Treacher Collins Syndrome: Genetics, Clinical Features and Management.

Treacher Collins syndrome (TCS) is associated with abnormal differentiation of the first and second pharyngeal arches, occurring during fetal development. Features of TCS include microtia with conductive hearing loss, slanting palpebral fissures with possibly coloboma of the lateral part of lower eyelids, midface hypoplasia, micrognathia as well as sporadically cleft palate and choanal atresia or stenosis. TCS occurs in the general population at a frequency of 1 in 50,000 live births. Four subtypes of Treacher Collins syndrome exist. TCS can be caused by pathogenic variants in the TCOF1, POLR1D, POLR1C and POLR1B genes. Genetically, the TCOF1 gene contains 27 exons which encodes the Treacle protein. In TCOF1, over 200 pathogenic variants have been identified, of which most are deletions leading to a frame-shift, that result in the formation of a termination codon. In the presented article, we review the genetics and phenotype of TCS as well as the management and surgical procedures utilized for treatment.

Identification of three novel TCOF1 mutations in patients with Treacher Collins Syndrome.

Here we describe three novel TCOF1 mutations found in unrelated patients with Treacher Collins syndrome. These mutations include one deletion, NM_001135243.2:c.2604_2605delAG (p.Gly869Glufs*3), and two substitutions, NM_001135243.2:c.2575C>T (p.Gln859*) and NM_001135243.2:c.4111G>T (p.Glu1371*). These mutations cause shortening of a protein called Treacle in patients with features typical of TCS. Continuous identification of new mutations is important to expand the mutation base, which is helpful in the diagnosis of both patients and their families.

Estimation of the Path-Loss Exponent by Bayesian Filtering Method.

Regarding wireless sensor network parameter estimation of the propagation model is a most important issue. Variations of the received signal strength indicator (RSSI) parameter are a fundamental problem of a system based on signal strength. In the present paper, we propose an algorithm based on Bayesian filtering techniques for estimating the path-loss exponent of the log-normal shadowing propagation model for outdoor RSSI measurements. Furthermore, in a series of experiments, we will demonstrate the usefulness of the particle filter for estimating the RSSI data. The stability of this algorithm and the differences in determined path-loss exponent for both method were also analysed. The proposed method of dynamic estimation results in significant improvements of the accuracy of RSSI values when compared with the experimental measurements. It should be emphasised that the path-loss exponent mainly depends on the RSSI data. Our results also indicate that increasing the number of inserted particles does not significantly raise the quality of the estimated parameters.

PAX7 nucleotide variants and the risk of non-syndromic orofacial clefts in the Polish population.

OBJECTIVE: The etiology of non-syndromic cleft lip with or without cleft palate (nsCL/P) is multifactorial, heterogeneous, and still not completely understood. The aim of the present study was to examine the associations between common and rare PAX7 nucleotide variants and the risk of this common congenital anomaly in a Polish population. SUBJECTS AND METHODS: Eight top nsCL/P-associated PAX7 variants identified in our cleft genome-wide association study (GWAS) were selected for replication analysis in an independent group of patients and controls (n = 247 and n = 445, respectively). In addition, mutation screening of the PAX7 protein-coding region was conducted. RESULTS: Analysis of the pooled data from the GWAS and replication study confirmed that common PAX7 nucleotide variants are significantly associated with the increased risk of nsCL/P. The strongest individual variant was rs1339062 (c.586 + 15617T > C) with a p-value = 2.47E-05 (OR = 1.4, 95%CI: 1.20-1.64). Sequencing analysis identified a novel synonymous PAX7 substitution (c.87G > A, p.Val29Val) in a single patient with nsCLP. This transition located in the early exonic position was predicted to disrupt potential splice enhancer elements. CONCLUSION: Our study confirmed that PAX7 is a strong candidate gene for nsCL/P. Nucleotide variants of this gene contribute to the etiology of nsCL/P in the homogenous Polish population.

Trigonocephaly: Long-term results after surgical correction of metopic suture synostosis.

BACKGROUND: Premature closure and ossification of the metopic suture results in a triangular head shape called trigonocephaly and is characterized by a wedge-shaped forehead and frontotemporal narrowing. Untreated craniosynostosis may lead to increased intracranial pressure (ICP) and, thereby, impaired neurodevelopment. Over the last decades, its incidence has been increasing, currently making it the 2nd most common type of isolated craniosynostosis. Treatment consist of cranioplasty, which should be performed before the age of 1 year. OBJECTIVES: The aim of this study was to evaluate the long-term surgical outcomes in children operated on for trigonocephaly. MATERIAL AND METHODS: The authors reviewed 30 consecutive cases of metopic synostosis treated over a 14-year period in the Plastic Surgery Department in Polanica-Zdrój, Poland. The data was evaluated using the patients' clinical records, and preoperative and postoperative photographs. The patients showed up on a follow-up visit at a median age of 9 years and were examined by an ophthalmologist and a neurologist. The surgical outcomes were evaluated according to the Whitaker classification. In 23 patients, remodeling and the advancement of fronto-orbital skull segments was performed at a median age of 18 months and in 7 milder cases, simple suturectomy or burring of the metopic ridge was sufficient. RESULTS: According to the Whitaker classification, results were considered good to excellent (category I and II). Only 1 patient was included into category III. None of the examined cases were included into category IV, which would require a major craniofacial procedure, duplicating or exceeding the original operation. Neurological abnormalities were found in 12 cases and vision defects in 15 cases. CONCLUSIONS: Trigonocephaly is currently the 2nd most common type of isolated synostosis. Surgical treatment based on Tessier's and Marchac's modified methods provides good results in patients at the age of about 12 months and prevents the consequences of ICP increase. Primary neurological and behavioral disorders may occur, despite corrective surgery.

Association of CDKAL1 nucleotide variants with the risk of non-syndromic cleft lip with or without cleft palate.

Although the aetiology of non-syndromic cleft lip with or without cleft palate (nsCL/P) has been studied extensively, knowledge regarding the role of genetic factors in the pathogenesis of this common craniofacial anomaly is still limited. We conducted a follow-up association study to confirm that CDKAL1 nucleotide variants identified in our genome-wide association study (GWAS) for nsCL/P are associated with the risk of this anomaly. In addition, we performed a sequence analysis of the selected CDKAL1 exons. A mega-analysis of the pooled individual data from the GWAS and a replication study revealed that six out of thirteen CDKAL1 variants were positively replicated and reached the threshold of statistical significance (Ptrend < 3.85E-03). They represented a single association signal and were located within the fifth intron of CDKAL1. The strongest individual variant was rs9356746 with a Ptrend value = 5.71E-06 (odds ratio (OR) = 1.60, 95% confidence interval (CI): 1.30-1.97). Sequencing analysis did not reveal any pathogenic mutations of this gene. This study provides the first evidence that chromosomal region 6p22.3 is a novel susceptibility locus for nsCL/P. The location of the risk variants within the CDKAL1 intronic sequence containing enhancer elements predicted to regulate the SOX4 transcription may suggest that SOX4, rather than CDKAL1, is a potential candidate gene for this craniofacial anomaly.

Binder syndrome: Clinical findings and surgical treatment of 18 patients at the Department of Plastic Surgery in Polanica Zdrój.

BACKGROUND: Binder syndrome (BS) is an uncommon congenital underdevelopment of the maxilla and nasal skeleton. Other clinical features include a hypoplastic or absent anterior nasal spine; a short, flat nose with short columella; an acute nasolabial angle; a convex upper lip and class III malocclusion. OBJECTIVES: The aim of the study was to outline the major characteristics of BS and to present a variety of surgical treatment methods. MATERIAL AND METHODS: The study included 18 patients treated in the authors' department from 1989 to 2013. RESULTS: The patients were predominantly women, aged 6 months to 34 years. Nine patients did not present any co-morbidities, but in the other 9 the most common co-morbidities were a unilateral cleft lip and palate, followed by a cleft palate, a bilateral cleft lip and palate, a cleft lip, GERD, gluten intolerance, oligophrenia, goiter and foot malformation. Most of the patients had not been operated on previously. The most common procedure carried out was an iliac crest bone graft. In 4 patients, no procedures other than cleft lip and palate repair were undertaken. In 3 cases a Le Fort I osteotomy was performed to correct the patients' orthognathic status. No major or life-threating complications were noted. In 2 cases, due to a high degree of resorption of bone grafts, multiple secondary grafting of bone, cartilage and deepithelialized skin was necessary to obtain satisfactory results. CONCLUSIONS: In BS surgical treatment is the treatment of choice. It results in adequate correction of facial retrusion. However, due to various degrees of bone resorption, the results are not lifelong. No unequivocally superior surgical strategy in BS has been presented so far. Most disagreement among authors is related to the need for and timing of maxillary osteotomy, the choice between bone and cartilage grafting in nose reconstruction and columella lengthening. Although alloplastic materials offer the tempting advantage of fast and simultaneous augmentation of deficient tissues, their use may risk prolonged infections and extrusion, resulting in exacerbations of deformities.

Genetic Factors in Selected Complex Congenital Malformations with Cleft Defect.

Cleft lips, alveolar ridges and palates are among the most common birth defects. There are over 500 different complex genetic disorders that include cleft defects. The most common related defects include abnormalities of the skeleton, skull, cardiovascular and nervous system. The occurrence of a cleft results from the interplay of multiple genes and environmental factors. Several thousand different mutations responsible for these syndromes have been discovered, whereas there are still numerous phenotypic cases of unknown genetic origin. The aim of this study was to present various clinical aspects and the latest discoveries with regard to genetic research in complex malformations, such as Van der Woude syndrome, popliteal pterygium syndrome, EEC syndrome, Pierre Robin sequence, various forms of Stickler syndrome, and Treacher Collins syndrome. These complex syndromes have different incidences, and most of them also have allelic variants with characteristic severities that differ even among close relatives. Easier access to genetic counseling and the lower cost of DNA testing in recent years can lead to new findings on the causes of such syndromes.

Nucleotide Variants of the BH4 Biosynthesis Pathway Gene GCH1 and the Risk of Orofacial Clefts.

A deficiency of GTP cyclohydrolase, encoded by the GCH1 gene, results in two neurological diseases: hyperphenylalaninaemia type HPABH4B and DOPA-responsive dystonia. Genes involved in neurotransmitter metabolism and motor systems may contribute to palatogenesis. The purpose of the study was to analyse polymorphic variants of the GCH1 gene as risk factors for non-syndromic cleft lip with or without cleft palate (NSCL/P). Genotyping of nine polymorphisms was conducted in a group of 281 NSCL/P patients and 574 controls. The GCH1 variant rs17128077 was associated with a 1.7-fold higher risk for NSCL/P (95 %CI = 1.224-2.325; p = 0.001). We also found a significant correlation between the rs8004018 and rs17128050 variants and an increased risk of oral clefts (p trend = 0.003 and 0.004, respectively). The best evidence of the global haplotype association was observed for rs17128050 and rs8004018 (p corr = 0.0152). This study demonstrates that the risk of NSCL/P is associated with variants of the GCH1 gene related to BH4 metabolism and provides some evidence of the relationships between morphological/functional shifts in the central nervous system and orofacial clefts.

Association between polymorphisms at the GREM1 locus and the risk of nonsyndromic cleft lip with or without cleft palate in the Polish population.

BACKGROUND: The locus on chromosome 15q13.3 containing GREM1 is correlated with the risk of nonsyndromic cleft lip with or without cleft palate (NSCL/P). The aim of the present study was to find the GREM1 functional variants implicated in the aetiology of this common developmental anomaly in the Polish population. METHODS: Eight polymorphisms were genotyped in 334 NSCL/P patients and 955 controls. In addition, the GREM1 protein-coding region was sequenced in 96 NSCL/P patients. RESULTS: Significant association with a risk of oral clefts was found for 5 tested polymorphisms. The lowest p(trend) values were identified for rs16969681, rs16969816, and rs1258763 (p(trend) 4.09E-05, 3.35E-05, and 0.0002, respectively). The putative functional variant rs16969681, located in a region that has enhancer activity, was associated with a 2.6-fold lower risk for NSCL/P (odds ratio [OR] = 0.38; 95% confidence interval [CI], 0.24-0.61, p = 2.37E-05). The previously reported association of rs1258763 with NSCL/P was replicated (OR = 0.57; 95% CI, 0.44-0.73; p = 1.10E-05). For all tested GREM1 variants, no significant sex-by-genotype interaction effects were observed. The sequencing analysis did not detect any rare variants implicated in the development of oral clefts. CONCLUSION: Our results might suggest that variants influencing GREM1 expression levels, rather than variants affecting the function of the encoded protein, are significant factors in NSCL/P etiology.

Genetic variants in BRIP1 (BACH1) contribute to risk of nonsyndromic cleft lip with or without cleft palate.

BACKGROUND: The etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) is very complex and still not well elucidated. Given the critical role of DNA damage repair in the embryonic development, we decided to test the hypothesis that polymorphisms of selected DNA repair genes might contribute to the risk of NSCL/P in the Polish population. METHODS: Analysis of 36 polymorphisms in 12 DNA damage repair genes (ATM, BLM, BRCA1, BRIP1, E2F1, MLH1, MRE11A, MSH2, MSH6, NBN, RAD50, and RAD51) was conducted using TaqMan assays in a group of 263 NSCL/P patients and matched control group (n = 526). RESULTS: Statistical analysis of genotyping results revealed that nucleotide variants in the BRIP1 (BACH1) gene were associated with the risk of NSCL/P. Under assumption of a dominant model, the calculated odds ratios (ORs) for BRIP1 rs8075370 and rs9897121 were 1.689 (95% confidence interval [CI], 1.249-2.282; p = 0.0006) and 1.621 (95% CI, 1.200-2.191; p = 0.0016), respectively. These results were statistically significant even after applying multiple testing correction. Additional evidence for a causative role of BRIP1 in NSCL/P etiology was provided by haplotype analysis. Borderline association with a decreased risk of this anomaly was also observed for BLM rs401549 (ORrecessive = 0.406; 95% CI, 0.223-1.739; p = 0.002) and E2F1 rs2071054 (ORdominant = 0.632; 95% CI, 0.469-0.852; p = 0.003). CONCLUSION: Our study suggests that polymorphic variants of DNA damage repair genes play a role in the susceptibility to NSCL/P. BRIP1 might be novel candidate gene for this common developmental anomaly.

Epidemiology, diagnostics and treatment of vascular tumours and malformations.

Vascular tumours and vascular malformations are common vasculose anomalies characteristic for dissimilar clinical course, specific biological as well as immune cytological and histological properties. Vascular lesions classification system and their detailed division into groups and subgroups were elaborated and implemented in Rome, in 1996, during meeting of the International Society for the Study of Vascular Anomalies (ISSVA). It was based on modification of an earlier going division by Mullikien and Glowacki from 1982. Infantile hemangiomas are the most numerous group of benign tumours of mesenchymal origin. Vascular malformations appear definitely less often. They are composed of normal endothelium lined displastic vessels which originate from vascular tissue abnormal morphogenesis. In contrast, in hemangiomas, at the proliferation stage, increased, multiplication of endothelial cells is observed as well as of fibroblasts, mastocytes and macrophages. Infantile hemangiomas are usually not present at the moment of birth and white chloasma with superficial teleangiectasis appears which increases within 3-4 weeks and gets bright red colour and reveal very characteristic clinical course basing on intensive growth period and involution long process. Vascular malformations are observed most often at the delivery moment or they may appear at an early childhood. They enlarge proportionally along with the child's growth and their sudden expansion may be triggered by an infection, hormonal changes or trauma. Contrary to hemangiomas, they do not subside spontaneously and their abrupt increase may result in impairment or deformation of important anatomical structures. Infantile hemangiomas and vascular malformations require different and individual treatments which are often multi-stage procedures carried on in specialistic centres of plastic surgery, vascular surgery or maxillofacial surgery.

Nucleotide variants of the cancer predisposing gene CDH1 and the risk of non-syndromic cleft lip with or without cleft palate.

The CDH1 gene plays an important role during carcinogenesis and craniofacial morphogenesis. Germline mutations in this gene have been described in families presenting syndromic diffuse gastric cancer and orofacial clefts. The aim of this study was to evaluate the association between nucleotide variants of CDH1 and the risk of non-syndromic cleft lip with or without cleft palate (NSCL/P). Six single nucleotide polymorphisms (SNPs) of the CDH1 gene (rs16260, rs9929218, rs7186053, rs4783573, rs16958383, and rs1801552) were genotyped using the TaqMan SNP genotyping assays in 250 patients with NSCL/P and 540 controls from the Polish population. Comparison between patient and control groups showed that the CDH1 rs1801552 variant, under the assumption of recessive model, was associated with a two-fold decrease in the risk of NSCL/P (ORTT vs CT + CC = 0.481, 95 % CI 0.281-0.824, p = 0.007). This association remained statistically significant even after the multiple testing correction. No significant associations with NSCL/P risk were found for the other five tested SNPs. We found a strong association between the cancer predisposing gene CDH1 and the risk of NSCL/P in the Polish population. This result, together with previous observations of co-occurrence of orofacial clefts and a variety of cancer types, suggests the need for replication studies testing rs1801552 in NSCL/P cohorts with a known cancer history.

Association of common variants in PAH and LAT1 with non-syndromic cleft lip with or without cleft palate (NSCL/P) in the Polish population.

BACKGROUND: Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common structural malformation with a complex and multifactorial aetiology. Associations of abnormalities in phenylalanine metabolism and orofacial clefts have been suggested. METHODS: Eight single nucleotide polymorphisms (SNPs) of genes encoding phenylalanine hydroxylase (PAH) and large neutral l-amino acid transporter type 1 (LAT1), as well as the PAH mutation that is most common in the Polish population (rs5030858; R408W), were investigated in 263 patients with NSCL/P and 270 matched controls using high resolution melting curve analysis (HRM). RESULTS: We found that two polymorphic variants of PAH appear to be risk factors for NSCL/P. The odds ratio (OR) for individuals with the rs7485331 A allele (AC or AA) compared to CC homozygotes was 0.616 (95% confidence interval [CI]=0.437-0.868; p=0.005) and this association remains statistically significant after multiple testing correction. The PAH rs12425434, previously associated with schizophrenia, was borderline associated with orofacial clefts. Moreover, haplotype analysis of polymorphisms in the PAH gene revealed a 4-marker combination that was significantly associated with NSCL/P. The global p-value for a haplotype comprised of SNPs rs74385331, rs12425434, rs1722392, and the mutation rs5030858 was 0.032, but this association did not survive multiple testing correction. CONCLUSION: This study suggests the involvement of the PAH gene in the aetiology of NSCL/P in the tested population. Further replication will be required in separate cohorts to confirm the consistency of the observed association.

The use of stem cells in plastic and reconstructive surgery.

As part of their clinical practice, plastic surgeons perform procedures in the fields of skin and adipose tissue grafting, the reconstruction of compound tissue loss and congenital malformations, the treatment of acute and chronic wounds and burns, as well as cosmetic surgery. On account of the great expectations associated with their use in therapy, stem cells (SCs) are increasingly frequently employed in in vitro experiments, animal models and clinical trials. The most commonly utilized SCs for these purposes are adult stem cells (AS), which are present in small amounts in every tissue; among these are two types of cells: bone marrow mesenchymal stem cells (BM-MSCs) and adipose-derived stem cells (ADSCs). The aim of this review is to present current findings in experimental research on the use of stem cells in the field of plastic and reconstructive surgery. Many studies have described the progress of trials using ADSCs and BM-MSCs mainly in the treatment of compound tissue loss and chronic wounds. The use of their paracrine, proangiogenic and osteogenic functions is emphasized. However, because of the very high harvesting and culturing expenses and the limited availability of data on their safety for human use, SCs are not a first-choice therapy. Further developments in SC research and gradually decreasing costs mean that along with commercial-scale SC culturing, the use of SCs will become a viable alternative to traditional surgical procedures.

A mutation in mouse Pak1ip1 causes orofacial clefting while human PAK1IP1 maps to 6p24 translocation breaking points associated with orofacial clefting.

Orofacial clefts are among the most common birth defects and result in an improper formation of the mouth or the roof of the mouth. Monosomy of the distal aspect of human chromosome 6p has been recognized as causative in congenital malformations affecting the brain and cranial skeleton including orofacial clefts. Among the genes located in this region is PAK1IP1, which encodes a nucleolar factor involved in ribosomal stress response. Here, we report the identification of a novel mouse line that carries a point mutation in the Pak1ip1 gene. Homozygous mutants show severe developmental defects of the brain and craniofacial skeleton, including a median orofacial cleft. We recovered this line of mice in a forward genetic screen and named the allele manta-ray (mray). Our findings prompted us to examine human cases of orofacial clefting for mutations in the PAK1IP1 gene or association with the locus. No deleterious variants in the PAK1IP1 gene coding region were recognized, however, we identified a borderline association effect for SNP rs494723 suggesting a possible role for the PAK1IP1 gene in human orofacial clefting.

The treatment of extensive arteriovenous malformations in the head.

Vascular tumours and malformations are revealed at birth and do not subside. The aim of the study was to present the principles and outcomes of treatment of patients with arteriovenous malformations treated at the Clinic of Plastic Surgery in Polanica Zdrój in the years 2009- 2010. Only one patient, who had not been treated previously, had the lesion on the cheek removed subtotally and the defect was closed by means of local repair. In the remaining patients, with primary lesions located in the auricle, scalp, and cheeks, the indications for operation included recurrent infections, ulcerations, and first of all, massive, life-threatening haemorrhages. All the patients, treated for many years in other centres, had underwent numerous resection procedures, vessel ligations, embolizations and obliterations. The patients were followed up after the surgery every 6 months. The therapy aim was achieved in all the patients. Vascular tumours were removed totally or subtotally, the lost structures were reconstructed and permanent healing of the wound was achieved. None of the patients developed recurrence of the disease, infection, or bleeding.

Anatomical variability of the anterolateral thigh flap perforators between sexes: a cadaveric study.

BACKGROUND: Anterolateral thigh flap (ALTF) has gain popularity as a workhorse flap in the management of simple as well as complex tissue defects. The purpose of this study was to investigate the differences in ALTF's perforators' location in male and female human cadavers. METHODS: The study involved 30 fresh human cadavers of both sexes. A total of 60 flaps were examined. The flaps were raised as originally designed. After location of vessels, the distance from the anterior superior iliac spine (ASIS) to subsequent perforators was measured. Also, the kind of the perforator, its diameter and origin were marked. Perforators were designated according to Yu's classification (A, B, and C). The perforators were divided into thin (<0.5 mm), medium (0.5-1 mm), and thick (>1 mm). Ratio of the ASIS-patella distance to the distance of a given perforator from the ASIS (AP rate) was calculated. RESULTS: The mean AP rate (perforator location) was different in both sexes. Mean AP rate in men was calculated as 0.498 ± 0.117, and in women, 0.559 ± 0.114. Differences in AP rate between female and male were statistically significant (t = -3.144; p < 0.002). Mean flap thickness was 3.65 cm in women and 1.17 cm in men (t = -14.444; p < 0.00001). In men, 63 perforators originated from descending branch, and seven perforators originated from oblique branch. In women, there were 67 and one, respectively. CONCLUSIONS: In men, perforators are located closer to the ASIS in comparison to women. Clinically significant perforators (Φ > 0.5 mm), in majority of cases, occur in A and B positions. Thickness of the flap was higher in women. The oblique branch was more common in men.

Osteoplasty of the alveolar cleft defect.

Cleft of lip, alveolar process and palate is the most common congenital defect affecting the face. It occurs at the time of early embryogenesis as a result of disturbed differentiation of the primordial cell layer and is associated with genetic and environmental factors. The most severe type of the defect is complete cleft of the lip, alveolar process and palate, unilateral or bilateral, which is accompanied by impaired breathing, sucking, swallowing, chewing, hearing and speaking. The treatment consists in the surgical reconnection (reconstruction) of the cleft anatomical structures and their formation to gain proper appearance, occlusal conditions and speech. The part of the surgical treatment is reconstruction of alveolar bone by means of autogenic spongy bone grafting (osteoplasty). The surgery performed at the stage of mixed dentition following an orthodontic treatment is a recognized standard management modality. Its effects provide stabilization of the dental arches fixed in the orthodontic treatment, possibility of growth of permanent teeth adjoining the cleft as well as separation of the nasal and oral cavities. The grafted bone becomes a platform for the collapsed base of the ala nasi and facilitates restoration of teeth loss. In the graft healing process the volume of the regenerated bone tissue is lower than the graft volume. Methods to augment the healed bone volume are being searched for, as this factor decides substantially on successful outcome of the surgery.

Association of DVL2 and AXIN2 gene polymorphisms with cleft lip with or without cleft palate in a Polish population.

BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common congenital anomalies, with a complex and still not fully understood etiology. Given the important role of the Wnt/ß-catenin pathway during craniofacial development, we decided to test the hypothesis that common polymorphic variants of the genes encoding crucial components of this signaling pathway might contribute to the risk of NSCL/P in the Polish population. METHODS: A set of 19 single nucleotide polymorphisms (SNPs) in the APC, AXIN1, AXIN2, CTNNB1, DVL2, and GSK-3ß genes were analyzed using restriction fragment length polymorphism and high-resolution melting curve methods in a group of 280 patients with NSCL/P and a properly matched control group (n = 330). RESULTS: Both single-marker and haplotype analyses showed an association between SNPs in the DVL2 gene and the risk for NSCL/P. The strongest association was found under an overdominant model for the rs35594616 variant located in the exonic sequence of DVL2 (odds ratio [OR], 1.90; 95% confidence interval [CI], 1.37-2.62; p < 0.0001). Moreover, the gene-gene interaction analysis revealed a significant epistatic interaction between DVL2 gene SNPs in the susceptibility to orofacial clefts. Borderline association with a decreased risk of NSCL/P was also observed for the AXIN2 rs3923087 variant (dominant model OR, 0.69; 95% CI, 0.50-0.95; p = 0.03). CONCLUSION: This study suggests that polymorphic variants of the Wnt/ß-catenin pathway genes have a role in the susceptibility to orofacial clefts. The DVL2 and AXIN2 genes might be candidate genes for this craniofacial anomaly in the Polish population. Birth Defects Research (Part A), 2012.