Bobby Kin Wah Ng

Melatonin receptor 1B (MTNR1B) gene polymorphism is associated with the occurrence of adolescent idiopathic scoliosis.

Study Design. A genetic association study to comprehensively investigate variations of melatonin receptor 1B gene polymorphism by a set of tagging single nucleotide polymorphisms (tagSNPs) derived from the International Hapmap project. Objectives. To determine whether melatonin receptor 1B (MTNR1B) gene polymorphisms are associated with the predisposition and/or disease severity of adolescent idiopathic scoliosis (AIS). Summary of Background Data. Linkage studies suggested a genetic predisposition for AIS. In addition, evidence showed that AIS might be related to melatonin deficiency and dysfunction of melatonin signaling pathway. Locating in one of the chromosomal regions linked to AIS, MTNR1B gene is a potential candidate gene for AIS. Methods. This study was carried out in 2-stage case-control analysis: 1) initial screening (472 cases and 304 controls) and 2) separate replication test (342 cases and 347 controls) to confirm results in the screening. In the first screening stage, 5 tagSNPs were selected to cover most of the genetic variation in the MTNR1B gene. In the second stage, SNPs showing association in the screening stage were studied in a separate replication sample set to confirm the association. Genotyping was performed by PCR-RFLP. Results. The first stage showed a putative association between rs4753426 and AIS, which was confirmed in the replication sample set. By meta-analysis, the frequency of C allele of this SNP locating in the promoter was significantly higher in the cases than controls (P = 0.006 aftermeta-analysis). Subjects with the CC genotype had an odds ratio of 1.29 for AIS. Another SNP rs741837 in promoter region, being moderate linkage disequilibrium with rs4753426, was also marginally associated with AIS. Conclusion. Polymorphisms of the promoter of MTNR1B gene were associated with AIS, but not with the curve severity in AIS patients. This suggested that MTNR1B was an AIS predisposition gene.

Clinical effectiveness of school screening for adolescent idiopathic scoliosis: A large population-based retrospective cohort study

Study Design. Retrospective cohort study. Objective. To evaluate the clinical effectiveness of school scoliosis screening using a large and long–term-followed cohort of students in Hong Kong. Summary of Background Data. School screening for adolescent idiopathic scoliosis has been criticized as resulting in over-referrals for radiography and having low predictive values. Indeed, all but one previous retrospective cohort studies had no follow-up assessments of students until their skeletal maturity, leaving any late-developed curves undetected. The one study that completed this follow-up was well conducted but had low precisions due to its small sample size. Methods. A total of 157,444 students were eligible for a biennial scoliosis screening, and their screening results and medical records up to 19 years of age were available. Students first had forward bending test and angle of trunk rotation (ATR) performed. Those with ATR between 5° and 14° or signs of adolescent idiopathic scoliosis were assessed by moiré topography regularly. Students with an ATR ≥15°, ≥2 moiré lines, or significant clinical signs were referred for radiography and had their Cobb angle measured. Results. Of the 115,190 screened students in the cohort, 3228 (2.8%, 95% confidence interval [CI] = 2.7%–2.9%) were referred for radiography. At the final follow-up, the positive predictive values were 43.6% (41.8%–45.3%) for a Cobb angle ≥20° and 9.4% (8.4%–10.5%) for needing treatment, while the sensitivities were 88.1% (86.4%–89.6%) and 80.0% (75.6%–83.9%), respectively. Conclusion. This is the largest study that has demonstrated that school scoliosis screening in Hong Kong is predictive and sensitive with a low referral rate. Screening should thus be continued in order to facilitate early administration of conservative treatments.

Relative shortening and functional tethering of spinal cord in adolescent idiopathic scoliosis?: study with multiplanar reformat magnetic resonance imaging and somatosensory evoked potential.

Study Design. MR imaging and multiplanar reconstruction were used to evaluate relative length of the spinal cord to the vertebral column in adolescent idiopathic scoliosis (AIS). Objectives. Ratio of spinal cord length to vertebral column length and position of the cerebellar tonsils were evaluated and correlated with somatosensory cortical evoked potentials (SSEP). Summary of Background Data. Tonsillar herniation, abnormal anthropometric growth, relative spinal overgrowth, and abnormal somatosensory function have been reported in AIS. All these observations suggest a possible neural origin of the etiopathogenesis of AIS, which can be linked to a disproportional growth between spinal column and cord. Methods. Two-dimensional sagittal MRI of the spine was performed in 28 AIS patients (14 mild curve; 14 severe curve) and 14 age-matched controls. Measurements of spinal cord, vertebral column length, and tonsillar position were made on reformat images and correlated with SSEP studies. Results. No significant differences in the absolute spinal cord length were found. However, there was significant relative segmental lengthening of the spinal column at the thoracic level in AIS patients with severe curve; hence, ratios of cord to vertebral column length were significantly reduced (P < 0.01). There was high interobserver reliability (0.9); 28% (8 of 28) scoliosis patients had low-lying cerebellar tonsils and abnormal SSEP, respectively. Conclusion. There was significantly reduced spinal cord to vertebral column ratios in the AIS patients with severe curve, suggesting a disproportional growth between the skeletal and the neural systems. The relative shortening and functional tethering of spinal cord may play an important role in the etiopathogenesis of AIS.

A meta-analysis of the clinical effectiveness of school scoliosis screening

Study Design. A meta-analysis that systematically reviewed the evaluation studies of a scoliosis screening program reported in the literature. Objective. To evaluate the best current evidence on the clinical effectiveness of school screening for adolescent idiopathic scoliosis. Summary of Background Data. The use of school scoliosis screening is controversial, and its clinical effectiveness has been diversely reported. Methods. Data sources included 3 databases, namely, PubMed, Google scholar, CINAHL database, and the references from identified reviews and studies. Studies were included if: (1) they adopted a retrospective cohort design; (2) were screened using either the forward bending test (FBT), angle of trunk rotation, or Moiré topography; (3) reported results of screening tests and radiographic assessments; (4) screened adolescents only; (5) reported the incidence of curves with a minimum Cobb angle of 10° or greater; and (6) reported the number of referrals for radiography. Reviews, comments, case studies, and editorials were excluded. Results. Thirty-six studies, including 34 from the 775 initially identified studies and 2 from the references, met the selection criteria. The pooled referral rate for radiography was 5.0%, and the pooled positive predictive values for detecting curves ≥10°, curves ≥20°, and treatment were 28.0%, 5.6%, and 2.6%, respectively. There was substantial heterogeneity across studies. Meta-regression showed that programs using the FBT alone reported a higher referral rate (odds ratio [OR] = 2.91) and lower positive predictive values for curves ≥10° (OR = 0.49) and curves ≥20° (OR = 0.34) than programs using other tests. Only one small study followed students until skeletal maturity and reported the sensitivity of screening; however, the specificity was not reported. No severe publication bias was noted. Conclusion. The use of the FBT alone in school scoliosis screening is insufficient. We need large, retrospective cohort studies with sufficient follow-up to properly assess the clinical effectiveness of school scoliosis screening.

The effect of rigid versus flexible spinal orthosis on the clinical efficacy and acceptance of the patients with adolescent idiopathic scoliosis.

Study Design. A prospective study on the comparison of the clinical efficacy and patient’s acceptance of the 2 orthotic management methods. Objective. To compare the treatment effectiveness and patients’ acceptance of the flexible spinal orthosis, SpineCor with that of the rigid spinal orthosis for the patients with moderate adolescent idiopathic scoliosis. Summary of Background Data. The patients’ acceptance to the rigid spinal orthoses is always a concern as it could greatly affect the clinical outcome. SpineCor is a relatively new design for tackling those inevitable drawbacks found in rigid orthosis. However, there was no study to compare this design with the conventional method regarding their treatment efficacy and the patient’s acceptance. Methods. Forty-three subjects with moderate adolescent idiopathic scoliosis were randomly assigned to the SpineCor group (S group, n = 22) and rigid orthosis group (R group, n = 21). Their survival rate in the first 45 months of intervention was studied. The subjects’ acceptance to the orthoses was evaluated by a purpose-designed questionnaire, which was administered in the 3rd, 9th, and 18th months of intervention. Results. In the study period, there were 68% of the subjects in the S group and 95% of the subjects in the R group did not show curve progression. Significant difference (P = 0.046, by Fisher exact test) in failure rate between the 2 subject groups was found although the 2 groups had similar responses to the questionnaire. Conclusion. The current study showed that the failure rate of the SpineCor was significantly higher than that of the rigid spinal orthosis, and the patients’ acceptance to the SpineCor was comparable to the conventional rigid spinal orthosis.

Percutaneous transphyseal intramedullary Kirschner wire pinning: a safe and effective procedure for treatment of displaced diaphyseal forearm fracture in children.

Percutaneous transphyseal intramedullary Kirschner wire (K-wire) fixation was performed for diaphyseal fracture of the forearm in 84 children. In 60 patients (71%) closed reduction was performed, while in the remaining 24 (29%) closed reduction was supplemented with a mini-open reduction The K-wire was inserted transphyseally through the radial styloid or the Lister tubercle for the radius, and through the tip of the olecranon for the ulna. With an average follow-up of 70 months and a minimum follow-up of 2 years, all the patients reviewed were found to have good functional results; none had nonunion, deep infection, or premature physeal closure. Moreover, initial preoperative translation of the fracture of more than 100% displacement was found to be associated with a significantly higher chance of requiring a mini-open reduction. The authors concluded that percutaneous transphyseal intramedullary K-wire pining for forearm diaphyseal fracture in children is a convenient, effective, and safe operation, without any deleterious effects on subsequent growth of the distal radius.

A Relook Into the Association of the Estrogen Receptor α Gene (PvuII, XbaI) and Adolescent Idiopathic Scoliosis : A Study of 540 Chinese Cases

Study Design. A genetic association study of estrogen receptor-α gene (ESR1) with adolescent idiopathic scoliosis (AIS) in Chinese. Objectives. To investigate whether: 1) PvuII and XbaI polymorphisms in ESR1 are predisposition factor for AIS and 2) these polymorphisms correlate with the severity of curvature in AIS. Summary of Background Data. A common single nucleotide polymorphism (SNP) in ESR1 (XbaI) was found to be associated with curve severity in Japanese AIS patients recently. The role of ESR1 as a predisposition gene using a case-control design in other ethnic groups is required to confirm the previous associations. Methods. A total of 540 Chinese AIS girls with Cobb angle above 20° were recruited as cases together with 260 healthy controls. The effect of ESR1 SNPs on severity of scoliosis was analyzed in a subgroup of AIS patients (n = 364) followed up until skeletal maturity with the maximum Cobb angle recorded. Two SNPs in ESR1 were genotyped by PCR-restriction fragment length polymorphism in all subjects. Results. The allelic frequency of X allele was 23% in both case and control groups. The P allele was found at allelic frequency of 40% and 36% in the case and control groups, respectively. No association between the two ESR1 SNPs and the occurrence of AIS by both genotype and haplotype analysis could be established, suggesting that both SNPs were not predisposition alleles for AIS. AIS patients with different genotypes showed no difference in the maximum Cobb angle. No association was found between the genotype and anthropometric measurements in AIS patients. Conclusion. The previously reported association with curve severity could not be replicated in our large series of Chinese AIS patients. The current study also did not show any association of the 2 SNPs with increased risk of having AIS.

Morphological and Functional Electrophysiological Evidence of Relative Spinal Cord Tethering in Adolescent Idiopathic Scoliosis

Study Design. Magnetic resonance (MR) imaging and multiplanar reconstruction was used to evaluate the morphology and relative position of the spinal cord in adolescent idiopathic scoliosis (AIS). Objective. To determine the longitudinal and cross-sectional morphology of spinal cord in AIS subjects versus normal controls and their correlation with relative position of cerebellar tonsils and somatosensory cortical evoked potentials (SSEP). Summary of Background Data. Our previous studies revealed significantly reduced spinal cord to vertebral column length ratios in AIS patients with severe scoliotic curves suggesting the presence of disproportional growth between the neural and skeletal system. A possible neural origin of etiopathogenesis of AIS is suggested. Methods. MR multiplanar reconstruction was performed in 97 adolescent girls (35 moderate, 26 severe AIS with right-sided thoracic/thoracolumbar curve, and 36 age-matched controls). Measurements of the ratio of anteroposterior (AP) and transverse (TS) diameter of the cord, the concave and convex lateral cord space (LCS) were obtained at the apical level in AIS subjects. Same parameters were obtained in normal controls at matched vertebral levels. Correlations were made with cord to vertebral column length ratio, cerebellar tonsil position and SSEP findings. Results. AP/TS cord ratio and LCS ratio were increased in AIS subjects in the presence of reduced spinal cord to vertebral length ratio when compared with normal controls (P < 0.05). The above ratios were exaggerated in AIS subjects with abnormal SSEP findings. The AP/TS cord ratio and LCS ratio were negatively correlated with the cord to vertebral column length ratio (rho = −0.410 and −0.313, P < 0.01) and cerebellar tonsillar level (rho = −0.309 and −0.432, P < 0.01). Conclusion. Our study suggests presence of tethering and increased tension along the longitudinal axis of spinal cord with associated morphologic changes of cross-sectional shape and relative position of the cord.

Dynamic Magnetic Resonance Imaging in Assessing Lung Volumes, Chest Wall, and Diaphragm Motions in Adolescent Idiopathic Scoliosis Versus Normal Controls

Study Design. Dynamic breath-hold (BH)- magnetic resonance (MR) imaging was used to evaluate lung function in adolescent idiopathic scoliosis (AIS). Objectives. Changes in lung volume, chest wall, and diaphragmatic motions were evaluated in AIS patients and compared with normal controls. Summary of Background Data. Little is known about whether pulmonary function impairment in AIS is related to restriction of lung volume, poor chest wall expansibility, or impaired diaphragmatic motion. This is a study on the underlying pathophysiology of the abnormal pulmonary function in AIS using the ultrafast BH-MR imaging technique. Methods. Forty-two patients with moderate to severe right thoracic scoliosis (Cobb angle, 40°–98°), 22 patients with mild right thoracic scoliosis (Cobb angle 10°–30°), and 12 healthy subjects (age ranged, 11–18 years; all girls) were recruited for the following assessments: 1) inspiratory, expiratory, and change in lung volume; 2) change in anteroposterior (AP) and transverse (TS) diameter of the chest wall at two levels: carina and apical vertebra level; and 3) change in diaphragmatic heights. Results. Inspiratory, expiratory lung volume and diaphragmatic heights were significantly reduced in the severe scoliosis group (P < 0.05), but the change in lung volume was not affected. There was no significant difference in the change of AP or TS diameter of the chest wall as well as diaphragmatic motions among groups. Conclusion. Impairment in lung function in AIS patients is predominantly due to restriction of lung volume.

Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis

Adolescent idiopathic scoliosis (AIS) causes spinal deformity in 3% of children. Despite a strong genetic basis, few genes have been associated with AIS and the pathogenesis remains poorly understood. In a genome-wide rare variant burden analysis using exome sequence data, we identified fibrillin-1 (FBN1) as the most significantly associated gene with AIS. Based on these results, FBN1 and a related gene, fibrillin-2 (FBN2), were sequenced in a total of 852 AIS cases and 669 controls. In individuals of European ancestry, rare variants in FBN1 and FBN2 were enriched in severely affected AIS cases (7.6%) compared with in-house controls (2.4%) (OR = 3.5, P = 5.46 × 10(-4)) and Exome Sequencing Project controls (2.3%) (OR = 3.5, P = 1.48 × 10(-6)). Scoliosis severity in AIS cases was associated with FBN1 and FBN2 rare variants (P = 0.0012) and replicated in an independent Han Chinese cohort (P = 0.0376), suggesting that rare variants may be useful as predictors of curve progression. Clinical evaluations revealed that the majority of AIS cases with rare FBN1 variants do not meet diagnostic criteria for Marfan syndrome, though variants are associated with tall stature (P = 0.0035) and upregulation of the transforming growth factor beta pathway. Overall, these results expand our definition of fibrillin-related disorders to include AIS and open up new strategies for diagnosing and treating severe AIS.