A new publication offers an extensive examination of clubfoot, a congenital deformity known as congenital talipes equinovarus (CTEV), affecting about 0.3% of all live births. Clubfoot is characterized by the inward rotation of the foot, often causing significant mobility challenges if not treated early. The article explores the underlying genetic factors, epidemiological patterns, and current management techniques associated with this condition.

Genetic investigations reveal that TBX4, PITX1, and members of the HOXA, HOXC, and HOXD gene clusters are crucial in limb development, muscle formation, and tissue differentiation. Disruptions in these genetic pathways, including mutations in Axin1, are linked to anomalies in joint formation and skeletal development. The Axin1 gene influences the β-catenin-BMP signaling pathway, a crucial regulator of joint integrity. Notably, targeting Axin1 could provide therapeutic avenues for conditions like fibular hemimelia and multiple synostoses syndrome, which are linked to clubfoot.

The article also discusses how apoptotic genes (such as CASP8 and CASP10) contribute to limb patterning and how their dysregulation may result in skeletal deformities. Further genetic analysis reveals the role of HOX genes in specifying limb structures during embryonic development. Disruptions in the β-catenin signaling pathway are particularly noted for their involvement in lower limb malformations, suggesting a complex interplay of genetic mutations rather than a single causative factor.

Current treatment modalities primarily emphasize non-surgical approaches, with the Ponseti method being the most widely recognized technique. This method involves gentle manipulation, casting, and, when necessary, Achilles tendon tenotomy, significantly reducing the need for invasive surgical interventions. The methodology focuses on early diagnosis and structured follow-up to ensure sustained correction, reducing the risk of relapse. The role of brace compliance is highlighted as a key factor in maintaining long-term outcomes. Additionally, alternative approaches like the French method and surgical options are discussed, each tailored to patient-specific factors and severity of the deformity.

The publication underscores the importance of continued research into the genetic foundations of clubfoot to develop more targeted and personalized therapeutic interventions. Understanding the molecular mechanisms involved will enhance clinical management strategies and potentially reduce the incidence of post-treatment complications. This comprehensive approach addresses both clinical practices and genetic research, fostering a deeper understanding of this challenging congenital anomaly.

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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Reference
Muhammad Umar, Liping Tong, Hongting Jin, Tamas Terebessy, Di Chen, Genetics, epidemiology and management of clubfoot and related disorders, Genes & Diseases, Volume 12, Issue 6, 2025, 101690, https://doi.org/10.1016/j.gendis.2025.101690

Funding
National Key Research and Development Program of China 2022YFA1207500
National Natural Science Foundation of China 82394445
National Natural Science Foundation of China 82161160342
National Natural Science Foundation of China 82030067
Shenzhen Science and Technology Innovation Bureau (Guangdong, China) LCYSSQ20220823091402005-E-001