Introduction to the special issue on orofacial clefts

The face that you see in the mirror each morning is likely the product of precision in cell behavior, balanced molecular regulation, and a nurturing environment relatively free from toxins or teratogens. Dr. Chengji Zhou and team from UC Davis provide us with four comprehensive reviews on aspects of orofacial clefts (OFCs) to bring us up to date on how our face develops and what happens when these processes are disrupted. Drs. Yulai Zhou and Julian Little and team from the Universities of Ottawa and Dundee and Duke evaluated the data that folic acid supplementation may effectively prevent OFCs. The study of OFCs could provide a better understanding of developmental programs common to the morphogenesis of a variety of embryonic structures, as well as in identifying therapeutic strategies specific to OFC prevention. OFCs are the most common of craniofacial birth defects and one of the most common of all birth defects, affecting on average 1 in 700 newborns worldwide (Mossey & Modell, 2012). OFCs include the failure of the upper lip and/or palate (the roof of the mouth) to close properly during development, leaving a gap or gaps that often require surgical closure. Aside from the psychosocial consequences of OFCs that are not trivial (Al-Namankany & Alhubaishi, 2018; Broder, Smith, & Strauss, 1994; Hunt, Burden, Hepper, & Johnston, 2005), difficulties in eating, speaking, and breathing can result from OFCs (Goswami, Bhushan, & Jangra, 2016). These individuals also have higher risk for ear infections and dental issues. In humans, orofacial formation is mostly active from the fourth through sixth week of embryonic development (Schoenwolf, Bleyl, Brauer, & Francis-West, 2014). Face formation occurs in mice at embryonic days 8–14.5 (Tamarin & Boyde, 1977), in zebrafish during 36–48 hr postfertilization (hpf; Swartz, Sheehan-Rooney, Dixon, & Eberhart, 2011), and in chicken at incubation of 3–6.5 days (HH stages 20–29; Abramyan & Richman, 2018). The typical face is the result of several primordial tissues growing in concert and fusing at just the right time and place (Figure 1). These tissues are largely derived from or orchestrated by neural crest cell (NCC) progenitors in communication with surrounding epithelia. The NCCs proliferate and migrate while receiving and sending signals (Helms, Cordero, & Tapadia, 2005). After migration, they differentiate into a wide range of cell types. The cranial NCC derivatives form mounds of mesenchymal tissues covered by epithelial cells that are called prominences or processes that fuse with each other in a stereotyped way to form orofacial structures and separate oral and nasal chambers. Each step occurs with bilateral symmetry. Ji et al. (2020) explain and explore many cellular events that are involved in the development of the normal face and which ones are disrupted in OFCs. In view of the complexity of face development, it is not surprising that networks of genes and factors have been implicated in its malformation. Reynolds et al. clarify this complexity and provide comprehensive tables of the conditions and associated or candidate genes. OFCs can be found as isolated defects or as part of syndromes. The genetic causes of syndromic OFCs are easier to track than isolated OFCs. For example, 68% of individuals with Van der Woude syndrome and 97% of families with popliteal pterygium syndrome have mutations in the interferon regulatory factor 6 (IRF6) gene (1q32.2-q32.3) that transcribes a transcription factor involved in many developmental processes, including epidermal development (de Lima et al., 2009). It is expressed in the orofacial epithelial cells to maintain epithelial integrity and prevent ectopic epithelial fusions during palatogenesis. “Modern sequencing technologies have accelerated our ability to identify specific sequences and variants that are linked with clefts, and at least 350 candidate genes have been identified through association studies in human OFC patients alone.” However, the genomic DNA sequence needs no change at all to initiate OFCs. Regulating access of transcriptional machinery to DNA sequences can be powerful in itself. The epigenetic causes of OFCs are presented by Garland and colleagues. Epigenetics has a significant impact on OFC pathogenesis. Conformational changes to the DNA after methylation allow or prohibit binding of the transcriptional machinery. Other epigenetic factors include histone modifications and noncoding RNAs (such as miRNA), which also play important roles in OFC etiology. Embryos are highly vulnerable to environmental factors such as maternal smoking, alcohol intake, poor diet, overheating, and exposure to drugs and pollutants. These environmental factors can cause developmental disorders including OFCs and can also have transgenerational consequences. Embryonic face development is not only vulnerable to in utero exposure but is also affected by exposures to the mother and even the father before pregnancy. Maternal and paternal environmental effects can be transferred as epigenetic marks that can manifest as OFCs in the embryo without direct in utero exposure. While we know that some of these negative environmental factors can be eliminated, others cannot be avoided. Can the research help to protect us from OFCs through other avenues such as with the use of preconception and prenatal supplements? Drs. Yulai Zhou, Julian Little, and collaborators from the Universities of Ottawa and Dundee and Duke provide a set of meta-analyses to determine the relationship between different indicators of folate intake/status and OFCs. Since the last such analysis published in 2008 (Johnson & Little, 2008), 56 papers published in the years 2007–2020 were identified. Based on the 2008 study, the conclusion was that there was an 18% decline in the risk of cleft lip/cleft palate (CL/P) associated with the use of folic acid containing supplements but no significant reduction in cleft palate (CP). They also reported a reduction of about 23% in CL/P risk with intake of multivitamins. The updated findings suggest that taking multivitamin supplements that include folic acid during periconception may prevent CL/P, reducing the risk by 40%, and CP only, reducing the risk by 19%. Folic acid supplementation alone did not seem to help. The update differs from the 2008 study in that study participants were from a wider range of countries, broadening the socioeconomic variability. Comparison across these meta-analyses illustrates the difficulties inherent in these types of analyses and the need for more studies to get a clearer picture of just what is needed to prevent OFCs. Nonetheless, the good news is that supplements appear to be effective in preventing some OFCs. The authors have no conflict of interest to report. Data sharing is not applicable to this article as no new data were created or analyzed in this study.

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