Are left sided orofacial clefts a different entity to right sided orofacial clefts? 

Matt Fell1, Dr Kate Fitzsimons2, Amy Davies3, Dr Daniel Bradley4, Ambika Chadha5, Sophie Butterworth2, Dr Mark Hamilton6, Jibby Medina2, Dr Hussein Wahedally2, Dr Min Hae Park2, Prof Jan Van Der Meulen2, Bruce Richard7, Craig Russell6, Prof Yvonne Wren3, Prof Sarah Lewis3, Associate Prof David Chong8 

1Spires Cleft Centre, Oxford, UK, 2Royal College of Surgeons of England, London, UK, 3University of Bristol, Bristol, UK, 4Operation Smile, Virginia, United States of America, 5Addenbrooke's Hospital, Cambridge, UK, 6Royal Hospital for Children, Glasgow, UK 6, 7Birmingham Women and Children's Hospital, Birmingham, UK, 8Royal Children's Hospital, Melbourne, Australia 

Background: The prevalence of left unilateral cleft lip with or without cleft palate (UCL/P) is consistently observed to be twice that of right UCL/P, yet it is not known whether the two represent different underlying phenotypes. 

Aims and Objectives: To assess the co-occurrence of sidedness in unilateral cleft lip only (UCLO) and unilateral cleft lip and palate (UCLP) with additional diagnostic features. 

Methods: A multimodal approach: 

• Scoping review of UCL/P sidedness in literature databases. 
• Data linkage of CRANE database to Hospital Episode Statistics (HES) to investigate association between UCL/P sidedness and additional congenital anomalies. 
• Cleft Collective parental questionnaires from birth and 5-year cohorts to assess association between UCL/P sidedness and additional comorbidities. 

Results/Conclusions: The scoping review included 12 studies relating to the co-occurrence of UCL/P sidedness, which focused on dental anomalies, handedness, and congenital anomalies. There was a trend for right UCL/P to represent a more severe phenotype. 

The CRANE data linkage included 3,788 children and reported a greater prevalence of additional congenital anomalies for right compared to left UCLP (32% vs 23%, OR 1.54, 95% CI 1.25 to 1.90: p<0.001). There was no evidence for a difference in the prevalence of additional congenital anomalies by sidedness in the UCLO phenotype. 

The Cleft Collective data included 447 children and reported increased prevalence of vision anomalies for right compared to left UCLP (11% vs 3%, OR 3.68, 95% CI 1.22-11.13; p=0.021). There was no evidence for a difference in vision by sidedness in the UCLO phenotype. 

These findings challenge previously held beliefs that UCL/P sidedness is simply an administrative feature for classification purposes alone and instead suggest that left and right are distinct entities and furthermore are different for UCLO and UCLP phenotypes. Future work to improve understanding requires adequately powered GWAS and DNA sequencing studies. 

Furlow Palatoplasty as Day Case Surgery – A Regional Cleft Unit Experience.

Background and Purpose

A feasibility study was performed for same day discharge following Furlow palatoplasty at a regional cleft centre. Based on the initial analysis, non-syndromic children without co-morbidities had lower post-operative pain requirements and were deemed suitable for discharge on the day of surgery. Since 2017 suitable patients undergoing Furlow palatoplasty have been planned as day case procedures.

Description

Over this time period eighty-four Furlow palatoplasty procedures were performed. Twenty-eight patients (33%) had associated syndromes or genetic conditions including Robin sequence (n=11, 13%) and 22q1.1 deletion (n=10, 12%).

Indications for primary Furlow palatoplasty included submucous cleft palate (n=26, 31%), and soft palate cleft (n=29, 34%). Twenty-nine patients had a Furlow palatoplasty for secondary speech surgery (35%).

Thirty-five patients (42%) had surgery performed as a day case, 60% primary and 40% secondary. The majority of patients discharged on the day of surgery had no underlying genetic condition (n=25, 71%).

Indications for admission included; co-morbidity, syndromic diagnosis, poor oral intake and ongoing pain requirements.

Five patients re-presented to the emergency department following surgery, three of which were day case patients. Reasons for presentation included; bleeding (n=1), vomiting and diarrhoea (n=1), reduced oral intake (n=1) and wound dehiscence (n=2). Only one patient required re-admission for intravenous fluid administration and was discharged the following day, this patient had been discharged on the day of surgery.

Conclusions

This study demonstrates the feasibility and safety of performing Furlow palatoplasty as day case surgery for a select patient cohort.

Cleft lip/palate and educational attainment: Cause, consequence or correlation? - Christina Dardani

Background

Previous studies have found that children with non-syndromic cleft lip/palate (nsCL/P) have lower educational attainment than their peers. It is unclear whether these differences are due to 1) a genetic predisposition to low intelligence caused by undiagnosed congenital differences in brain structure or function, 2) factors related to having a cleft (e.g. higher school absences, social stigmatization, or impaired speech and language development), or 3) confounding factors such as family socioeconomic position or parental health behaviours (e.g. smoking or drinking alcohol).

Aim

We assessed whether common genetic variants that increase the chance of being born with nsCL/P also influence educational attainment and intelligence. 

Methods

We approached our aim by using data from large genome-wide association studies (GWAS) and performing state-of-the-art statistical methods; LDscore regression and Mendelian randomization.

Results

Using LD score regression, we found little evidence that genetic liability to nsCL/P was correlated with genetic liability to lower educational attainment (r -0.03, 95%CI -0.14 to 0.08, P 0.58) or intelligence (rg -0.01, 95%CI -0.12 to 0.10, P 0.85). Using Mendelian randomization, we also found little evidence that genetic liability to nsCL/P causally influences educational attainment (βMR 0.002, 95% CI -0.001 to 0.005, P 0.42) or intelligence (βMR 0.002, 95%CI -0.010 to 0.014, P 0.67).

Conclusions

Common genetic variants are unlikely to predispose individuals born with nsCL/P to low educational attainment or intelligence. Further research is required to identify environmental influences and help tailor clinical-, school-, social- and family-level interventions to improve educational attainment in this group.

Receptive and expressive language characteristics of school aged children with non-syndromic cleft lip and/or palate Jessica O. Boyce, Nicky Kilpatrick, Annette Da Costa, Angela T. Morgan

Surgical lip repair protocol in patients with bilateral cleft lip and palate does affect bilabial sound development - Holly Peryer & Members of the West Midlands Cleft Lip & Palate Service

Background: There is a paucity of literature on bilateral cleft lip & palate (BCLP) and speech outcomes. BCLP accounts for approximately 10% of annual cleft referral per year, resulting in difficulty obtaining large enough sample sizes for comparison. Where cleft lip occurs in isolation with no cleft of the palate, Cleft Speech Characteristics (CSCs) are not associated (Vallino et. al 2008). 

Purpose: This study was developed following a clinical question related to acquisition of bilabial sounds [m] [p] [b] and CSCs associated with two differing lip repair protocols in BCLP patients; Primary Lip Adhesion (followed by definitive lip repair as a secondary procedure between 13 and 38 months) versus Primary Definitive Lip Repair (at 4 months).

Method : A retrospective case note investigation of 49 consecutive BCLP (Lip Adhesion cohort: 23, Definitive Lip Repair cohort: 26 patients) born between 2000 and 2009 documents the development of bilabial sounds and CSCs at 3 critical assessment stages; 18 months, 3 years and 5 years.

Results:  Findings indicate statistically significant differences in the development of bilabial sounds between the two lip repair protocols. CSCs were more prevalent and severe in the 2-stage lip repair (lip adhesion) cohort.

Conclusions : As a result of this finding, a revised BCLP care pathway has been developed, with definitive lip repair taking place earlier following primary lip adhesions, in addition to an enhanced SLT Assessment and Intervention pathway.

A CLINCIAL AND MOLECULAR GENETIC STUDY OF ORAL-FACIAL-DIGITAL SYNDROMES. S Faily, R Perveen, Urquhart J, Clayton-Smith J

INTRA-ORAL THREE DIMENSIONAL SCANNING FOR ASSESSMENT OF SURGICAL OUTCOME IN PATIENTS WITH UCLP. E Chalmers, G McIntyre, W Wang, T Gillgrass, C Martin, P Mossey

Aim: To examine the reliability of intra-oral 3D scans as an alternative to study models for the assessment of dental arch relationships in 9-21 year olds with UCLP.

To evaluate patient and parent satisfaction with 3D intra-oral scanning compared with dental alginate impressions for study models.

Methods: 43 patients underwent intra-oral 3D scanning and impressions. Participants and parents scored their perception and time required for the 3D scan and impressions via a questionnaire. Three examiners scored both model formats using the MHB and GOSLON indices.

Results: All examiners achieved an intraexaminer reliability score greater than 0.98. The direct digital scans demonstrated superior interexaminer reliability to plaster models.

Conclusions: Reliability of GOSLON and MHB scoring using intra-oral 3D scans was superior to plaster models. Participants and their parents preferred the experience of the intra-oral 3D scan.
This study supports the replacement of conventional impressions with intra-oral 3D in longitudinal evaluations of the outcomes of cleft care.

Fistula incidence after primary cleft palate repair – a meta-analysis of 9,444 patients. Joseph Hardwicke, Bruce Richard

Aim: The development of an oronasal fistula after primary cleft palate repair has a wide variation reported in the literature. The aim of this review is to identify the reported oronasal fistula incidence to provide a benchmark for surgical practice.

Methods: A systematic review was undertaken to investigate the incidence of fistula. Multiple meta-analyses were performed to pool proportions of reported fistulae, in each dataset corresponding to the continent of origin of the study, type of cleft, and techniques of cleft palate repair employed.

Results: A total of 9,444 patients were included. The overall incidence of reported fistula was 8.5% (95% CI: 6.3 - 10.9). There was no significant difference in the fistula incidence corresponding to the continent of origin of each study, nor the repair technique employed. The incidence of fistula in cleft lip and palate was 17.9%, which was significantly higher (p = 0.03) than in cases of cleft palate alone (5.1%).

Conclusions: Palatal fistula were more likely to occur in cases of combined cleft lip and palate, compared to cleft palate alone. We would recommend the use of a well-practiced surgical repair technique and treatment schedule, and audit of outcomes against the reported fistula incidence of 6-11%.

Radical Muscle Dissection In Cleft Palate Repair – What About The Lesser Palatine Nerves? Jeremy Mortimer, Felicity Mehendale and Simon Parson.

Aim: The lesser palatine nerves (LPNs) are overlooked in radical muscle dissection techniques for cleft palate repair. As well as supplying sensation, taste and glandular secretion to the velum, reports suggest they carry facial nerve motor fibres to levator veli palatini (LVP). This study explores LPN anatomy with reference to a Sommerlad dissection.

Methods: LPNs and LVP were dissected under magnification in 3 cadavers. Sihler nerve staining was carried out for the first time in the velopharyngeal region. A literature review was also undertaken to identify trends in the reported inconsistencies of LVP innervation.

Results: LPN branches ran oral to the tensor aponeurosis, terminating within the glandular layer oral to the muscular velum. No LPN fibres entered LVP. The main LVP nerve emerged from the lateral pharyngeal wall. Evidence refuting LPN facial nerve motor contribution to LVP seems only found in non-primate studies.

Conclusions: Radical muscle dissection severs LPNs, which carry fibres of sensation, taste and glandular secretion to the velum. Primates may have evolved facial nerve motor relays between the facial speech muscles and LVP via LPNs that would also be lost. Post-cleft palate repair outcome studies of non-motor velar function should be undertaken, possibly informing modifications in technique and timing of surgery.

Two potential novel loci for orofacial clefting identified on Array CGH. Rita Ibitoye, Usha Kini, Joanna Roberts.

Aim: To present two potential new genetic loci for orofacial clefting.

Methods: A family presenting with a syndromic cleft palate in the child and another family with non-syndromic bilateral cleft lip and palate (BCLP) across 3 generations were investigated using Agilent Array comparative genomic hybridisation (Array CGH).

Results:We identified a de novo 4.3Mb deletion on chromosome 5q23 in the patient with syndromic cleft palate. Five other patients with cleft palate and 5q23 microdeletion were identified using a national database (DECIPHER). A potential critical locus for cleft palate has been narrowed.

A 350 kb chromosome 17p13.3 microduplication was identified in the family with non-syndromic BCLP, segregating with four affected family members. There is one other patient described with a similar duplication and BCLP.

We discuss the potential candidate genes for orofacial clefting in these regions.

Conclusions:We have identified two potential new loci for orofacial clefting using array CGH. This relatively new technique is now easily accessible through the NHS cytogenetics laboratories. Further work is needed to refine the causative candidate genes. Prenatal testing will now be available for these families.

The 5-year old index: Determining the optimal media for rating dental arch relationships in unilateral cleft lip and palate. Ourvinder Chawla, Scott Deacon, Nikki Atack, Anthony Ireland, Jonathan Sandy

Aim: To determine the optimal format for presenting the 5-year olds’ Index reference models, for the assessment of dental arch relationships in unilateral cleft lip and palate (UCLP).

Design: The 5-year olds’ Index reference models were presented in four different formats; plaster models, coloured acrylic models and two digital formats which included three dimensional digital models (3D) and black & white photographs. For each format, scoring was undertaken one week apart and used to rate 45 models of patients with UCLP. To determine intra-examiner agreement, the same examiners repeated the scoring three weeks later under similar conditions. The level of inter-examiner agreement was calculated using the plaster reference models as the “gold” standard to which the other formats were then compared.

Participants: Seven examiners, comprising experienced and inexperienced examiners

Results: Kappa statistics revealed the level of intra-examiner agreement for all the formats of the 5-year olds’ Index were good to very good between examiners.   Compared to the “gold”, kappa values for acrylic models ranged from 0.68 to 0.87, kappa values for the digital photographs ranged from 0.68 to 0.90 and finally, for the 3D digital models ranged from 0.67 to 0.91.

Conclusions: At present, 3D digital models are not in widespread use but this study clearly demonstrated that 3D models of the 5-year olds’ Index could prove to be a promising alternative to physical models of the 5-year olds’ Index.

Surgical management of the spectrum of submucous cleft palate(SMCP): Speech outcome following anatomical muscle dissection.repair of the palate. Mr Ali M. Ghanem with O. Gilleard, D. Sell, M. Birch and B.C. Sommerlad.

Aim: to evaluate the role of velar surgery in the management of SMCP.

Results: 93 patients were included with 81 having rateable speech records. 30 patients had other malformations (syndrome group). Anatomical muscle dissection palate repair significantly improved intelligibility, hypernasality, nasal emission and passive CTCs scores. Successful achievement of normal post-op hypernasality was possible in 77% of cases (70% in the syndrome group). On videofluoroscopy velar repair significantly increased functional palate length, palate lift and closure ratio. The surgical repair also significantly decreased the velopharyngeal gap size at attempt closure. No significant changes were observed in velopharyngeal gap size at rest or velar extensibility. Pre-op hypernasality, passive CTCs high scores as well as large pre-operative gap size were predictive of less satisfactory post-operative speech outcome. There was no post operative complication. Secondary pharyngoplasty was necessary in 20% of cases.

Conclusion: Anatomical muscle dissection repair of the palate is safe and effective first line treatment option of hypernasality in patients with SMCP.

Effect of Buccinator Mucomuscular Flaps on Speech in Cleft Palate Patients. Ms Arwa Meki and members of the cleft team at Addenbrookes Hospital, Cambridge

Aim - To investigate the efficacy of unilateral and bilateral buccinator mucomuscular flaps in secondary surgery for speech in patients with cleft palate.

Method - 49 patients were assessed pre- and post- operatively on a range of speech parameters using GOSSPASS assessments.

Results- The complex relationship between these speech characteristics and cleft-type consonant production was also considered.

Conclusion - Use of buccinator flaps in secondary surgery results in a considerable improvement in several speech characteristics. The techniques and rationale for use of buccinator flaps will be outlined and a preliminary algorithm for the use of these flaps is presented. The speech characteristics most frequently affected by surgery were identified; this study provides an opportunity to consider the possibility of weighting specific characteristics in reporting speech outcomes.

Pre and perioperative Dexamethasone improves postoperative recovery following cleft palate surgery. Matthew Potter, Specialist Registrar in Plastic Surgery, Radcliffe Hospital Oxford

Aims - To investigate the hypothesis that peri and postoperative steroid use in cleft palate surgery does not influence recovery.

Design - Perioperative and postoperative Dexamethasone was administered to paediatric patients (n=100) undergoing routine posterior palate surgery by a single surgeon. Patients were evaluated post operatively against an aged and case matched control group for a change in:

Heart rate

Respiratory rate

Temperature    

Analgesia

Pain score

Respiratory effort

Sedation

Time to feed

Nausea

Data sets were compared using one way analysis of variance tests.

Participants ranged from 3 months to 16 years, were of equal sex distribution and underwent surgery between 2003-2007.

Results - Less pain (P= 0.003, Dunn’s), a lower sedation score (P= 0.026, Dunn’s) and less nausea and vomiting (P= 0.012, Dunn’s) was found in the active group. This effect was lost at 24 hours. Respiratory rate was less at day 3 in the steroid group (P=0.042, Dunn’s). Other observed changes were statistically insignificant.

Conclusion - This study has demonstrated beneficial effects of preoperative steroid use and its postoperative continuation in cleft palate surgery. Whilst this small single operator study has given promising and significant results it gives the evidence base foundation and structure for a future, larger multicentre randomised controlled trial. 

The effect of presurgical orthopaedics on archform in unilateral cleft lip and palate. N.Adali, and M.Mars, A. Petrie, J.Noar, B. Sommerlad

Objectives of Investigation - To identify archform dimensional change in unilateral clip lip and palate infants treated with pre-surgical orthopaedics compared with those not receiving PSO, up to age 6 months.

Subjects and Methods - The study included 75 study model sets of patients with complete UCLP patients (PSO=14, non PSO=61), treated by one surgeon and orthodontist. Each set comprised of study models taken close to birth, before lip repair / vomer flap (3 months), before palate repair (6 months). Suction-retained active PSO was used.

Thirteen landmarks were measured three-dimensionally using Reflex Microscope and COMP3D software. Sixteen variables were computed to describe the archform in transverse, anteroposterior, vertical dimensions, and arch circumference. The groups were comparable at birth in all variables.

Intraoperator repeatability tests and Repeated Measures Hierarchical ANOVA (significance level p,0.01) were performed.

Results - Repeatability tests showed good measurement precision. There were no statistically significant mean changes in any archform variable between the groups. The power of the study was 93%.

Conclusions - PSO treatment produced no effect on archform. Lip repair had a greater impact on archform than PSO.

Potential Applications of the Study - The use of PSO has now been discontinued in the cleft unit. Psychosocial benefits should also be studied.

Intra Operative Blood Loss – Anaesthetic Type and Adrenaline Concentration. Patrick Gillespie, Specialist Registrar in Plastic Surgery, Addenbrookes Hospital, Cambridge

A prospective study of intraoperative blood loss for all Cleft procedures was undertaken from January 2003 to May 2005 for 2 surgeons and their respective anaesthetists. Local anesthetic infiltration with chirocaine (0.25% or 0.5%) was performed in all cases with the concentration of adrenaline being determined by the anaesthetic type - a maximum strength of 1/200,000 being used in Gaseous Anaesthesia (GA) whereas the stronger 1/100,000 was allowed when a Total Intravenous Anaesthetic technique (TIVA) was used. In all cases a minimum wait of 7 minutes from injection to incision was enforced. We wanted to determine if this made a difference to blood loss.

235 useable datasets were analysed and results fell into the following grid.

The results suggest a trend towards almost double the bleeding volume when the weaker concentration of adrenaline is used. This seems independent of surgeon or surgical procedure undertaken.

The study continues to enable detailed statistical analysis with larger numbers.

Dimensional Stereophotogrammetry. Mark Devlin, Cleft Surgery Fellow, South Thames Cleft Unit, Guy's Hospital.

Aim - To assess 3 Dimensional (3D) facial symmetry in repaired UCLP patients with residual nasal deformity before and after bone grafting to the deficient alar base on the cleft side

Method - A method of 3-dimensional (3D), quantitative assessment of facial symmetry in patients with treated UCLP deformity is described. The outcome of bone grafting using a cortico-cancellous block of iliac crest to reconstruct the support for the deformed, volume-deficient alar base is assessed using 3D stereophotogrammetry is assessed with specific reference to facial symmetry scoring. Sixteen patients are included in the study. The facial symmetry score using landmark data is assessed pre- and post-operatively.

Results - The reconstruction results in statistically significant improvement in facial symmetry postoperatively as assessed by this method.

Effects of the Fgfr2 Crouzon-type Mutation on Palatal Shelf Development. Chad Perlyn, Dept of Human Anatomy & Genetics, University of Oxford

Introduction: The purpose of this project is to investigate the mechanisms through which the Crouzon mutation causes palatal abnormality. The project exploits a mouse model that has the Crouzon-type mutations Fgfr2Cys342Tyr.

Methods: Approaches used were: (1) comparative morphology; (2) cell proliferation analysis; (3) in situ hybridisation. Histological techniques were used for evaluating palatal sections. Cell proliferation analysis was performed using 5'Bromodeoxyuridine (BrdU). Nuclei that took up BrdU (indicating that they were synthesising DNA) were detected using an anti-BrdU antibody technique. Changes in gene expression are being analyzed by in situ hybridization, using molecular probes for markers of bone differentiation and FGFR signalling.

Results: Results from embryonic day (E)13.5-15.5 show significant morphologic differences in palatal development in wild-type mice as compared with heterozygote and homozygote mutants. There appears to be a pattern of development delay by one embryonic day in the heterozygotes and two days in the homozygotes as evidenced by orientation of palatal shelves and degree of shelf fusion. Result of cell proliferation studies for the embryonic day 12.5 (the time at which palatal shelf outgrowth begins) show a significantly higher number of proliferating cells in the homozygote and heterozygote shelves as compared to the wild-types. The effects of this are seen in a decrease in hyaluronic acid in the mutant shelves on the following day. This may lead to decreased osmosis within the extracellular matrix and diminished shelf elevation. Gene expression studies, using in-situ hybridizatio, show abnormal expression of FGFR1 and FGFR2 in the palatal shelves, which correlates to the above findings.

Conclusion: The Fgfr2Cys342Tyr mutation leads to developmental delay of palatal shelf elevation and fusion. FGFR2 remains expressed in the mutant shelves, possibly delaying the switch from cell proliferation to cell differentiation. As such, the necessary factors for palatal development are not present at the appropriate embryonic stage. Further work will be performed to examine this in more detail.

Assessment of Early Dental and Facial Deformity in Repaired Unilateral Cleft Lip and Palate. Dr A Garrahy, Glasgow Dental Hospital

Objective - To assess the relationship between deformity of soft tissue facial morphology and of the dental arches in children with repaired UCLP. Deformity is defined as deviation from normal.

Methods - 16 healthy Caucasian children aged 3 years with repaired UCLP and 78 matched control children were recruited. A set of images of each child's face at rest was recorded within 6 weeks of his or her third birthday using computerised stereophotogrammetry and dental impressions were recorded. Analysis of facial and dental interlandmark distances was performed. The correlation between two features of the dental arch and one feature of soft tissue facial morphology with greatest deviation from normal was analysed.

Results - The correlation coefficient for nasal base width and maxillary arch cleft-affected quadrant length was 0.4 (p value 0.14) in children with repaired UCLP. The correlation coefficient for nasal base and maxillary arch intercanine widths was 0.28 (p value 0.32).

Conclusion - The cleft-related deformities of soft tissue morphology and bone based dental arches are not directly related to each other.Suggested application - Further radiation-free exploration of facial, appearance and dental arch development in combination.