Although some progress has been made in the study of the etiology, pathology and pathogenesis of congenital clubfoot, opinions are still divided. The unknown etiology of the disease directly disturbs the clinical selection of more rational therapies; therefore, research on the etiology of the disease is of great importance to guide and improve treatment. The main views of the current research on the etiology of this disease are as follows. 1, genetic factors The prevalence of congenital clubfoot varies significantly by race and gender, and increases with the number of affected relatives, suggesting that its prevalence is at least partially influenced by genetic factors. The prevalence varies by race, from 0.39 per 1,000 in Chinese to 1.2 per 1,000 in Caucasians to 6.8 per 1,000 in Polynesians, and Lochmiller et al. recently reported a male to female ratio of 2.5:1. Patients with clubfoot are 30 times more likely to have a sibling with the condition. The prevalence of two siblings having the same disease was 32.5% in monozygotic twins and only 2.9% in dizygotic twins. The inheritance pattern of congenital clubfoot is called compound inheritance, which is characterized by: (1) polygenic inheritance; (2) non-genetic factors such as environmental toxins and viruses; (3) a vegetative gene, but regulated by other factors such as genes and the environment; and (4) similar phenotypes, although the causes of the deformity are different. The Hox gene family is a cluster of homozygous heterozygous cassette genes with a homologous sequence about 180 bp long. The basic roles of Hox genes in limbogenesis are: (i) regulating the rate and timing of chondrocyte proliferation and differentiation; (ii) regulating the proliferation of undifferentiated mesenchyme; (iii) participating in the condensation of chondrochondrocytes into protoplasmic progenitors; and (iv) participating in the formation of chondrocytes. A large number of animal experiments have confirmed that Hox genes are the main regulatory genes in vertebrate embryonic development and organ formation, exercising specific expression regulation at different stages of transcription and translation, and their functional alterations directly affect development, so they are likely to be candidate genes for human congenital malformations. During embryonic development, limb development begins with the appearance of limb buds on the lateral surface of the mesoderm, and the apical ectodermal ridge (AER) is formed at the tip of the limb buds, and AER plays a controlling role in proximal-distal limb development, and Lu et al [5] demonstrated a significant increase in the expression of Hox genes in AER. Davis et al [6] proposed a pattern of Hox gene expression during limb development: the paralogs of Hox genes Hox9, Hox10, Hox11, Hox12 and Hox13 correspond to regulate the formation of the limb bones (scapula and hip), column bones (humerus and femur), union bones (ulnar radius), telangiectasias (carpal and tarsal) and phalanges (ring finger, middle finger and index finger), respectively. The Hox gene is closely related to the development of the limbs and regulates the formation of the limbs. The Hox gene may not only regulate the development of the lower limbs during embryogenesis, leading to congenital clubfoot deformity, but also continue to be expressed after birth, causing the pathological changes of clubfoot to appear successively and get progressively worse. gradually aggravate. Isaacs et al. demonstrated ultrastructural abnormalities of the muscles, and Handelsman and Badalamente found that the ratio of type I to type II muscle fibers increased from a normal 1:2 to 7:1, suggesting a possible association with primary neurological abnormalities. However, Bill and Versfeld [10] failed to find neurogenic and myogenic alterations by studying electromyography. As early as 1963, Irani and Sherman proposed that a defect in the primitive limb bud led to a developmental malformation of the talus navicularis. shapiro and Glimcher confirmed a defect in the development of cartilage in the horseshoe clubfoot. ippolito confirmed a malformation of the talus and that the talar neck was angled inward and the talus was internally inclined and internally rotated, accompanied by an inward inclination and internal rotation of the heel, thus, leading to a hindfoot pronation Davidson et al. applied MRI studies to confirm that the talus, heel and dice bones of infants with clubfoot have plantarflexion and inversion angular deformity. Ippolito et al. recently demonstrated a significant increase in fibrous tissue in the calf gastrocnemius and connective tissue in four aborted fetuses by anatomical and histological studies, and proposed the theory that soft tissue contracture causes clubfoot deformity. deitz et al. found a decrease in the number of cells and cytoplasm in the posterior tibial tendon compared to the anterior tibial tendon, and proposed that localized regional growth disorder is the cause of clubfoot. zimny et al. used electron microscopy to observe the medial and lateral fascia of children with clubfoot and concluded that myogenic fibroblasts are the ultrastructural basis for the soft tissue contracture that causes the deformity of clubfoot.Sano et al. performed immunohistochemistry and electron microscopy on 41 biopsy specimens of clubfoot aged 6 to 30 months and found different stages of myocardial contractile proteins and fibroblasts to myogenic fibroblasts. The authors noted that this was similar to the wound healing process and that it was the presence of these proteins and cells that caused the recurrence of clubfoot and postoperative deformity. Some authors believe that congenital clubfoot is the result of early fetal muscle imbalance, and that the altered muscle strength is based on neurological abnormalities, and that skeletal, joint, and soft tissue contractures are adaptive changes secondary to the muscle imbalance. Handelsman [18] found that in addition to an increase in type I muscle fibers (2-100-fold) and an increase in the ratio of type I to type II muscle fibers (mean 7.05:1) in the muscles of the foot and the posterior medial part of the calf, there was an increase in the number of type I nerve endings in the areas where type I muscle fibers were increased and aggregated, suggesting that the muscles of the foot and the posterior medial part of the calf in clubfoot have abnormal muscle fiber maturation and that this abnormalities are associated with nerve abnormalities. Since the increase in type I muscle fibers provides a small but persistent teratogenic force, fetal bone and cartilage are sensitive to the persistent imbalance force, which eventually produces clubfoot deformity.Feldbrin et al [19] performed a neurophysiological study on both lower limbs of 52 children with congenital clubfoot aged 3 months to 15 years and found that only 9 cases (17%) had no abnormal findings, 14 cases (27%) had separate fibular The neurophysiological complexity of the neurophysiology correlated with the severity of the foot deformity and also with the treatment effect. The results showed that the incidence of lumbosacral occult cleft was as high as 78.3%, the resting pressure of the anal canal and the differential pressure of the rectal canal were significantly higher than those of the control group, and the red muscle fibers of the three groups were increased and aggregated, and the muscle fibers were of different sizes and shapes. The ultrastructure also showed denervated atrophic changes. Nadeen et al. and Macnicol et al. performed somatosensory evoked potential (SSEP) measurements in children with congenital clubfoot and found that SSEP was not only altered but also positively correlated with the severity of the deformity. This finding also supports the neurogenic theory of clubfoot and proves that congenital clubfoot has neuromuscular abnormalities. Sodre et al [23] found that the majority of clubfoot deformities had hypoplastic or absent anterior tibial arteries, thus suggesting that vascular developmental abnormalities may be the cause of clubfoot, and Muir et al [24] found that most parents of children with clubfoot had absent dorsalis pedis artery pulsations. In recent years, Stolter et al. and Kanfman et al [26] applied chorionic villus sampling to establish animal models of limb malformation, respectively, and found that the incidence of clubfoot was highest, and this defect originated from vascular dissection or developmental defects, which occurred from ischemia or thrombosis leading to hypoxia, affecting the formation of limb buds and finally leading to clubfoot deformity. 5, Intrauterine factors Hippocrates believes that clubfoot deformity is caused by ectopic compression and low amniotic fluid, resulting in the foot being squeezed in a fixed position in the clubfoot. Turco, however, argued that during the first trimester of pregnancy, when the clubfoot is formed, there is enough intrauterine space that such increased pressure should not produce the deformity, and his review of the literature, combined with his own clinical data, revealed that the clubfoot deformity is equal on both sides, but the position of the right and left foot in the uterus is not symmetrical, which does not support the intrauterine position theory. Bohm described four stages of foot development and suggested that clubfoot is a manifestation of arrested normal foot development; however, medial navicular dislocation, which is common in clubfoot, was not found at any stage of normal foot development.Kawashima and Uhthoff made an anatomical study of 147 feet in the 8th to 21st week of pregnancy and showed that the normal foot in the 9th week of intrauterine life was similar to clubfoot. The results showed that the normal foot in the 9th week of intrauterine life was similar to the horseshoe clubfoot, suggesting that the horseshoe clubfoot deformity may be due to obstructed intrauterine development. Farrell et al. reported a 1.1% incidence of clubfoot after amniocentesis, which is approximately 10 times higher than the 0.1% incidence in normal infants, and the same incidence on both sides as in the normal population. The incidence of clubfoot was as high as 15% after early amniocentesis when amniotic fluid leakage often occurred, but later, when there was no amniotic fluid leakage, the incidence of clubfoot decreased to 1.1%. Therefore, Farrell et al. hypothesized that the foot was in the position of the clubfoot at the time of early amniocentesis and that the amniotic fluid leak blocked the development of the foot at this time, and they did not find low amniotic fluid on subsequent ultrasonography; Farrell et al. also hypothesized that the amniotic fluid leak altered the intrauterine pressure and changed the development of the foot, resulting in the clubfoot deformity. Robertson and Corbett [30] retrospectively analyzed 330 children with clubfoot deformity and found that the average time of conception of these children was in June. They hypothesized that summer and fall is the high season for enteroviral infections, which cause intrauterine damage to the anterior horn of the fetal spinal cord, resulting in clubfoot deformity. In summary, there are multiple views on the etiology of clubfoot, with genetic studies being the most respected. However, the underlying cause has yet to be studied in more depth with more advanced techniques and methods to guide the selection of more rational therapies.