Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Orthopaedic Surgery and Research
Published in: Journal of Orthopaedic Surgery and Research 1/2018

Open Access 01-12-2018 | Systematic review

The etiology of idiopathic congenital talipes equinovarus: a systematic review

Authors: Vito Pavone, Emanuele Chisari, Andrea Vescio, Ludovico Lucenti, Giuseppe Sessa, Gianluca Testa

Published in: Journal of Orthopaedic Surgery and Research | Issue 1/2018

Login to get access

Abstract

Background

Also known as clubfoot, idiopathic congenital talipes equinovarus (ICTEV) is the most common pediatric deformity and occurs in 1 in every 1000 live births. Even though it has been widely researched, the etiology of ICTEV remains poorly understood and is often described as being based on a multifactorial genesis. Genetic and environmental factors seem to have a major role in the development of this disease. Thus, the aim of this review is to analyze the available literature to document the current evidence on ICTEV etiology.

Methods

The literature on ICTEV etiology was systematically reviewed using the following inclusion criteria: studies of any level of evidence, reporting clinical or preclinical results, published in the last 20 years (1998–2018), and dealing with the etiology of ICTEV.

Results

A total of 48 articles were included. ICTEV etiology is still controversial. Several hypotheses have been researched, but none of them are decisive. Emerging evidence suggests a role of several pathways and gene families associated with limb development (HOX family; PITX1-TBX4), the apoptotic pathway (caspases), and muscle contractile protein (troponin and tropomyosin), but a major candidate gene has still not been identified. Strong recent evidence emerging from twin studies confirmed major roles of genetics and the environment in the disease pathogenesis.

Conclusions

The available literature on the etiology of ICTEV presents major limitations in terms of great heterogeneity and a lack of high-profile studies. Although many studies focus on the genetic background of the disease, there is lack of consensus on one or multiple targets. Genetics and smoking seem to be strongly associated with ICTEV etiology, but more studies are needed to understand the complex and multifactorial genesis of this common congenital lower-limb disease.
Literature
1.
Lovell ME, Morcuende JA. Neuromuscular disease as the cause of late clubfoot relapses: report of 4 cases. Iowa Orthop J. 2007;27:82–4.PubMedPubMedCentral
2.
Hester TW, Parkinson LC, Robson J, Misra S, Sangha H, Martin JE. A hypothesis and model of reduced fetal movement as a common pathogenetic mechanism in clubfoot. Med Hypotheses. 2009;73:986–8.CrossRefPubMed
3.
Basit S, Khoshhal KI. Genetics of clubfoot; recent progress and future perspectives. Eur J Med Genet. 2018;61(2):107–13.CrossRefPubMed
4.
Yong BC, Xun FX, Zhao LJ, Deng HW, Xu HW. A systematic review of association studies of common variants associated with idiopathic congenital talipes equinovarus (ICTEV) in humans in the past 30 years. Springerplus. 2016;5(1):896.CrossRefPubMedPubMedCentral
5.
Smythe T, Kuper H, Macleod D, Foster A, Lavy C. Birth prevalence of congenital talipes equinovarus in low- and middle-income countries: a systematic review and meta-analysis. Trop Med Int Heal. 2017;22(3):269–85.CrossRef
6.
7.
Zionts LE, Jew MH, Ebramzadeh E, Sangiorgio SN. The influence of sex and laterality on clubfoot severity. J Pediatr Orthop. 2017;37(2):e129–33.CrossRefPubMed
8.
Pavone V, Bianca S, Grosso G, Pavone P, Mistretta A, Longo MR, et al. Congenital talipes equinovarus: an epidemiological study in Sicily. Acta Orthop. 2012;83(3):294–8.CrossRefPubMedPubMedCentral
9.
Wijayasinghe SR, Abeysekera WYM, Dharmaratne TSS. Descriptive epidemiology of congenital clubfoot deformity in Sri Lanka. J Coll Physicians Surg Pak. 2018;28(2):166–8.CrossRefPubMed
10.
McConnell L, Cosma D, Vasilescu D, Morcuende J. Descriptive epidemiology of clubfoot in Romania: a clinic-based study. Eur Rev Med Pharmacol Sci. 2016;20(2):220–4.PubMed
11.
Palma M, Cook T, Segura J, Pecho A, Morcuende JA. Descriptive epidemiology of clubfoot in Peru: a clinic-based study. Iowa Orthop J. 2013;33:167–71.PubMedPubMedCentral
12.
Kruse LM, Dobbs MB, Gurnett CA. Polygenic threshold model with sex dimorphism in clubfoot inheritance: the Carter effect. J Bone Joint Surg Am. 2008;90(12):2688–94.CrossRefPubMedPubMedCentral
13.
14.
Pavone V, Testa G, Costarella L, Pavone P, Sessa G. Congenital idiopathic talipes equinovarus: an evaluation in infants treated by the Ponseti method. Eur Rev Med Pharmacol Sci. 2013;17(19):2675–9.PubMed
15.
Hosseinzadeh P, Kelly DM, Zionts LE. Management of the relapsed clubfoot following treatment using the Ponseti method. J Am Acad Orthop Surg. 2017;25(3):195–203.CrossRefPubMed
16.
Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred Reporting Items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.CrossRefPubMedPubMedCentral
17.
Gurnett CA, Alaee F, Kruse LM, Desruisseau DM, Hecht JT, Wise CA, et al. Asymmetric lower-limb malformations in individuals with homeobox PITX1 gene mutation. Am J Hum Genet. 2008;83(5):616–22.CrossRefPubMedPubMedCentral
18.
19.
Pagnotta G, Boccanera F, Rizzo G, Agostino R, Gougoulias N, Maffulli N. Bilateral clubfoot in three homozygous preterm triplets. J Foot Ankle Surg. 2011;50(6):718–20.CrossRefPubMed
20.
Sahin O, Yildirim C, Akgun RC, Haberal B, Yazici AC, Tuncay IC. Consanguineous marriage and increased risk of idiopathic congenital talipes equinovarus: a case-control study in a rural area. J Pediatr Orthop. 2013;33(3):333–8.CrossRefPubMed
21.
Alvarado DM, Buchan JG, Frick SL, Herzenberg JE, Dobbs MB, Gurnett CA. Copy number analysis of 413 isolated talipes equinovarus patients suggests role for transcriptional regulators of early limb development. Eur J Hum Genet. 2013;21(4):373–80.CrossRefPubMed
22.
Shyy W, Dietz F, Dobbs MB, Sheffield VC, Morcuende JA. Evaluation of CAND2 and WNT7a as candidate genes for congenital idiopathic clubfoot. Clin Orthop Relat Res. 2009;467(5):1201–5.CrossRefPubMedPubMedCentral
23.
Shyy W, Wang K, Sheffield VC, Morcuende JA. Evaluation of embryonic and perinatal myosin gene mutations and the etiology of congenital idiopathic clubfoot. J Pediatr Orthop. 2010;30(3):231–4.CrossRefPubMed
24.
Herceg MB, Weiner DS, Agamanolis DP, Hawk D. Histologic and histochemical analysis of muscle specimens in idiopathic talipes equinovarus. J Pediatr Orthop. 2006;26(1):91–3.CrossRefPubMed
25.
Wang LL, Fu WN, Li-Ling J, Li ZG, Li LY, Sun KL. HOXD13 may play a role in idiopathic congenital clubfoot by regulating the expression of FHL1. Cytogenet Genome Res. 2008;121(3–4):189–95.CrossRefPubMed
26.
Ippolito E, De Maio F, Mancini F, Bellini D, Orefice A. Leg muscle atrophy in idiopathic congenital clubfoot: is it primitive or acquired? J Child Orthop. 2009;3(3):171–8.CrossRefPubMedPubMedCentral
27.
Hecht JT, Ester A, Scott A, Wise CA, Iovannisci DM, Lammer EJ, et al. NAT2 variation and idiopathic talipes equinovarus (clubfoot). Am J Med Genet Part A. 2007;143A(19):2285–91.CrossRefPubMed
28.
Ošt'ádal M, Eckhardt A, Herget J, Mikšík I, Dungl P, Chomiak J, et al. Proteomic analysis of the extracellular matrix in idiopathic pes equinovarus. Mol Cell Biochem. 2015;501(1–2):133–9.CrossRef
29.
Gurnett CA, Alaee F, Desruisseau D, Boehm S, Dobbs MB. Skeletal muscle contractile gene (TNNT3, MYH3, TPM2) mutations not found in vertical talus or clubfoot. Clin Orthop Relat Res. 2009;467(5):1195–200.CrossRefPubMedPubMedCentral
30.
Wang Z, Yan N, Liu L, Cao D, Gao M, Lin C, Jin C. SOX9 overexpression plays a potential role in idiopathic congenital talipes equinovarus. Mol Med Rep. 2013;7(3):821–5.CrossRefPubMed
31.
Cao D, Jin C, Ren M, Lin C, Zhang X, Zhao N. The expression of Gli3, regulated by HOXD13, may play a role in idiopathic congenital talipes equinovarus. BMC Musculoskelet Disord. 2009;10(1):142.CrossRefPubMedPubMedCentral
32.
33.
Parker SE, Mai CT, Strickland MJ, Olney RS, Rickard R, Marengo L, et al. Multistate study of the epidemiology of clubfoot. Birth Defects Res A Clin Mol Teratol. 2009;85(11):897–904.CrossRefPubMed
34.
Hackshaw A, Rodeck C, Boniface S. Maternal smoking in pregnancy and birth defects: a systematic review based on 173 687 malformed cases and 11.7 million controls. Hum Reprod Update. 2011;17(5):589–604.CrossRefPubMedPubMedCentral
35.
Dickinson KC, Meyer RE, Kotch J. Maternal smoking and the risk for clubfoot in infants. Birth Defects Res A Clin Mol Teratol. 2008;82(2):86–91.CrossRefPubMed
36.
Honein MA, Paulozzi LJ, Moore CA. Family history, maternal smoking, and clubfoot: an indication of a gene-environment interaction. Am J Epidemiol. 2000;152(7):658–65.CrossRefPubMed
37.
Wang L, Jin C, Liu L, Zhang X, Ji S, Sun K. Analysis of association between 5’ HOXD gene and idiopathic congenital talipes equinovarus. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2005;22(6):653–6.PubMed
38.
Ester AR, Weymouth KS, Burt A, Wise CA, Scott A, Gurnett CA. Altered transmission of HOX and apoptotic SNPs identify a potential common pathway for clubfoot. Am J Med Genet A. 2009;149A(12):2745–52.CrossRefPubMedPubMedCentral
39.
Alvarado DM, McCall K, Hecht JT, Dobbs MB, Gurnett CA. Deletions of 5’ HOXC genes are associated with lower extremity malformations, including clubfoot and vertical talus. J Med Genet. 2016;53(4):250–5.CrossRefPubMedPubMedCentral
40.
Weymouth KS, Blanton SH, Powell T, Patel CV, Savill SA, Hecht JT. Functional assessment of clubfoot associated HOXA9, TPM1, and TPM2 variants suggests a potential gene regulation mechanism. Clin Orthop Relat Res. 2016;474(7):1726–35.CrossRefPubMedPubMedCentral
41.
Liu LY, Jin CL, Jiang L, Lin CK. Expression of COL9A1 gene and its polymorphism in children with idiopathic congenital talipes equinovarus. Zhongguo Dang Dai Er Ke Za Zhi. 2011;13(6):478–81.PubMed
42.
Zhao XL, Wang YJ, Wu YL, Han WH. Role of COL9A1 genetic polymorphisms in development of congenital talipes equinovarus in a Chinese population. Genet Mol Res. 2016;15(4).
43.
Zhang X, Jin CL, Liu LY, Zhao N, Zhang LJ, Ji SJ. Association and mutation analysis of GLI3 gene in idiopathic congenital talipes equinovarus. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2006;23(5):551–4.PubMed
44.
Lu W, Bacino CA, Richards BS, Alvarez C, VanderMeer JE, Vella M, et al. Studies of TBX4 and chromosome 17q23.1q23.2: an uncommon cause of nonsyndromic clubfoot. Am J Med Genet A. 2012;158(7):1620–7.CrossRef
45.
Peterson JF, Ghaloul-Gonzalez L, Madan-Khetarpal S, Hartman J, Surti U, Rajkovic A, et al. Familial microduplication of 17q23.1-q23.2 involving TBX4 is associated with congenital clubfoot and reduced penetrance in females. Am J Med Genet A. 2014;164(2):364–9.CrossRef
46.
Alvarado DM, McCall K, Aferol H, Silva MJ, Garbow JR, Spees WM, et al. Pitx1 haploinsufficiency causes clubfoot in humans and a clubfoot-like phenotype in mice. Hum Mol Genet. 2011;20(20):3943–52.CrossRefPubMedPubMedCentral
47.
Alvarado DM, Aferol H, McCall K, Huang JB, Techy M, Buchan J, et al. Familial isolated clubfoot is associated with recurrent chromosome 17q23.1q23.2 microduplications containing TBX4. Am J Hum Genet. 2010;87:154–60.CrossRefPubMedPubMedCentral
48.
Dobbs MB, Gurnett CA, Pierce B, Exner GU, Robarge J, Morcuende JA, et al. HOXD10 M319K mutation in a family with isolated congenital vertical talus. J Orthop Res. 2006;24(3):448–53.CrossRefPubMed
49.
Shrimpton AE, Levinsohn EM, Yozawitz JM, Packard DS Jr, Cady RB, Middleton FA, et al. A HOX gene mutation in a family with isolated congenital vertical talus and Charcot-Marie-Tooth disease. Am J Hum Genet. 2004;75(1):92–6.CrossRefPubMedPubMedCentral
50.
Heck AL, Bray MS, Scott A, Blanton SH, Hecht JT. Variation in CASP10 gene is associated with idiopathic talipes equinovarus. J Pediatr Orthop. 2005;25(5):598–602.CrossRefPubMed
51.
Duce SL, D’Alessandro M, Du Y, Jagpal B, Gilbert FJ, Crichton L, et al. 3D MRI analysis of the lower legs of treated idiopathic congenital talipes equinovarus (clubfoot). PLoS One. 2013;8(1):e54100.CrossRefPubMedPubMedCentral
52.
Zhang Z, Kong Z, Zhu M, Lu W, Ni L, Bai Y. Whole genome sequencing identifies ANXA3 and MTHFR mutations in a large family with an unknown equinus deformity associated genetic disorder. Mol Biol Rep. 2016;43(10):1147–55.CrossRefPubMed
53.
Lochmiller C, Johnston D, Scott A, Risman M, Hecht JT. Genetic epidemiology study of idiopathic talipes equinovarus. Am J Med Genet. 1998;79(2):90–6.CrossRefPubMed
54.
Yang H, Zheng Z, Cai H, Li H, Ye X, Zhang X. Three novel missense mutations in the filamin B gene are associated with isolated congenital talipes equinovarus. Hum Genet. 2016;135(10):1181–9.CrossRefPubMed
55.
Zhang TX, Haller G, Lin P, Alvarado DM, Hecht JT, Blanton SH, et al. Genome-wide association study identifies new disease loci for isolated clubfoot. J Med Genet. 2014;51(5):334–9.CrossRefPubMed
56.
Weymouth KS, Blanton SH, Bamshad MJ, Beck AE, Alvarez C, Richards S. Variants in genes that encode muscle contractile proteins influence risk for isolated clubfoot. Am J Med Genet A. 2011;155(9):2170–9.CrossRefPubMedCentral
57.
Gilbert JA, Roach HI, Clarke NMP. Histological abnormalities of the calcaneum in congenital talipes equinovarus. J Orthop Sci. 2001;6(6):519–26.CrossRefPubMed
58.
Ester AR, Tyerman G, Wise CA, Blanton SH, Hecht JT. Apoptotic gene analysis in idiopathic talipes equinovarus (clubfoot). Clin Orthop Relat Res. 2007;462(462):32–7.CrossRefPubMed
59.
Ippolito E, Dragoni M, Antonicoli M, Farsetti P, Simonetti G, Masala S. An MRI volumetric study for leg muscles in congenital clubfoot. J Child Orthop. 2012;6(5):433–8.CrossRefPubMedPubMedCentral
60.
Sharp L, Miedzybrodzka Z, Cardy AH, Inglis J, Madrigal L, Barker S. The C677T polymorphism in the methylenetetrahydrofolate reductase gene (MTHFR), maternal use of folic acid supplements, and risk of isolated clubfoot: a case-parent-triad analysis. Am J Epidemiol. 2006;164(9):852–61.CrossRefPubMed
61.
62.
Chesney D, Barker S, Miedzybrodzka Z, Haites N, Maffulli N. Epidemiology and genetic theories in the etiology of congenital talipes equinovarus. Bull Hosp Jt Dis. 1999;58(1):59–64.PubMed
63.
Barker S, Chesney D, Miedzybrodzka Z, Maffulli N. Genetics and epidemiology of idiopathic congenital talipes equinovarus. J Pediatr Orthop. 2003;23(2):265–72.PubMed
64.
Dobbs MB, Gurnett CA. The 2017 ABJS Nicolas Andry award: advancing personalized medicine for clubfoot through translational research. Clin Orthop Relat Res. 2017;475(6):1716–25.CrossRefPubMedPubMedCentral
65.
66.
67.
Brachvogel B, Zaucke F, Dave K, Norris EL, Stermann J, Dayakli M, et al. Comparative proteomic analysis of normal and collagen IX null mouse cartilage reveals altered extracellular matrix composition and novel components of the collagen IX interactome. J Biol Chem. 2013;288(19):13481–92.CrossRefPubMedPubMedCentral
68.
Menke DB, Guenther C, Kingsley DM. Dual hindlimb control elements in the Tbx4 gene and region-specific control of bone size in vertebrate limbs. Development. 2008;135(15):2543–53.CrossRefPubMed
69.
Irani RN, Sherman MS. The pathological anatomy of idiopathic clubfoot. Clin Orthop Relat Res. 2012;84:14–20.CrossRef
70.
Isaacs H, Handelsman JE, Badenhorst M, Pickering A. The muscles in club foot--a histological histochemical and electron microscopic study. J Bone Joint Surg Br. 1977;59–B(4):465–72.CrossRefPubMed
71.
Moon DK, Gurnett CA, Aferol H, Siegel MJ, Commean PK, Dobbs MB. Soft-tissue abnormalities associated with treatment-resistant and treatment-responsive clubfoot. J Bone Jt Surg. 2014;96(15):1249–56.CrossRef
72.
Cardy A, Barker S, Chesney D, Sharp L, Maffulli N, Miedzybrodzka Z. Pedigree analysis and epidemiological features of idiopathic congenital talipes equinovarus in the United Kingdom: a case-control study. BMC Musculoskelet Disord. 2007;8(1):62.CrossRefPubMedPubMedCentral
73.
Collinson JM, Lindström NO, Neves C, Wallace K, Meharg C, Charles RH, et al. The developmental and genetic basis of ‘clubfoot’ in the peroneal muscular atrophy mutant mouse. Development. 2018;145(3):dev160093.
Metadata
Title
The etiology of idiopathic congenital talipes equinovarus: a systematic review
Authors
Vito Pavone
Emanuele Chisari
Andrea Vescio
Ludovico Lucenti
Giuseppe Sessa
Gianluca Testa
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Orthopaedic Surgery and Research / Issue 1/2018
Electronic ISSN: 1749-799X
DOI
https://doi.org/10.1186/s13018-018-0913-z

Other articles of this Issue 1/2018

Journal of Orthopaedic Surgery and Research 1/2018 Go to the issue

Research article

Endoscopic release of congenital muscular torticollis with radiofrequency in teenagers

Research article

How do we deliver our findings? Analysis of podium presentations at shoulder meetings

Systematic review

Adjacent segment degeneration or disease after cervical total disc replacement: a meta-analysis of randomized controlled trials

Research article

Modic changes in the cervical endplate of patients suffering from cervical spondylotic myelopathy

Research article

Egr-1 increases angiogenesis in cartilage via binding Netrin-1 receptor DCC promoter

Research article

Suture wear particles cause a significant inflammatory response in a murine synovial airpouch model