Matthew Barrett Dobbs, MD, and Christina Gurnett, MD, PhD, will receive the Kappa Delta Ann Doner Vaughn Award for their paper "Advancing Personalized Medicine for Clubfoot Through Translational Research." The award will be presented in San Diego during the 2017 AAOS Annual Meeting.

"Our work leverages scientific advances of the past decades, including human gene sequencing, molecular genetic engineering of mouse models, and magnetic resonance imaging, as well as new treatment technologies," write the authors. Their paper outlines their efforts to understand the genetic and morphologic abnormalities contributing to foot development and their use of this information to devise personalized treatment paradigms.

Clubfoot
Clubfoot is one of the most common pediatric orthopaedic disorders, and may affect 1 of every 1,000 children. Clubfoot is recognizable at birth and is readily distinguishable from positional foot anomalies because it is rigid and not passively correctable. Historically, clubfoot treatment has been based on different methods of manipulating and immobilizing the foot; other treatments have focused on more invasive surgical options.

The Ponseti method of clubfoot treatment, developed by Ignacio Ponseti, MD, and first described in 1964, consists of weekly manipulation and serial casting. Ideally, treatment would start within the first month of life and culminate with a percutaneous Achilles tenotomy performed in the office, followed by a final cast and prolonged use of a foot abduction brace. Over the past 40 years, this method has gradually replaced extensive soft-tissue surgeries.

Although the Ponseti method revolutionized clubfoot treatment, it is not effective for all patients. If the Ponseti method fails, patients often require more extensive surgeries, exposing them to potential complications and life-long disabilities. This prompted Drs. Dobbs and Gurnett to pursue a basic science approach to understanding the pathogenesis of this heterogeneous disorder.

Noting that family history is positive for clubfoot in approximately 25 percent of all patients with idiopathic clubfoot, the two began genetic studies to see if they could identify the genes responsible for isolated clubfoot.

Genetic studies
These genetic studies capitalized on the rapid advances in sequencing technology for the human genome. After identifying a large, five-generation family with cases of isolated clubfoot along with a spectrum of lower limb birth defects, they used positional cloning methods to discover that a single mutation in the gene PITX1 was associated with some cases of clubfoot.

"PITX1 is a transcription factor involved in early limb development," explained Dr. Dobbs in his paper, "and is one of a handful of genes expressed preferentially in the lower limb, making it critical to leg development." Later, they were able to identify a genomic deletion of PITX1 in a small family, which resulted in the occurrence of isolated clubfoot in three generations. Subsequent studies in mice enabled them to identify growth deficits (smaller fibula, peroneal artery, and peroneus muscles), which they were also able to correlate during ensuing human studies (Fig. 1).

"Because PITX1 mutations are associated with a high rate of additional comorbidities, including hip dysplasia and tibial hemimelia," write the authors, "they are of major significance. However, mutations in PITX1 have only been found in a handful of patients and are overall a relatively rare cause of clubfoot."

Genomic analysis also revealed recurrent copy number variations (CNVs) in chromosome 17q23, present in about 5 percent of all familial clubfoot patients. "Chromosome 17q23 CNVs, which can be identified clinically with chromosomal microarray studies, are important to identify because of their association with treatment-resistant clubfoot and hip dysplasia," they wrote.

In addition, they identified a genetic deletion of homeobox transcription factor HOXC genes that segregated with clubfoot in a three-generation family, as well as in two other families with autosomal dominant isolated congenital vertical talus, suggesting that this may be a common cause of familial vertical talus. Further genetic studies suggested a role for common genetic variation near several transcriptional regulators that previously had not been implicated in clubfoot pathogenesis.

Drs. Dobbs and Gurnett note that these genetic abnormalities account for only a small amount of the heritability of clubfoot, and suggest a more important role for rare variants. "Vast new gene discovery awaits," they wrote.

Morphologic abnormalities
"Surprisingly, few magnetic resonance imaging (MRI) studies of clubfoot limbs had been published before we began to analyze the clubfoot-like feet of our PITX1 haploinsufficient mice," noted the authors. Their high-tech imaging studies in mice provided evidence that mutations in the PITX1-TBX4-HOXC pathway are associated with specific muscle hypoplasia.

"Hypoplasia of lateral muscles manifests clinically as loss of foot evertor function, which is, in our experience, often associated with clubfoot treatment resistance," they wrote. "Others have found the drop-toe sign to be a clinical indicator of poor response to traditional clubfoot treatment, and we confirmed that this clinical sign is also associated with more severe imaging abnormalities."

Drs. Dobbs and Gurnett also developed a noninvasive, noncontrast electrocardiography-gated magnetic resonance angiography method to image the vasculature of the lower extremity. This enabled them to identify similar vascular anomalies in patients with both clubfoot and vertical talus, suggesting a shared etiology.

Further studies revealed that morphologic abnormalities—increased perimysial fat, increased intramuscular fat, or muscle aplasia/hypoplasia—were common in patients with treatment-resistant clubfoot and rarely seen in patients whose clubfoot was easily treated. Identifying these abnormalities early in a treatment course would enable a more patient-specific treatment plan, they note.

Personalized treatment methods
Strategies to deal with treatment-resistant clubfoot are a priority, according to Drs. Dobbs and Gurnett. The Ponseti method has been applied to patients with clubfoot associated with arthrogryposis, myelomeningocele, and other concomitant limb defects, as well as to treat older patients whose clubfoot was neglected. Although treating these patients may be difficult, outcomes can be excellent.

A firm understanding of the principles underlying the Ponseti method led Dr. Dobbs to develop a casting technique to correct congenital vertical talus. His method relies on applying a casting method in which some of the applied forces are opposite to those used in the Ponseti method (reverse Ponseti method). This treatment method for vertical talus has been reproduced successfully around the world, and results in better outcomes than surgical treatment.

Because bracing compliance is one of the strongest predictors of outcome, addressing issues that contribute to noncompliance is important. These issues include poorly fitted braces, blistering, irritability due to the restrictiveness of the brace, and lack of knowledge about the importance of bracing.

"After listening to parents in clinic and chatting on Internet blogs," wrote the authors, "we developed a dynamic, articulating clubfoot brace to improve brace comfort and compliance (Fig. 2). Many other aspects of brace wear, including the optimal length and timing of bracing, can now be studied because temperature monitoring devices can be placed in the brace to quantitatively determine compliance."

FAB 24 clinical trial
Drs. Dobbs and Gurnett are currently leading a multicenter randomized clinical trial (FAB24) to understand how to best prevent clubfoot recurrence following initial correction. They hope to identify the optimal length of foot abduction bracing (FAB) and to determine which clinical and genetic factors negatively affect treatment outcome.

The prospective study involves 139 patients at eight participating centers. All patients had clubfoot that was successfully corrected with the Ponseti method. Patients are randomized to receive either 2 years or 4 years of bracing.

Clinical variables being collected include foot length and circumference, calf circumference, and neurologic information such as the ability to dorsiflex and plantarflex the toes and fire the foot evertors with stimulation. Their goal is to define characteristics that the treating pediatric orthopaedic surgeon can identify during the initial visit that will help predict response to treatment.

The expected completion date is 2020, and based on this study, Drs. Dobbs and Gurnett hope to develop individualized treatment protocols for patients with clubfoot. Because all clubfeet do not respond the same to treatment, such protocols may eliminate the need for years of unnecessary bracing in some patients or identify those patients who may benefit from earlier tendon transfer surgery or physical therapy intervention focused on evertor strengthening.

"The ultimate goal of our research is to develop novel treatment methods that are based on an understanding of the underlying biology," concluded the authors. "Knowledge of the genetic diagnosis and resultant anatomic abnormalities will enable us to develop personalized therapies that minimize the extent of surgery by addressing specific muscular, skeletal, vascular, or neuronal abnormalities. Although the treatment and care of children with clubfoot has advanced significantly since Ponseti developed his treatment method, we hope our work will inspire scientists and clinicians to build upon the foundation that we and others have built."