Etiology and Pathogenesis of Clubfoot and Vertical Talus

Clubfoot and vertical talus are closely related congenital lower limb malformations. While there is evidence that environmental factors and prenatal drug exposures may contribute to their pathogenesis, genetic factors appear to play a significant role. Morphological analysis of tissues from clubfoot patients using a variety of invasive and noninvasive modalities, including muscle biopsy and magnetic resonance imaging, show a spectrum of muscle, vasculature, and nerve abnormalities that provide evidence against a singular etiology for clubfoot. Consistent with this, genes involved in early limb development, including PITX1, TBX4, and HOX genes, have now been implicated in some cases of familial clubfoot and vertical talus. Individuals with genetic abnormalities in these transcriptional regulators of early limb development are more likely to have treatment resistant clubfoot and clinical exam abnormalities such as the “drop-toe sign” or weakness with eversion that are hallmarks of treatment resistance. Unlike familial cases, most non-familial clubfoot and vertical talus cases are likely oligogenic or polygenic in origin and reflect complex inheritance patterns. Currently, routine genetic testing in patients with isolated clubfoot or vertical talus is likely to be low yield, even in familial cases. Further research is needed to identify additional pathophysiological mechanisms, particularly in regard to oligogenic combinations of rare genetic variants. Consideration of clinical exam findings and underlying morphological abnormalities, as well as the impact of gene variants when known, is essential for tailoring diagnostic and treatment plans to address the specific needs of individuals with clubfoot and vertical talus.