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Concept: PHF8


Nonsyndromic orofacial clefts are common birth defects with multifactorial etiology. The most common type is cleft lip, which occurs with or without cleft palate (nsCLP and nsCLO, respectively). Although genetic components play an important role in nsCLP, the genetic factors that predispose to palate involvement are largely unknown. In this study, we carried out a meta-analysis on genetic and clinical data from three large cohorts and identified strong association between a region on chromosome 15q13 and nsCLP (P = 8.13×10-14 for rs1258763; relative risk (RR): 1.46, 95% confidence interval (CI): 1.32-1.61)) but not nsCLO (P = 0.27; RR: 1.09 (0.94-1.27)). The 5 kb region of strongest association maps downstream of Gremlin-1 (GREM1), which encodes a secreted antagonist of the BMP4 pathway. We show during mouse embryogenesis, Grem1 is expressed in the developing lip and soft palate but not in the hard palate. This is consistent with genotype-phenotype correlations between rs1258763 and a specific nsCLP subphenotype, since a more than two-fold increase in risk was observed in patients displaying clefts of both the lip and soft palate but who had an intact hard palate (RR: 3.76, CI: 1.47-9.61, Pdiff<0.05). While we did not find lip or palate defects in Grem1-deficient mice, wild type embryonic palatal shelves developed divergent shapes when cultured in the presence of ectopic Grem1 protein (P = 0.0014). The present study identified a non-coding region at 15q13 as the second, genome-wide significant locus specific for nsCLP, after 13q31. Moreover, our data suggest that the closely located GREM1 gene contributes to a rare clinical nsCLP entity. This entity specifically involves abnormalities of the lip and soft palate, which develop at different time-points and in separate anatomical regions.

Concepts: Gene, Genetics, Mouth, Cleft lip and palate, PHF8, Palatine uvula, Soft palate, Cleft



The philtral column and dimple are especially important in patients with cleft lip. Recently, we have found that, at maximal puckering, the appearance of the philtrum worsens although the philtral column is well formed at rest. In this study, we explore the effectiveness of the coronal muscle splitting technique in a microform cleft lip through comparative analysis of the postoperative results between the control group (patients without coronal muscle splitting) and the study group (patients with coronal muscle splitting).

Concepts: Controlling for a variable, Scientific control, Mouth, Cleft lip and palate, Facial features, PHF8, Philtrum




Clefts of the palate and/or lip are the most common among human craniofacial malformations and involve multiple genetic and environmental factors. Defects can only be corrected surgically and require complex life-long treatments. Our studies utilized the well-characterized Pax9(-/-) mouse model with a consistent cleft palate phenotype to test small-molecule Wnt agonist therapies. We first show that the absence of Pax9 alters the expression of Wnt pathway genes including Dkk1 and Dkk2, proven antagonists of Wnt signaling. The functional interactions between Pax9 and Dkk1 is shown by the genetic rescue of secondary palate clefts in Pax9(-/-)Dkk1(f/+);Wnt1Cre embryos. The controlled intravenous delivery of small-molecule Wnt agonists (Dkk inhibitors) into pregnant Pax9(+/-) mice restored Wnt signaling and led to the growth and fusion of palatal shelves as marked by an increase in cell proliferation and osteogenesis in-utero while other organ defects were not corrected. This work underscores the importance of Pax9-dependent Wnt signaling in palatogenesis and suggests that such a functional upstream molecular relationship can be exploited for the development of therapies for human cleft palates that arise from single gene disorders.

Concepts: Gene, Cell, Cleft lip and palate, Oral and maxillofacial surgery, PHF8


Despite health system advances, residents of low- and middle-income countries continue to experience substantial barriers in accessing health care, particularly for specialized care such as plastic and reconstructive surgery.

Concepts: Health care, Medicine, Cleft lip and palate, Reconstructive surgery, Oral and maxillofacial surgery, PHF8, Craniofacial team


BACKGROUND: Previous studies of prenatal exposure to drinking water nitrate and birth defects in offspring have not accounted for water consumption patterns or potential interaction with nitrosatable drugs. OBJECTIVES: We examined the relation between prenatal exposure to drinking water nitrate and selected birth defects, accounting for maternal water consumption patterns and nitrosatable drug exposure. METHODS: With data from the National Birth Defects Prevention Study, we linked addresses of 3300 case-mothers and 1121 control-mothers from the Iowa and Texas sites to public water supplies and respective nitrate measurements. We assigned nitrate levels for bottled water from collection of representative samples and standard laboratory testing. Daily nitrate consumption was estimated from self-reported water consumption at home and work. RESULTS: With the lowest tertile of nitrate intake around conception as the referent group, mothers of babies with spina bifida were 2.0 times more likely (95% CI: 1.3, 3.2) to ingest ≥ 5 mg nitrate daily from drinking water (vs. <0.91 mg) than control-mothers. During one month preconception through the first trimester, mothers of limb deficiency, cleft palate, and cleft lip cases were, respectively, 1.8 (95% CI: 1.1, 3.1), 1.9 (95% CI: 1.2, 3.1), and 1.8 (95% CI: 1.1, 3.1) times more likely than control-mothers to ingest ≥ 5.42 mg of nitrate daily (vs. <1.0 mg). Higher water nitrate intake did not increase associations between prenatal nitrosatable drug use and birth defects. CONCLUSIONS: Higher water nitrate intake was associated with several birth defects in offspring, but did not strengthen associations between nitrosatable drugs and birth defects.

Concepts: Drug addiction, Folic acid, Bottled water, Cleft lip and palate, Drinking water, PHF8, Desalination, Water crisis


  Early life exposure to anesthesia and surgery is suspected to associate with cognitive impairment later in life. We compared academic achievement among adolescents with cleft lip only (CL), cleft palate only (CP), and cleft lip and cleft palate (CLP) with a noncleft control group to investigate whether outcome depends on timing and number of operations during childhood and/or type of oral cleft.

Concepts: Cleft lip and palate, PHF8


Children with disabilities are at an increased risk for maltreatment. However, the risk of maltreatment is unknown for children with specific types of birth defects. This study was conducted to determine whether the risk and predictors of maltreatment differ between children with and without 3 birth defects: Down syndrome, cleft lip with/without cleft palate, and spina bifida.

Concepts: Folic acid, Disability, Cleft lip and palate, PHF8