discordant HMMS was observed in 21 of 30 (70%) patients and in all patients with >3 hemivertebrae. Diagnosing HMMS, whether unison or discordant, is clinically important and should be done with careful analysis of bone models and/or radiologic images to determine the correct spinal levels. LEVEL OF EVIDENCE: Level IV-diagnostic study.

Clinical Impact of Corrective Cast Treatment for Early Onset Scoliosis: Is It a Worthwhile Treatment Option to Suppress Scoliosis Progression Before Surgical Intervention?

BACKGROUND: Although corrective cast (CC) has been back in use for the treatment of early onset scoliosis (EOS), no studies have reported how clinically meaningful CC was in comparison with brace-only treatment (BT) in EOS. The aim of this study was to investigate the effect of CC treatment in terms of suppression of scoliosis progression before surgery. METHODS: This study was designed to conduct a comparison of patients treated at 2 spine institutions differing in treating methods (one: mainly CC with brace, the other: BT). Applying casts were performed without general anesthesia and repeatedly with the interval of 2 to 6 months combined with corrective brace application called alternatively repetitive cast and brace treatment (ARCBT). In total, 58 patients met the following criteria: (1) age at the first visit ≤6 years, (2) scoliosis ≥40 degrees, (3) conservative treatment≥2 years. Patients with congenital scoliosis were excluded in this study. In total, 58 patients were divided into 2 groups; cast/brace group (C/B-G) and BT group (B-G). RESULTS: There were no significant differences of diagnosis (P=0.2773), sex (P=0.0670), age at the first visit (P=0.1457), scoliosis magnitude (P=0.1980), and duration for conservative treatment (P=0.2578) between 2 groups. Most of the patients who were treated with ARCBT, were switched to BT due to lower compliance for CC after the age of around 7 years. The progression of scoliosis during ARCBT and BT were 4.4 and 5.8 degree/y, respectively. Those during ARCBT in C/B-G was 2.8 degree/y comparing with 8.4 degree/y after switch to BT after 7 years of age. There was a significant difference between scoliosis progression during ARCBT in C/B-G and that of B-G (P=0.0086). CONCLUSIONS: This study showed that ARCBT had a significant impact on suppression of scoliosis progression compared with BT in EOS. However, the termination of cast application and the switch to BT may be still a clinical question considering the time to surgical intervention. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Modic changes and disc degeneration in adolescent idiopathic scoliosis patients who reach middle age without surgery: Can residual deformity cause lumbar spine degeneration?

BACKGROUND: We have yet to determine what types of lumbar degenerative changes can be observed on MRI in middle-aged adolescent idiopathic scoliosis (AIS) patients without undergoing surgery. The aims of this study were to investigate AIS patients who have reached middle age without undergoing surgery and to clarify if residual spinal deformities may have affected health-related quality of life (HRQOL) and lumbar spine degeneration. METHODS: Subjects comprised AIS patients who reached middle age without surgery and who underwent whole-spine X-rays, lumbar MRI, and SRS-22 surveys. Of the 60 cases collected from five scoliosis centers, 25 patients who met the inclusion criteria were enrolled into the residual deformity (RD) group and analyzed. Controls (CTR) group comprised 25 individuals matched for age, sex, and BMI with the patient group. RESULTS: MRI revealed no significant differences in the percentage of individuals with Pfirrmann grade 4 or 5 disc degeneration in 1 or more segments (RD group: 84%, CTR group: 60%, p = 0.059). Significantly more patients with Modic changes in 1 or more segments were observed in the RD group (RD group: 56%, CTR group: 8%, p < 0.001). All SRS-22 scores were significantly lower in the RD group. The lumbar curve cutoff point based on whether or not Modic change could be observed using ROC analysis was 39.5°. CONCLUSIONS: Compared to healthy individuals, AIS patients with residual deformity who have never had surgery showed similar prevalence of disc degeneration, but they had more Modic changes and poor HRQOL. The cutoff point for lumbar curves of patients with and without Modic changes in middle age was 39.5°.

Compound Heterozygosity for Null Mutations and a Common Hypomorphic Risk Haplotype in TBX6 Causes Congenital Scoliosis.

Congenital scoliosis (CS) occurs as a result of vertebral malformations and has an incidence of 0.5-1/1,000 births. Recently, TBX6 on chromosome 16p11.2 was reported as a disease gene for CS; about 10% of Chinese CS patients were compound heterozygotes for rare null mutations and a common haplotype defined by three SNPs in TBX6. All patients had hemivertebrae. We recruited 94 Japanese CS patients, investigated the TBX6 locus for both mutations and the risk haplotype, examined transcriptional activities of mutant TBX6 in vitro, and evaluated clinical and radiographic features. We identified TBX6 null mutations in nine patients, including a missense mutation that had a loss of function in vitro. All had the risk haplotype in the opposite allele. One of the mutations showed dominant negative effect. Although all Chinese patients had one or more hemivertebrae, two Japanese patients did not have hemivertebra. The compound heterozygosity of null mutations and the common risk haplotype in TBX6 also causes CS in Japanese patients with similar incidence. Hemivertebra was not a specific type of spinal malformation in TBX6-associated CS (TACS). A heterozygous TBX6 loss-of-function mutation has been reported in a family with autosomal-dominant spondylocostal dysostosis, but it may represent a spectrum of the same disease with TACS.

A Japanese nationwide multicenter survey on perioperative complications of corrective fusion for elderly patients with adult spinal deformity.

BACKGROUND: Recently, corrective fusion surgery for patients with adult spinal deformity (ASD) has become common in Japan. This study aimed to clarify the status of surgeries for ASD in Japan, focusing on perioperative complications. A nationwide multicenter survey gathering information on surgically treated ASD patients was conducted by the committee for Adult Spinal Deformity of the Japanese Scoliosis Society. METHODS: This study was a review of retrospectively collected data from 18 spine scoliosis centers belonging to the Japanese Scoliosis Society. Patients who underwent corrective fusion surgery for ASD between 2011 and 2013 were included. Demographics, comorbidities, surgical data, and complications were investigated. RESULTS: A total of 1192 patients (mean age, 57.7 years) were included in this study. Of these, 611 patients were aged less than 65 years and 581 patients were aged 65 years or greater. The age distribution had two peaks, in the third and eighth decades. Deformities caused by degeneration represented 67% of the pathology in patients aged over 65 years; however, non-degenerative disease such as adult idiopathic scoliosis and syndromic or congenital deformity represented over 60% of pathology in patients aged less than 65 years. The iatrogenic deformity and reoperation rates were both less than 3%. The mean operation time and estimated blood loss were 370 min and 1642 ml, respectively. Major perioperative complications occurred in 160 patients (14.5%). The incidence of complications was significantly higher in patients aged over 65 years, including neurological deficits, hemorrhagic shock, hematoma, heart failure, and surgical site infection (p < 0.05). CONCLUSIONS: Older (aged over 65 years) ASD patients showed greater rates of deformity due to the occurrence of degeneration and vertebral fractures, as well as a higher incidence of peri-and postoperative complications. Efforts to reduce perioperative complications are therefore imperative, especially for elderly ASD patients in our aging society.