Abstract
Clubfoot, a common complex birth defect, affects 135,000 newborns each year worldwide. While tremendous strides have been made in treatment with the Ponsetti nonsurgical method, the post-treatment foot generally remains small with hypoplastic calf musculature. Even though clubfoot has been studied for more than 100 years, only a few contributing factors have been identified. Prenatal tobacco smoke exposure is the only consistently associated environmental factor and confers an increased risk in a dose dependent manner. Moreover, maternal smoking and a family history of clubfoot increases the risk 20-fold confirming that genetic factors play a role. Genetic studies have shown that variation in TBX4 and PITX1 cause syndromic forms of clubfoot; however, there is no evidence that variation in these genes contribute to nonsyndromic clubfoot. Recent work suggests that variants in the regulatory regions of muscle-specific genes play a role by subtly affecting gene expression and it is hypothesized that variation in the expression of multiple genes is necessary for clubfoot development. This mechanism is consistent with the multifactorial model first proposed for clubfoot over 50 years ago. Confirmation of this work should enable identification of unique gene risk signatures that will aid in genetic counseling. Next generation approaches should speed gene identification in clubfoot.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Bohm M. Embryologic origin of clubfoot. J Bone Joint Surg. 1929;11:229–59.
Hulme A. The management of congenital talipes equinovarus. Early Hum Dev. 2005;81:797–802.
Laaveg SJ, Ponseti IV. Long-term results of treatment of congenital club foot. J Bone Joint Surg Am. 1980;62:23–31.
Ponseti IV. Treatment of congenital club foot. J Bone Joint Surg Am. 1992;74:448–54.
Fromental-Ramain C, et al. Hoxa-13 and Hoxd-13 play a crucial role in the patterning of the limb autopod. Development. 1996;122:2997–3011.
Gurnett CA, Boehm S, Connolly A, Reimschisel T, Dobbs MB. Impact of congenital talipes equinovarus etiology on treatment outcomes. Dev Med Child Neurol. 2008;50:498–502.
Gurnett MBDaCA. Genetics of clubfoot. J Pediatr Orthop B. 2011;21:7–9.
Brewer C, Holloway S, Zawalnyski P, Schinzel A, FitzPatrick D. A chromosomal deletion map of human malformations. Am J Hum Genet. 1998;63:1153–9.
Brewer C, Holloway S, Zawalnyski P, Schinzel A, FitzPatrick D. A chromosomal duplication map of malformations: regions of suspected haplo- and triplolethality-and tolerance of segmental aneuploidy-in humans. Am J Hum Genet. 1999;64:1702–8.
Parker SE, et al. Multistate study of the epidemiology of clubfoot. Birth Defects Res A Clin Mol Teratol. 2009;85:897–904.
Pirani S, et al. Towards effective Ponseti clubfoot care: the Uganda sustainable clubfoot care project. Clin Orthop Relat Res. 2009;467:1154–63.
Wallander H, Hovelius L, Michaelsson K. Incidence of congenital clubfoot in Sweden. Acta Orthop. 2006;77:847–52.
Culverwell AD, Tapping CR. Congenital talipes equinovarus in Papua New Guinea: a difficult yet potentially manageable situation. Int Orthop. 2009;33:521–6.
Mkandawire NC, Kaunda E. Incidence and patterns of congenital talipes equinovarus (clubfoot) deformity at Queen Elizabeth Central Hospital, Banter, Malawi. East and Cent Afr J Surg. 2004;9:28–31.
Yamamoto H. A clinical, genetic and epidemiologic study of congenital club foot. Jinrui Idengaku Zasshi. 1979;24:37–44.
Mittal RL, Sekhon AS, Singh G, Thakral H. The prevalence of congenital orthopaedic anomalies in a rural community. Int Orthop. 1993;17:11–2.
Ching GH, Chung CS, Nemechek RW. Genetic and epidemiological studies of clubfoot in Hawaii: ascertainment and incidence. Am J Hum Genet. 1969;21:566–80.
Krogsgaard MR, et al. Increasing incidence of club foot with higher population density: incidence and geographical variation in Denmark over a 16-year period-an epidemiological study of 936,525 births. Acta Orthop. 2006;77:839–46.
Paton RW, Fox AE, Foster A, Fehily M. Incidence and aetiology of talipes equino-varus with recent population changes. Acta Orthop Belg. 2010;76:86–9.
Carey M, Bower C, Mylvaganam A, Rouse I. Talipes equinovarus in Western Australia. Paediatr Perinat Epidemiol. 2003;17:187–94.
Chung CS, Nemechek RW, Larsen IJ, Ching GH. Genetic and epidemiological studies of clubfoot in Hawaii. General and medical considerations. Hum Hered. 1969;19:321–42.
Lochmiller C, Johnston D, Scott A, Risman M, Hecht JT. Genetic epidemiology study of idiopathic talipes equinovarus. Am J Med Genet. 1998;79:90–6.
Beals RK. Club foot in the Maori: a genetic study of 50 kindreds. N Z Med J. 1978;88:144–6.
Moorthi RN, et al. Idiopathic talipes equinovarus (ITEV) (clubfeet) in Texas. Am J Med Genet A. 2005;132:376–80.
Cardy AH, Sharp L, Torrance N, Hennekam RC, Miedzybrodzka Z. Is there evidence for aetiologically distinct subgroups of idiopathic congenital talipes equinovarus? A case-only study and pedigree analysis. PLoS One. 2011;6:e17895.
Dietz F. The genetics of idiopathic clubfoot. Clin Orthop Relat Res. 2002;401: 39–48.
Dobbs MB, Gurnett CA. Genetics of clubfoot. J Pediatr Orthop B. 2012;21:7–9.
Barker SL, Macnicol MF. Seasonal distribution of idiopathic congenital talipes equinovarus in Scotland. J Pediatr Orthop B. 2002;11:129–33.
Loder RT, et al. Lack of seasonal variation in idiopathic talipes equinovarus. J Bone Joint Surg Am. 2006;88:496–502.
Pryor GA, Villar RN, Ronen A, Scott PM. Seasonal variation in the incidence of congenital talipes equinovarus. J Bone Joint Surg Br. 1991;73:632–4.
Pavone V, et al. Congenital talipes equinovarus: an epidemiological study in Sicily. Acta Orthop. 2012;83:294–8.
Heydanus R, Ledward RS. Failed mifepristone termination of pregnancy and talipes equinovares: coincidence? J Obstet Gynaecol. 1995;15:211.
Czeizel AE, Puho E, Sorensen HT, Olsen J. Possible association between different congenital abnormalities and use of different sulfonamides during pregnancy. Congenit Anom (Kyoto). 2004;44:79–86.
Ulrich M, et al. The influence of folic acid supplement on the outcome of pregnancies in the county of Funen in Denmark. PartIII. Congenital anomalies. An observational study. Eur J Obstet Gynecol Reprod Biol. 1999;87:115–8; (discussion 103–4).
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;17:589–604.
Niemann S, et al. Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family. Am J Hum Genet. 2004;74:558–63.
Honein MA, Paulozzi LJ, Moore CA. Family history, maternal smoking, and clubfoot: an indication of a gene-environment interaction. Am J Epidemiol. 2000;152:658–65.
Skelly AC, Holt VL, Mosca VS, Alderman BW. Talipes equinovarus and maternal smoking: a population-based case-control study in Washington state. Teratology. 2002;66:91–100.
Dickinson KC, Meyer RE, Kotch J. Maternal smoking and the risk for clubfoot in infants. Birth Defects Res A Clin Mol Teratol. 2008;82:86–91.
Idelberger K. Die Ergebnisse der Zwillingsforschung beim angeborenen Klumpfuss. Verh Deutsch Orthopdd Ges. 1939;33:272–6.
Barker S, Chesney D, Miedzybrodzka Z, Maffulli N. Genetics and epidemiology of idiopathic congenital talipes equinovarus. J Pediatr Orthop. 2003;23:265–72.
Strach E. Club-foot through the centuries. Prog Pediatr Surg. 1986;20:215–237.
Yang HY, Chung CS, Nemechek RW. A genetic analysis of clubfoot in Hawaii. Genet Epidemiol. 1987;4:299–306.
Wynne-Davies R. Family studies and the cause of congenital club foot. Talipes equinovarus, talipes calcaneo-valgus and metatarsus varus. J Bone Joint Surg Br. 1964;46:445–63.
Wynne-Davies R. Family studies and aetiology of club foot. J Med Genet. 1965;2:227–32.
de Andrade M, et al. Segregation analysis of idiopathic talipes equinovarus in a Texan population. Am J Med Genet. 1998;79:97–102.
Kruse LM, Dobbs MB, Gurnett CA. Polygenic threshold model with sex dimorphism in clubfoot inheritance: the Carter effect. J Bone Joint Surg Am. 2008;90:2688–94.
Kitamura M, Kasai A. Cigarette smoke as a trigger for the dioxin receptor-mediated signaling pathway. Cancer Lett. 2007;252:184–94.
Czekaj P, Wiaderkiewicz A, Florek E, Wiaderkiewicz R. Tobacco smoke-dependent changes in cytochrome P450 1A1, 1A2, and 2E1 protein expressions in fetuses, newborns, pregnant rats, and human placenta. Arch Toxicol. 2005;79:13–24.
Hecht JT, et al. NAT2 variation and idiopathic talipes equinovarus (clubfoot). Am J Med Genet A. 2007;143A:2285–91.
Sommer A, et al. Smoking, the xenobiotic pathway, and clubfoot. Birth Defects Res A Clin Mol Teratol. 2011;91:20–8.
Zuzarte-Luis V, Hurle JM. Programmed cell death in the developing limb. Int J Dev Biol. 2002;46:871–6.
Capdevila J, Izpisua Belmonte JC. Patterning mechanisms controlling vertebrate limb development. Annu Rev Cell Dev Biol. 2001;17:87–132.
Duboc V, Logan MP. Building limb morphology through integration of signalling modules. Curr Opin Genet Dev. 2009;19:497–503.
Logan M. Finger or toe: the molecular basis of limb identity. Development. 2003;130:6401–10.
Yang Y. Growth and patterning in the limb: signaling gradients make the decision. Sci Signal. 2009;2:pe3.
Duboc V, Logan MP. Regulation of limb bud initiation and limb-type morphology. Dev Dyn. 2011;240:1017–27.
Bareither D. Prenatal development of the foot and ankle. J Am Podiatr Med Assoc. 1995;85:753–64.
Gurnett CA, et al. Asymmetric lower-limb malformations in individuals with homeobox PITX1 gene mutation. Am J Hum Genet. 2008;83:616–22.
Klopocki E, et al. Deletions in PITX1 cause a spectrum of lower-limb malformations including mirror-image polydactyly. Eur J Hum Genet. 2012;20:705–8.
Alvarado DM, et al. Pitx1 haploinsufficiency causes clubfoot in humans and a clubfoot-like phenotype in mice. Hum Mol Genet. 2011;20:3943–52.
Alvarado DM, et al. Familial isolated clubfoot is associated with recurrent chromosome 17q23.1q23.2 microduplications containing TBX4. Am J Hum Genet. 2010;87:154–60.
Logan M, Tabin CJ. Role of Pitx1 upstream of Tbx4 in specification of hindlimb identity. Science. 1999;283:1736–9.
Rodriguez-Esteban C, et al. The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity. Nature. 1999;398:814–8.
Hasson P, et al. Tbx4 and tbx5 acting in connective tissue are required for limb muscle and tendon patterning. Dev Cell. 2010;18:148–56.
Lu W, et al. Studies of TBX4 and chromosome 17q23.1q23.2: an uncommon cause of nonsyndromic clubfoot. Am J Med Genet A. 2012;158A:1620–7.
Rahimov F, et al. Disruption of an AP-2alpha binding site in an IRF6 enhancer is associated with cleft lip. Nat Genet. 2008;40:1341–7.
Bamshad M, Jorde LB, Carey JC. A revised and extended classification of the distal arthrogryposes. Am J Med Genet. 1996;65:277–81.
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.
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;30:231–4.
Weymouth KS, et al. Variants in genes that encode muscle contractile proteins influence risk for isolated clubfoot. Am J Med Genet A. 2011;155A:2170–9.
Weymouth KS, Patel CV, Savill SA, Hecht JT. Variation in HOXA9, TPM1 and TPM2 contributes to clubfoot. Clin Orthop Relat Res. 2013 (in preparation).
Heck AL, Bray MS, Scott A, Blanton SH, Hecht JT. Variation in CASP10 gene is associated with idiopathic talipes equinovarus. J Pediatr Orthop. 2005;25:598–602.
Ester AR, et al. Altered transmission of HOX and apoptotic SNPs identify a potential common pathway for clubfoot. Am J Med Genet A. 2009;149A:2745–52.
Ester AR, Tyerman G, Wise CA, Blanton SH, Hecht JT. Apoptotic gene analysis in idiopathic talipes equinovarus (clubfoot). Clin Orthop Relat Res. 2007;462:32–7.
McGinnis W, Krumlauf R. Homeobox genes and axial patterning. Cell. 1992;68:283–302.
Mark M, Rijli FM, Chambon P. Homeobox genes in embryogenesis and pathogenesis. Pediatr Res. 1997;42:421–9.
Houghton L, Rosenthal N. Regulation of a muscle-specific transgene by persistent expression of Hox genes in postnatal murine limb muscle. Dev Dyn. 1999;216:385–97.
Dobbs MB, et al. HOXD10 M319K mutation in a family with isolated congenital vertical talus. J Orthop Res. 2006;24:448–53.
Shrimpton AE, et al. A HOX gene mutation in a family with isolated congenital vertical talus and Charcot–Marie-Tooth disease. Am J Hum Genet. 2004;75:92–6.
Rebbeck TR, Dietz FR, Murray JC, Buetow KH. A single-gene explanation for the probability of having idiopathic talipes equinovarus. Am J Hum Genet. 1993;53:1051–63.
Wang JH, Palmer RM, Chung CS. The role of major gene in clubfoot. Am J Hum Genet. 1988;42:772–6.
Bonafe L, et al. DTDST mutations are not a frequent cause of idiopathic talipes equinovarus (club foot). J Med Genet. 2002;39:e20.
Acknowledgements
We thank Hilary Page (www.hilarypage.com) for the depiction of clubfeet in Fig. 6.1. Parts of the work described in this chapter were supported by grants from NIH (R01-HD043342) and Shriners Hospital for Children.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer Science+Business Media New York
About this chapter
Cite this chapter
Weymouth, K., Blanton, S., Hecht, J. (2015). Insights into the Genetics of Clubfoot. In: Wise, C., Rios, J. (eds) Molecular Genetics of Pediatric Orthopaedic Disorders. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2169-0_6
Download citation
DOI: https://doi.org/10.1007/978-1-4939-2169-0_6
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4939-2168-3
Online ISBN: 978-1-4939-2169-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)