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. 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. ResultsWe 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.

The etiology of idiopathic congenital talipes equinovarus: a systematic review

“…There is also reported a unique case of bilateral ICTEV in preterm triplets, which provides even further support for a genetic etiology [ 19 ]. Many different families of genes were identified to play a role in the disease and a prospective role in the development of personalized conservative and surgical approaches [ 64 ]. Several families of genes and pathways were identified and investigated using mainly the candidate gene approach.…”

“…Interestingly, HOXD10 mutations were previously identified in two families with vertical talus [ 48 , 49 ], which strongly supports a role of homeobox gene mutations in the etiology of isolated vertical talus. However, because mutations in the PITX1-TBX4-HOXC pathway are infrequent in patients with clubfoot, other genetic mechanisms remain to be discovered and investigated [ 64 ].…”

Clinical assessment of three-dimensional printing assisted osteotomy guide plates in precise osteotomy of adult talipes equinovarus

“…Moreover, Gozar et al [15] and Barker et al [22] applied computer modeling analysis technology to the correction of TE malformation, and obtained the satisfactory short-term outcomes, but still lacked a long-term prognostic comparison with routine group. In this research, there was no significant difference between the two groups in total rate of complications (13.3% vs 16.7%, P = 0.291). This outcome was consistent with the research results of Zhang et al [23] who used the 3D printing for the patients with complicated ankle fractures, indicating that 3D printing presents no apparent superiorities in avoiding complications.…”

“…During the operation, it is hard for operators to accurately adjust the osteotomy direction and angle of each dimension, so it is often need to repeatedly adjust or determine the correction strategy only based on subjective assumptions, which eventually leads to a huge deviation from the preoperative planning, and the prognosis will be unoptimistic. Hence, it is vital to develop an appropriate and personalized treatment plan for different etiology, deformity location and degree of ATE malformation for the excellent functional reconstruction [15,16].…”

Klumpfußtherapie nach Ponseti – aktueller Standard

“…der Ätiologie des bisher idiopathisch genannten Klumpfußes [28]. So wurde gezeigt, dass insbesondere die zu Rezidiven neigenden Klumpfüße mit ausgeprägter initialer Deformität und begleitender Hüftdysplasie mit Fehlern im PITX1-TBX4-HOXC-Pfad assoziiert sind [47]. Ein weiterer Anhaltspunkt ist die gefundene genetische Assoziation von Einzelnukleotidpolymorphismen mit verschiedenen die Extremitätenentwicklung beeinflussenden Transkriptionsfaktoren bei der Klumpfußentstehung [48].…”