A polygenic burden of rare variants across extracellular matrix genes among individuals with adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is a complex inherited spinal deformity whose etiology has been elusive. While common genetic variants are associated with AIS, they explain only a small portion of disease risk. To explore the role of rare variants in AIS susceptibility, exome sequence data of 391 severe AIS cases and 843 controls of European ancestry were analyzed using a pathway burden analysis in which variants are first collapsed at the gene level then by Gene Ontology terms. Novel non-synonymous/splice-site variants in extracellular matrix genes were significantly enriched in AIS cases compared with controls (P = 6 × 10(-9), OR = 1.7, CI = 1.4-2.0). Specifically, novel variants in musculoskeletal collagen genes were present in 32% (126/391) of AIS cases compared with 17% (146/843) of in-house controls and 18% (780/4300) of EVS controls (P = 1 × 10(-9), OR = 1.9, CI = 1.6-2.4). Targeted resequencing of six collagen genes replicated this association in combined 919 AIS cases (P = 3 × 10(-12), OR = 2.2, CI = 1.8-2.7) and revealed a highly significant single-gene association with COL11A2 (P = 6 × 10(-9), OR = 3.8, CI = 2.6-7.2). Importantly, AIS cases harbor mainly non-glycine missense mutations and lack the clinical features of monogenic musculoskeletal collagenopathies. Overall, our study reveals a complex genetic architecture of AIS in which a polygenic burden of rare variants across extracellular matrix genes contributes strongly to risk.

The 2018 Nicholas Andry Award: The Evidence Base for the Treatment of Developmental Dysplasia of the Hip: The Iowa Contribution.

This review summarizes evidence developed at the University of Iowa concerning the management and outcomes of developmental dysplasia of the hip beginning with the observations and analyses of Dr Arthur Steindler in the early 1900s. The strong evidence-based practice tradition established by Steindler 100 years ago continues as we critically evaluate our procedures and patient outcomes, only altering approaches when warranted by strong personal and research evidence. Our practice continues to be conservative in that we strive to produce the best environment possible for the hip to develop on its own and operate only when less invasive methods have failed.

Results of Ponseti Brasil Program: Multicentric Study in 1621 Feet: Preliminary Results.

BACKGROUND: The Ponseti method has been shown to be the most effective treatment for congenital clubfoot. The current challenge is to establish sustainable national clubfoot treatment programs that utilize the Ponseti method and integrate it within a nation's governmental health system. The Brazilian Ponseti Program (Programa Ponseti Brasil) has increased awareness of the utility of the Ponseti method and has trained >500 Brazilian orthopaedic surgeons in it. METHODS: A group of 18 of those surgeons had been able to reproduce the Ponseti clubfoot treatment, and compiled their initial results through structured spreadsheet. RESULTS: The study compiled 1040 patients for a total of 1621 feet. The average follow-up time was 2.3 years with an average correction time of approximately 3 months. Patients required an average of 6.40 casts to achieve correction. CONCLUSIONS: This study demonstrates that good initial correction rates are reproducible after training; from 1040 patients only 1.4% required a posteromedial release. LEVEL OF EVIDENCE: Level IV.

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.

A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes.

We report a mouse model of multiple osteochondromas (MO), an autosomal dominant disease in humans, also known as multiple hereditary exostoses (MHE or HME) and characterized by the formation of cartilage-capped osseous growths projecting from the metaphyses of endochondral bones. The pathogenesis of these osteochondromas has remained unclear. Mice heterozygous for Ext1 or Ext2, modeling the human genotypes that cause MO, occasionally develop solitary osteochondroma-like structures on ribs [Lin et al. (2000) Dev Biol 224(2):299-311; Stickens et al. (2005) Development 132(22):5055-5068]. Rather than model the germ-line genotype, we modeled the chimeric tissue genotype of somatic loss of heterozygosity (LOH), by conditionally inactivating Ext1 via head-to-head loxP sites and temporally controlled Cre-recombinase in chondrocytes. These mice faithfully recapitulate the human phenotype of multiple metaphyseal osteochondromas. We also confirm homozygous disruption of Ext1 in osteochondroma chondrocytes and their origin in proliferating physeal chondrocytes. These results explain prior modeling failures with the necessity for somatic LOH in a developmentally regulated cell type.

Online information exchanges for parents of children with a rare health condition: key findings from an online support community.

BACKGROUND: The Internet provides new opportunities for parents of children with difficult illnesses and disabilities to find information and support. The Internet is particularly important for caregivers of children with special needs due to numerous health-related decisions they face. For at-risk populations, online support communities can become key settings and channels for health promotion and communication. OBJECTIVE: This study is an initial exploration of the information-seeking and information-provision processes present in an online support community, which is an area of opportunity and interest for Internet-based medical research and practice. The aim of this study was to explore and describe information-related processes of uncertainty management in relationship to clubfoot. Specifically, the study explored interpersonal communication (information seeking and provision) in an online support community serving the needs of parents of children with clubfoot. METHODS: The study population consisted of messages posted to an online community by caregivers (parents) of children with clubfoot. The theoretical framework informing the study was the Uncertainty Management Theory (UMT). The study used content analysis to explore and categorize the content of 775 messages. RESULTS: Women authored 664 of 775 messages (86%) and men authored 47 messages (6%). Caregivers managed uncertainty through information seeking and provision behaviors that were dynamic and multilayered. The ratio of information-seeking messages to information-provision responses was 1 to 4. All five types of information-seeking behaviors proposed by Brashers' schema were identified, most of them being correlated. Information seeking using direct questions was found to be positively correlated to self-disclosure (r=.538), offering of a candidate answer (r=.318), and passive information seeking (r=.253). Self-disclosure was found to be positively correlated to provision of a candidate answer (r=.324), second-guessing (r=.149), and passive information seeking (r=.366). Provision of a candidate answer was found to be positively correlated with second-guessing (r=.193) and passive information seeking (r=.223). Second-guessing was found to be positively correlated to passive information seeking (r=.311). All correlations reported above were statistically significant (P<0.01). Of the 775 messages analyzed, 255 (33%) identified a medical professional or institution by name. Detailed medical information was provided in 101 (13%) messages, with the main source of information identified being personal experience rather than medical sources. CONCLUSION: Online communities can be an effective channel for caregivers, especially women, to seek and offer information required for managing clubfoot-related uncertainty. To enhance communication with parents, health care institutions may need to invest additional resources in user-friendly online information sources and online interactions with caregivers of children with special illnesses such as clubfoot. Furthermore, explorations of information-seeking and information-provision behaviors in online communities can provide valuable data for interdisciplinary health research and practice.

Exploring the link between dystonia genes and idiopathic scoliosis.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) is characterized by a complex curvature of the spine of unknown etiology. Unknown genetic factors likely play a role in disease pathogenesis. Recent studies suggest that AIS could result from central nervous system dysfunction and be related to dystonia. On the basis of this information, we hypothesized that genes linked to dystonia contribute to the pathogenesis of AIS. METHODS: To test this hypothesis, we evaluated the potential association between sequence variants in candidate dystonia genes and AIS. We sequenced the coding region of 5 selected dystonia-causing genes in 24 subjects with AIS, followed by targeted confirmation in additional 89 patients and 73 controls. RESULTS: No mutations were identified in any of the dystonia genes studied. CONCLUSIONS: We found no genetic link between dystonia and AIS. CLINICAL RELEVANCE: This investigation is a genetic evaluation of the association between dystonia and AIS. Despite the support in the literature for a pathogenic link between both the disorders, we have not identified any mutations in dystonia genes in patients with AIS.

Relapse after tibialis anterior tendon transfer in idiopathic clubfoot treated by the Ponseti method.

BACKGROUND: The Ponseti method for clubfoot correction has demonstrated excellent results. However, relapses are common and continue to be the most important problem facing clubfoot practitioners. Relapses usually require repeated casting and/or surgical intervention with tibialis anterior tendon transfer (TATT). However, recent data on relapses suggest that performing a successful TATT may not be a definitive cure as there may be other processes, such as neuromuscular deficits, that may result in subsequent relapses. METHODS: The authors reviewed 66 patients (102 clubfeet) treated by TATT for clubfoot relapses after successful initial treatment by the Ponseti method. Ten patients (15 clubfeet) experienced a subsequent relapse. Demographic, clinical, and treatment data was recorded. RESULTS: These patients had a tendency toward a greater number of casts at initial treatment (P=0.14) and they underwent relapse surgery earlier than those who did not relapse after TATT (P=0.05). Two of these patients had a neuromyopathy, diagnosed by muscle biopsy. The treatment of post-TATT relapse included casting (6 patients), ankle foot orthotic (4 patients), physical therapy (2 patients), or bracing (1 patient). One patient was treated by osteotomies of the cuboid and medial cuneiform and 1 patient had a peroneus longus to peroneus brevis tendon transfer. CONCLUSIONS: Performing a TATT may not be the definitive treatment for clubfoot relapses as neuromuscular deficits may be involved. In addition, these patients may be at an increased risk of relapse due to the earlier age at which TATT was performed. When there is a high index of suspicion, prompt diagnosis with muscle biopsy is warranted. LEVEL OF EVIDENCE: Level III (Case-control study).

Treatment results of late-relapsing idiopathic clubfoot previously treated with the Ponseti method.

BACKGROUND: Idiopathic clubfoot has a stubborn tendency for relapse, with most relapses happening within the first few years. However, a few patients relapse later, adding to the complexity of management. This study investigates the treatment results of relapsing clubfoot deformity after age 4. METHODS: Thirty-nine patients (60 feet) met the inclusion criteria. Age at initial treatment, previous treatment, number of casts and tenotomies, length of bracewear, and relapse presentation were recorded. Treatment of late relapse followed 1 of the 5 courses: (1) observation only (4 feet); (2) bracing (26 feet); (3) casting followed by bracing (7 feet); (4) casting followed by tibialis anterior tendon transfer (TATT) with or without open tendo Achilles lengthening (TAL) (8 feet); or (5) primary TATT±TAL (15 feet). Of the 37 feet treated initially with observation, bracing, or casting, 33 went on to have TATT (89%). Multiple other concurrent procedures were performed according to the specific deformities. These included plantar fasciotomy (6 feet), extensor hallicus longus recession (5 feet), limited posterior release 5 feet, and others (3 feet). Five feet underwent revision surgery after TATT, 2 of which ended in triple arthrodeses. RESULTS: Average age at final follow-up was 23.3 years (range, 8.5 to 50.6 y). Ninety percent of patients wore regular shoes, 41% had pain with activities, but only 18% were limited in function by their feet. Average ankle dorsiflexion was 6 degrees (range, -15 to 25 degrees). Mild residual deformities were noted in 55% of feet. CONCLUSIONS: This challenging group of patients with apparently persistent deforming biology achieves acceptable results with individualized evaluation and treatment of their foot deformities. LEVEL OF EVIDENCE: Therapeutic level IV.

Development of a surrogate biomodel for the investigation of clubfoot bracing.

Congenital talipes equinovarus (clubfoot) is a complex deformity of the lower extremity and foot occurring in 1/1000 live births. Regardless of treatment, whether conservative or surgical, clubfoot has a stubborn tendency to relapse, thus requiring postcorrection bracing. However, to date, there are no investigations specifically focused on clubfoot bracing from a bioengineering perspective. This study applied engineering principles to clubfoot bracing through construction of a surrogate biomodel. The surrogate was developed to represent an average 5-year-old human subject capable of biomechanical characteristics including joint articulation and kinematics. The components include skeleton, articulating joints, muscle-tendon systems, and ligaments. A protocol was developed to measure muscle-tendon tension in resting and braced positions of the surrogate. Measurement error ranged from 1% to 6% and was considered variance due to brace and investigator. In conclusion, this study shows that surrogate biomodeling is an accurate and repeatable method to investigate clubfoot bracing. The methodology is an effective means to evaluate wide ranging brace options and can be used to assist in future brace development and the tuning of brace parameters. Such patient-specific brace tuning may also lead to advanced braces that increase compliance.

The current management of idiopathic clubfoot revisited: results of a survey of the POSNA membership.

BACKGROUND: In 2001, the members of the Pediatric Orthopaedic Society of North America (POSNA) were surveyed regarding their approach to treating idiopathic clubfoot deformity. Since that time, several studies have advocated a change in the approach to treating this deformity, moving away from surgical release and toward less invasive methods. The purpose of this study was to assess the recent approach to treating clubfoot among the POSNA membership. METHODS: A survey was emailed to all POSNA members to define their current treatment of idiopathic clubfoot deformity. RESULTS: We received 323 responses. Ninety-three percent of participants were fellowship trained and were in practice for an average of 17.2 years. On an average, physicians reported each treating 23.5 new clubfoot patients during the year of survey. Nearly all (96.7%) of those surveyed stated that they use the Ponseti treatment method. The average time to initial correction was estimated at 7.1 weeks. Eighty-one percent of patients were estimated to require a tenotomy; 52.7% were performed under general anesthesia or conscious sedation, whereas 39.4% were done under local. Those surveyed estimated that 22% of clubfeet relapsed and 7% required a comprehensive release. Seventy-five percent of the respondents stated that their current treatment approach differed from how they were trained, and 82.7% were trained in the Ponseti method in the last few years. CONCLUSIONS: Our study provides convincing evidence that a large majority of pediatric orthopaedic surgeons now prefer the Ponseti method to treat idiopathic clubfoot and indicates that the move away from extensive release surgery occurred during the past decade. LEVEL OF EVIDENCE: Not applicable.

Common polymorphisms in human lysyl oxidase genes are not associated with the adolescent idiopathic scoliosis phenotype.

BACKGROUND: Although adolescent idiopathic scoliosis affects approximately 3% of adolescents, the genetic contributions have proven difficult to identify. Work in model organisms, including zebrafish, chickens, and mice, has implicated the lysyl oxidase family of enzymes in the development of scoliosis. We hypothesized that common polymorphisms in the five human lysyl oxidase genes (LOX, LOXL1, LOXL2, LOXL3, and LOXL4) may be associated with the phenotype of adolescent idiopathic scoliosis. METHODS: This was a case-control genetic association study. A total of 112 coding and tag SNPs in LOX, LOXL1, LOXL2, LOXL3, and LOXL4 were genotyped in a discovery cohort of 138 cases and 411 controls. Genotypes were tested for association with adolescent idiopathic scoliosis by logistic regression with a two degree of freedom genotypic model and gender as a covariate. Fourteen SNPs with p < 0.1 in the discovery phase were genotyped in an independent replication cohort of 400 cases and 506 controls. RESULTS: No evidence for significant association was found between coding or tag SNPs in LOX, LOXL1, LOXL2, LOXL3, and LOXL4 and the phenotype of adolescent idiopathic scoliosis. CONCLUSIONS: Despite suggestive evidence in model organisms, common variants and known coding SNPs in the five human lysyl oxidase genes do not confer increased genotypic risk for adolescent idiopathic scoliosis. The above methodology does not address rare variants or individually private mutations in these genes, and future research may focus on this area.

Health Literacy in Clubfoot: A Quantitative Assessment of the Readability, Understandability and Actionability of Online Patient Education Material.

BACKGROUND: Parents often access online resources to educate themselves when a child is diagnosed with clubfoot and/ or prior to treatment initiation. In order to be fully understood by the average adult American, online health information must be written at an elementary school reading level. It was hypothesized that current available online resources regarding clubfoot would score poorly on objective measures of readability (syntax reading grade-level), understandability (ability to process key messages), and actionability (providing actions the reader may take). Additionally, it was hypothesized that the outcomes measured would not correlate with the order of listed search results. METHODS: Patient education materials were identified utilizing two independent online searches (Google.com) of the term "Clubfoot". From the top 50 search results, websites were included if directed at educating patients and their families regarding clubfoot. News articles, non-text material (video), research and journal articles, industry websites, and articles not related to clubfoot were excluded. The readability of included resources was quantified using the Flesch Reading Ease Score (FRES), Flesch-Kincaid Grade Level (FKGL), Simple Measure of Gobbledygook (SMOG) Grade, Coleman-Liau Index (CLI), Gunning-Fog Index( GFI) and Automated Reading Index (ARI). The Patient Education Materials Assessment Tool (PEMAT) was used to assess actionability and understandability using a 0-100% scale for both measures of interest. RESULTS: Of the 55 unique websites, 37 websites (65.2%) met inclusion criteria. The mean FKGL was 9.2 (+/- 2.1) with only three websites (7.32%) having a reading level ≤6. Mean understandability and actionability scores were 67.2±12.6 and 25.4±25.2, respectively. Thirteen (35%) websites met the understandability threshold of ≥70% but no websites met the actionability criteria. No readability statistics were statistically associated with Google™ search rank (p=0.07). There was no association between readability (p=0.94) nor actionability (p=0.18) scores and Google™ rank. However, understandability scores did correlate with Google™ rank (p=0.02). CONCLUSION: Overall, online clubfoot educational materials scored poorly with respect to readability, understandability, and actionability. There is an association with Google™ search rank for understandability of clubfoot materials. However, readability and actionability are not significantly associated with search rank. In the era of shared decision-making, efforts should be made by medical professionals to improve the readability, understandability, and actionability of online resources in order to optimize parent understanding and facilitate effective outcomes.Level of Evidence.

Microenvironment alters epigenetic and gene expression profiles in Swarm rat chondrosarcoma tumors.

BACKGROUND: Chondrosarcomas are malignant cartilage tumors that do not respond to traditional chemotherapy or radiation. The 5-year survival rate of histologic grade III chondrosarcoma is less than 30%. An animal model of chondrosarcoma has been established--namely, the Swarm Rat Chondrosarcoma (SRC)--and shown to resemble the human disease. Previous studies with this model revealed that tumor microenvironment could significantly influence chondrosarcoma malignancy. METHODS: To examine the effect of the microenvironment, SRC tumors were initiated at different transplantation sites. Pyrosequencing assays were utilized to assess the DNA methylation of the tumors, and SAGE libraries were constructed and sequenced to determine the gene expression profiles of the tumors. Based on the gene expression analysis, subsequent functional assays were designed to determine the relevancy of the specific genes in the development and progression of the SRC. RESULTS: The site of transplantation had a significant impact on the epigenetic and gene expression profiles of SRC tumors. Our analyses revealed that SRC tumors were hypomethylated compared to control tissue, and that tumors at each transplantation site had a unique expression profile. Subsequent functional analysis of differentially expressed genes, albeit preliminary, provided some insight into the role that thymosin-ß4, c-fos, and CTGF may play in chondrosarcoma development and progression. CONCLUSION: This report describes the first global molecular characterization of the SRC model, and it demonstrates that the tumor microenvironment can induce epigenetic alterations and changes in gene expression in the SRC tumors. We documented changes in gene expression that accompany changes in tumor phenotype, and these gene expression changes provide insight into the pathways that may play a role in the development and progression of chondrosarcoma. Furthermore, specific functional analysis indicates that thymosin-ß4 may have a role in chondrosarcoma metastasis.

Epidemiology of congenital idiopathic talipes equinovarus in Iowa, 1997-2005.

Congenital idiopathic talipes equinovarus (ITEV), also known as clubfoot, is a well-recognized foot deformity. To date, prevalence estimates and descriptive data reported for ITEV have varied due to differences in study methodology. Using population-based surveillance data collected by the Iowa Registry for Congenital and Inherited Disorders, we examined isolated ITEV births delivered from 1997 through 2005 and compared to live births in Iowa during the same time period. An overall prevalence was calculated for live, singleton full-term births only. Prevalence odds ratios (POR)s and 95% confidence intervals (CI)s were examined for selected infant and parental characteristics. The prevalence of isolated ITEV was 11.4 per 10,000 live, singleton full-term births (95% CI = 10.3, 12.6), with no significant variation in prevalence during the study period. Increased PORs were found for males (POR 1.8; 95% CI = 1.5, 2.3) and maternal smoking during pregnancy (POR = 1.5, 95% CI = 1.2, 1.9); low birth weight (<2,500 g) showed an increase among females (POR = 3.2, 95% CI = 1.5, 6.9) but not males (POR = 0.9, 95% CI = 0.3, 2.8). Elevated, but non-significant, PORs were found for season of birth, maternal education, and trimester prenatal care was initiated; decreased PORs were found for fetal presentation, maternal race/ethnicity, parity, area of residence, and parental age at delivery. Our study of a well-defined, homogenous sample suggested that prevalence of isolated ITEV in Iowa was similar to that reported in other population-based studies and provided support for some, but not all, previously reported associations with infant and parental characteristics. More detailed, longitudinal studies of isolated ITEV are recommended.

Evaluation of embryonic and perinatal myosin gene mutations and the etiology of congenital idiopathic clubfoot.

BACKGROUND: Congenital idiopathic clubfoot is the most common musculoskeletal birth defect that develops during the fetal period, but with no known etiology. MYH 2, 3, 7, and 8 are expressed embryonically or perinatally, the period during which congenital idiopathic clubfoot develops; are all components of Type II muscle, which is consistently decreased in clubfoot patients; and are associated with several muscle contracture syndromes that have associated clubfoot deformities. In this study, we hypothesized that a mutation in an embryonic or perinatal myosin gene could be associated with congenital idiopathic clubfoot. METHODS: We screened the exons, splice sites, and predicted promoters of 24 bilateral congenital idiopathic clubfoot patients and 24 matched controls in MYH 1, 2, 3, and 8 via sequence-based analysis, and screened an additional 76 patients in each discovered SNP. RESULTS: Although many single-nucleotide polymorphisms were found; none proved to be significantly associated with the phenotype of congenital idiopathic clubfoot. Also, no known mutations that cause distal arthrogryposis syndromes were found in the congenital idiopathic clubfoot patients. CONCLUSIONS: These findings demonstrate that congenital idiopathic clubfoot has a different pathophysiology than the clubfoot seen in distal arthrogryposis syndromes, and defects in myosin are most likely not directly responsible for the development of congenital clubfoot. Given the complexity of early myogenesis, many regulatory candidate genes remain that could cause defects in the hypaxial musculature that is invariably observed in congenital idiopathic clubfoot. CLINICAL RELEVANCE: This study further differentiates congenital idiopathic clubfoot as distinct from other complex genetic syndromes that can present with similar deformities, and thus facilitates further research to improve the clinical diagnosis and treatment of congenital idiopathic clubfoot.

Evaluation of GPR50, hMel-1B, and ROR-alpha melatonin-related receptors and the etiology of adolescent idiopathic scoliosis.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity in children. Studies have shown low melatonin levels resulting from pinealectomy in chickens and mice result in the development scoliosis, whereas supplementation with melatonin after the pinealectomy prevented it. The mere characterization of low melatonin levels is not sufficient to explain the development of idiopathic scoliosis in primates and humans, but we hypothesize that a mutation in melatonin-related receptors may be involved with the development of scoliosis. METHODS: The coding, splice-site, and promoter regions of 3 melatonin-related receptors (hMel-1B, RORalpha, and GPR50) were evaluated by DNA sequencing for variants associated with the phenotype of adolescent idiopathic scoliosis. An initial screening of 50 scoliosis patients with adolescent idiopathic scoliosis was compared with 50 controls by DNA sequencing of the 3 receptors. Additional cases and controls were evaluated when genetic variants were observed (for a total of 885 individuals). RESULTS: No significant differences were found in the hMel-1B and RORalpha receptors. We found 2 cSNPs in GPR50 (rs561077 and rs13440581) in the initial 50 patients. To evaluate the significance of these cSNPs, an additional 356 patients and 429 controls were analyzed. When the combined groups were analyzed, no significant associations were observed. CONCLUSIONS: Despite the observed relationship between melatonin and scoliosis, there is no significant association between mutations found in any known melatonin-related receptors with adolescent idiopathic scoliosis. The strong evidence of a melatonin-related cause for the development of idiopathic scoliosis still encourages research into undiscovered melatonin-related receptors, melatonin-related hormones, and the catalytic enzymes for the serotonin-melatonin pathway. CLINICAL RELEVANCE: This investigation is a genetic testing of the remaining currently known melatonin-related receptors that have not been analyzed earlier for association with AIS. Given the support in the literature of a relationship between melatonin and AIS, we have shown no mutations in any of the known melatonin-related receptor in patients with AIS.

Adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) affects 1-3% of children in the at-risk population of those aged 10-16 years. The aetiopathogensis of this disorder remains unknown, with misinformation about its natural history. Non-surgical treatments are aimed to reduce the number of operations by preventing curve progression. Although bracing and physiotherapy are common treatments in much of the world, their effectiveness has never been rigorously assessed. Technological advances have much improved the ability of surgeons to safely correct the deformity while maintaining sagittal and coronal balance. However, we do not have long-term results of these changing surgical treatments. Much has yet to be learned about the general health, quality of life, and self-image of both treated and untreated patients with AIS.

Evaluation of CAND2 and WNT7a as candidate genes for congenital idiopathic clubfoot.

Congenital idiopathic clubfoot is a common pediatric musculoskeletal deformity with no known etiology. The deformity reportedly follows a Mendelian pattern of inheritance. Recent work has demonstrated linkage in chromosome 3 and 13 in a large, multigeneration, highly penetrant family with idiopathic clubfoot. From the linkage region on chromosome 3, we selected the candidate genes CAND2 and WNT7a, which are involved in lower extremity development, and hypothesized mutations in these genes would be associated with the phenotype of congenital idiopathic clubfoot. The CAND2 gene was sequenced in 256 clubfoot patients, and 75 control patients, while WNT7a was screened using 56 clubfoot patients and 50 control patients. We found a polymorphism in each gene, but the single nucleotide change in CAND2 was a silent mutation that did not alter the amino acid product, and the single nucleotide change in WNT7a was in the upstream, non-coding or promoter region before the start codon. Based on these results it is unlikely CAND2 and WNT7a are the major genes that causes clubfoot, however WNT7a might be one of many genes that could increase susceptibility to develop clubfoot but do not directly cause it.

Results of the Ponseti method in patients with clubfoot associated with arthrogryposis.

Clubfoot associated with arthrogryposis has been traditionally considered very resistant to manipulation and casting, and therefore has required surgical correction. The purpose of this study was to evaluate the results of the Ponseti method of clubfoot casting in this patient population. We reviewed the records of patients with clubfoot associated with arthrogryposis consecutively treated at our respective institutions from January 1992 to December 2004. All patients were treated by serial manipulations and casting following the principles of the Ponseti method. Main outcome measures included initial correction of the deformity, relapses and the need for surgical releases or any other surgeries. Average age at last follow up was 4.6 years. There were 16 patients, all with bilateral deformities (32 clubfeet). there were 11 males and 5 females. Nine patients had both upper and lower extremity involvement. Seven patients had previous treatment elsewhere and one patient had an Achilles tenotomy. Initial correction was obtained in all but 1 patient. Average number of casts required for correction was 7 (range: 5 to 12). Average post-tenotomy dorsiflexion was 5 degrees. One patient required a posterior-medial release (PMR) for insufficient initial correction. Four cases required subsequent surgery for relapses (1 bilateral PMR with a repeat left PMR; 2 posterior releases (PR), 1 PR and anterior tibialis transfer (ATT), and 1 ATT). No talectomies were required. This study demonstrates that the Ponseti method is very effective for the correction of patients with clubfoot associated to arthrogryposis. Although this deformity is more rigid than in idiopathic clubfoot, many cases can be corrected when started in the first few weeks after birth.