Craniofacial Birth Defects In Humans Research Articles

Engineered mucoperiosteal scaffold for cleft palate regeneration towards the non-immunogenic transplantation

Cleft lip and palate (CL/P) is the most prevalent craniofacial birth defect in humans. None of the surgical procedures currently used for CL/P repair lead to definitive correction of hard palate bone interruption. Advances in tissue engineering and regenerative medicine aim to develop new strategies to restore palatal bone interruption by using tissue or organ-decellularized bioscaffolds seeded with host cells. Aim of this study was to set up a new natural scaffold deriving from a decellularized porcine mucoperiosteum, engineered by an innovative micro-perforation procedure based on Quantum Molecular Resonance (QMR) and then subjected to in vitro recellularization with human bone marrow-derived mesenchymal stem cells (hBM-MSCs). Our results demonstrated the efficiency of decellularization treatment gaining a natural, non-immunogenic scaffold with preserved collagen microenvironment that displays a favorable support to hMSC engraftment, spreading and differentiation. Ultrastructural analysis showed that the micro-perforation procedure preserved the collagen mesh, increasing the osteoinductive potential for mesenchymal precursor cells. In conclusion, we developed a novel tissue engineering protocol to obtain a non-immunogenic mucoperiosteal scaffold suitable for allogenic transplantation and CL/P repair. The innovative micro-perforation procedure improving hMSC osteogenic differentiation potentially impacts for enhanced palatal bone regeneration leading to future clinical applications in humans.

Pleiotropy method reveals genetic overlap between orofacial clefts at multiple novel loci from GWAS of multi-ethnic trios.

Based on epidemiologic and embryologic patterns, nonsyndromic orofacial clefts– the most common craniofacial birth defects in humans– are commonly categorized into cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP), which are traditionally considered to be etiologically distinct. However, some evidence of shared genetic risk in IRF6, GRHL3 and ARHGAP29 regions exists; only FOXE1 has been recognized as significantly associated with both CL/P and CP in genome-wide association studies (GWAS). We used a new statistical approach, PLACO (pleiotropic analysis under composite null), on a combined multi-ethnic GWAS of 2,771 CL/P and 611 CP case-parent trios. At the genome-wide significance threshold of 5 × 10−8, PLACO identified 1 locus in 1q32.2 (IRF6) that appears to increase risk for one OFC subgroup but decrease risk for the other. At a suggestive significance threshold of 10−6, we found 5 more loci with compelling candidate genes having opposite effects on CL/P and CP: 1p36.13 (PAX7), 3q29 (DLG1), 4p13 (LIMCH1), 4q21.1 (SHROOM3) and 17q22 (NOG). Additionally, we replicated the recognized shared locus 9q22.33 (FOXE1), and identified 2 loci in 19p13.12 (RAB8A) and 20q12 (MAFB) that appear to influence risk of both CL/P and CP in the same direction. We found locus-specific effects may vary by racial/ethnic group at these regions of genetic overlap, and failed to find evidence of sex-specific differences. We confirmed shared etiology of the two OFC subtypes comprising CL/P, and additionally found suggestive evidence of differences in their pathogenesis at 2 loci of genetic overlap. Our novel findings include 6 new loci of genetic overlap between CL/P and CP; 3 new loci between pairwise OFC subtypes; and 4 loci not previously implicated in OFCs. Our in-silico validation showed PLACO is robust to subtype-specific effects, and can achieve massive power gains over existing approaches for identifying genetic overlap between disease subtypes. In summary, we found suggestive evidence for new genetic regions and confirmed some recognized OFC genes either exerting shared risk or with opposite effects on risk to OFC subtypes.

Stem cells and tissue engineering: an alternative treatment for craniofacial congenital malformations and articular degenerative diseases

The life quality of patients with craniofacial malformations is severely affected by the physical disabilities caused by the malformation itself, but also by being subjected to bullying, which leads to a series of relevant psychological and societal effects that have an economic impact on the health sector. Orofacial clefts, notably cleft lip (CL), cleft palate, and microtia, are the most common craniofacial birth defects in humans and represent a substantial burden, both personal and societal. On the other hand, osteoarthritis is a widespread degenerative disease that is becoming more common due to the extension of the human lifespan and to an increase in injuries in young people as a result of their lifestyle. Advances in tissue engineering as a part of regenerative medicine offer new hope to patients that can benefit from new tissue engineering therapies based on the supportive action of tailored 3D biomaterials and the synergic action of stem cells that can be driven to the process of bone and cartilage regeneration. This review provides an update on recent considerations for stem cells and studies on the use of advanced biomaterials and cell therapies for the regeneration of craniofacial congenital malformations and articular degenerative diseases.

Genome‐wide interaction studies identify sex‐specific risk alleles for nonsyndromic orofacial clefts

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect in humans and is notable for its apparent sexual dimorphism where approximately twice as many males are affected as females. The sources of this disparity are largely unknown, but interactions between genetic and sex effects are likely contributors. We examined gene-by-sex (G × S) interactions in a worldwide sample of 2,142 NSCL/P cases and 1,700 controls recruited from 13 countries. First, we performed genome-wide joint tests of the genetic (G) and G × S effects genome-wide using logistic regression assuming an additive genetic model and adjusting for 18 principal components of ancestry. We further interrogated loci with suggestive results from the joint test ( p < 1.00 × 10 -5 ) by examining the G × S effects from the same model. Out of the 133 loci with suggestive results ( p < 1.00 × 10 -5 ) for the joint test, we observed one genome-wide significant G × S effect in the 10q21 locus (rs72804706; p = 6.69 × 10 -9 ; OR = 2.62 CI [1.89, 3.62]) and 16 suggestive G × S effects. At the intergenic 10q21 locus, the risk of NSCL/P is estimated to increase with additional copies of the minor allele for females, but the opposite effect for males. Our observation that the impact of genetic variants on NSCL/P risk differs for males and females may further our understanding of the genetic architecture of NSCL/P and the sex differences underlying clefts and other birth defects.

Treatment of Nonsyndromic Cleft Lip and/or Palate in Brazil: Existing Consensus and Legislation, Scope of the Unified Health System, Inconsistencies and Future Perspectives.

Cleft lip and/or palate (CL/P) are the most prevalent craniofacial birth defects in humans, affecting around ten and a half million people across the world and over three hundred thousand in Brazil. Of that, about 70% of the cases occur as a nonsyndromic form, while the remaining 30% are syndromic. In turn, individuals with nonsyndromic CL/P (NSCL/P) often have anatomic deformities involving the lip, alveolar ridge and palate. In this case, the treatments generally require multiple surgeries and various other health interventions throughout childhood, adolescence and adulthood. Another relevant point is that various problems regarding the treatment of NSCL/P in Brazil through the Unified Health System (SUS) have been reported. There are also many inconsistencies in this scenario, including the territorial coverage of healthcare assistance from the craniofacial centres across the country. However, very little data can be found in the scientific literature about the current situation for the treatment of NSCL/P in Brazil. Thus, the present article discusses the existing consensus and legislation, the scope of the SUS, as well as inconsistencies and future perspectives related to the treatment of these craniofacial abnormalities at a national level.

Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity

Non-syndromic cleft lip with palate (NSCLP) is the most serious sub-phenotype of non-syndromic orofacial clefts (NSOFC), which are the most common craniofacial birth defects in humans. Here we conduct a GWAS of NSCLP with multiple independent replications, totalling 7,404 NSOFC cases and 16,059 controls from several ethnicities, to identify new NSCLP risk loci, and explore the genetic heterogeneity between sub-phenotypes of NSOFC. We identify 41 SNPs within 26 loci that achieve genome-wide significance, 14 of which are novel (RAD54B, TMEM19, KRT18, WNT9B, GSC/DICER1, PTCH1, RPS26, OFCC1/TFAP2A, TAF1B, FGF10, MSX1, LINC00640, FGFR1 and SPRY1). These 26 loci collectively account for 10.94% of the heritability for NSCLP in Chinese population. We find evidence of genetic heterogeneity between the sub-phenotypes of NSOFC and among different populations. This study substantially increases the number of genetic susceptibility loci for NSCLP and provides important insights into the genetic aetiology of this common craniofacial malformation.

Haplotype-based gene-gene interaction of bone morphogenetic protein 4 and interferon regulatory factor 6 in the etiology of non-syndromic cleft lip with or without cleft palate in a Chilean population.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect in humans, the etiology of which can be dependent on the interactions of multiple genes. We previously reported haplotype associations for polymorphic variants of interferon regulatory factor 6 (IRF6), msh homeobox 1 (MSX1), bone morphogenetic protein 4 (BMP4), and transforming growth factor beta 3 (TGFB3) in Chile. Here, we analyzed the haplotype-based gene-gene interaction for markers of these genes and NSCL/P risk in the Chilean population. We genotyped 15 single nucleoptide polymorphisms (SNPs) in 152 Chilean patients and 164 controls. Linkage disequilibrium (LD) blocks were determined using the Haploview software, and phase reconstruction was performed by the Phase program. Haplotype-based interactions were evaluated using the multifactor dimensionality reduction (MDR) method. We detected two LD blocks composed of two SNPs from BMP4 (Block 1) and three SNPs from IRF6 (Block 2). Although MDR showed no statistical significance for the global interaction model involving these blocks, we found four combinations conferring a statistically significantly increased NSCL/P risk (Block 1-Block 2): T-T/T-G C-G-T/G-A-T; T-T/T-G C-G-C/C-G-C; T-T/T-G G-A-T/G-A-T; and T-T/C-G G-A-T/G-A-T. These findings may reflect the presence of a genomic region containing potential causal variants interacting in the etiology of NSCL/P and may contribute to disentangling the complex etiology of this birth defect.

Evidence for SNP-SNP interaction identified through targeted sequencing of cleft case-parent trios.

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect in humans, affecting 1 in 700 live births. This malformation has a complex etiology where multiple genes and several environmental factors influence risk. At least a dozen different genes have been confirmed to be associated with risk of NSCL/P in previous studies. However, all the known genetic risk factors cannot fully explain the observed heritability of NSCL/P, and several authors have suggested gene-gene (G × G) interaction may be important in the etiology of this complex and heterogeneous malformation. We tested for G × G interactions using common single nucleotide polymorphic (SNP) markers from targeted sequencing in 13 regions identified by previous studies spanning 6.3 Mb of the genome in a study of 1,498 NSCL/P case-parent trios. We used the R-package trio to assess interactions between polymorphic markers in different genes, using a 1 degree of freedom (1df) test for screening, and a 4 degree of freedom (4df) test to assess statistical significance of epistatic interactions. To adjust for multiple comparisons, we performed permutation tests. The most significant interaction was observed between rs6029315 in MAFB and rs6681355 in IRF6 (4df P = 3.8 × 10-8 ) in case-parent trios of European ancestry, which remained significant after correcting for multiple comparisons. However, no significant interaction was detected in trios of Asian ancestry.

Subphenotyping and Classification of Orofacial Clefts: Need for Orofacial Cleft Subphenotyping Calls for Revised Classification.

Nonsyndromic orofacial clefting (OFC) describes a range of phenotypes that represent the most common craniofacial birth defects in humans, with an overall birth prevalence of 1:700 live births. Because of the lifelong negative implications on health and well-being associated with OFC and the numbers of people affected, quality research into its etiology, diagnosis, treatment outcomes, and preventative strategies is essential. A range of different methods is used for recording and classifying OFC subphenotypes, one of which is the International Classification of Diseases (ICD) system. However, there is a general perception that research is being hampered by a lack of sensitivity and specificity in grouping those with OFC into subphenotypes, with potential heterogeneity and confounding in epidemiologic, genetic, and genotype-phenotype correlation studies. This article provides a background to the necessity of OFC research, discusses current controversies within cleft subphenotyping, and provides a brief overview of current OFC classifications as well as their limitations. The LAHSHAL classification is described in the context of a potentially useful tool for OFC that could complement the ICD-10/ICD-11 Beta coding systems to become a simply understood, universally accepted, clinically friendly, and research-sensitive instrument. Empowering registries, clinicians, and researchers to use a common classification system would have significant implications for OFC research across the world at a time when accurate subphenotyping is crucial and health care research is becoming increasingly tailored toward the individual.

A LINE-1 Insertion in DLX6 Is Responsible for Cleft Palate and Mandibular Abnormalities in a Canine Model of Pierre Robin Sequence

Cleft palate (CP) is one of the most commonly occurring craniofacial birth defects in humans. In order to study cleft palate in a naturally occurring model system, we utilized the Nova Scotia Duck Tolling Retriever (NSDTR) dog breed. Micro-computed tomography analysis of CP NSDTR craniofacial structures revealed that these dogs exhibit defects similar to those observed in a recognizable subgroup of humans with CP: Pierre Robin Sequence (PRS). We refer to this phenotype in NSDTRs as CP1. Individuals with PRS have a triad of birth defects: shortened mandible, posteriorly placed tongue, and cleft palate. A genome-wide association study in 14 CP NSDTRs and 72 unaffected NSDTRs identified a significantly associated region on canine chromosome 14 (24.2 Mb–29.3 Mb; praw = 4.64×10−15). Sequencing of two regional candidate homeobox genes in NSDTRs, distal-less homeobox 5 (DLX5) and distal-less homeobox 6 (DLX6), identified a 2.1 kb LINE-1 insertion within DLX6 in CP1 NSDTRs. The LINE-1 insertion is predicted to insert a premature stop codon within the homeodomain of DLX6. This prompted the sequencing of DLX5 and DLX6 in a human cohort with CP, where a missense mutation within the highly conserved DLX5 homeobox of a patient with PRS was identified. This suggests the involvement of DLX5 in the development of PRS. These results demonstrate the power of the canine animal model as a genetically tractable approach to understanding naturally occurring craniofacial birth defects in humans.

Patched1 is required in neural crest cells for the prevention of orofacial clefts

Defects such as cleft lip with or without cleft palate (CL/P) are among the most common craniofacial birth defects in humans. In many cases, the underlying molecular and cellular mechanisms that result in these debilitating anomalies remain largely unknown. Perturbed hedgehog (HH) signalling plays a major role in craniofacial development, and mutations in a number of pathway constituents underlie craniofacial disease. In particular, mutations in the gene encoding the major HH receptor and negative regulator, patched1 (PTCH1), are associated with both sporadic and familial forms of clefting, yet relatively little is known about how PTCH1 functions during craniofacial morphogenesis. To address this, we analysed the consequences of conditional loss of Ptch1 in mouse neural crest cell-derived facial mesenchyme. Using scanning electron microscopy (SEM) and live imaging of explanted facial primordia, we captured defective nasal pit invagination and CL in mouse embryos conditionally lacking Ptch1. Our analysis demonstrates interactions between HH and FGF signalling in the development of the upper lip, and reveals cell-autonomous and non-autonomous roles mediated by Ptch1. In particular, we show that deletion of Ptch1 in the facial mesenchyme alters cell morphology, specifically in the invaginating nasal pit epithelium. These findings highlight a critical link between the neural crest cells and olfactory epithelium in directing the morphogenesis of the mammalian lip and nose primordia. Importantly, these interactions are critically dependent on Ptch1 function for the prevention of orofacial clefts.

MSX1 gene and nonsyndromic oral clefts in a Southern Brazilian population

Nonsyndromic oral clefts (NSOC) are the most common craniofacial birth defects in humans. The etiology of NSOC is complex, involving both genetic and environmental factors. Several genes that play a role in cellular proliferation, differentiation, and apoptosis have been associated with clefting. For example, variations in the homeobox gene family member MSX1, including a CA repeat located within its single intron, may play a role in clefting. The aim of this study was to investigate the association between MSX1 CA repeat polymorphism and NSOC in a Southern Brazilian population using a case-parent triad design. We studied 182 nuclear families with NSOC recruited from the Hospital de Clínicas de Porto Alegre in Southern Brazil. The polymorphic region was amplified by the polymerase chain reaction and analyzed by using an automated sequencer. Among the 182 families studied, four different alleles were observed, at frequencies of 0.057 (175 bp), 0.169 (173 bp), 0.096 (171 bp) and 0.67 (169 bp). A transmission disequilibrium test with a family-based association test (FBAT) software program was used for analysis. FBAT analysis showed overtransmission of the 169 bp allele in NSOC (P=0.0005). These results suggest that the CA repeat polymorphism of the MSX1 gene may play a role in risk of NSOC in populations from Southern Brazil.

Association of candidate genes with nonsyndromic clefts in Honduran and Colombian populations

Orofacial clefts are the most common craniofacial birth defects in humans, with the majority of orofacial clefts occurring as nonsyndromic cleft lip with or without cleft palate (NSCLP). We previously demonstrated associations between single-nucleotide polymorphisms (SNPs) in the IRF6 gene and NSCLP in the Honduran population. Here we investigated other candidate genes and chromosomal regions associated with NSCLP identified from genome-wide association studies (GWAS), including MAFB, ABCA4, 8q24, 9q22, 10q25, and 17q22 in two independent Hispanic populations. Case-control and family-based association testing. Honduran families with two or more members with NSCLP (multiplex) were identified. DNA was collected from affected and unaffected family members (488) and 99 gender-matched controls. NSCLP Colombian families were identified; DNA was collected from 26 proband-parent trios. All participants were genotyped for 17 SNPs in six chromosomal regions. Case-control association and family-based association testing (FBAT) analyses were conducted. Seven SNPs demonstrated association in at least one model in the Honduran population. In the Colombian families, five SNPs demonstrated significance in FBAT when patients with isolated cleft palate (CP) were included; four overlapped with SNPs demonstrating significance in the Honduran population, two with the same allele. One SNP retained significance with CP excluded. This study supports the previous GWAS findings and is the first to suggest a role for FOXE1, ABCA4, and MAFB in orofacial clefting in two separate Hispanic populations.

Small players with a big role: MicroRNAs in pathophysiology of cleft lip and palate

Cleft lip with or without cleft palate (CL/P) and isolated cleft palate (CPI) are two of the most common congenital craniofacial birth defects in humans. These orofacial clefts (OFC) cause profound psychosocial distress as well as an enormous economic burden to the affected individual, their families, and the community. While genetic and environmental factors contribute to the complex etiology of OFC. Affected infants have an increased risk of death due to associated conditions, such as prematurity, respiratory and infectious diseases, and central nervous system disorders, while affected adults have been shown to have increased risk of cardiac disease, suicide, epilepsy, and various cancers. [1] Thus, it is considered a pressing public health problem. Thirteen loci (genomic positions) on various chromosomal regions and 20 genes associated with CL/P have been reported by linkage and association analysis. Nevertheless, the etiology of this disorder is still poorly defined. Recent studies indicate that disruption on microRNAs (miRNAs) activity may also play a role on the onset of these deformities. [2‑4] miRNAs are approximately 22 nucleotide

Prevention of oro-facial clefts in developing world

Oro-facial cleft (OFC) remains a prominent health issue in developed and developing countries alike. It is the commonest craniofacial birth defect in humans. Mounting evidence suggest a polygenic, multifactorial and a list of epigenetic events. Primary prevention of OFC is based on recognition of the etiologic and risk factors. While a number of preventive strategies are in place for OFC in most developed countries of the world, the majority of developing countries are distant from achieving this goal for a number of reasons. Notable among these are a huge knowledge and practice gap in the field of genetics and dearth of accurate data. In addition, improper coordination and absenteeism from antenatal care contributed greatly to this set back. With ongoing efforts aimed at determining the genetics of nonsyndromic OFC in developing countries, researches directed at identifying environmental factors should equally be in place. Pending the outcome of these, implicated environmental and attitudinal risk factors in other populations could serve as preventive template in health education and interventions. Since risk factors vary between populations, definitive and effective preventive strategies and models would vary from place to place and from time to time. Frantic effort directed at identifying specific implicated risk factors in developing countries should include developing and keeping comprehensive national perinatal database and centralization of antenatal care protocol. Additionally, active health education at every level and a focus on developing manpower in the field of genetics should be in place. These would be designed and tailored toward identified, proven, and emerging risk factors.

Genetics of Nonsyndromic Orofacial Clefts

With an average worldwide prevalence of approximately 1.2/1000 live births, orofacial clefts are the most common craniofacial birth defects in humans. Like other complex disorders, these birth defects are thought to result from the complex interplay of multiple genes and environmental factors. Significant progress in the identification of underlying genes and pathways has benefited from large populations available for study, increased international collaboration, rapid advances in genotyping technology, and major improvements in analytic approaches. Here we review recent advances in genetic epidemiological approaches to complex traits and their applications to studies of nonsyndromic orofacial clefts. Our main aim is to bring together a discussion of new and previously identified candidate genes to create a more cohesive picture of interacting pathways that shape the human craniofacial region. In future directions, we highlight the need to search for copy number variants that affect gene dosage and rare variants that are possibly associated with a higher disease penetrance. In addition, sequencing of protein-coding regions in candidate genes and screening for genetic variation in noncoding regulatory elements will help advance this important area of research.

Microdeletion 20p12.3 involving BMP2 contributes to syndromic forms of cleft palate

Orofacial clefts of the lip and/or palate comprise one of the most common craniofacial birth defects in humans. Though a majority of cleft lip and/or cleft palate (CL/P) occurs as isolated congenital anomalies, there exist a large number of Mendelian disorders in which orofacial clefting is part of the clinical phenotype. Here we report on two individuals and one multi-generational family with microdeletions at 20p12.3 that include the bone morphogenetic protein 2 (BMP2) gene. In two propositi the deletion was almost identical at ∼600 kb in size, and BMP2 was the only gene deleted; the third case had a ∼5.5-Mb deletion (20p13p12.2) that encompassed at least 20 genes including BMP2. Clinical features were significant for cleft palate and facial dysmorphism in all three patients, including Pierre-Robin sequence in two. Microdeletion 20p13p12 involving BMP2 is rare and has been implicated in Wolff-Parkinson-White (WPW) syndrome with neurocognitive deficits and with Alagille syndrome when the deletion includes the neighboring JAG1 gene in addition to BMP2. Despite a significant role for the BMPs in orofacial development, heterozygous loss of BMP2 has not been previously reported in patients with syndromic clefting defects. Because BMP2 was the sole deleted gene in Patients 1 and 2 and one of the genes deleted in Patient 3, all of whom had clinical features in common, we suggest that haploinsufficiency for BMP2 is a crucial event that predisposes to cleft palate and additional anomalies. Lack of significant phenotypic components in family members of Patient 1 suggests variable expressivity for the phenotype.

Effects of phenytoin onSatb2andHoxa2gene expressions in mouse embryonic craniofacial tissueThis paper is one of a selection of papers published in this special issue entitled “Second International Symposium on Recent Advances in Basic, Clinical, and Social Medicine” and has undergone the Journal's usual peer review process.

Cleft lip and cleft palate are common congenital craniofacial birth defects in humans. Phenytoin (PHT) is a risk factor of cleft palate formation; however, the molecular mechanisms by which phenytoin exerts its teratogenic effects resulting in cleft palate remain unknown. The Satb2 gene mutation is associated with cleft palate. Satb2-deficient mice exhibit cleft palate deformity and an up-regulation of Hoxa2 in the fronto-nasal region. In this study, phenytoin was administered intraperitoneally to pregnant C57BL/6 mice on the 10th day of gestation. Real-time PCR results showed that the expressions of Satb2 and Hoxa2 in craniofacial tissues of mouse embryos were obviously different at different time points. The Satb2 gene was down-regulated and the Hoxa2 gene was up-regulated in phenytoin-treated mouse embryonic craniofacial tissue. We conclude that phenytoin may regulate the expression of these two genes in C57BL/6 mice and it may also be involved in the formation of cleft palate.

The basal chordate amphioxus as a simple model for elucidating developmental mechanisms in vertebrates

This review examines the basal chordate, amphioxus, as a simple model for providing insights into the development and evolution of the vertebrates, with which it shares many features, including a pharynx perforated with gill slits, a dorsal nerve cord, segmented muscles, and a notochord. Conversely, amphioxus is simpler than vertebrates in lacking neural crest and paired cephalic sensory organs. Amphioxus embryos are less derived than those of vertebrates, because it lacks large quantities of yolk and/or extra-embryonic tissues. Embryogenesis involves only a simple folding of tissue layers. In addition, the amphioxus genome lacks the large-scale gene duplications of vertebrates. However, in spite of the comparative simplicity of amphioxus, its developmental mechanisms are proving to be highly conserved with those of vertebrates. Thus, studies of amphioxus development can shed light on similar, but more complex, development of vertebrates. Such studies are especially interesting for their insights into the genetic basis of craniofacial birth defects in humans.

Tissue Engineering Solutions for Cleft Palates

Clefts of the lip and palate are the most prevalent congenital craniofacial birth defect in humans. The developing field of tissue engineering is considered for the management of clefts of the lip and palate. A review of the literature was carried out by using electronic databases (such as PubMed and ISI Web of Science) to search topics including "cleft palate," "tissue engineering," "bone engineering," "palate engineering," and "alveolar bone grafting." To reflect current practice and research, these searches were limited primarily to articles published after the year 2000. Current approaches for the treatment of clefts of the lip and palate include surgery and bone grafts; however, there are limitations associated with these therapies. Tissue engineering strategies, particularly alveolar bone engineering and soft tissue engineering, may provide clinicians with new alternatives. The application of these emerging technologies to a pediatric population must be well considered. A tissue engineering approach may be a useful alternative for the treatment of cleft palates as it mitigates the concerns of donor site morbidity as well as provides additional options including scaffold implantation and growth factor delivery.