TY - JOUR
T1 - The 2017 ABJS Nicolas Andry Award
T2 - Advancing Personalized Medicine for Clubfoot Through Translational Research
AU - Dobbs, Matthew B.
AU - Gurnett, Christina A.
N1 - Funding Information:
Acknowledgments We thank our patients and their families for their continued support and participation in our research studies. Funding was provided by Shriners Hospitals for Children, March of Dimes Foundation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Orthopaedic Research and Education Foundation, The Discovery Institute of Saint Louis Children’s Hospital and Washington University, National Institute of Arthritis and Musculoskeletal and Skin Diseases (Grant No. RO1AR067715-01), and University of Missouri Spinal cord Injury Research Program. Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number U54 HD087011 to the Intellectual and Developmental Disabilities Research Center at Washington University. The project described was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1 TR001414. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
We thank our patients and their families for their continued support and participation in our research studies. Funding was provided by Shriners Hospitals for Children, March of Dimes Foundation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Orthopaedic Research and Education Foundation, The Discovery Institute of Saint Louis Children's Hospital and Washington University, National Institute of Arthritis and Musculoskeletal and Skin Diseases (Grant No. RO1AR067715-01), and University of Missouri Spinal cord Injury Research Program. Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number U54 HD087011 to the Intellectual and Developmental Disabilities Research Center at Washington University. The project described was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National?Institutes of Health, through Grant UL1?TR001414.?The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. One or more authors certifies that he (MBD), or a member of her immediate family (CAG) has received or may receive payments or benefits, during the study period, an amount of USD 10,000 to USD 100,000 from D-Bar Enterprises (St Louis, MO, USA). The institution of one or more of the authors (MBD and CAG) has received, during the study period, funding from Shriners Hospital for Children (St Louis, MO, USA).
Publisher Copyright:
© 2017, The Association of Bone and Joint Surgeons®.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - 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. Questions/Purposes: (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.
AB - 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. Questions/Purposes: (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.
UR - http://www.scopus.com/inward/record.url?scp=85013839864&partnerID=8YFLogxK
U2 - 10.1007/s11999-017-5290-0
DO - 10.1007/s11999-017-5290-0
M3 - Article
C2 - 28236079
AN - SCOPUS:85013839864
SN - 0009-921X
VL - 475
SP - 1716
EP - 1725
JO - Clinical orthopaedics and related research
JF - Clinical orthopaedics and related research
IS - 6
ER -