Wound Complications After Cleft Repair in Children With Van der Woude Syndrome

Abstract

Van der Woude Syndrome (VWS, OMIM #119300) is an autosomal dominant condition associated with clefts of the lip and/or palate and lower lip pits and is caused by mutations in Interferon Regulatory Factor 6 (IRF6). The standard of practice for children born with cleft lip/ palate is surgical repair, which requires proper wound healing. We tested the hypothesis that children with VWS are more likely to have wound complications following cleft repair than children with non-syndromic cleft lip/palate (NSCLP). Furthermore, we hypothesized that children with VWS have more surgical procedures. A retrospective, case-controlled study was performed. Seventeen children with VWS and 68 matched controls with NSCLP were scored for presence of wound complications following cleft repair, severity of complications and number of surgeries from ages 0-10. Of the 17 children with VWS, 8 had wound complications. Thirteen of 68 controls had wound complications (P=0.02). Six of eight wound complications in the VWS group were major with nine of 13 complications in the control group major (P=0.04). The majority of wound complications were fistulae and occurred in isolated cleft palate and bilateral cleft lip. The mean number of surgeries in the VWS group was 3.0 compared to 2.8 in the control group (P=0.67). Our studies suggest that children with VWS have an increased risk for wound complications following cleft repair compared to children with NSCLP. Furthermore the data supports a role for IRF6 in wound healing.

The toll-like receptor 3 pathway in homeostasis, responses to injury and wound repair

“…Patients with IRF6 mutation-associated cleft lip/palate disorders were more likely to have wound complications after corrective surgery (47% of patients), compared to patients with other forms of cleft lip/palate (19% of patients) [66]. This conclusion is supported by an in vitro study showing that IRF6 mRNA expression was upregulated in normal keratinocytes during scratch wounding [67].…”

Interferon regulatory factor 6 regulates keratinocyte migration

“…These molecular changes result in increased formation of actin stress fibers, increased cellular area and slower migration. This provides a potential molecular rationale for the observed increased likelihood of post-surgical complications in patients with mutations in IRF6 compared with those without (Jones et al, 2010). Our data show delays in wound closure using both an ex vivo murine embryo culture wound-healing assay and an in vitro keratinocyte scratch assay.…”

“…In humans, mutations in IRF6 cause Van der Woude syndrome (VWS) and popliteal pterygium syndrome, two orofacial clefting disorders (Kondo et al, 2002). Interestingly, patients with VWS were more likely to have wound complications following corrective cleft surgery than patients with non-syndromic cleft (Jones et al, 2010), consistent with a role for IRF6 in wound healing. Although Irf6 is expressed in suprabasal keratinocytes of the epidermis and plays a crucial role in epidermal differentiation in vivo and in vitro Ingraham et al, 2006), its function in keratinocyte migration is currently unknown.…”

Knockdown of IRF6 Attenuates Hydrogen Dioxide-Induced Oxidative Stress via Inhibiting Mitochondrial Dysfunction in HT22 Cells

“…Mutations in IRF6 gene cause two syndromic forms of cleft lip and palate: Van der Woude and Popliteal Pterygium syndromes (Kondo et al 2002). In addition, it is shown to play important roles in wound healing, breast epithelium differentiation, and tumor metabolism in squamous cell carcinoma (Jones et al 2010;Bailey et al 2008;Botti et al 2011). However, the regulation and function of IRF6 in the central nervous system remain unknown.…”