Review Question - QID 218730

Congenital clubfoot also known as congenital talipes equinovarus (TEV), is associated with genetic variations within the PITX1-TBX4 transcription pathway. The pathophysiology of clubfoot includes musculature contractures leading to the characteristic deformity of cavus, forefoot adductus, varus, and equinus (Answer 5).

Congenital clubfoot is a prevalent birth defect occurring in 1 in 1000 live births and presents as either isolated (80% of cases, presumed idiopathic) or associated with malformations, genetic syndromes, or neuromuscular conditions. Of the idiopathic cases, 25% exhibit a familial link, with a higher concordance in monozygotic twins compared to dizygotic twins, suggesting a genetic role. Notably, the PITX1-TBX4 genetic pathway governs hindfoot development, and genetic variations within this pathway have been implicated in isolated clubfoot phenotypes in animal studies.

Basit et al. sought to review the molecular mechanisms of TEV. They concluded that while strides have been made in managing limb defects, the molecular mechanisms and signaling pathways contributing to TEV remain largely unknown. The intricate interplay between lateral plate mesoderm cells and outer ectoderm, involving HOX signaling and PITX1-TBX4 pathways, influences limb development and homeostasis. The susceptibility to TEV involves a complex interplay of genetic and environmental factors, with documented familial occurrences and phenotypic variability.

Sadler et al. completed a review expanding on the understanding of the genetic component of TEV and determined that there are a variety of pathways implicated in the development of isolated and syndromic clubfoot in addition to the PITX1-TBX4 pathway. For instance, Homeobox (HOX) genes, specifically within clusters HOXD and HOXA-D, play crucial roles in limb development, with single nucleotide polymorphisms (SNPs) in HOXD12 and HOXD13 associated with idiopathic clubfoot.

Incorrect Answers:
Answer 1: Achondroplasia is caused by a gain-of-function mutation in the FGFR3 gene which can influence the signaling pathway PI3K-AKT but this is not associated with the development of TEV.
Answer 2: Kniest dysplasia is associated with an autosomal dominant mutation in the COL2A1 gene which causes a defect in cartilage matrix formation but is not associated with TEV.
Answer 3: Apert Syndrome is caused by an autosomal dominant mutation in the gene FGFR2 leading to inhibition of chondrocyte proliferation but is not commonly associated with TEV.
Answer 4: Cleidocranial dysplasia is associated with the genes RUNX2/CBFA1 which leads to impaired intramembranous ossification and is not routinely associated with TEV.