CELSR2 is a candidate susceptibility gene in idiopathic scoliosis.

A Swedish pedigree with an autosomal dominant inheritance of idiopathic scoliosis was initially studied by genetic linkage analysis, prioritising genomic regions for further analysis. This revealed a locus on chromosome 1 with a putative risk haplotype shared by all affected individuals. Two affected individuals were subsequently exome-sequenced, identifying a rare, non-synonymous variant in the CELSR2 gene. This variant is rs141489111, a c.G6859A change in exon 21 (NM_001408), leading to a predicted p.V2287I (NP_001399.1) change. This variant was found in all affected members of the pedigree, but showed reduced penetrance. Analysis of tagging variants in CELSR1-3 in a set of 1739 Swedish-Danish scoliosis cases and 1812 controls revealed significant association (p = 0.0001) to rs2281894, a common synonymous variant in CELSR2. This association was not replicated in case-control cohorts from Japan and the US. No association was found to variants in CELSR1 or CELSR3. Our findings suggest a rare variant in CELSR2 as causative for idiopathic scoliosis in a family with dominant segregation and further highlight common variation in CELSR2 in general susceptibility to idiopathic scoliosis in the Swedish-Danish population. Both variants are located in the highly conserved GAIN protein domain, which is necessary for the auto-proteolysis of CELSR2, suggesting its functional importance.

Incidence of cancer in adolescent idiopathic scoliosis patients treated 25 years previously.

PURPOSE: To report the incidence of cancer in a cohort of adolescent idiopathic scoliosis (AIS) patients treated 25 years previously. METHODS: 215 consecutive AIS patients treated between 1983 and 1990 were identified and requested to return for clinical and radiographic examination. The incidence of cancer was determined through chart review and follow-up interviews. Using the original radiographic log file that included patient position, mAs, kV and the total number of X-rays taken, a radiation physicist calculated the total radiation dose during treatment and follow-up adjusted for BMI and sex. RESULTS: From the original cohort of 215 consecutive AIS patients, radiation information was available in 211 of the patients, and medical charts were available in 209 AIS patients. 170 (83 %) of the 205 AIS patients participated in the follow-up study with questionnaires. The calculated mean total radiation exposure was 0.8-1.4 mSV per examination and 2.4-5.6 mSv/year. An average of 16 radiographs were taken during the treatment period. Nine AIS patients developed cancer, mostly breast (3) and endometrial (4). The AIS patients had a relative risk of 4.8 (CI 2.3-5.8, p < 0.000) for developing cancer compared to the normal Danish population. CONCLUSIONS: The overall cancer rate in this AIS cohort was 4.3 % which is five times higher than compared to the age-matched Danish population, and endometrial and breast cancer was most frequent. The radiation dose applied to the patients in this study, is comparable to modern equipment. This is to our knowledge the first study to report increased rates of endometrial cancers in a cohort of AIS patients, and future attention is needed to reduce the radiation dose distributed to the AIS patients both pre-operatively and during surgery.

Health-related quality-of-life in adolescent idiopathic scoliosis patients 25 years after treatment.

BACKGROUND: Since 1962 to the mid eighties the Harrington Rod instrumentation was the Golden standard for surgical treatment of Adolescent Idiopathic Scoliosis (AIS). The Boston braces were introduced in the 1970´s and are still used as a conservative treatment, for curves less than 40°. Very few long-term studies exists, focusing on the health related quality of life. The purpose of this study was to evaluate the long-term health related outcome, in a cohort of AIS patients, treated 25 years ago. METHOD: 219 consecutive patients treated with Boston brace (Brace) or posterior spinal fusion (PSF) using Harrington- DDT instrumentation between 1983 and 1990 at Rigshospitalet Copenhagen, were invited to participate in a long-term evaluation study. A validated Danish version of the Scoliosis Research Society 22R (SRS22R) and Short Form-36 (SF36v1) were administrated to the patients two weeks before the clinical and radiological examination. RESULTS: 159 (72,6 %) patients participated in the clinical follow up and questionnaires, 11 patients participated only in the questionnaires, 8 emigrated, 4 were excluded due to progressive neurological disease and 2 were deceased. The total follow up was 170 patients (83 %), and the average follow up was 24.5 years (22-30 years). SRS22R domain scores were within the range described as normal for the general population with no statistical difference between the groups except in the Satisfaction domain, where the PSF group had better scores than the braced group. The SF36 PCS and MCS scores in both AIS cohorts were similar to the scores for the general population. CONCLUSION: HRQOLs, as measured by the SRS22R and SF-36, of adult AIS patients treated with Boston brace or PSF during adolescence were similar to the general population. No clinical progression of the deformity has been detected during the 25-year follow up period. The PSF group had a small but statistically significant higher score in the Satisfaction domain compared to the braced group. TRIAL REGISTRATION: S-20110025 Regional Committees on Health Research Ethics for Southern Denmark.

Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for idiopathic scoliosis.

BACKGROUND CONTEXT: Idiopathic scoliosis is a spinal deformity affecting approximately 3% of otherwise healthy children or adolescents. The etiology is still largely unknown but has an important genetic component. Genome-wide association studies have identified a number of common genetic variants that are significantly associated with idiopathic scoliosis in Asian and Caucasian populations, rs11190870 close to the LBX1 gene being the most replicated finding. PURPOSE: The aim of the present study was to investigate the genetics of idiopathic scoliosis in a Scandinavian cohort by performing a candidate gene study of four variants previously shown to be associated with idiopathic scoliosis and exome sequencing of idiopathic scoliosis patients with a severe phenotype to identify possible novel scoliosis risk variants. STUDY DESIGN: This was a case control study. PATIENT SAMPLE: A total of 1,739 patients with idiopathic scoliosis and 1,812 controls were included. OUTCOME MEASURE: The outcome measure was idiopathic scoliosis. METHODS: The variants rs10510181, rs11190870, rs12946942, and rs6570507 were genotyped in 1,739 patients with idiopathic scoliosis and 1,812 controls. Exome sequencing was performed on pooled samples from 100 surgically treated idiopathic scoliosis patients. Novel or rare missense, nonsense, or splice site variants were selected for individual genotyping in the 1,739 cases and 1,812 controls. In addition, the 5'UTR, noncoding exon and promoter regions of LBX1, not covered by exome sequencing, were Sanger sequenced in the 100 pooled samples. RESULTS: Of the four candidate genes, an intergenic variant, rs11190870, downstream of the LBX1 gene, showed a highly significant association to idiopathic scoliosis in 1,739 cases and 1,812 controls (p=7.0×10(-18)). We identified 20 novel variants by exome sequencing after filtration and an initial genotyping validation. However, we could not verify any association to idiopathic scoliosis in the large cohort of 1,739 cases and 1,812 controls. We did not find any variants in the 5'UTR, noncoding exon and promoter regions of LBX1. CONCLUSIONS: Here, we confirm LBX1 as a susceptibility gene for idiopathic scoliosis in a Scandinavian population and report that we are unable to find evidence of other genes of similar or stronger effect.

Radiological Outcomes in Adolescent Idiopathic Scoliosis Patients More Than 22 Years After Treatment.

STUDY DESIGN: Longitudinal cohort. OBJECTIVES: To evaluate the long-term radiologic outcomes in adolescent idiopathic scoliosis (AIS) patients more than 22 years after treatment. SUMMARY OF BACKGROUND DATA: Although treatment for AIS is prophylactic and is aimed at preventing curve progression, very few studies report long-term outcomes of treatment. METHODS: AIS patients treated with Boston brace or posterior spinal fusion (PSF) with Harrington-dorso-transverse traction (DTT) instrumentation from 1983 to 1990 were requested to return to clinic. Subsequently, 36-inch standing radiographs were obtained after patient consent. Cobb angles were compared with pretreatment and immediate posttreatment radiographs. Any evidence of adjacent-level disease or local kyphosis was also noted. RESULTS: One hundred fifty-nine (78%) of 219 patients were available for follow-up, 66 braced and 93 surgical. There were 85 females with an average age at surgery of 14.3 years and an average age at follow-up of 37.6 years. The mean length of follow-up was 24.5 years (range, 22-30 years). There was a statistically significant curve progression of 2.9° in the PSF group. There was a greater degree of curve progression in the braced group (5.5°), but this was not statistically significant. Proximal segment degeneration was seen in 8 (5%), 2 in the brace cohort and 6 in the PSF cohort. Distal segment degeneration was seen in 26 (16%) patients, 4 treated with brace and 22 treated with PSF. No patient developed proximal junction kyphosis. Three patients in the PSF cohort required additional surgery for distal adding-on. Four patients had a noncontiguous L5-S1 fusion, three from the PSF cohort and one from the braced cohort. CONCLUSION: In this cohort with an average follow-up of 24.5 years, with 78% available for follow-up, both the braced and surgically treated patients had a very small degree of curve progression, with a small incidence of distal segment degeneration and reoperation. LEVEL OF EVIDENCE: III.

Increasing incidence of club foot with higher population density: incidence and geographical variation in Denmark over a 16-year period--an epidemiological study of 936,525 births.

BACKGROUND: The occurrence of club foot (CF) varies between countries and populations, and may be related to endogenous and exogenous factors. We analyzed the occurrence of CF in a whole country over a long period of time (16 years). METHODS: Patients born in Denmark with a foot deformity 1978-93 were identified from the National Patient Register and the Register of Inborn Malformations. The records for each patient were studied in the hospital departments to establish the diagnoses and to obtain additional information. Demographic data were obtained from the Danish National Demographical Institute and from the Danish Population Register. RESULTS: The incidence of isolated CF was 1.2/1,000 live births. It increased significantly during the study period, and the incidence of CF and the standardized morbidity ratio for CF were significantly positively correlated to population densities in the counties and the districts. There was no significant increase in the relative proportion of children with CF born to non-Scandinavian parents during the period. INTERPRETATION: The increasing incidence of isolated CF with higher population density indicates that there may be exogenous factors that are pathogenic.

Early weaning might reduce the psychological strain of Boston bracing: a study of 136 patients with adolescent idiopathic scoliosis at 3.5 years after termination of brace treatment.

From 1983 to 1990 a total of 136 patients with adolescent idiopathic scoliosis were treated with the Boston brace. With the aim of examining the social and psychological impact of the brace treatment all patients received a questionnaire at an average of 3.5 years after termination of the treatment. Ninety-three percent responded to the questionnaire. The overall picture was that the patient's daily activities and social contacts, not least with the opposite sex, were affected both during the bracing period and at follow-up. It is important that the indications for the treatment are assured, and weaning should be initiated at the latest 3 years after menarche.