Similar to the case of Sox9, multiple enhancers stabilize transcription of the hindlimb-determining transcription factor Pitx1. Deletion of subsets of these enhancers affect transcription to some extent, yet the homozygous deletion of the Pen enhancer alone reduces transcription to about 55% of control levels, which is sufficient to produce mice with a clubfoot phenotype that mirrors the effect of a heterozygous loss of function of Pitx1 itself in both mice and humans. The gene discussed is PITX1; the disease is familial clubfoot with or without associated lower limb anomalies.