Our previous work demonstrating enrichment of outflow tract (OFT) congenital heart disease (CHD) in children with cleft lip and/or palate (CL/P) suggests derangements in common underlying developmental pathways. The current pilot study examines the underlying genetics of concomitant nonsyndromic CL/P and OFT CHD phenotype. Of 575 patients who underwent CL/P surgery at Children's Hospital Los Angeles, seven with OFT CHD, negative chromosomal microarray analysis, and no recognizable syndromic association were recruited with their parents (as available). Whole genome sequencing of blood samples paired with whole‐blood‐based RNA sequencing for probands was performed. A pathogenic or potentially pathogenic variant was identified in 6/7 (85.7%) probands. A total of seven candidate genes were mutated (CHD7, SMARCA4, MED12, APOB, RNF213, SETX, and JAG1). Gene ontology analysis of variants predicted involvement in binding (100%), regulation of transcription (42.9%), and helicase activity (42.9%). Four patients (57.1%) expressed gene variants (CHD7, SMARCA4, MED12, and RNF213) previously involved in the Wnt signaling pathway. Our pilot analysis of a small cohort of patients with combined CL/P and OFT CHD phenotype suggests a potentially significant prevalence of deleterious mutations. In our cohort, an overrepresentation of mutations in molecules associated with Wnt‐signaling was found. These variants may represent an expanded phenotypic heterogeneity within known monogenic disease genes or provide novel evidence of shared developmental pathways. The mechanistic implications of these mutations and subsequent developmental derangements resulting in the CL/P and OFT CHD phenotype require further analysis in a larger cohort of patients.

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Background: Cleft lip and palate (CLP) comprise over 90% of the world’s congenital anomalies and cause significant disability worldwide, while disproportionally burdening low- and middle-income countries (LMICs). Research can help inform strategies that reduce disparities in accessing CLP care. We performed a scientometric analysis of CLP research in LMICs to identify influential contributors and themes. Methods: The authors searched seven citation databases accessed via Web of Science, from inception to March 2, 2021. Social network analysis was done using VOSviewer. The Kruskal-Wallis test and linear regression were used. Results: In total, 1561 articles authored by 6414 researchers affiliated with 2113 organizations in 119 countries were included. Most authors (n = 6387, 99.6%) had published two or more articles. The USA (454 articles), Brazil (211 articles), China (175 articles), and India (127 articles) published the most. The most prolific institutions were the University of Sao Paulo (94 articles), the University of Pittsburgh (57 articles), and the University of Iowa (55 articles). Marazita ML (33 articles), Shi B (27 articles), and Murray JC (22 articles) had the highest number of publications. An estimated 510 articles (32.7%) were focused on epidemiology, 240 (15.4%) on management, and 54 (3.5%) on global plastic surgery for CLP. Conclusions: LMICs are disproportionally burdened by CLP, but research is limited and often produced by high-income countries. This study elucidates partnership and health system strengthening opportunities to improve LMIC research capacity and ultimately informs the management and outcomes for patients with CLP.

Background Children with orofacial clefts are highly susceptible to malnutrition, with severe malnutrition restricting their eligibility to receive safe surgery. Ready-to-use therapeutic foods (RUTF) are an effective treatment for malnutrition; however, the effectiveness has not been demonstrated in this patient population prior to surgery. We studied the effectiveness of short-term RUTF use in transitioning children with malnutrition, who were initially ineligible for surgery, into surgical candidates. Methods A cohort of patients from Ghana, Honduras, Malawi, Madagascar, Nicaragua, and Venezuela enrolled in a nutrition program were followed by Operation Smile from June 2017 to January 2020. Age, weight, and length/height were tracked at each visit. Patients were included until they were sufficiently nourished (Z >  = -1) with a secondary outcome of receiving surgery. The study was part of a collaborative program between Operation Smile (NGO), Birdsong Peanuts (peanut shellers and distributors), and MANA Nutrition (RUTF producer). Results A total of 556 patients were recruited between June 2017 and January 2020. At baseline 28.2% (n = 157) of patients were diagnosed with severe, 21.0% (n = 117) moderate, and 50.7% (n = 282) mild malnutrition. 324 (58.3%) presented for at least one return visit. Of those, 207 (63.7%) reached optimal nutrition status. By visit two, the mean z-score increased from -2.5 (moderate) to -1.7 (mild) (p < 0·001). The mean time to attain optimal nutrition was 6 weeks. There was a significant difference in the proportion of patients who improved by country(p < 0.001). Conclusion Malnutrition prevents many children with orofacial clefts in low- and middle-income countries from receiving surgical care even when provided for free. This creates an even larger disparity in access to surgery. In an average of 6 weeks with an approximate cost of $25 USD per patient, RUTF transitioned over 60% of patients into nutritionally eligible surgical candidates, making it an effective, short-term preoperative nutritional intervention. Through unique partnerships, the expansion of cost-effective, large-scale nutrition programs can play a pivotal role in ensuring those at the highest risk of living with unrepaired orofacial clefts receive timely and safe surgical care.

Background: Children with orofacial clefts (OFCs) are highly susceptible to malnutrition, with severe malnutrition restricting their eligibility to surgery. Ready-to-use therapeutic foods (RUTF) are an effective treatment for children with malnutrition; however, the effectiveness of short-term preoperative nutritional supplementation in in patients with OFCs has not been demonstrated. We studied the effectiveness of RUTF in patients with OFCs prior to surgery. Methods: A cohort of patients with OFC from Ghana, Honduras, Malawi, Madagascar, Nicaragua, and Venezuela was followed by Operation Smile from June 2017 to January 2020. These patients were enrolled in a nutrition program that provided RUTF and tracked age, weight, and length/height at each visit. A WHO Weight-for-Length (WLZ) or Weight-for-Height (WHZ) Z-score was calculated for each patient to longitudinally track malnutrition status. Patients were tracked to being sufficiently nourished (Z >= -1) with a secondary outcome of receiving surgery. Results: A total of 556 patients were recruited between June 2017 and January 2020. Initially, 28.2% (N=157) were diagnosed with severe, 21.0% (n=117) with moderate, and 50.7% (n=282) with mild malnutrition. 324 (58.3%) patients presented for at least one return visit. Of the 324 patients who returned, 207 (63.7%) reached optimal nutrition status– 32 (15.5%) with initial severe, 30 (14.5%) with moderate, and 145 (70.0%) with mild malnutrition. By the second visit, the mean z-score increased significantly from -2.5 (moderate malnutrition) to -1.7 (mild malnutrition) (p<0·001). The mean time to attain Z >= -1 was 6 weeks with a range of 1 to 103 weeks. There was a significant difference by country in the proportion of patients who improved (p<0.001). Conclusion: Malnutrition prevents many children with OFC from receiving surgical care even when provided for free creating a larger disparity in access to surgery. In an average of 6 weeks and approximately $25 USD per patient, RUTF supported over 60% of patients to nutritionally healthy and eligible for surgery, making it an effective, short-term preoperative nutritional intervention. Through unique partnerships, cost-effective, large-scale nutrition programs can play a pivotal role in ensuring those at the highest risk of living with unrepaired OFC receive timely and safe surgical care.