title: The 2017 ABJS Nicolas Andry Award: Advancing Personalized Medicine for Clubfoot Through Translational Research.
abstract: BACKGROUND
  Clubfoot is one of the most common pediatric orthopaedic disorders. While the Ponseti method has revolutionized clubfoot treatment, it is not effective for all patients. When the Ponseti method does not correct the foot, patients are at risk for lifelong disability and may require more-extensive surgery.
  
  
  OBJECTIVE
  (1) What genetic and morphologic abnormalities contribute to the development of clubfoot? (2) How can this information be used to devise personalized treatment paradigms for patients with clubfoot?
  
  
  METHODS
  Human gene sequencing, molecular genetic engineering of mouse models of clubfoot, MRI of clubfoot, and development of new treatment methods all have been used by our group to understand the biological basis and improve therapy for this group of disorders.
  
  
  RESULTS
  We gained new insight into clubfoot pathogenesis from our discovery that mutations in the PITX1-TBX4-HOXC transcriptional pathway cause familial clubfoot and vertical talus in a small number of families, with the unique lower limb expression of these genes providing an explanation for the lack of upper extremity involvement in these disorders. MRI studies revealed corresponding morphologic abnormalities, including hypomorphic muscle, bone, and vasculature, that are not only associated with these gene mutations, but also are biomarkers for treatment-resistant clubfoot.
  
  
  CONCLUSIONS
  Based on an understanding of the underlying biology, we improved treatment methods for neglected and syndromic clubfoot, developed new treatment for congenital vertical talus based on the principles of the Ponseti method, and designed a new dynamic clubfoot brace to improve strength and compliance.
authors.affiliation: Department of Orthopaedics, St. Louis Children's Hospital, 1 Children's Place, Suite 4S-60, St. Louis, MO, 63110, USA. dobbsm@wudosis.wustl.edu.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Dobbs
authors.affiliation: Department of Neurology, Washington University School of Medicine in St Louis, St. Louis, MO, USA.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Gurnett
mesh_terms: D000818:Animals; D001363:Awards and Prizes; D001915:Braces; D002648:Child; D002675:Child, Preschool; D003025:Clubfoot / Q000235:genetics* / Q000628:therapy*; D005413:Flatfoot; D005532:Foot Deformities, Congenital / Q000235:genetics / Q000628:therapy; D053263:Gene Regulatory Networks / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007223:Infant; D051379:Mice; D019637:Orthopedic Procedures / Q000379:methods*; D051761:Paired Box Transcription Factors / Q000235:genetics; D057285:Precision Medicine / Q000379:methods*; D017422:Sequence Analysis, DNA; D020825:T-Box Domain Proteins / Q000235:genetics; D057170:Translational Research, Biomedical
chemical_list: D018398:Homeodomain Proteins; D051761:Paired Box Transcription Factors; D020825:T-Box Domain Proteins; C491193:TBX4 protein, human; C101485:homeobox protein PITX1