Search tips
Search criteria

Results 1-25 (34)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
more »
1.  Genetics of Clubfoot 
Modern advances in genetics have allowed investigators to begin to identify the complex etiology of clubfoot. It has become increasingly apparent that clubfoot is a heterogeneous disorder with a polygenetic threshold model explaining its inheritance patterns. Several recent genetics studies have identified a key developmental pathway, the PITX1-TBX4 transriptional pathway, as being important in clubfoot etiology. Both PITX1 and TBX4 are uniquely expressed in the hindlimb which helps explain the foot phenotype seen with mutations in these transcription factors. Future studies are needed to develop animal models to determine the exact mechanisms by which these genetic abnormalities cause clubfoot and to test other hypotheses of clubfoot pathogenesis.
PMCID: PMC3229717  PMID: 21817922
2.  MYBPC1 mutations impair skeletal muscle function in zebrafish models of arthrogryposis 
Human Molecular Genetics  2013;22(24):4967-4977.
Myosin-binding protein C1 (MYBPC1) is an abundant skeletal muscle protein that is expressed predominantly in slow-twitch muscle fibers. Human MYBPC1 mutations are associated with distal arthrogryposis type 1 and lethal congenital contracture syndrome type 4. As MYBPC1 function is incompletely understood, the mechanism by which human mutations result in contractures is unknown. Here, we demonstrate using antisense morpholino knockdown, that mybpc1 is required for embryonic motor activity and survival in a zebrafish model of arthrogryposis. Mybpc1 morphant embryos have severe body curvature, cardiac edema, impaired motor excitation and are delayed in hatching. Myofibril organization is selectively impaired in slow skeletal muscle and sarcomere numbers are greatly reduced in mybpc1 knockdown embryos, although electron microscopy reveals normal sarcomere structure. To evaluate the effects of human distal arthrogryposis mutations, mybpc1 mRNAs containing the corresponding human W236R and Y856H MYBPC1 mutations were injected into embryos. Dominant-negative effects of these mutations were suggested by the resultant mild bent body curvature, decreased motor activity, as well as impaired overall survival compared with overexpression of wild-type RNA. These results demonstrate a critical role for mybpc1 in slow skeletal muscle development and establish zebrafish as a tractable model of human distal arthrogryposis.
PMCID: PMC3836476  PMID: 23873045
3.  Exome Sequencing Identifies a Rare HSPG2 Variant Associated with Familial Idiopathic Scoliosis 
G3: Genes|Genomes|Genetics  2014;5(2):167-174.
Idiopathic scoliosis occurs in 3% of individuals and has an unknown etiology. The objective of this study was to identify rare variants that contribute to the etiology of idiopathic scoliosis by using exome sequencing in a multigenerational family with idiopathic scoliosis. Exome sequencing was completed for three members of this multigenerational family with idiopathic scoliosis, resulting in the identification of a variant in the HSPG2 gene as a potential contributor to the phenotype. The HSPG2 gene was sequenced in a separate cohort of 100 unrelated individuals affected with idiopathic scoliosis and also was examined in an independent idiopathic scoliosis population. The exome sequencing and subsequent bioinformatics filtering resulted in 16 potentially damaging and rare coding variants. One of these variants, p.Asn786Ser, is located in the HSPG2 gene. The variant p.Asn786Ser also is overrepresented in a larger cohort of idiopathic scoliosis cases compared with a control population (P = 0.024). Furthermore, we identified additional rare HSPG2 variants that are predicted to be damaging in two independent cohorts of individuals with idiopathic scoliosis. The HSPG2 gene encodes for a ubiquitous multifunctional protein within the extracellular matrix in which loss of function mutation are known to result in a musculoskeletal phenotype in both mouse and humans. Based on these results, we conclude that rare variants in the HSPG2 gene potentially contribute to the idiopathic scoliosis phenotype in a subset of patients with idiopathic scoliosis. Further studies must be completed to confirm the effect of the HSPG2 gene on the idiopathic scoliosis phenotype.
PMCID: PMC4321025  PMID: 25504735
HSPG2; perlecan; idiopathic scoliosis; exome sequencing
5.  Use of the Ponseti method for recurrent clubfoot following posteromedial release 
Indian Journal of Orthopaedics  2008;42(1):68-72.
A child with recurrent or incompletely corrected clubfoot after previous extensive soft tissue release is treated frequently with revision surgery. This leads to further scarring, pain and limitations in range of motion. We have utilized the Ponseti method of manipulation and casting and when indicated, tibialis anterior tendon transfer, instead of revision surgery for these cases.
Materials and Methods:
A retrospective review of all children treated since 2002 (n = 11) at our institution for recurrent or incompletely corrected clubfoot after previous extensive soft tissue release was done. Clinical and operative records were reviewed to determine procedure performed. Ponseti manipulation and casting were done until the clubfoot deformity was passively corrected. Based on the residual equinus and dynamic deformity, heel cord lengthening or tenotomy and tibialis anterior transfer were then done. Clinical outcomes regarding pain, function and activity were reviewed.
Eleven children (17 feet) with ages ranging from 1.1 to 8.4 years were treated with this protocol. All were correctable with the Ponseti method with one to eight casts. Casts were applied until the only deformities remaining were either or both hindfoot equinus and dynamic supination. Nine feet required a heel cord procedure for equinus and 15 required tibialis anterior transfer for dynamic supination. Seven children have follow-up greater than one year (average 27.1 months) and have had excellent results. Two patients had persistent hindfoot valgus which required hemiepiphyseodesis of the distal medial tibia.
The Ponseti method, followed by tibialis anterior transfer and/or heel cord procedure when indicated, can be successfully used to correct recurrent clubfoot deformity in children treated with previous extensive soft tissue release. Early follow-up has shown correction without revision surgery. This treatment protocol prevents complications of stiffness, pain and difficulty in ambulating associated with multiple soft tissue releases for clubfeet.
PMCID: PMC2759586  PMID: 19823658
Recurrent clubfoot; posteromedial release; Ponseti method; tibialis anterior; tendon transfer
6.  Effects of Bracing in Adolescents with Idiopathic Scoliosis 
The New England journal of medicine  2013;369(16):1512-1521.
The role of bracing in patients with adolescent idiopathic scoliosis who are at risk for curve progression and eventual surgery is controversial.
We conducted a multicenter study that included patients with typical indications for bracing due to their age, skeletal immaturity, and degree of scoliosis. Both a randomized cohort and a preference cohort were enrolled. Of 242 patients included in the analysis, 116 were randomly assigned to bracing or observation, and 126 chose between bracing and observation. Patients in the bracing group were instructed to wear the brace at least 18 hours per day. The primary outcomes were curve progression to 50 degrees or more (treatment failure) and skeletal maturity without this degree of curve progression (treatment success).
The trial was stopped early owing to the efficacy of bracing. In an analysis that included both the randomized and preference cohorts, the rate of treatment success was 72% after bracing, as compared with 48% after observation (propensity-score–adjusted odds ratio for treatment success, 1.93; 95% confidence interval [CI], 1.08 to 3.46). In the intention-to-treat analysis, the rate of treatment success was 75% among patients randomly assigned to bracing, as compared with 42% among those randomly assigned to observation (odds ratio, 4.11; 95% CI, 1.85 to 9.16). There was a significant positive association between hours of brace wear and rate of treatment success (P<0.001).
Bracing significantly decreased the progression of high-risk curves to the threshold for surgery in patients with adolescent idiopathic scoliosis. The benefit increased with longer hours of brace wear. (Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and others; BRAIST number, NCT00448448.)
PMCID: PMC3913566  PMID: 24047455
7.  Copy number analysis of 413 isolated talipes equinovarus patients suggests role for transcriptional regulators of early limb development 
Talipes equinovarus is one of the most common congenital musculoskeletal anomalies and has a worldwide incidence of 1 in 1000 births. A genetic predisposition to talipes equinovarus is evidenced by the high concordance rate in twin studies and the increased risk to first-degree relatives. Despite the frequency of isolated talipes equinovarus and the strong evidence of a genetic basis for the disorder, few causative genes have been identified. To identify rare and/or recurrent copy number variants, we performed a genome-wide screen for deletions and duplications in 413 isolated talipes equinovarus patients using the Affymetrix 6.0 array. Segregation analysis within families and gene expression in mouse E12.5 limb buds were used to determine the significance of copy number variants. We identified 74 rare, gene-containing copy number variants that were present in talipes equinovarus probands and not present in 759 controls or in the Database of Genomic Variants. The overall frequency of copy number variants was similar between talipes equinovarus patients compared with controls. Twelve rare copy number variants segregate with talipes equinovarus in multiplex pedigrees, and contain the developmentally expressed transcription factors and transcriptional regulators PITX1, TBX4, HOXC13, UTX, CHD (chromodomain protein)1, and RIPPLY2. Although our results do not support a major role for recurrent copy number variations in the etiology of isolated talipes equinovarus, they do suggest a role for genes involved in early embryonic patterning in some families that can now be tested with large-scale sequencing methods.
PMCID: PMC3598331  PMID: 22892537
talipes equinovarus; microduplication; microdeletion; transcription
8.  CORR Insights™: Can a Triple Pelvic Osteotomy for Adult Symptomatic Hip Dysplasia Provide Relief of Symptoms for 25 Years? 
This CORR Insights™ is a commentary on the article ‘‘Can a Triple Pelvic Osteotomy for Adult Symptomatic Hip Dysplasia Provide Relief of Symptoms for 25 Years?” By van Stralen and colleagues available at DOI 10.1007/s11999-012-2701-0.
PMCID: PMC3549156  PMID: 23212770
9.  Autosomal Dominant Transmission of Accessory Navicular 
The accessory navicular bone is one of the most symptomatic bones of the foot. Although it has been reported to be present in various members of the same family, there is a lack of knowledge about its inheritance pattern. We report two large pedigrees in which accessory navicular is inherited in an autosomal dominant fashion with incomplete penetrance.
PMCID: PMC1888424  PMID: 15296212
11.  Treatment of Idiopathic Clubfoot 
Idiopathic clubfoot, one of the most common problems in pediatric orthopaedics, is characterized by a complex three-dimensional deformity of the foot. The treatment of clubfoot is controversial and continues to be one of the biggest challenges in pediatric orthopaedics. This controversy is due in part to the difficulty in measuring and evaluating the effectiveness of different treatment methods. We believe the heart of the debate is a lack of understanding of the functional anatomy of the deformity, the biological response of young connective tissue to injury and repair, and their combined effect on the long-term treatment outcomes. The aim of this review is not only to assess the different methods of clubfoot treatment used over the years in light of an evolving understanding of the pathoanatomy of the deformity, but to also clarify factors that allow a safe, logical approach to clubfoot management. Further research will be needed to fully understand the pathogenesis of clubfoot, as well as the long-term results and quality of life for the treated foot.
PMCID: PMC1888755  PMID: 10934626
12.  Pitx1 haploinsufficiency causes clubfoot in humans and a clubfoot-like phenotype in mice 
Human Molecular Genetics  2011;20(20):3943-3952.
Clubfoot affects 1 in 1000 live births, although little is known about its genetic or developmental basis. We recently identified a missense mutation in the PITX1 bicoid homeodomain transcription factor in a family with a spectrum of lower extremity abnormalities, including clubfoot. Because the E130K mutation reduced PITX1 activity, we hypothesized that PITX1 haploinsufficiency could also cause clubfoot. Using copy number analysis, we identified a 241 kb chromosome 5q31 microdeletion involving PITX1 in a patient with isolated familial clubfoot. The PITX1 deletion segregated with autosomal dominant clubfoot over three generations. To study the role of PITX1 haploinsufficiency in clubfoot pathogenesis, we began to breed Pitx1 knockout mice. Although Pitx1+/− mice were previously reported to be normal, clubfoot was observed in 20 of 225 Pitx1+/− mice, resulting in an 8.9% penetrance. Clubfoot was unilateral in 16 of the 20 affected Pitx1+/− mice, with the right and left limbs equally affected, in contrast to right-sided predominant hindlimb abnormalities previously noted with complete loss of Pitx1. Peroneal artery hypoplasia occurred in the clubfoot limb and corresponded spatially with small lateral muscle compartments. Tibial and fibular bone volumes were also reduced. Skeletal muscle gene expression was significantly reduced in Pitx1−/− E12.5 hindlimb buds compared with the wild-type, suggesting that muscle hypoplasia was due to abnormal early muscle development and not disuse atrophy. Our morphological data suggest that PITX1 haploinsufficiency may cause a developmental field defect preferentially affecting the lateral lower leg, a theory that accounts for similar findings in human clubfoot.
PMCID: PMC3177645  PMID: 21775501
13.  Variants in genes that encode muscle contractile proteins influence risk for isolated clubfoot 
Isolated clubfoot is a relatively common birth defect that affects approximately 4,000 newborns in the US each year. Calf muscles in the affected leg(s) are underdeveloped and remain small even after corrective treatment. This observation suggests that variants in genes that influence muscle development are priority candidate risk factors for clubfoot. This contention is further supported by the discovery that mutations in genes that encode components of the muscle contractile complex (MYH3, TPM2, TNNT3, TNNI2, and MYH8) cause congenital contractures, including clubfoot, in distal arthrogryposis (DA) syndromes. Interrogation of fifteen genes encoding proteins that control myofiber contractility in a cohort of both nonHispanic white (NHW) and Hispanic families, identified positive associations (p<0.05) with SNPs in twelve genes; only one was identified in a family-based validation dataset. Six SNPs in TNNC2 deviated from Hardy Weinberg Equilibrium (HWE) in mothers in our NHW discovery dataset. Relative risk and likelihood ratio tests showed evidence for a maternal genotypic effect with TNNC2/rs383112 and an inherited/child genotypic effect with two SNPs, TNNC2/rs4629 and rs383112. Associations with multiple SNPs in TPM1 were identified in the NHW discovery (rs4075583, p=0.01), family-based validation (rs1972041, p=0.000074) and case-control validation (rs12148828, p=0.04) datasets. Gene interactions were identified between multiple muscle contraction genes with many of the interactions involving at least one potential regulatory SNP. Collectively, our results suggest that variation in genes that encode contractile proteins of skeletal myofibers may play a role in the etiology of clubfoot.
PMCID: PMC3158831  PMID: 21834041
clubfoot; genetics; muscle; contraction; distal arthrogryposis; association study
14.  Vascular Abnormalities Correlate with Decreased Soft Tissue Volumes in Idiopathic Clubfoot 
Lower extremity vascular anomalies have been described for patients with clubfoot but few imaging studies have investigated effects on soft tissues such as fat and muscle. To make these assessments we need noninvasive, noncontrast agents to more safely image children.
We describe a novel noninvasive imaging protocol to identify vascular and soft tissue abnormalities in the lower limbs of patients with clubfoot and determine whether these abnormalities are present in patients who had recurrent clubfoot.
Patients and Methods
Three-dimensional noncontrast-enhanced MR angiography was used to identify vascular, bone, and soft tissue abnormalities in patients with clubfoot. We determined whether these abnormalities were more common in patients who had experienced recurrent clubfoot.
Four patients with isolated unilateral clubfoot had arterial anomalies in the clubfoot limb. All patients had less muscle volume in the affected limb, and nine of 11 patients (82%) had less subcutaneous fat, with a mean difference of 0.56 cm3 ± 0.36 cm3 (range, 0.08–1.12 cm3). Vascular anomalies and decreased fat and muscle volumes were present in all three patients with recurrent clubfoot.
We found a high frequency of vascular and soft tissue anomalies in the affected limbs of patients with unilateral clubfoot that may correlate with response to treatment.
Clinical Relevance
This approach has the potential to enhance our understanding of the anatomy of clubfoot and lead to a larger MRI study that may allow more accurate prediction of the risk of recurrent clubfoot.
PMCID: PMC3069258  PMID: 21042891
15.  Skeletal Muscle Abnormalities and Genetic Factors Related to Vertical Talus 
Congenital vertical talus is a fixed dorsal dislocation of the talonavicular joint and fixed equinus contracture of the hindfoot, causing a rigid deformity recognizable at birth. The etiology and epidemiology of this condition are largely unknown, but some evidence suggests it relates to aberrations of skeletal muscle. Identifying the tissue abnormalities and genetic causes responsible for vertical talus has the potential to lead to improved treatment and preventive strategies.
We therefore (1) determined whether skeletal muscle abnormalities are present in patients with vertical talus and (2) identified associated congenital anomalies and genetic abnormalities in these patients.
We identified associated congenital anomalies and genetic abnormalities present in 61 patients affected with vertical talus. We obtained abductor hallucis muscle biopsy specimens from the affected limbs of 11 of the 61 patients and compared the histopathologic characteristics with those of age-matched control subjects.
All muscle biopsy specimens (n = 11) had abnormalities compared with those from control subjects including combinations of abnormal variation in muscle fiber size (n = 7), type I muscle fiber smallness (n = 6), and abnormal fiber type predominance (n = 5). Isolated vertical talus occurred in 23 of the 61 patients (38%), whereas the remaining 38 patients had associated nervous system, musculoskeletal system, and/or genetic and genomic abnormalities. Ten of the 61 patients (16%) had vertical talus in one foot and clubfoot in the other. Chromosomal abnormalities, all complete or partial trisomies, were identified in three patients with vertical talus who had additional congenital abnormalities.
Vertical talus is a heterogeneous birth defect resulting from many diverse etiologies. Abnormal skeletal muscle biopsies are common in patients with vertical talus although it is unclear whether this is primary or secondary to the joint deformity. Associated anomalies are present in 62% of all cases.
PMCID: PMC3048242  PMID: 20645034
16.  Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes 
Human Molecular Genetics  2011;20(7):1456-1466.
Adolescent idiopathic scoliosis (AIS) is an unexplained and common spinal deformity seen in otherwise healthy children. Its pathophysiology is poorly understood despite intensive investigation. Although genetic underpinnings are clear, replicated susceptibility loci that could provide insight into etiology have not been forthcoming. To address these issues, we performed genome-wide association studies (GWAS) of ∼327 000 single nucleotide polymorphisms (SNPs) in 419 AIS families. We found strongest evidence of association with chromosome 3p26.3 SNPs in the proximity of the CHL1 gene (P < 8 × 10−8 for rs1400180). We genotyped additional chromosome 3p26.3 SNPs and tested replication in two follow-up case–control cohorts, obtaining strongest results when all three cohorts were combined (rs10510181 odds ratio = 1.49, 95% confidence interval = 1.29–1.73, P = 2.58 × 10−8), but these were not confirmed in a separate GWAS. CHL1 is of interest, as it encodes an axon guidance protein related to Robo3. Mutations in the Robo3 protein cause horizontal gaze palsy with progressive scoliosis (HGPPS), a rare disease marked by severe scoliosis. Other top associations in our GWAS were with SNPs in the DSCAM gene encoding an axon guidance protein in the same structural class with Chl1 and Robo3. We additionally found AIS associations with loci in CNTNAP2, supporting a previous study linking this gene with AIS. Cntnap2 is also of functional interest, as it interacts directly with L1 and Robo class proteins and participates in axon pathfinding. Our results suggest the relevance of axon guidance pathways in AIS susceptibility, although these findings require further study, particularly given the apparent genetic heterogeneity in this disease.
PMCID: PMC3049353  PMID: 21216876
17.  Evaluation of GPR50, hMel-1B, and ROR-Alpha Melatonin-Related Receptors and the Etiology of Adolescent Idiopathic Scoliosis 
Journal of pediatric orthopedics  2010;30(6):539-543.
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, while 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.
The coding, splice-site, and promoter regions of three melatonin-related receptors (hMel-1B, RORα, 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 three receptors. Additional cases and controls were evaluated when genetic variants were observed (for a total of 885 individuals).
No significant differences were found in the hMel-1B and RORα receptors. We found two 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.
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 previously been analyzed 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.
PMCID: PMC2928583  PMID: 20733416
adolescent idiopathic scoliosis; melatonin; genetics
18.  Common polymorphisms in human lysyl oxidase genes are not associated with the adolescent idiopathic scoliosis phenotype 
BMC Medical Genetics  2011;12:92.
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.
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.
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.
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.
PMCID: PMC3154146  PMID: 21740577
19.  Altered Transmission of HOX and Apoptotic SNPs Identify a Potential Common Pathway for Clubfoot 
Clubfoot is a common birth defect that affects 135,000 newborns each year worldwide. It is characterized by equinus deformity of one or both feet and hypoplastic calf muscles. Despite numerous study approaches, the cause(s) remains poorly understood although a multifactorial etiology is generally accepted. We considered the HOXA and HOXD gene clusters and insulin-like growth factor binding protein 3 (IGFBP3) as candidate genes because of their important roles in limb and muscle morphogenesis. Twenty SNPs from the HOXA and HOXD gene clusters and 12 SNPs in IGFBP3 were genotyped in a sample composed of nonHispanic white and Hispanic multiplex and simplex families (discovery samples) and a second sample of nonHispanic white simplex trios (validation sample). Four SNPs (rs6668, rs2428431, rs3801776 and rs3779456) in the HOXA cluster demonstrated altered transmission in the discovery sample, but only rs3801776, located in the HOXA basal promoter region, showed altered transmission in both the discovery and validation samples (p=0.004 and p=0.028). Interestingly, HOXA9 is expressed in muscle during development. A SNP in IGFBP3, rs13223993, also showed altered transmission (p=0.003) in the discovery sample. Gene-gene interactions were identified between variants in HOXA, HOXD and IGFBP3 and with previously associated SNPs in mitochondrial-mediated apoptotic genes. The most significant interactions were found between CASP3 SNPS and variants in HOXA, HOXD and IGFBP3. These results suggest a biologic model for clubfoot in which perturbation of HOX and apoptotic genes together affect muscle and limb development, which may cause the downstream failure of limb rotation into a plantar grade position.
PMCID: PMC2795347  PMID: 19938081
association study; genotyping; complex disease; clubfoot; HOXA; IGFBP3
20.  Magnetic Resonance Angiography in Clubfoot and Vertical Talus: A Feasibility Study 
Congenital vascular alterations of the normal adult arterial pattern have been associated with multiple congenital limb deformities including clubfoot and vertical talus. Investigators have observed absence of the anterior tibial artery and dorsalis pedis artery in most patients with clubfoot, and absence of the posterior tibial artery in all patients with vertical talus. We used magnetic resonance angiography to define the lower extremity vascular anatomy of two patients with left-sided vertical talus and right-sided clubfoot and one patient with bilateral vertical talus and cartilage-derived morphogenetic protein-1 (CDMP-1) gene mutation. Of the three patients, one had bilateral posterior tibial artery deficiencies while the other had bilateral anterior tibial artery deficiencies. The third patient with bilateral vertical talus and CDMP-1 mutation had normal arterial structure bilaterally. Though clubfoot and vertical talus have distinctly different clinical phenotypes, the association of each with arterial abnormalities suggests a common etiology during development. The presence of normal arterial structure in our patient with vertical talus and CDMP-1 mutation suggests that other nonvascular etiologies may be responsible for some cases of foot deformities.
Level of Evidence: Level IV, prognostic case series. See the Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC2664419  PMID: 19127394
21.  Skeletal Muscle Contractile Gene (TNNT3, MYH3, TPM2) Mutations Not Found in Vertical Talus or Clubfoot 
Arthrogryposis presents with lower limb contractures that resemble clubfoot and/or vertical talus. Recently, mutations in skeletal muscle contractile genes MYH3 (myosin heavy chain 3), TNNT3 (troponin T3), and TPM2 (tropomyosin 2) were identified in patients with distal arthrogryposis DA2A (Freeman-Sheldon syndrome) or DA2B (Sheldon-Hall syndrome). We asked whether the contractile genes responsible for distal arthrogryposis are also responsible for cases of familial clubfoot or vertical talus. We determined the frequency of MYH3, TNNT3, and TPM2 mutations in patients with idiopathic clubfoot, vertical talus, and distal arthrogryposis type 1 (DA1). We resequenced the coding exons of the MYH3, TNNT3, and TPM2 genes in 31 patients (five with familial vertical talus, 20 with familial clubfoot, and six with DA1). Variants were evaluated for segregation with disease in additional family members, and the frequency of identified variants was determined in a control population. In one individual with DA1, we identified a de novo TNNT3 mutation (R63H) previously identified in an individual with DA2B. No other causative mutations were identified, though we found several previously undescribed single-nucleotide polymorphisms of unknown importance. Although mutations in MYH3, TNNT3, and TPM2 are frequently associated with distal arthrogryposis syndromes, they were not present in patients with familial vertical talus or clubfoot. The TNNT3 R63H recurrent mutation identified in two unrelated individuals may be associated with either DA1 or DA2B.
Level of Evidence: Level II, prospective study. See the Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC2664426  PMID: 19142688
22.  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.
PMCID: PMC2664430  PMID: 19159115
23.  Update on Clubfoot: Etiology and Treatment 
Although clubfoot is one of the most common congenital abnormalities affecting the lower limb, it remains a challenge not only to understand its genetic origins but also to provide effective long-term treatment. This review provides an update on the etiology of clubfoot as well as current treatment strategies. Understanding the exact genetic etiology of clubfoot may eventually be helpful in determining both prognosis and the selection of appropriate treatment methods in individual patients. The primary treatment goal is to provide long-term correction with a foot that is fully functional and pain-free. To achieve this, a combination of approaches that applies the strengths of several methods (Ponseti method and French method) may be needed. Avoidance of extensive soft-tissue release operations in the primary treatment should be a priority, and the use of surgery for clubfoot correction should be limited to an “a la carte” mode and only after failed conservative methods.
Level of Evidence: Level V, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC2664438  PMID: 19224303
24.  Clubfoot: Etiology and Treatment: Editorial Comment 
PMCID: PMC2664446  PMID: 19241114
25.  Surgical treatment of traumatic pediatric humeral diaphyseal fractures with titanium elastic nails 
Nearly all pediatric humeral shaft fractures can be successfully treated with closed methods. Some patients, however, require internal fixation either because of an inability to maintain an adequate reduction, significant soft tissue injury, or concomitant fractures.
This is a retrospective review of all traumatic humeral shaft fractures treated at our hospitals between 1999 and 2006. Thirteen pediatric patients ranging in age from 4.8 to 16.7 years (mean age 12.0 years) were treated surgically with titanium elastic nails (TENs). Relative surgical indications included open fractures, inability to maintain an acceptable reduction, the presence of ipsilateral forearm fractures (floating elbow), concomitant lower extremity fractures, and closed head injury. Two patients had associated radial nerve injury at presentation.
The patients were followed for a mean of 29 months. All fractures healed in good alignment. There were no intraoperative complications, including neurologic or vascular injury, and no patient developed an infection postoperatively. Two patients had nail migration, one of whom developed nail protrusion through the skin. One patient with preoperative radial nerve injury ultimately underwent tendon transfer to restore wrist extension. Of the 13 patients, 12 reported a full return to sports and other activities with no limitations or discomfort.
When surgical stabilization of pediatric humeral shaft fractures is indicated, TEN fixation is effective and has a high rate of union and a low rate of complications. This technique is familiar to most orthopaedic surgeons treating pediatric fractures.
Level of evidence
Level of evidence: IV (case series)
PMCID: PMC2656946  PMID: 19308623
Complications; Elastic nails; Fixation; Fracture; Humerus; Intramedullary; Pediatric; Trauma

Results 1-25 (34)