Robin Wu

Co-occurrence of frameshift mutations in SMAD6 and TCF12 in a child with complex craniosynostosis

Non-syndromic craniosynostosis (CS) affects 1 in 2350 live births. Recent studies have shown that a significant fraction of cases are caused by de novo or rare transmitted mutations that promote premature osteoblast differentiation in cranial sutures. Rare heterozygous loss-of-function (LOF) mutations in SMAD6 and TCF12 are highly enriched in patients with non-syndromic sagittal and coronal CS, respectively. Interestingly, both mutations show striking incomplete penetrance, suggesting a role for modifying alleles; in the case of SMAD6, a common variant near BMP2 drastically increases penetrance of sagittal CS. Here, we report a proband presenting with both sagittal and coronal craniosynostosis with the highly unusual recurrence of CS within two months of initial surgery, requiring a second operation to re-establish suture patency at six months of age. Exome sequencing revealed a rare transmitted frameshift mutation in SMAD6 (p. 152 fs*27) inherited from an unaffected parent, absence of the common BMP2 risk variant, and a de novo frameshift mutation in TCF12 (p.E548fs*14). SMAD6 and TCF12 independently inhibit transcriptional targets of BMP signaling. The findings are consistent with epistasis of these mutations, increasing penetrance and severity of CS in this proband. They also add to the list of composite phenotypes resulting from two Mendelian mutations, and support the utility of exome sequencing in atypical CS cases.

Does Cleft Palate Width Correlate With Veau Classification and Outcome

Purpose: Wider cleft palates are thought to be associated with increased complications and poorer outcomes following cleft palate repair. Objective cleft palate photographic measurement and assessment of complications have not been previously performed. The purpose of this study is to quantitatively characterize a series of cleft palate dimensions and to investigate possible correlations with Veau classification and intra-, peri-, and postoperative outcomes. Methods: The analytic sample included primary cleft palate repairs performed by the senior author over a 2-year period. Standard photographs of clefts taken at the time of repair were analyzed using Image-J software. Demographic, intraoperative, perioperative, and postoperative information were collected. Width measurements were correlated with Veau classification, intraoperative variables, perioperative variables, and adverse outcomes. Statistical tests performed included simple regression analyses and multiple regression analysis. Results: Out of 70 patients, 50 had adequate photographic documentation for inclusion in the study; 44% of patients were classified as Veau I with an average cleft width of 5.4 mm, 28% Veau II with an average of 8.9 mm, 16% Veau III with an average of 11.3 mm, and 12% Veau IV with an average of 10.0 mm. No patients exhibited postoperative bleeding, dehiscence, airway problems, infection, fistula formation, or return to the operating room. The authors found that increasing cleft width significantly predicts increasing Veau classification (P < 0.01), increasing operating time (P < 0.05), increased hypernasality (P < 0.05), and speech delay (P < 0.001). Additionally, the presence of an intentional alveolar fistula (Veau III or Veau IV clefts) significantly predicts fluid emission (P < 0.001) but cleft width did not predict fluid emission. Increased cleft width did not significantly predict length of stay. Conclusion: Our data demonstrate that wider preoperative cleft palates correlate with Veau classification, increased operating time, and slightly worsened postoperative sequela. There were no perioperative instances of bleeding, dehiscence, respiratory complications, infection, fistula formation, and return to operating room. Hypernasality and speech delay were associated with increased cleft palate width. Length of stay did not correlate with cleft palate width.

Fibrin Tissue Sealant as an Adjunct to Cleft Palate Repair

Purpose: Fibrin glue is a common tissue sealant used to promote hemostasis, adhere tissues, and accelerate healing. Cleft palate repair can be technically challenging, creating dead space between tissue planes, and can be prone to complications such as would dehiscence or bleeding. The purpose of this study is to assess the role of fibrin glue as an adjunct to cleft palate repair. The authors hypothesize a beneficial impact on complication rates, including bleeding, dehiscence, and fistula formation, among others. Methods: Primary cleft palate repairs using fibrin glue were retrospectively analyzed. Demographic, intraoperative, perioperative, and postoperative data were combed for outcome variables. Complication rates were calculated in percentages and the results were compared to the published literature. Z-test statistics were performed for comparison. Results: A total of 45 patients, 21 females and 24 males, who underwent primary cleft palate repair with fibrin glue between 2011 and 2014, had sufficient data to be reviewed. There were no instances of bleeding, dehiscence, airway obstruction, infection, oronasal fistula, or return to the operating room in any patients. One patient exhibited mild postoperative coughing and secretions that resolved with conservative measures. Another patient displayed postoperative seizure activity due to a pre-existing condition. All complication rates in our fibrin glue series were lower than those reported without the use of fibrin glue. Overall complication rates with fibrin sealant are significantly lower than overall complication rates without. Conclusion: Our data suggest that fibrin sealant is a beneficial adjunct to cleft palate repair. Its application is well-tolerated and the complication profile in our cohort was much less than the reported rates. The results of this preliminary study should be vetted with a prospective analysis involving a control group.

Abstract: Direct Brain Recordings in Craniosynostosis Can Predict Future Language Development

BACKGROUND: The mid-tibia region is a challenging reconstructive region given the paucity of soft tissue options and local muscle flaps available for reconstruction. A free-tissue transfer may not be an option in all cases due to patient comorbid conditions, personal preferences or operative resources availability. An extended medial gastrocnemius rotational flap may provide a safe, versatile and effective treatment option in the mid tibia region.

Abstract P14. Cleft Palate Width: Does it correlate with Veau Classification and Outcome?

RESULTS: Of the 24 patients identified, 75% were male, mean age was 8.6, mean ISS 23.7 and mean GCS 9.7. The two most common causes of these fractures patterns were MVA (67%) and pedestrian (25%). 60% were managed operatively. 58% patients had skull fractures, 45.8% intracranial trauma, and 17% developed meningitis. One patient had a C-Spine injury. Group 1 had 8, group 2 had 4 and group 3 had 12 patients. Significant differences were age 5.9 vs 10.4 between group 1 vs group 3 (p=0.004). No differences in ISS, operative repair, complications, LOS, presence of skull fractures or intracranial trauma were found between these groups.