Philip Kuo-Ting Chen

A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4

Case-parent trios were used in a genome-wide association study of cleft lip with and without cleft palate. SNPs near two genes not previously associated with cleft lip with and without cleft palate (MAFB, most significant SNP rs13041247, with odds ratio (OR) per minor allele = 0.704, 95% CI 0.635–0.778, P = 1.44 × 10−11; and ABCA4, most significant SNP rs560426, with OR = 1.432, 95% CI 1.292–1.587, P = 5.01 × 10−12) and two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance. Stratifying trios into European and Asian ancestry groups revealed differences in statistical significance, although estimated effect sizes remained similar. Replication studies from several populations showed confirming evidence, with families of European ancestry giving stronger evidence for markers in 8q24, whereas Asian families showed stronger evidence for association with MAFB and ABCA4. Expression studies support a role for MAFB in palatal development.

Interdental distraction osteogenesis and rapid orthodontic tooth movement. A novel approach to approximate a wide alveolar cleft or bony defect

The closure of a wide alveolar cleft and fistula in cleft patients and the reconstruction of a maxillary dentoalveolar defect in traumatic patients are challenging for both orthodontists and surgeons. This is due to the difficulty in achieving complete closure by using local attached gingiva and the great volume of bone required for the graft. In this article, the authors propose using interdental distraction osteogenesis to create a segment of new alveolar bone and attached gingiva for the complete approximation of a wide alveolar cleft/fistula and the reconstruction of a maxillary dentoalveolar defect. They performed this procedure on one patient with a traumatic maxillary dentoalveolar defect and 10 patients with unilateral or bilateral cleft lips and palates who had varied dentoalveolar clefts/fistulas. Interdental and maxillary osteotomies were performed on one side of the dental arch by the cleft or defect. After a latency period of 3 days, the osteotomized distal segment of the dental arch was then distracted and transported toward the cleft or defect by using a toothborne intraoral distraction device. The alveoli and gingivae on both ends of the cleft or defect were approximated after distraction osteogenesis. The need for extensive alveolar bone grafting was eliminated. A segment of new edentulous alveolus and attached gingiva was created interdentally at a site distant to the cleft or defect. In the cleft patients, teeth were moved orthodontically into the regenerate (newly formed alveolar bone) dental crowding 1 week after distraction. The orthodontic tooth movement was rapidly completed in 3 months, and the edentulous space was eliminated. Interdental distraction osteogenesis minimizes an alveolar cleft/fistula and helps reconstruct a maxillary dentoalveolar defect by approximating the native alveoli and gingivae; it also creates new alveolar bone and gingiva for rapid orthodontic tooth movement. (Plast. Reconstr. Surg. 105: 1262, 2000.)

Correction of Secondary Velopharyngeal Insufficiency in Cleft Palate Patients with the Furlow Palatoplasty

To avoid the serious complications of pharyngeal flap surgery, a Furlow palatoplasty was used to correct velopharyngeal insufficiency after primary palatoplasty in 18 Chinese cleft palate patients (3 to 23 years old) from 1988 to 1992. The follow-up duration was 1 to 4 years. These patients were selected after a complete study for velopharyngeal insufficiency, including intraoral examination, perceptual speech assessment, videonasopharyngoscopy, and/or multiview videofluoroscopy. The criteria for selection included age, pattern of velopharyngeal closure, size of the velopharyngeal gap, extent of lateral pharyngeal wall movement, existence of a Passavants ridge, and abnormal levator veli palatini muscle insertion. Complete velopharyngeal closure was achieved for 16 patients after surgery. The majority of these patients (15) had a velopharyngeal gap less than 5 mm. The 2 patients who still had velopharyngeal insufficiency after the surgery had a velopharyngeal gap larger than 10 mm before the surgery. The most important factor seemed to be the size of the velopharyngeal gap. Pattern of velopharyngeal closure or age of the patient also might play an important role. The results showed that a Furlow palatoplasty can satisfactorily correct velopharyngeal insufficiency in carefully selected patients. Although the criteria for the selection of this operation need further study, present results are encouraging.

Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate.

Nonsyndromic cleft palate (CP) is a common birth defect with a complex and heterogeneous etiology involving both genetic and environmental risk factors. We conducted a genome‐wide association study (GWAS) using 550 case‐parent trios, ascertained through a CP case collected in an international consortium. Family‐based association tests of single nucleotide polymorphisms (SNP) and three common maternal exposures (maternal smoking, alcohol consumption, and multivitamin supplementation) were used in a combined 2 df test for gene (G) and gene‐environment (G × E) interaction simultaneously, plus a separate 1 df test for G × E interaction alone. Conditional logistic regression models were used to estimate effects on risk to exposed and unexposed children. While no SNP achieved genome‐wide significance when considered alone, markers in several genes attained or approached genome‐wide significance when G × E interaction was included. Among these, MLLT3 and SMC2 on chromosome 9 showed multiple SNPs resulting in an increased risk if the mother consumed alcohol during the peri‐conceptual period (3 months prior to conception through the first trimester). TBK1 on chr. 12 and ZNF236 on chr. 18 showed multiple SNPs associated with higher risk of CP in the presence of maternal smoking. Additional evidence of reduced risk due to G × E interaction in the presence of multivitamin supplementation was observed for SNPs in BAALC on chr. 8. These results emphasize the need to consider G × E interaction when searching for genes influencing risk to complex and heterogeneous disorders, such as nonsyndromic CP. Genet. Epidemiol. 2011.  © 2011 Wiley‐Liss, Inc. 35: 469‐478, 2011

Association between IRF6 and nonsyndromic cleft lip with or without cleft palate in four populations

Purpose: The interferon regulatory factor 6 (IRF6), the gene that causes van der Woude syndrome has been shown to be associated with nonsyndromic cleft lip with or without palate in several populations. This study aimed to confirm the contribution of IRF6 to cleft lip with or without palate risk in additional Asian populations.Methods: A set of 13 single nucleotide polymorphisms was tested for association with cleft lip with or without palate in 77 European American, 146 Taiwanese, 34 Singaporean, and 40 Korean case-parent trios using both the transmission disequilibrium test and conditional logistic regression models.Results: Evidence of linkage and association was observed among all four populations; and two specific haplotypes [GC composed of rs2235373-rs2235371 (p.V274I) and AAG of rs599021-rs2235373-rs595918] showed the most significant over- and undertransmission among Taiwanese cases (P = 9 × 10−6 and P = 5 × 10−6, respectively). The AGC/CGC diplotype composed of rs599021-rs2235373-rs2013162 showed almost a 7-fold increase in risk among the Taiwanese sample (P < 10−3). These results confirmed the contribution of this gene to susceptibility of oral clefts across different populations; however, the specific single nucleotide polymorphisms showing statistical significance differed among ethnic groups.Conclusion: The high-risk genotypes and diplotypes identified here may provide a better understanding of the etiological role of this gene in oral clefts and potential options for genetic counseling.

Incidence and Severity of Obstructive Sleep Apnea Following Pharyngeal Flap Surgery in Patients With Cleft Palate

OBJECTIVE To investigate the incidence and severity of obstructive sleep apnea (OSA) associated with pharyngeal flap surgery in patients with cleft palate at least 6 months postoperatively and to determine whether age or the flap width had an effect on them. The hypothesis tested in this study was that the severity of OSA associated with pharyngeal flap surgery is greater in children than in adults. SUBJECTS Ten adults, six men and four women, with a mean age of 28.0 years at pharyngeal flap (adult group). Twenty-eight children, 13 boys and 15 girls, with a mean age of 6.3 years at pharyngeal flap (child group). DESIGN A prospective analysis. MAIN OUTCOME MEASURES An overnight polysomnographic study was used to determine the incidence and severity of OSA 6 months after pharyngeal flap. RESULTS The incidence of OSA following pharyngeal flap was high but not significantly different between these two groups (90% in adults and 93% in children, p = 1.000). When OSA was stratified into different levels of severity according to the values of respiratory disturbance index, there were noticeable differences between these two groups (p =.022). In the adult group, eight patients (89%) had mild OSA and 1 patient (11%) had moderate to severe OSA. In the child group, 11 patients (42%) were found to have mild OSA, and 15 patients (58%) had moderate to severe OSA. No relation was found between the flap width and the incidence (p =.435 in adults and.640 in children) or the severity (p =.325 in adults and.310 in children) of OSA in each group. CONCLUSIONS Six months following pharyngeal flap surgery, more than 90% of the patients with cleft palate still had OSA. The severity of OSA associated with pharyngeal flap surgery tended to be greater in children than in adults. The flap width was unrelated to the incidence and severity of OSA, no matter in adults or in children.

Long-term comparison of four techniques for obtaining nasal symmetry in unilateral complete cleft lip patients: a single surgeon's experience.

Background: This study was the result of a constant evaluation of surgical techniques and results to obtain excellence in primary cleft rhinoplasty. Methods: This was a retrospective study from 1992 to 2003 comparing the long-term outcomes of four techniques of nasal reconstruction. There were 76 patients divided into four groups: group I (n = 23 patients), primary rhinoplasty alone; group II (n = 16 patients), nasoalveolar molding alone; group III (n = 14 patients), nasoalveolar molding plus primary rhinoplasty; and group IV (n = 23 patients), nasoalveolar molding plus primary rhinoplasty plus overcorrection. The surgical results were analyzed using photographic records obtained at 5 years of age. A ratio of six measurements was obtained comparing the cleft and noncleft sides. A panel assessment was obtained to grade the appearance of the surgical results. All surgery was performed by the senior author (P.K.T.C.). Results: The results are given for groups I to IV, respectively. The nostril height ratio was 0.73, 0.77, 0.81, and 0.95. The nostril width ratio was 1.23, 1.36, 1.23, and 1.21. The one-fourth medial part of nostril height ratio was 0.70, 0.87, 0.92, and 1.00. The nasal sill height ratio was 0.75, 1.02, 1.07, and 1.07. The nostril area ratio was 0.86, 0.89, 0.95, and 1.08. The nostril height-to-width ratio was 0.58, 0.58, 0.71, and 0.92. Finally, group IV had the best panel assessment. Conclusions: The results revealed that group IV had the best overall result. Overcorrection of 20 percent was necessary to maintain the nostril height. Further technical modifications are necessary to minimize widening of the nostril width.

Ex vivo gene therapy in autologous critical-size craniofacial bone regeneration.

In therapeutic bone repairs, autologous bone grafts, conventional or vascularized allografts, and biocompatible artificial bone substitutes all have their shortcomings. The bone formed from peptides [recombinant human bone morphogenetic proteins (BMPs)], demineralized bone powder, or a combination of both is small in size. Tissue engineering may be an alternative for cranial bone repair. In this study, the authors developed an animal model to test the hypothesis that replication-defective, adenovirus-mediated human BMP-2 gene transfer to bone marrow stromal cells enhances the autologous bone formation for repairing a critical-size craniofacial defect. The mesenchymal stromal cells of miniature swine were separated from the iliac crest aspirate and expanded in monolayer culture 1 month before implantation. The cultured mesenchymal stromal cells were infected with recombinant, replication-defective human adenovirus BMP-2, 7 days before implantation. Bilateral 2 × 5-cm2 cranial defects were created, leaving no osteogenic periosteum and dura behind. Mesenchymal stromal cells at 5 × 107/ml were mixed with collagen type I to form mesenchymal stromal cell/polymer constructs. Mesenchymal stromal cells used for the control site were infected with adenovirus &bgr;-Gal under the same conditions. After 6 weeks and 3 months, 10 miniature swine were euthanized and the cranium repair was examined. Near-complete repair of the critical-size cranial defect by tissue-engineered mesenchymal stromal cell/collagen type I construct was observed. The new bone formation area (in square centimeters) measured by three-dimensional computed tomography demonstrated that the improvement from 6 weeks to 3 months was significantly greater on the experimental side than on the control side (2.15 cm2 versus 0.54 cm2, p < 0.001) and significantly greater at 3 months than at 6 weeks (2.13 cm2 versus 0.52 cm2, p < 0.001). The difference between the experimental and control groups was significant at 3 months (mean difference, 2.13 cm2; p < 0.001). The maximal compressive strength of the new bone was similar to that of the normal cranial bone when evaluated by biomechanical testing (cranium bone versus tissue-engineered bone, 88.646 ± 5.121 MPa versus 80.536 ± 19.302 MPa; p = 0.227). Adenovirus was absent from all constructs by immunochemical staining at 6 weeks and 3 months after implantation. The successful repair of cranial defects in this experiment demonstrates the efficacy of the integration of the autologous stem cell concept, gene medicine, and polymers in producing tissue-engineered bone.

The use of nasal splints in the primary management of unilateral cleft nasal deformity.

Primary surgical correction of the cleft lip nasal deformity is routinely performed at the Craniofacial Center at Chang Gung Memorial Hospital. Over time, however, there is a tendency for the lower lateral cartilage to retain its memory and, subsequently, recreate the preoperative nasal deformity. Therefore, it is current practice to use a nostril retainer for a period of at least 6 months to maintain the corrected position of the nose. The aim of this study was to qualitatively assess the benefit of postoperative nasal splinting in the primary management of unilateral cleft nasal deformity. Data from two groups of 30 patients with complete unilateral cleft lips each were retrospectively collected and analyzed. The first group served as a control (no nasal splints), and the second group used the nasal retainer compliantly for at least 6 months postoperatively. All patients had their primary lip repair at 3 months of age. A photographic evaluation of the results when the patients were between 5 and 8 years of age was conducted. The parameters used to assess the nasal outcome were nostril symmetry, alar cartilage slump, alar base level, and columella tilt. The first scores were based on residual nasal deformity, and the second set were based on overall appearance. It was found that the mean scores of residual nasal deformity for all four parameters in patients who used the nasal stent were statistically better than the scores of patients who did not (p values ranged from 0.0001 to 0.005). The overall appearance scores for the four parameters in the patients who used the nasal stent after surgery were also statistically better than the scores for those who did not (p values ranged from 0.0001 to 0.01). The results show that postoperative nasal splinting in the primary management of the unilateral cleft nasal deformity serves to preserve and maintain the corrected position of the nose after primary lip and nasal correction, resulting in a significantly improved aesthetic result. Therefore, it is recommended that all patients undergoing primary correction of complete unilateral cleft deformity use the nasal retainer postoperatively for a period of at least 6 months.

Progressive changes of columella length and nasal growth after nasoalveolar molding in bilateral cleft patients: a 3-year follow-up study.

Background: The purpose of this study was to assess the progressive changes of columella length and nasal growth after presurgical nasoalveolar molding and primary cheiloplasty in bilateral complete cleft lip–cleft palate infants. Methods: Twenty-two consecutive complete bilateral cleft lip–cleft palate infants were included. All of them underwent nasoalveolar molding for columella lengthening and retraction of the premaxilla for 3 to 4.5 months before primary cheiloplasty. Standard 1:1 basilar photographs were taken before and after nasoalveolar molding, 1 week after cheiloplasty, and yearly for 3 years. Nasal height and width were measured directly on the photographs. Results: The results revealed that columella length was significantly lengthened after nasoalveolar molding and was further improved after primary cheiloplasty. The columella decreased in length slightly in the first and second years postoperatively and started to increase in length slightly in the third year postoperatively, whereas the rest of the nose grew significantly in height year by year. This consequently appeared as relapse of columella length. The shortage of the columella length was 1.9 mm. Conclusions: Both presurgical nasoalveolar molding and primary cheiloplasty lengthened the columella in bilateral cleft lip–cleft palate patients. However, there was a relative relapse in columella length because of the differential growth between the columella and the rest of the nose in the first and second years postoperatively.