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We aimed to identify novel deletions and variants of TP63 associated with orofacial clefting (OFC). Copy number variants were assessed in three OFC families using microarray analysis. Subsequently, we analyzed TP63 in a cohort of 1072 individuals affected with OFC and 706 population-based controls using molecular inversion probes (MIPs). We identified partial deletions of TP63 in individuals from three families affected with OFC. In the OFC cohort, we identified several TP63 variants predicting to cause loss-of-function alleles, including a frameshift variant c.569_576del (p.(Ala190Aspfs*5)) and a nonsense variant c.997C>T (p.(Gln333*)) that introduces a premature stop codon in the DNA-binding domain. In addition, we identified the first missense variants in the oligomerization domain c.1213G>A (p.(Val405Met)), which occurred in individuals with OFC. This variant was shown to abrogate oligomerization of mutant p63 protein into oligomeric complexes, and therefore likely represents a loss-of-function allele rather than a dominant-negative. All of these variants were inherited from an unaffected parent, suggesting reduced penetrance of such loss-of-function alleles. Our data indicate that loss-of-function alleles in TP63 can also give rise to OFC as the main phenotype. We have uncovered the dosage-dependent functions of p63, which were previously rejected.

Common variants in interferon regulatory factor 6 ( IRF6) have been associated with nonsyndromic cleft lip with or without cleft palate (NSCL/P) as well as with tooth agenesis (TA). These variants contribute a small risk towards the 2 congenital conditions and explain only a small percentage of heritability. On the other hand, many IRF6 mutations are known to be a monogenic cause of disease for syndromic orofacial clefting (OFC). We hypothesize that IRF6 mutations in some rare instances could also cause nonsyndromic OFC. To find novel rare variants in IRF6 responsible for nonsyndromic OFC and TA, we performed targeted multiplex sequencing using molecular inversion probes (MIPs) in 1,072 OFC patients, 67 TA patients, and 706 controls. We identified 3 potentially pathogenic de novo mutations in OFC patients. In addition, 3 rare missense variants were identified, for which pathogenicity could not unequivocally be shown, as all variants were either inherited from an unaffected parent or the parental DNA was not available. Retrospective investigation of the patients with these variants revealed the presence of lip pits in one of the patients with a de novo mutation suggesting a Van der Woude syndrome (VWS) phenotype, whereas, in other patients, no lip pits were identified.

Cleft lip and/or palate (CL/P) is one of the most frequent congenital malformations, with a frequency of 1 in 700 live births. Non-syndromic orofacial clefting is a multifactorial condition, with both a genetic and an environmental component. Although numerous studies have been published addressing the genetic etiology of CL/P, this factor remains incompletely understood. A promising approach to find candidate gene regions for CL/P is the investigation of endophenotypes, which are characteristics associated with a certain condition and that can be an expression of underlying susceptibility genes. This review focuses on the known facial endophenotypes in CL/P (such as distortion of the orbicularis oris muscle and facial features in non-affected relatives of patients with CL/P) and genes that could be associated with these characteristics. Possibilities for further endophenotype-related studies in the field of non-syndromic CL/P are discussed.

Objective : The purpose of this longitudinal retrospective study was to evaluate transverse maxillary expansion after a Schuchardt or segmental posterior subapical maxillary osteotomy (SPSMO) in patients with cleft lip and palate (CLP). A second aim was to compare these data with data for adult patients without CLP who were receiving a surgical assisted rapid palatal expansion (SARPE). Method : The study group comprised 19 patients with CLP and a severe transversally collapsed maxilla who were treated with SPSMO followed by hyrax expansion at the University Hospitals Leuven. Dental casts of the 19 patients were analyzed before treatment, at maximum expansion, during orthodontic treatment, at the completion of orthodontic treatment. and 2 years after orthodontic treatment and were measured at the canine, premolar, and molar levels. Adult patients without CLP who were enrolled in a prospective study served as the control group. Results : Maxillary expansion within the study group was significantly greater (P < .05) at all measured levels compared with the maxillary arch before treatment. No significant relapse was measured in the study group 2 years after orthodontic treatment. When comparing the study and control groups, the only statistical difference was that canine expansion was significantly greater in the study group. Conclusion : SPSMO followed by maxillary expansion and orthodontic treatment is an appropriate treatment option to correct a severe transversally collapsed maxilla in patients with CLP. The overall treatment effect of SPSMO expansion is comparable with the effects of SARPE, although canine expansion was greater in the SPSMO group.

Aim: The purpose of this study was to investigate the presence of developmental defects of enamel on maxillary premolars in patients with cleft lip and/or palate. In addition, the relationship with the surgical technique of soft palate closure was studied. Such a relationship could be suspected since formation of enamel occurs around the same time period as soft palate closure., Materials and Methods: The study consisted of three groups. Patients from the first group (n = 123) were recruited from the Cleft Lip and Palate Team of the University Hospitals Leuven (CLPT-UHL). The second group (n = 81) consisted of patients consulting the Cleft Lip and Palate Team of the Radboud University Medical Centre Nijmegen (CLPT-UMCN). Healthy non-cleft lip and/or palate patients (n = 100) recruited from a private orthodontic practice were enrolled in group 3. All maxillary premolars were examined., Results: Out of the total sample, 43 patients showed developmental defects on one or more premolars. All defects occurred in patients of group 1 who received surgical closure by the CLPT-UHL. None of the patients from group 2 and 3 showed defects., Conclusions: It can be suggested that the surgical technique, used by the CLPT-UHL for soft palate closure, causes these defects. It is postulated that the technique used by the CLPT-UHL leads to interference with the blood supply of the developing premolar at a critical stage of tooth enamel development. More research is needed to confirm these findings.

Objectives: We surveyed the subjective outcome of secondary rhinoplasty in cleft lip patients., Methods: Questionnaires were sent to 38 patients who had undergone a secondary rhinoplasty. A total of 30 questionnaires were returned and analyzed. Patients were asked to score their preoperative and postoperative nasal function and form. The validated Rhinoplasty Outcome Evaluation (ROE) questionnaire was supplemented with questions on the subjective burden of the procedure and general satisfaction. In parallel, the objective aesthetic outcome was judged by 2 surgeons using preoperative and postoperative photographs., Results: There was a significant subjective improvement in ROE scores (from 39.3 ± 3.1 to 73.1 ± 2.0, p < 0.001), and in specific scores for nasal aesthetical appearance (from 3.6 ± 0.3 to 7.9 ± 0.2, p < 0.0001) and breathing capacity (from 4.9 ± 0.4 to 6.8 ± 0.3, p < 0.01). Subjective improvement in nasal aesthetics was generally evaluated to be better than improvement in nasal breathing. In retrospect, all patients would undergo the procedure again. Patient satisfaction did not correlate with the surgeon's appreciation of the aesthetic outcome of the rhinoplasty., Conclusion: Patient satisfaction after secondary rhinoplasty in cleft lip patients is high and comparable to that of non-cleft lip rhinoplasty patients., (Copyright © 2011 American Rhinologic Society-American Academy of Otolaryngic Allergy, LLC.)

Background: From 1989 to 1993, 113 previously untreated patients were admitted to the Multi-disciplinary Cleft Lip and Palate Team of the University Hospitals Leuven. Palate repair was performed in our centre by one surgeon (FO) in 88 patients. Our current surgical technique consists of a single-stage supraperiosteal retropositioning (modified Veau-Wardill-Kilner) for patients with a soft cleft palate only (SCP) or a soft cleft palate with up to 1 cm of the hard palate (HSCPpa). Patients with a larger or complete cleft of the secondary hard palate (HSCP) and patients with unilateral (UCLP) or bilateral (BCLP) cleft lip and palate undergo two surgical stages for palate closure: a supra-periosteal retropositioning is performed around 12 months of age, and a modified Langenbeck closure of the hard palate around 60 months of age., Aim: To assess velopharyngeal function with speech as outcome measure., Patients and Methods: Velopharyngeal function was assessed in two ways. In one assessment, a "hard" outcome measure was the number of patients undergoing pharyngoplasty following palate repair in our centre (n = 88). In the other assessment, velopharyngeal function was evaluated in a homogeneous sub-population of 44 non-syndromic cleft patients with normal to slight impairment of the following functions: mental development, language development, and hearing. In this group, prospectively collected data about hypernasality and nasal emission were analysed retrospectively using a semi-objective nasality index (NI). Articulation was evaluated using a subjective articulation index (AI) representing articulation errors (retro-articulation, glottal stops and facial grimacing) associated with velopharyngeal insufficiency (VPI). Mean follow-up was 114 months., Results: Despite rigid assessment by a phoniatrician and speech pathologist, only 1 patient out of 88 patients with soft palate surgery in our institution was thought to need pharyngoplasty. In the sub-cohort of 44 non-syndromic patients, nobody needed a pharyngoplasty. In the latter cohort, at the age of about eight years, 27 patients (61.5%) had undetectable nasality, 13 patients (29.5%) had an NI of 1 or "mild" nasality, and 4 patients (9%) had moderate nasality. At this point in time, articulation errors associated with VPI were noted in 14% of patients., Conclusion: In this subgroup of cleft palate patients treated following the Leuven protocol, there was no need for secondary pharyngoplasty. Ninety-one per cent of patients had no, or only mild, rhinolalia aperta by the age of eight years, and 84% did not display VPI-related articulation disorders. This suggests that velopharyngeal function in patients treated by this protocol is excellent compared to results in the literature.

Objective: The treatment of a patient with a complete unilateral left cleft lip and palate, agenesis of the left upper second premolar, and a severely malformed left upper lateral incisor is reported. Treatment included placement of an autologous bone graft from the left iliac crest into the alveolar cleft at 8 years of age and transplantation of a lower premolar into the reconstructed alveolar process at 10 years of age. During the succeeding orthodontic treatment, the dental arches were aligned and corrected toward a Class I molar occlusion. One year after the end of treatment, the status of the transplanted premolar was good.

34 patients (40 sides) received alveolo-palatal bone grafts for closure of the residual cleft, thus guiding a lateral incisor or canine into the arch. Long-term follow-up shows that in 41% of the patients uninterrupted arches were achieved with a normal relationship by orthodontic treatment only. 38% needed segmental osteotomies to eliminate the edentulous space, and in only 20% were bridges made to restore the dental arch. 9 (25%) patients still required a Le Fort I advancement osteotomy, despite optimal orthodontic treatment. The use of segmental osteotomies for eliminating edentulous spaces in cleft palate patients is discussed, and their advantage in relation to nasal base support is emphasized. It should be the aim to achieve in every cleft palate patient a complete archform without the need for bridges or removable prostheses. A rational orthodontic-surgical approach to the cleft, lip and palate patient is suggested with respect to naso-maxillary growth and development.

The use of segmental osteotomies to treat surgically severe malocclusion in cleft patients is discussed. The coordinated approach by orthodontist and surgeon is advocated and the advantage of such an approach is stressed. The method allows for the simultaneous correction of the skeletal deformity and closure of residual oro-nasal perforation. The relapse tendency in both antero-posterior and transverse dimensions appeared to be minimal as found in this study of 18 patients.

Objective: The purpose of this longitudinal retrospective study was to evaluate transverse maxillary expansion after a Schuchardt or segmental posterior subapical maxillary osteotomy (SPSMO) in patients with cleft lip and palate (CLP). A second aim was to compare these data with data for adult patients without CLP who were receiving a surgical assisted rapid palatal expansion (SARPE). Method: The study group comprised 19 patients with CLP and a severe transversally collapsed maxilla who were treated with SPSMO followed by hyrax expansion at the University Hospitals Leuven. Dental casts of the 19 patients were analyzed before treatment, at maximum expansion, during orthodontic treatment, at the completion of orthodontic treatment. and 2 years after orthodontic treatment and were measured at the canine, premolar, and molar levels. Adult patients without CLP who were enrolled in a prospective study served as the control group. Results: Maxillary expansion within the study group was significantly greater (P < .05) at all measured levels compared with the maxillary arch before treatment. No significant relapse was measured in the study group 2 years after orthodontic treatment. When comparing the study and control groups, the only statistical difference was that canine expansion was significantly greater in the study group. Conclusion: SPSMO followed by maxillary expansion and orthodontic treatment is an appropriate treatment option to correct a severe transversally collapsed maxilla in patients with CLP. The overall treatment effect of SPSMO expansion is comparable with the effects of SARPE, although canine expansion was greater in the SPSMO group. [ABSTRACT FROM AUTHOR]

Objectives To review early clinical manifestations of Pierre Robin sequence (PRS) and their management during the first year of life in the University Hospitals Leuven. Methods Retrospective series of 48 patients with PRS born between 2001 and 2011 and treated at a tertiary referral hospital. Review of the current literature about management of respiratory and breathing difficulties in the early life of PRS patients. Results Of our cleft palate patients 15.3% presented with PRS. A syndrome was diagnosed in 14.6%, associated anomalies without a syndromic diagnosis in 56.3% and isolated PRS in 29.2% of the cases. Mortality rate directly related to PRS was 2.1%. Respiratory difficulties were observed in 83.3% and feeding difficulties in 95.6% of the patients. Respiratory problems were addressed in a conservative way in 75%, in a non-surgical invasive way in 42.5% and in a surgical way in 12.5%. A statistically significant relationship between the association of a syndrome or other anomalies, and a higher need for resuscitation and invasive treatment were found (chi-square test, p -values = 0.019 and 0.034). Feeding difficulties were managed conservatively in 91.3%, invasively in 80.4% and surgically in 15.2%. Conclusions PRS is frequently associated with other abnormalities or syndromes. Therefore routine screening for associated anomalies in neonates with PRS is recommendable. Respiratory and feeding complications are highly frequent and possibly severe, particularly in patients with associated anomalies or syndromes, and should be recognized and addressed appropriately in an early stage. There is a potential role for the nasopharyngeal airway in reducing the need for the more traditional surgical interventions for respiratory problems. [ABSTRACT FROM AUTHOR]

Objectives We reviewed the outcomes of patients who underwent a velopharyngoplasty and subsequent speech therapy for velopharyngeal insufficiency (VPI) to determine possible prognostic variables. Methods During the period 2002–2010, 91 patients with VPI underwent a velopharyngoplasty (either the Honig velopharyngoplasty, the modified Honig velopharyngoplasty or the Hynes pharyngoplasty). Of these, 62 had complete data for long-term evaluation of speech outcome and analysis of variables potentially influencing this outcome. Speech outcome was assessed using five criteria that were evaluated pre- and postoperatively: hypernasality, nasal emission, facial grimacing, retro-articulation and glottal stops. The former two variables were transformed into a semi-objective nasality index (NI), the latter three variables were assembled to form a subjective articulation index (AI). Prognostic variables for outcome that were studied included age at velopharyngoplasty, associated 22q11.2 deletion syndrome, intervention type, primary or secondary surgery and pre-intervention speech therapy. Results Before surgery, based on the NI, 15 patients had mild VPI and 44 patients had moderate to severe VPI. Postoperatively at 12 months, 46 patients had a good speech outcome (normal or mild VPI), 13 patients had moderate VPI and no more severe VPI was observed. The overall success rate of 78% after one year increased to 90% in the long-term (median 27 months) with further speech therapy. Patients without the diagnosis of 22q11.2 deletion syndrome had better speech outcomes than patients with the syndrome. No statistically significant effect of the age at velopharyngoplasty on speech outcome was found. No cases of sleep apnea syndrome were reported. Conclusions Our protocol of patient tailored surgical interventions and further postoperative speech therapy results in good speech outcomes, with no or only mild remaining VPI for the majority of patients. The correction of VPI is more difficult for the subgroup of patients with 22q11.2 deletion syndrome. [ABSTRACT FROM AUTHOR]