Etiology Of Clubfoot Research Articles

Exome sequencing of 1190 non-syndromic clubfoot cases reveals HOXD12 as a novel disease gene

BackgroundClubfoot, presenting as a rigid inward and downward turning of the foot, is one of the most common congenital musculoskeletal anomalies. The aetiology of clubfoot is poorly understood and variants...

Does Generalized Hypermobility Increase the Risk of Relapse or Overcorrection in Idiopathic Clubfoot Treated with the Ponseti Method

Purpose: Previous studies have suggested a role for joint laxity in the etiology of clubfoot, however, the influence of joint laxity on the treatment and outcome idiopathic clubfoot has not been thoroughly investigated. An earlier study found that the presence of hypermobility lead to overcorrection of clubfoot in patients treated with extensive soft tissue release. The goal of this study was to determine if the presence of hypermobility influenced the treatment or short-term outcome of patients …

English

Talipes equinovarus (Clubfoot) is the commonest foot deformity with variable incidence across races. Exact etiology remains elusive. The objective of this study is to describe the epidemiology of clubfoot in our centre, looking for predisposing factors. This is a descriptive clinic based epidemiologic study of 106 feet belonging to 69 subjects from January 2014 – December 2015 was conducted. Structured questionnaires were administered to clinically confirmed clubfoot subject’s guardian or biologic mothers. Phenotypic data from clubfoot subject were also recorded. Analysis was done using IBM SPSS version 22 for windows. Results revealed the age range of the patients as 3 days to 9 years, with a mean age of 46.17 ± 92.03 weeks. Thirty-seven (53.7%) patients had bilateral deformity while 13 (18.8%) patients had right-sided deformity, and 19 (27.5%) patients had left-sided deformity. Majority 40 (58.0%) of the patients were firstborn out of which 28 were males. Only 2 (2.89%) patients are products of multiple gestations. All mothers were none smokers and there was no reported family history of foot deformities or clubfoot. The mean maternal age was 25.81 years ± 4.99 years. The average length/height of patients at presentation was 64.27 ± 23.93 cm. The average shoulder span of the patients at presentation was 23.93 ± 15.86 cm. The study thus revealed that young maternal age, gender and firstborn are predisposing factors in the etiology of clubfoot. Key words: Clubfoot, idiopathic, predisposing factors, epidemiology.

Are incidence and severity of clubfoot related to the season of birth?

This study was designed to determine whether the occurrence of clubfoot follows a seasonal pattern in neonates from eastern and south-eastern China and to speculate the potential etiology of clubfoot. We reviewed 239 neonates with clubfeet during a period of 4 years as well as the monthly neonatal population of the Sixth National Population Census. Seasonal variations in terms of month of birth and severity were analyzed. The incidence of clubfoot in neonates from eastern and south-eastern China showed seasonal variations, and the incidence was higher in autumn with a reference to the average birth rate in this corresponding area. No significant difference was found in severity of clubfoot. This seasonal pattern is of significant value to further understanding the etiology and pathogenesis of clubfoot in the corresponding area of China.

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 15 genes encoding proteins that control myofiber contractility in a cohort of both non-Hispanic White (NHW) and Hispanic families, identified positive associations (P < 0.05) with SNPs in 12 genes; only 1 was identified in a family-based validation dataset. Six SNPs in TNNC2 deviated from Hardy-Weinberg equilibrium 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.

Maternal smoking and the risk for clubfoot in infants

Clubfoot is one of the most common major birth defects, with a prevalence of approximately 1 per 1,000 live births. The etiology of clubfoot is complex and not well understood, and yet, few epidemiologic studies of risk factors have been conducted. Maternal smoking has been suggested as a possible risk factor. The purpose of this population-based, case-control study was to examine the association between maternal smoking and clubfoot. Data from the North Carolina Birth Defects Monitoring Program matched to North Carolina birth certificates and health services data were used in the analysis of 443 cases of clubfoot and 4,492 randomly sampled controls for the years 1999-2003. Smoking data were ascertained from the birth certificates, and the reliability of the data was assessed by comparing them with reported smoking from the North Carolina Pregnancy Risk Assessment Monitoring System. Multiple logistic regression was used to calculate crude and adjusted ORs and 95% CIs for smoking and clubfoot. The crude OR for maternal smoking during pregnancy and clubfoot was 1.49 (95% CI: 1.15, 1.92). Controlling for maternal age, race/ethnicity, infant's sex, and timing of prenatal care initiation did not appreciably change the results (adjusted OR 1.40; 95% CI: 1.07, 1.83). This study is consistent with the hypothesis that smoking during pregnancy is associated with a slightly increased risk of an infant being born with clubfoot. Further research is needed to confirm this association, and to identify potential genetic factors that may modify the magnitude of the risk.

NAT2 variation and idiopathic talipes equinovarus (clubfoot)

Idiopathic talipes equinovarus (ITEV), or isolated clubfoot, is a common developmental anomaly that is characterized by a rigid foot, adducted forefoot, cavus midfoot, equinovarus of the hindfoot, and hypoplastic calf musculature. The etiology of this common birth defect is largely unknown, but genetic factors have been implicated in population and family studies and maternal smoking during pregnancy has been identified as an environmental risk factor. The biotransformation of exogenous substances, such as tobacco smoke, is modulated by numerous genes including N-acetylation genes, NAT1 and NAT2. Functional variants of these genes exist and can be distinguished by genotyping. We hypothesized that variation in NAT1 and NAT2 genes might be associated with ITEV. To test this hypothesis, NAT1 and NAT2 were genotyped in a sample of 56 multiplex ITEV families, 57 trios with a positive family history and 160 simplex trios with ITEV. The results detected a slight decrease in the expected number of homozygotes for the NAT2 normal allele in the Hispanic simplex trios. In addition, in a pilot case-control study of ITEV, there were significantly more slow NAT2 acetylators among the cases. This suggests that slow acetylation may be a risk factor for ITEV. This study is the first to find evidence suggesting a role for a biotransformation candidate gene in the etiology of ITEV and provides a scientific foundation to further explore the contributions of other tobacco metabolism genes in the etiology of clubfoot.

Variation in CASP10 Gene Is Associated With Idiopathic Talipes Equinovarus

Idiopathic talipes equinovarus (ITEV), more commonly known as clubfoot, is a developmental deformity characterized by rigid ankle equinus, hindfoot varus, and forefoot adduction. This common birth defect is treatable, but the etiology of ITEV is largely unknown. Recently, a deletion in the chromosomal region 2q31-33 was found to be associated with clubfoot. Microsatellite markers spanning the region were genotyped in 57 multiplex ITEV families and 83 simplex trios. Family-based analysis revealed that two microsatellite markers, GATA149B10 and D2S1371, were associated with ITEV in the simplex trios. The 6cM region between the two markers contained the candidate genes CASP8, CASP10, and CFLAR. These genes encode proteins that are regulators of apoptosis, which is important during growth and development. Genotyping of SNPs throughout the genes in this sample of ITEV families has revealed positive linkage with association to the major allele of a variant in CASP10 in simplex ITEV white and Hispanic trios. This study is the first to find evidence for a candidate gene for ITEV and provides a scientific foundation to further explore the contributions of other apoptotic genes in the etiology of clubfoot.

Family history, maternal smoking, and clubfoot: an indication of a gene-environment interaction.

Although epidemiologic studies of some birth defects have suggested a gene-smoking interaction, the possibility of this interaction in clubfoot has not been examined. The authors analyzed risk factors among 346 infants with isolated clubfoot and 3,029 infants without defects from the Atlanta Birth Defects Case-Control Study. All infants were born during 1968-1980, and mothers were interviewed in 1982-1983. The authors examined the family history-smoking interaction as an indication of a gene-environment interaction. They defined "smoking" as smoking any time during the first 3 months of pregnancy and "family history" as having a first-degree relative with clubfoot. Conditional logistic regression (matching variables: race, birth hospital, and birth period) was used to obtain effect estimates. The adjusted odds ratios were 1.34 (95% confidence interval (CI): 1.04, 1.72) for smoking only, 6.52 (95% CI: 2.95, 14.41) for family history only, and 20.30 (95% CI: 7.90, 52.17) for a joint exposure of smoking and family history. The effect estimate for the joint exposure was higher than would be expected under either an additive or a multiplicative model of interaction and showed a statistically significant departure from additivity. This study confirms the importance of familial factors and smoking in the etiology of clubfoot and identifies a potentially important interaction.

Genetics of club foot in Maori and Pacific people

The role of major gene and multifactorial inheritance in the aetiology of club foot in the New Zealand Polynesian population was studied using 287 New Zealand Maori and Pacific club...

Aetiology of club foot

The Journal of Bone and Joint Surgery. British volumeVol. 76-B, No. 6 ArticlesFree AccessAetiology of club footHP AidemHP AidemSearch for more papers by this authorPublished Online:1 Nov 1994https://doi.org/10.1302/0301-620X.76B6.7983141AboutSectionsPDF/EPUB ToolsAdd to FavouritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetails Vol. 76-B, No. 6 Metrics Downloaded 57 times History Published online 1 November 1994 Published in print 1 November 1994 InformationCopyright © 1994, The British Editorial Society of Bone and Joint Surgery: All rights reservedPDF download

Arterial Abnormalities in Talipes Equinovarus as Assessed by Angiography and the Doppler Technique

Preoperative angiography in 30 uncorrected clubfeet demonstrated abnormal vascular patterns in all but two limbs with hypoplasia or premature termination of the anterior tibial and medial plantar arteries in the remainder. Postoperative Doppler studies in nine of the limbs with abnormal vessels indicated that these arteries were present. We suggest that the continuous-wave Doppler technique is less useful for identifying major arteries than either dissection or angiography. Furthermore, arterial dysgenesis may play a role in the etiology of clubfoot. Since the posterior tibial artery usually provides the sole arterial supply to the foot, this vessel must be preserved at surgery and during subsequent ankle dorsiflexion.

A genetic analysis of clubfoot in Hawaii.

The roles of major genes and multifactorial inheritance in the etiology of clubfoot (talipes equinovarus) were investigated based on 365 nuclear families consisting of three major racial groups of Hawaiians, Caucasians, and Orientals in Hawaii. Complex segregation analysis was employed using the mixed model with four parameters: major gene displacement (t), degree of dominance (d), gene frequency (q), and heritability (H). Heterogeneity was evident among the racial groups in the pattern of segregation of clubfoot. The most plausible genetic model is the presence of major gene effects with the multifactorial component for the Hawaiian and Caucasian groups, whereas no major gene action is evident for the Oriental group.

Neuromuscular studies in clubfoot.

The fundamental pathology in rigid clubfoot appears to be a neuromuscular defect. In order to test this hypothesis, 90 muscle biopsies were obtained from the posteromedial, peroneal, and some intrinsic muscles at surgical correction of 13 clubfoot patients. All were examined ultrastructurally, and 48 biopsies in nine of these patients were studied using enzyme specific histochemical stains at the light microscopic level. Neuromuscular junctions were isolated in the latter group. Consistent ultrastructural abnormalities were observed in all specimens. Histochemistry revealed a dominant Type I fiber population and Type I fiber grouping. A correlated increase in Type I neuromuscular junctions occurred in these areas. Since these changes are recognized as being neurogenically determined, a neuromuscular abnormality may be significant in the etiology of clubfoot.

Family studies and aetiology of club foot.

Family studies and aetiology of club foot.