Clubfoot is a complex disorder meaning that more than one gene as well as environmental factors will be discovered to play a role in its etiology. Identifying the genes for clubfoot will allow for improved genetic counseling and may potentially lead to new and improved treatment and preventive strategies for this disorder.
ENIGMA?
You’re probably wondering the same thing almost every parent of a child with congenital clubfoot does. As you look back on your pregnancy, you search for a "gap" that could provide an answer to the question that still remains unanswered: Is clubfoot a genetic condition?
Research into the causes of this condition has been ongoing for many years, puzzling generations of scientists across the globe. Geneticists continue to search for the "magical" gene responsible for this deformity. Unfortunately, it is now known that there is no single magical factor, but rather many, including environmental influences, which complicates solving this mystery. This also allows for the hypothesis that multiple genes interact, and while they are collectively necessary, individually they are not sufficient to cause the condition.
So far, none of the conducted studies has clearly identified the cause of this defect. Clinicians have proposed many theories regarding the genetic basis of the defect. Some of these theories are in opposition to each other. Thus, throughout the history of research, one can encounter the theory of autosomal recessive gene inheritance (Fetscher (1921), Idelberger (1939), J. A. Böök (1948), Ducci and Grilli (1954)), autosomal dominant gene inheritance with reduced penetrance (R. Palmer (1964)), or sex-linked inheritance of a recessive gene (E. Isigkeit (1927)).
Increasingly better research techniques and the advancement of science have led researchers to the conclusion that, while individual genes that may participate in inheritance are important, the possibility of multifactorial inheritance involving several genes cannot be ruled out or ignored. Many scientists, such as Wynne-Davies in 1965, the previously mentioned Palmer in 1974, and Yamamoto in 1979, have discussed this in their studies.
It is now known that clubfoot is a heterogeneous defect (with many factors) of polygenic origin, meaning that it involves multiple genes simultaneously. The discovery of which genes are involved is the goal of research, as well as understanding the mechanism behind certain anomalies in genes or their combination and interaction with other genes.
Clubfoot is a complex disorder meaning that more than one gene as well as environmental factors will be discovered to play a role in its etiology. Identifying the genes for clubfoot will allow for improved genetic counseling and may potentially lead to new and improved treatment and preventive strategies for this disorder.
In 2008, a group of scientists from Washington University School of Medicine in St. Louis, USA, published research using the method of genome mapping. This technique involves creating precise maps that show the location of specific genes on chromosomes. Gene samples taken from 13 members of a 5-generation family were mapped and analyzed to identify mutations responsible for limb development in the early embryonic period. The family studied was predominantly affected by dominant idiopathic clubfoot, where the defect was segregated as autosomal dominant with incomplete penetrance. The carriers of the incomplete penetrance mutation were healthy women, which could potentially explain why fewer girls are born with congenital clubfoot. Men were free from transmitting the defect, even though they had it.
These mutations are identified as PITX1, a homeotic gene, and TBX4.
It has been shown that mutations in the PITX1 and TBX4 genes lead to reduced muscle development in the lower limbs and the classic phenotypes seen in children (and mice) with clubfoot. Therefore, it is not excluded that mutations in these specific genes are responsible for isolated cases of clubfoot (where individuals have no other genetic defects). Unfortunately, these same mutations may also be associated with syndromic defects in long bone growth.
Studies on the TBX4 gene have shown that in approximately 5% of cases in families with isolated clubfoot (without any associated defects), microduplications in the TBX4 gene are present.
Genes from the HOX family, such as HOXA and HOXD, are crucial for limb development in multicellular organisms. The clustered HOXA and HOXD genes are responsible for proper segmentation and formation of limbs, as well as the shaping of muscular and skeletal tissues.
IGFBP3 (insulin-like growth factor binding protein 3), which regulates the activity of insulin-like growth factors (IGF), plays a critical role in tissue development, including muscles and bones. Variants in this gene have been linked to the risk of developing congenital clubfoot. Single nucleotide polymorphisms (SNPs) in IGFBP3, such as rs13223993, have shown altered transmission in studies on clubfoot.
CASP3 is a gene responsible for modulating apoptosis in the later stages of muscle and tendon development. Interactions between the CASP3 gene and variants in the HOXA, HOXD, and IGFBP3 genes suggest that apoptotic processes may influence the development of congenital clubfoot.
Fgf (Fibroblast Growth Factors) and Tgfβ (Transforming Growth Factor Beta) are growth factors that influence the development of muscular and bone tissues. Changes in these signaling pathways can lead to disruptions in limb formation, including clubfoot.
A defect in collagen production or abnormalities in the collagen structure can affect the proper development of the foot and the musculoskeletal structure. In particular, the COL1A1 and COL2A1 genes (which code for type I and II collagen) have been analyzed in the context of congenital limb deformities, such as clubfoot.
Other genes that may be associated with congenital clubfoot include NKX3-2, TBX5, and WNT, which also regulate limb and muscle tissue development. However, their influence on clubfoot remains an area of ongoing research.
The LIMK1 gene (LIM kinase 1) is another gene that has been studied in the context of congenital clubfoot, although its role in this pathology is not yet fully understood. LIMK1 plays a crucial role in regulating the structure of the cellular cytoskeleton, including the organization of actin filaments, which is essential for the development and function of cells, including muscle cells and those involved in limb formation. Research suggests that LIMK1 may be associated with clubfoot because changes in this gene can lead to disturbances in the process of shaping muscle tissues, ligaments, and other limb structures.
Some genetic studies have investigated the potential involvement of MYH3 in the development of congenital clubfoot. These studies suggest that mutations or polymorphisms in MYH3 may be associated with an increased risk of the condition, especially in cases where clubfoot occurs as part of a larger syndrome (e.g., in the context of myopathies or other muscle disorders). However, studies directly linking MYH genes to idiopathic (unrelated to other conditions) clubfoot are limited and require further research to fully understand the role of these genes in this disorder.
Research into genetics is crucial, and the answer almost comes naturally – by understanding the cause, it will be easier to predict the defect and apply more effective treatments. Although new genes, mutations, and combinations are continuously being discovered, there is still no definitive answer. However, the efforts to solve the genetic puzzle must be pursued relentlessly.
This is, hopefully, another piece in the puzzle of what causes club foot in humans.
INHERITANCE
Idiopathic clubfoot is a common congenital deformity that can occur in families but does not follow typical Mendelian inheritance patterns. Studies on twins, varying occurrences across different ethnic groups, and intergenerational transmission suggest that clubfoot has a genetic component.
Clubfoot may be etiologically and/or genetically heterogeneous, resulting in a complex inheritance pattern. Alternatively, idiopathic clubfoot may require a predisposing gene acting within a specific background of polygenes or environmental influences. Identifying the cause or causes of clubfoot will enable better genetic counseling, improve treatment potential, and provide insights into the normal development of feet and legs.
of all patients with isolated clubfoot have a positive family history of this condition
THE OVERALL RISK OF CLUBFOOT OCCURRENCE IS THE SAME FOR THE ENTIRE POPULATION.
IN PRACTICE, THIS MEANS THAT EVEN A GENETICALLY HEALTHY COUPLE CAN HAVE A CHILD WITH THIS CONDITION, BUT ALSO THAT A COUPLE WITH A FAMILY HISTORY MAY HAVE A CHILD WITHOUT THE DEFECT (ALTHOUGH THE RISK OF OCCURRENCE IN SUCH CASES IS HIGHER).
- 2:1
- The defect occurs TWICE AS OFTEN in boys than in girls
- 50%
- approximately 50% of cases are BILATERAL
- NEXT
- if parents don’t have clubfoot but they have a child affected by it, their future children have 2-4% chance of having the same foot defect
- ONE
- if one parent is affected by clubfoot, there’s a 3,57% chance that their child will have the same abnormality
- TWO
- if both parents have clubfoot, they have a 10-20% chance that their child will be affected by it as well
- TWINS
- in the case of monozygotic twins, there’s a 32,5% chance that this deformation will affect both siblings compared to 2,9% among dizygotic twins
- I DEGREE
- there’s an approxilately 3% risk of clubfoot among first degree relatives (relations parent-child or sibling-sibling)
- II DEGREE
- there’s an approxilately 0,5-0,6% risk among second degree relatives (grandparents, aunt, uncle)
- III DEGREE
- there’s an approxilately 0,2% risk among third degree relatives (cousins)
RACIAL FACTORS
It seems that racial background is not insignificant when considering the genetic basis of the condition. According to research by C.S. Chung conducted between 1948 and 1958 in Hawaii—where the Hawaiian population and its subgroups (Hawaiians, Chinese, Koreans, Filipinos, Puerto Ricans, and various "mixed" Oriental groups) were studied in relation to clubfoot, metatarsus adductus, and calcaneovalgus—Hawaiians showed a significantly higher prevalence of congenital clubfoot compared to other ethnicities (with Caucasians as the baseline group). In mixed-ethnicity couples where one parent was Hawaiian, the risk increased, whereas among other Oriental "crosses," the risk decreased.
As many as 7 in 1,000 births among Hawaiians resulted in clubfoot, whereas among Chinese individuals, the prevalence was only 0.39 per 1,000 births.
The frequency of clubfoot occurrence, considering racial differences and genetic predispositions, remains inconclusive. Determining a precise correlation is challenging, mainly due to factors such as a small baseline population (as seen in Jianhua Wang's 1988 study), low representation of certain ethnic groups, and frequent migration. However, it cannot be entirely ruled out that race or ancestry plays a role in the inheritance of this condition.
| INCIDENCE/1000 LIVE BIRTHS | COUNTRY | SOURCE DATA |
|---|---|---|
| 3,49 | Australia: Aborigines | Carey M. et al.: "Talipes equinovarus in Western Australia. Paediatric Perinatal Epidemiology" (2003) |
| 1,11 | Australia: Caucasian | Carey M. et al.: "Talipes equinovarus in Western Australia. Paediatric Perinatal Epidemiology" (2003) |
| 1,6 | Belgium | Paton R. et al.: "Incidence and aetiology of talipes equino-varus with recent population changes." (2010) |
| 0,39 | China | Chung C.S. et al.: "Genetic and Epidemiological Studies of Clubfoot in Hawaii: Ascertainment and Incidence." (1969) |
| 1,2 | Denmark | Krogsgaard M. et al.: "Increasing incidence of club foot with higher population density: incidence and geographical variation in Denmark over a 16 year period." (2006) |
| 6,8 | Hawaii | Dietz F.: "The genetics of idiopathic clubfoot. Clinical Orthopaedics and Related Research" (2002) |
| 0,9 | India | R. Mittal et al.: "The presence of congenital orthopaedic anomalies in a rural community." |
| 0,87 | Japan | Yamamoto H.: "A clinical, genetic and epidemiologic study of congenital club foot." (1979) |
| 2 | Malawi | Mkandawire N.,Kaunda E.: "Incidence and patterns of congenital talipes equinovarus (clubfoot) deformity at Queen Elizabeth Central Hospital" (2004) |
| 2.7 | Papua/New Gwinea | Culverwell A.,Tapping C.: "Congenital Talipes Equinovarus in Papua New Guinea: a difficult yet potentially manageable situation." (2009) |
| 0.76 | Philippines | Aguilar J.: "Ponseti method for treating clubfoot in older children and children with previous unsuccessful subtalar releases: short term results." |
| 1.4 | Sweden | Wallander H. et al.: "Incidence of congenital clubfoot in Sweden." (2006) |
| 1.2 | Uganda | Pirani S. et al.: "Towards effective Ponseti clubfoot care: the Uganda Sustainable Clubfoot Care Project."(2009) |
| 1 | USA | Dietz F.: "The genetics of idiopathic clubfoot."(2002) |
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- First Gene For Clubfoot Identified