Cleft Lip

Valproic acid (VPA) is a very effective anticonvulsant and mood stabilizer with relatively few side effects. Being an epigenetic modulator, it undergoes clinical trials for the treatment of advanced prostatic and breast cancer. However, in pregnancy, it seems to be the most teratogenic antiepileptic drug. Among the proven effects are congenital malformations in about 10%. The more common congenital malformations are neural tube defects, cardiac anomalies, urogenital malformations including hypospadias, skeletal malformations and orofacial clefts. These effects are dose related; daily doses below 600 mg have a limited teratogenic potential. VPA, when added to other anti-seizure medications, increases the malformations rate. It induces malformations even when taken for indications other than epilepsy, adding to the data that epilepsy is not responsible for the teratogenic effects. VPA increases the rate of neurodevelopmental problems causing reduced cognitive abilities and language impairment. It also increases the prevalence of specific neurodevelopmental syndromes like autism (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). High doses of folic acid administered prior to and during pregnancy might alleviate some of the teratogenic effect of VPA and other AEDs. Several teratogenic mechanisms are proposed for VPA, but the most important mechanisms seem to be its effects on the metabolism of folate, SAMe and histones, thus affecting DNA methylation. VPA crosses the human placenta and was found at higher concentrations in fetal blood. Its concentrations in milk are low, therefore nursing is permitted. Animal studies generally recapitulate human data.

IntroductionCleft lip and/or palate (CL/P) affects 1 in 700 live births globally. Children born with CL/P and their families face various challenges throughout the child's development. Extant research is often limited by small numbers and single-centre data. The Cleft Collective, a national cohort study in the UK, aims to build a resource, available to collaborators across the globe, to understand causes, best treatments and long-term outcomes for those born with CL/P, ultimately seeking to enhance their quality of life through improved understanding and care.Methods and analysisA longitudinal prospective cohort study of children born with CL/P and their families. Recruitment occurs across the UK and started in November 2013. Recruitment will continue until September 2027 with an estimated final sample of 4822 children born with CL/P (1157 cleft lip including/excluding the alveolus; 2112 cleft palate only; 1042 unilateral cleft lip and palate and 511 bilateral cleft lip and palate). Biological samples are collected from all recruited members of the family. Parental and child questionnaires are collected at key time points throughout the child's development. Surgical data are collected at the time of surgical repair of the child's cleft. Consent is obtained to link to external data sources. Nested substudies can be hosted within the cohort. Regular engagement with participants takes place through birthday cards for the children, social media posts and newsletters. Patient and Public Involvement is conducted through the Cleft Lip And Palate Association and Cleft Collective Patient Consultation Group who provide insightful and essential guidance to the Cleft Collective throughout planning and conducting research.Ethics and disseminationThe Cleft Collective was ethically approved by the National Research Ethics Service committee South West-Central Bristol (REC13/SW/0064). Parental informed consent is required for participation. Findings from the Cleft Collective are disseminated through peer-reviewed publications, conference presentations, newsletters and social media.

Craniofacial abnormalities account for approximately one third of birth defects. The regulatory programs that build the face require precisely controlled spatiotemporal gene expression, achieved through tissue-specific enhancers. Clusters of coactivated enhancers and their target genes, known as superenhancers, are important in determining cell identity but have been largely unexplored in development. In this study we identified superenhancer regions unique to human embryonic craniofacial tissue. To demonstrate the importance of such regions in craniofacial development and disease, we focused on an ~600 kb noncoding region located between NPVF and NFE2L3. We identified long range interactions with this region in both human and mouse embryonic craniofacial tissue with the anterior portion of the HOXA gene cluster. Mice lacking this superenhancer exhibit perinatal lethality, and present with highly penetrant skull defects and orofacial clefts phenocopying Hoxa2-/- mice. Moreover, we identified two cases of de novo copy number changes of the superenhancer in humans both with severe craniofacial abnormalities. This evidence suggests we have identified a critical noncoding locus control region that specifically regulates anterior HOXA genes and copy number changes are pathogenic in human patients.

Low- and middle-income countries (LMICs) represent the highest incidence, morbidity, and Disability Adjusted Life Years for cleft lip and/or palate (CL/P) globally. Most cleft care models now include psychosocial support, yet the psychosocial impacts of CL/P in LMICs are understudied. This narrative review aimed to synthesize published literature to provide a foundation for future research and evidence-based psychosocial support. Seventy-one peer-reviewed articles published between September 2003 and July 2024 were included. Themes pertaining to caregivers included Social Experiences, Emotional Well-Being, Treatment Experiences, and overall Quality of Life. Themes regarding individuals with CL/P included Developmental Trajectory, Social Integration, Emotional Health, Satisfaction with Treatment, and Health-Related Quality of Life. Most articles focused on upper-middle-income countries. East Asia and Pacific was the most studied geographical region in LMICs, while Europe and Central Asia was the least studied. Only 28 of 135 LMICs (20.7%) were represented in the included psychosocial literature. Most studies (69%) utilized a quantitative design. Sample sizes ranged from 2 to 295, with 73% of studies recruiting from a single site. Few studies (28%) compared their data to reference or control groups. Just over half of studies used standardized, validated measures. Most studies were led by LMIC teams. This review calls for ongoing monitoring of psychological health in individuals with CL/P and their caregivers and coordinated investment into multifaceted psychosocial program in LMICs. Building practice-relevant research capacity in LMICs to develop the evidence-base is essential.