Histological analysis of the medial gastrocnemius muscle in young healthy children.

Introduction: Histological data on muscle fiber size and proportion in (very) young typically developing (TD) children is not well documented and data on capillarization and satellite cell content are also lacking. Aims: This study investigated the microscopic properties of the medial gastrocnemius muscle in growing TD children, grouped according to age and gender to provide normal reference values in healthy children. Methods: Microbiopsies of the medial gastrocnemius (MG) muscle were collected in 46 TD boys and girls aged 2-10 years subdivided into 4 age groups (2-4, 4-6, 6-8 and 8-10 years). Sections were immunostained to assess fiber type cross-sectional area (fCSA) and proportion, the number of satellite cells (SC), capillary to fiber ratio (C/F), capillary density for type I and II fiber (CFD), capillary domain, capillary-to-fiber perimeter exchange index (CFPE) and heterogeneity index. fCSA was normalized to fibula length2 and the coefficient of variation (CV) was calculated to reflect fCSA intrasubject variability. Results: Absolute fCSA of all fibers increased with age (r = 0.72, p < 0.001) but more in boys (+112%, p < 0.05) than in girls (+48%, p > 0.05) Normalized fCSA, CV and fiber proportion did not differ between age groups and gender. C/F was strongly correlated with age in boys (r = 0.83, p < 0.001), and to a lesser extent in girls (r = 0.37, p = 0.115), while other capillary parameters as well as the number of SC remained stable with increasing age in boys and girls. Discussion: This study provides reference values of histological measures in MG according to age in normally growing boys and girls. These data may be used as a reference to determine disease impact and efficacy of therapeutic approach on the muscle.

Relation between Maximum Oral Muscle Pressure and Dentoalveolar Characteristics in Patients with Cleft Lip and/or Palate: A Prospective Comparative Study.

BACKGROUND: Perioral muscle function, which influences maxillofacial growth and tooth position, can be affected in patients with oral clefts due to their inherent anatomical characteristics and the multiple surgical corrections performed. This research aims to (1) compare the maximum oral muscle pressure of subjects with and without isolated cleft palate (CP) or unilateral cleft lip and palate (UCLP), (2) investigate its influence on their dentoalveolar characteristics, and (3) investigate the influence of functional habits on the maximum oral muscle pressure in patients with and without cleft. MATERIAL AND METHODS: Subjects with and without CP and UCLP seeking treatment at the Department of Orthodontics of University Hospitals Leuven between January 2021 and August 2022 were invited to participate. The Iowa Oral Performance Instrument (IOPI) was used to measure their maximum tongue, lip, and cheek pressure. An imbalance score was calculated to express the relationship between tongue and lip pressure. Upper and lower intercanine (ICD) and intermolar distance (IMD) were measured on 3D digital dental casts, and the presence of functional habits was reported by the patients. The data were analyzed with multivariable linear models, correcting for age and gender. RESULTS: 44 subjects with CP or UCLP (mean age: 12.00 years) and 104 non-affected patients (mean age: 11.13 years) were included. No significant differences in maximum oral muscle pressure or imbalance score were detected between controls and clefts or between cleft types. Significantly smaller upper ICDs and larger upper and lower IMDs were found in patients with clefts. A significant difference between controls and clefts was found in the relationship between oral muscle pressure and transversal jaw width. In cleft patients, the higher the maximum tongue pressure, the wider the upper and lower IMD, the higher the lip pressure, the smaller the upper and lower ICD and IMD, and the higher the imbalance score, the larger the upper and lower IMD and lower ICD. An imbalance favoring the tongue was found in cleft patients. The influence of functional habits on the maximum oral muscle pressure was not statistically different between clefts and controls. CONCLUSION: Patients with CP or UCLP did not present reduced maximum oral muscle pressure compared with patients without a cleft. In cleft patients, tongue pressure was consistently greater than lip pressure, and those who presented a larger maxillary width presented systematically higher imbalance scores (favoring the tongue) than those with narrow maxillae. Therefore, the influence of slow maxillary expansion on maximum oral muscle pressure in cleft patients should not be underestimated.

A protocol for a randomized-controlled trial to investigate the effect of infant sign training on the speech-language development in young children born with cleft palate.

BACKGROUND: Children born with a cleft palate with or without cleft lip (CP ± L) are known to be at risk for speech-language disorders that impact educational and social-emotional growth. It is hypothesized that speech-language intervention delivered before the age of 3 years could decrease the impact of CP ± L on speech-language development. Infant sign training in combination with verbal input expands the natural communication of young children including multimodal speech-language input (i.e., verbal and manual input) via caregivers who act as co-therapists. AIMS: To determine the effectiveness of infant sign training in 1-year-old children with CP ± L by comparing different interventions. METHODS & PROCEDURES: This is a two-centre, randomized, parallel-group, longitudinal, controlled trial. Children are randomized to either an infant sign training group (IST group), a verbal training group (VT group) or no intervention control group (C group). Caregivers of children who are assigned to the IST group or VT group will participate in three caregiver training meetings to practise knowledge and skills to stimulate speech-language development. Outcome measures include a combination of questionnaires, language tests and observational analyses of communicative acts. OUTCOMES & RESULTS: It is hypothesized that speech-language development of children with CP ± L will benefit more from IST compared with VT and no intervention. Additionally, the number and quality of communicative acts of both children and caregivers are expected to be higher after IST. CONCLUSIONS & IMPLICATIONS: This project will contribute to the development of evidence-based clinical practice guidelines regarding early speech-language intervention in children with CP ± L under the age of 3 years. WHAT THIS PAPER ADDS: What is already known on the subject Children with CP ± L are known to be at risk for speech-language delays that impact educational and social emotional growth. Given the limited scientific prove of the impact of early speech-language intervention, no standardized clinical practice guidelines are available yet for children with CP ± L under the age of 3 years. Early intervention in this population mostly focuses on improving verbal input via caregivers or professionals without including a multimodal language input. A growing scientific interest has been seen in the use of infant signs to support speech-language development and caregiver-child interaction in typically developing children and children with developmental delays. What this study adds to existing knowledge No evidence is yet available for the effectiveness and feasibility of early intervention based on infant sign training in combination with verbal input to improve speech-language skills in young children with CP ± L. The current project will investigate the effect of infant sign training on the speech-language development in this population. Outcome measures are compared with those of two control groups: verbal training only and no intervention. It is hypothesized that infant signs may support the intelligibility of verbal utterances produced by children with CP ± L. Improving children's intelligibility may increase the opportunities for these children to engage in early, frequent and high-quality interactions with their caregivers resulting in a richer social and linguistic environment. As a result, infant sign training may result in better speech-language skills compared with the control interventions. What are the potential or actual clinical implications of this work? If providing early intervention based on infant sign training is effective, there is the potential for improved speech-language outcomes in early childhood, resulting in increased speech intelligibility, increased well-being of the child and family and less need for speech-language therapy on the long-term. This project will contribute to the development of evidence-based clinical practice guidelines regarding early speech-language intervention in children with CP ± L under the age of 3 years.

Achieving the next level in cleft speech intervention: A protocol of a randomized sham-controlled trial to provide guidelines for a personalized approach in children with cleft palate.

BACKGROUND: Compensatory cleft speech disorders can severely impact speech understandability and speech acceptability. Speech intervention is necessary to eliminate these disorders. There is, however, currently no consensus on the most effective speech therapy approach to eliminate the different subtypes of compensatory cleft speech disorders. AIMS: To compare the immediate, short- and long-term effects of three well-defined speech intervention approaches (i.e., a motor-phonetic approach, a linguistic-phonological approach and a combined phonetic-phonological approach) on the speech and health-related quality of life (HRQoL) in Belgian Dutch-speaking children with cleft palate with or without cleft lip (CP±L) and different subtypes of compensatory speech disorders (i.e., anterior oral cleft speech characteristics (CSCs), posterior oral CSCs or non-oral CSCs). Besides, the perceived acceptability of these three speech intervention approaches will be investigated from the perspectives of caregivers and children with a CP±L. METHODS & PROCEDURES: A two-centre longitudinal randomized sham-controlled trial was used. Children were randomly assigned to one of the three intervention programmes and received 10 h of speech intervention divided over 2 weeks. Block randomization was used, stratified by age and gender. Primary outcome measures included perceptual speech outcomes. Secondary outcome measures included patient-reported outcomes. OUTCOMES & RESULTS: The results of this trial will provide speech-language pathologists evidence-based guidelines to better tailor intervention approaches to the specific needs of a child with a defined compensatory speech disorder. WHAT THIS PAPER ADDS: What is already known on this subject Speech therapy approaches to address cleft palate speech disorders are broadly divided into two categories: motor-phonetic interventions and linguistic-phonological interventions. Some limited evidence demonstrated the positive effects of these approaches in eliminating compensatory cleft speech disorders. Different studies have reported inter-individual variation, suggesting that one child may benefit more from a particular intervention approach than the other child. Perhaps this variation can be attributed to the specific subtype of compensatory speech disorder (i.e., anterior oral CSC, posterior oral CSC or non-oral CSC). What this paper adds to existing knowledge This paper describes a randomized sham-controlled trial that compared the immediate, short- and long-term effects of three well-defined speech intervention approaches (i.e., a motor-phonetic approach, a linguistic-phonological approach and a combined phonetic-phonological approach) on the speech and HRQoL in Belgian Dutch-speaking children with CP±L and different subtypes of compensatory cleft speech disorders (i.e., anterior oral CSCs, posterior oral CSCs or non-oral CSCs) measured by perceptual and psychosocial outcome measures. Besides, the experienced acceptability of these three speech intervention approaches were investigated from the perspectives of caregivers and children. What are the potential or actual clinical implications of this work? This project provides evidence-based knowledge on patient-tailored cleft speech intervention considering both scientific evidence and the perspectives of caregivers and children. The results aid SLPs in better tailoring intervention approaches to the needs of a child with a specific type of compensatory cleft speech disorder.

How acceptable is the use of linguistic-phonological intervention in children with cleft palate? A qualitative study in speech therapists.

BACKGROUND & AIMS: Even though evidence for the use of linguistic-phonological intervention approaches in children with a cleft (lip and) palate (CP±L) is still limited, these approaches are being used by speech-language pathologists (SLPs) to treat active or compensatory cleft speech disorders in clinical practice. It is, however, unknown to what extent linguistic-phonological intervention is acceptable to SLPs. The aim of this study is to investigate the retrospective acceptability of linguistic-phonological intervention in children with a CP±L from the perspective of SLPs using the theoretical framework of acceptability (TFA). METHODS & PROCEDURES: A total of 18 female community SLPs, aged between 23 and 63 years, were included in the study. An independent interviewer conducted semi-structured interviews. Data were analysed using a deductive coding approach. Statements of the SLPs were related to the seven constructs of the TFA: affective attitude, burden, ethicality, intervention coherence, opportunity costs, perceived effectiveness and self-efficacy. OUTCOMES & RESULTS: The affective attitude and perceived effectiveness of linguistic-phonological intervention differed among the SLPs: some therapists had positive attitudes towards these approaches, while others did not. Positive attitudes were related to the successful use of linguistic-phonological intervention in the past. The construct 'ethicality' revealed that negative attitudes towards these approaches were attributed to the limited available scientific evidence or negative experiences while using these approaches. In contrast, SLPs who had positive attitudes considered these interventions as 'important' and 'valuable'. Some SLPs had negative reflections on linguistic-phonological intervention as these approaches were considered demanding in terms of time needed to gain knowledge on using them in children with a CP±L (constructs 'burden' and 'opportunity costs'). Additionally, some SLPs doubted their self-efficacy to use these approaches in clinical practice. CONCLUSIONS & IMPLICATIONS: The acceptability of linguistic-phonological intervention differed between the SLPs in this sample and was most likely related to their previous experiences with these linguistic-phonological approaches. It is important to increase not only the amount of scientific evidence for linguistic-phonological approaches but also the supply of evidence-based workshops and training courses on this topic. These initiatives should distribute scientific information that is translated into guidelines that are immediately applicable in clinical practice. This may potentially reduce the time-related burden that some SLPs currently experience to gain expertise in this matter. In future research, it is necessary to investigate if there exist differences in acceptability between the different types of linguistic-phonological therapy. WHAT THIS PAPER ADDS: What is already known on this subject Linguistic-phonological speech intervention approaches are often used by SLPs to treat active or compensatory cleft speech disorders in clinical practice. What this paper adds to existing knowledge This study investigated whether linguistic-phonological intervention cleft speech intervention is acceptable to SLPs. Some therapists had positive attitudes towards these approaches, while others did not. Positive attitudes were related to the successful use of these approaches in the past. If SLPs indicated having negative attitudes, these negative feelings were attributed to the limited available scientific evidence or negative experiences while using these approaches. What are the potential or actual clinical implications of this work Even though linguistic-phonological speech intervention approaches are being used in clinical practice, these approaches are not always considered acceptable by SLPs. Acceptability could be enhanced by increasing the amount of scientific evidence for linguistic-phonological approaches, but also by increasing the supply of workshops and training courses on this topic. These initiatives should distribute hands-on information that is immediately applicable in clinical practice. This may potentially reduce the time-related burden that some SLPs currently experience to gain expertise in this matter.

Doxycycline Sclerotherapy of Head and Neck Lymphatic Malformations: Intermediate Report of 27 Cases.

OBJECTIVE: To evaluate the safety and efficacy of percutaneous doxycycline sclerotherapy of head and neck lymphatic malformations (LM) with a 40-month follow-up of 27 cases. MATERIALS AND METHODS: Twenty-seven consecutive patients with head and neck LM who underwent doxycycline sclerotherapy from 2010 to 2019 were retrospectively reviewed. Pre- and peri-interventional data collection included patients' demographics, clinical and radiological presentation, number of treatment procedures, amount of doxycycline used for each session of sclerotherapy. Postinterventional clinical outcome data were assessed based on the electronic, medical reports with special attention to clinical improvement, measurement of the lesion on ultrasound and magnetic resonance imaging after the last session of sclerotherapy and complications of sclerotherapy. RESULTS: Twenty-seven patients underwent a mean of four doxycycline sclerotherapy sessions (range 1-23). The mean total dose of injected doxycycline per session was 170 mg. Maximal diameter of the LM decreased from mean 59.7 mm (median 58 mm; 25-130 mm) before treatment to mean of 29.6 mm (median 30 mm; 0 mm 64 mm) after the last session (P < 0.0001). Over a mean follow-up period of 40 months, complete or incomplete disappearance of symptoms was found in 23 (85%) and 3 (11%) of patients, respectively. In one patient, sclerotherapy did not result in better clinical outcome. Two out of 27 patients presented with minor post-procedural complications, and one patient with a post-procedural intralesional bleeding considered as a major complication. CONCLUSION: Ultrasound-guided, percutaneous doxycycline sclerotherapy is a safe and effective method of managing symptomatic LM of the head and neck.

Otomicroscopic and functional outcomes after cleft palate repair via Sommerlad intravelar veloplasty vs. modified Veau-Wardill-Kilner push-back.

OBJECTIVE: We aim to compare the modified Veau-Wardill-Kilner push-back technique (VWK) and the Sommerlad intravelar veloplasty (Sommerlad IVVP) in terms of middle ear outcomes and oronasal fistulae frequency in three years old children. METHODS: For this retrospective cohort study, data were collected and anonymized from consecutive patients with cleft palate (with or without cleft lip) who underwent surgery in our hospital between January 2008 and December 2018. Patients with syndromic diagnoses and patients who underwent surgical treatment elsewhere were excluded. We collected data from 101 children (202 ears) regarding middle ear complications at the age of three, including acute otitis media, middle ear effusion, tympanic membrane retraction, tympanic membrane perforation, tympanic membrane atelectasis and chronic otitis media with cholesteatoma. In addition, the presence of oronasal fistulae and the number of ventilation tubes received by the age of three were recorded. RESULTS: The odds of children having a normal middle ear evaluation were 3.07 (95% Confidence interval (95%CI): [1.52, 6.12]; p < 0.05) times higher when children received Sommerlad IVVP compared to modified VWK. With 40.7% compared to 26.7%, a significantly higher incidence of middle ear effusion was present in the modified VWK group compared to Sommerlad IVVP (X2(1) = 4.38, p < 0.05). Furthermore, this group needed significantly more ventilation tube reinsertions (X2(2) = 12.22, p < 0.05) and was found to have a significantly higher incidence of oronasal fistula (53.5% vs. 17.2%, X2(1) = 14.75, p < 0.05). The latter was significantly associated with a higher need for ventilation tube reinsertion (X2(1) = 7.34, p < 0.05). CONCLUSION: This study shows superior middle ear outcomes and fewer oronasal fistulae after Sommerlad IVVP compared to modified Veau-Wardill-Kilner push-back at the age of three.

Long-term follow-up of the inside-out technique for treatment of preauricular sinuses: observational study.

PURPOSE: This long-term follow-up study aims to externally validate the inside-out technique for surgical treatment of preauricular sinuses. METHODS: We analyzed the medical records of all patients who underwent the IO procedure at University Hospitals Leuven from 1 November 2005 to 30 November 2019 (N = 110). We were able to contact 77 of these 110 patients for a telephone interview, where we used a standardized questionnaire to evaluate recurrence, patient satisfaction and aesthetic result. RESULTS: We studied 110 patients (68 males, 77 females), resulting in 145 PAS (35 left, 40 right, 35 bilateral), with a median follow-up of 53 months. Fifteen PAS (10.3%) developed an early (< 4 weeks) postoperative complication (wound dehiscence, infection, abcedation, swelling). Two PAS (2 different patients) needed revision surgery because of recurrence, one after 15 months, the other after 4 years. The 5-year Kaplan-Meier recurrence-free percentage was 97.7%, equating to an estimated recurrence rate of 2.3%. Ninety-four percent was satisfied with the aesthetic result, giving 4 or 5 points on a 5-point Likert scale. CONCLUSIONS: This study was able to externally validate the IO technique for the treatment of PAS. The IO technique should be first choice, since it guarantees low recurrence rates, excellent aesthetic results, and good patient satisfaction.

One Size Doesn't Fit All: A Pilot Study Toward Performance-Specific Speech Intervention in Children With a Cleft (Lip and) Palate.

PURPOSE: Speech-language pathologists usually apply a "one size fits all" approach to eliminate compensatory cleft speech characteristics (CSCs). It is necessary to investigate what intervention works best for a particular patient. This pilot study compared the effectiveness of two therapy approaches (a motor-phonetic approach and a linguistic-phonological approach) on different subtypes of compensatory CSCs in Dutch-speaking children with a cleft (lip and) palate (CP ± L). METHOD: Fourteen children with a CP ± L (M age = 7.71 years) were divided into two groups using block randomization stratified by age, gender, and type of compensatory CSC. Six children received intervention to eliminate anterior oral CSCs (n = 3 motor-phonetic intervention, n = 3 linguistic-phonological intervention). Eight children received intervention to eliminate non-oral CSCs (n = 4 motor-phonetic intervention, n = 4 linguistic-phonological intervention). Each child received 10 hr of speech intervention divided over 2 weeks. Perceptual and psychosocial outcome measures were used to determine intervention effects. RESULTS: Children who received linguistic-phonological intervention to eliminate anterior oral CSCs had significantly higher correctly produced consonant scores and health-related quality of life (HRQoL) scores compared to children who received motor-phonetic intervention to eliminate anterior oral CSCs. In the group of children who received intervention to eliminate non-oral CSCs, no significant differences were found in the correctly produced consonant scores nor in the HRQoL scores between the two intervention approaches. CONCLUSIONS: Linguistic-phonological intervention seems to be more appropriate to eliminate anterior oral CSCs. The beneficial effects of linguistic-phonological intervention were less pronounced in children with non-oral CSCs. Perhaps, children with non-oral CSCs benefit more from a hybrid phonetic-phonological approach. This study is a step forward in the provision of performance-specific intervention in children with a CP ± L. Replication in larger samples is needed and will aid to tailor treatment plans to the needs of our patients.

Fourth Branchial Anomalies: Diagnosis, Treatment, and Long-Term Outcome.

Introduction: Fourth branchial anomalies, the rarest among anomalies of the branchial apparatus, often present diagnostic and therapeutic challenges. We evaluated the clinical presentation and radiographic features, the treatment and the long-term outcome of patients in this setting. Patients and Methods: Of 12 patients treated in the University Hospitals Leuven from 2004 until 2020, 12 variables were collected: date of birth, gender, age of onset of the symptoms, age at final diagnosis, presentation, laterality, previous procedures, diagnostic tools, treatment (open neck surgery, endoscopic laser excision, or combination), complications, recurrence, and period of follow-up. Descriptive statistics were calculated and results were compared to the existing literature. Results: The most common clinical manifestations were recurrent neck infections with and without abcedation. Definitive diagnosis using direct laryngoscopy, visualizing the internal sinus opening, was possible in all patients. A CT study revealed the typical features of fourth branchial anomalies in seven patients out of nine, an ultrasound study in five out of nine patients. All patients underwent open neck surgery. If this was insufficient, secondary endoscopic laser resection of the ostium at the apex of the piriform sinus was performed (n = 4). In eight patients a thyroid lobectomy was needed for safe complete resection. Postoperative complications were minimal and at long-term, none of the patients showed further recurrence. Average time of follow-up was 8.6 years. Conclusions: Direct laryngoscopy and CT are the most accurate diagnostic tools. Our recommended treatment schedule consists of complete excision of the sinus tract by open neck surgery as the primary treatment because this ensures the best results. In case of recurrence afterwards, endoscopic laser resection of the pharyngeal ostium solved the problem.

3D facial phenotyping by biometric sibling matching used in contemporary genomic methodologies.

The analysis of contemporary genomic data typically operates on one-dimensional phenotypic measurements (e.g. standing height). Here we report on a data-driven, family-informed strategy to facial phenotyping that searches for biologically relevant traits and reduces multivariate 3D facial shape variability into amendable univariate measurements, while preserving its structurally complex nature. We performed a biometric identification of siblings in a sample of 424 children, defining 1,048 sib-shared facial traits. Subsequent quantification and analyses in an independent European cohort (n = 8,246) demonstrated significant heritability for a subset of traits (0.17-0.53) and highlighted 218 genome-wide significant loci (38 also study-wide) associated with facial variation shared by siblings. These loci showed preferential enrichment for active chromatin marks in cranial neural crest cells and embryonic craniofacial tissues and several regions harbor putative craniofacial genes, thereby enhancing our knowledge on the genetic architecture of normal-range facial variation.

The Intersection of the Genetic Architectures of Orofacial Clefts and Normal Facial Variation.

Unaffected relatives of individuals with non-syndromic cleft lip with or without cleft palate (NSCL/P) show distinctive facial features. The presence of this facial endophenotype is potentially an expression of underlying genetic susceptibility to NSCL/P in the larger unselected population. To explore this hypothesis, we first partitioned the face into 63 partially overlapping regions representing global-to-local facial morphology and then defined endophenotypic traits by contrasting the 3D facial images from 264 unaffected parents of individuals with NSCL/P versus 3,171 controls. We observed distinct facial features between parents and controls across 59 global-to-local facial segments at nominal significance (p ≤ 0.05) and 52 segments at Bonferroni corrected significance (p < 1.2 × 10-3), respectively. Next, we quantified these distinct facial features as univariate traits in another dataset of 8,246 unaffected European individuals and performed a genome-wide association study. We identified 29 independent genetic loci that were associated (p < 5 × 10-8) with at least one of the tested endophenotypic traits, and nine genetic loci also passed the study-wide threshold (p < 8.47 × 10-10). Of the 29 loci, 22 were in proximity of loci previously associated with normal facial variation, 18 were near genes that show strong evidence in orofacial clefting (OFC), and another 10 showed some evidence in OFC. Additionally, polygenic risk scores for NSCL/P showed associations with the endophenotypic traits. This study thus supports the hypothesis of a shared genetic architecture of normal facial development and OFC.

Insights into the genetic architecture of the human face.

The human face is complex and multipartite, and characterization of its genetic architecture remains challenging. Using a multivariate genome-wide association study meta-analysis of 8,246 European individuals, we identified 203 genome-wide-significant signals (120 also study-wide significant) associated with normal-range facial variation. Follow-up analyses indicate that the regions surrounding these signals are enriched for enhancer activity in cranial neural crest cells and craniofacial tissues, several regions harbor multiple signals with associations to different facial phenotypes, and there is evidence for potential coordinated actions of variants. In summary, our analyses provide insights into the understanding of how complex morphological traits are shaped by both individual and coordinated genetic actions.

Pregnancy Termination in the Case of an Orofacial Cleft: An Investigation of the Concept of Reproductive Autonomy.

OBJECTIVE: To describe ethical approaches to the issue of pregnancy termination after prenatal detection of cleft lip ± palate. RESULTS: Gynecologists and cleft surgeons are sometimes confronted with the demand for a pregnancy termination after ultrasound detection of an isolated cleft lip/cleft palate. In this article, we discuss different ethical theories and principles that can be applied to the dilemma at hand. We formulate recommendations that will respect the right to autonomy of the pregnant woman and at the same time acknowledge that a termination of pregnancy for a cleft lip may in most cases not be the best option. CONCLUSION: The recognition of each person's right to reproductive autonomy also entails that clinicians should make sure that prospective parents are provided with up-to-date and relevant clinical information.

Morphing as a Selection Tool in the Rhinoplasty Consult: A Cross-Sectional Study.

Despite the recognized value of morphing in the literature, this preoperative tool has never been studied in the context of selection process in rhinoplasty. The main purpose of this article is to identify the use of morphing as a filter for unsuitable patients, the attrition rate from the initial consultation to surgery, and whether patients' appreciation on morphing influence their decision-making process. Three-hundred thirty-four consecutive patients, seeking rhinoplasty, underwent two-dimensional computer imaging and completed a 14-question survey about their opinion on morphing. Based on the presence or absence of patient/physician consensus on the expected outcomes during simulation, patients were divided into accepted or rejected candidates for surgery. Accepted candidates were scheduled for rhinoplasty and subdivided into those who underwent surgery, those who postponed their surgery (static), and those who cancelled their procedure. Their responses to the survey were compared between different patients' categories. Forty-four patients (13.2%) were rejected for rhinoplasty since consensus was not achieved during morphing. From 290 accepted patients, 178 underwent their operation (53.3%), 74 patients (22.1%) postponed their rhinoplasty, and 38 (11.4%) cancelled their surgery. Fifty-seven percent of rejected patients and 42% of the static group were not satisfied with the proposed results of morphing, in contrast with 16% of the operated group. Sixty-four percent of rejected patients, and 47% of the static group were not reassured after morphing, compared with 26% of the operated group. Presence or absence of consensus during morphing can guide the surgeon regarding a given patients' suitability for surgery. Patient satisfaction and reassurance with the morphed images can be a good predictor of patients who will proceed to surgery, calling attention to the value of morphing as a selection tool for surgeons and patients alike.

Non-Syndromic Cleft Lip with or without Cleft Palate: Genome-Wide Association Study in Europeans Identifies a Suggestive Risk Locus at 16p12.1 and Supports SH3PXD2A as a Clefting Susceptibility Gene.

Non-syndromic cleft lip with or without cleft palate (nsCL/P) ranks among the most common human congenital malformations, and has a multifactorial background in which both exogenous and genetic risk factors act in concert. The present report describes a genome-wide association study (GWAS) involving a total of 285 nsCL/P patients and 1212 controls from the Netherlands and Belgium. Twenty of the 40 previously reported nsC/LP susceptibility loci were replicated, which underlined the validity of this sample. SNV-based analysis of the data identified an as yet unreported suggestive locus at chromosome 16p12.1 (p-value of the lead SNV: 4.17 × 10-7). This association was replicated in two of three patient/control replication series (Central European and Yemeni). Gene analysis of the GWAS data prioritized SH3PXD2A at chromosome 10q24.33 as a candidate gene for nsCL/P. To date, support for this gene as a cleft gene has been restricted to data from zebrafish and a knockout mouse model. The present GWAS was the first to implicate SH3PXD2A in non-syndromic cleft formation in humans. In summary, although performed in a relatively small sample, the present GWAS generated novel insights into nsCL/P etiology.

Long-term outcome of pre- and perinatal management of congenital head and neck tumors and malformations.

INTRODUCTION: Congenital head and neck pathology may cause direct postnatal airway obstruction. Prenatal diagnosis facilitates safe delivery with pre- and perinatal airway assessment and management and Ex-Utero-Intrapartum-Treatment (EXIT) if necessary. Fetoscopic airway evaluation can optimize the selection of patients in need of an EXIT procedure. METHODS: Description of 11 consecutive fetuses, born with a potential airway obstruction between 1999 and 2011 and treated at the University Hospitals Leuven, with a long-term follow-up until 2018. An algorithm including fetoscopic airway evaluation is presented. RESULTS: In utero imaging revealed seven teratomas, one fourth branchial pouch cyst, one thymopharyngeal duct remnant, one lymphatic malformation and one laryngeal atresia. A multidisciplinary team could avoid EXIT in eight patients by ultrasonographic (n = 2) or fetoscopic (n = 6) documentation of accessible airways. Three patients needed an EXIT-to-airway-procedure. Neonatal surgery included tracheostomy during EXIT (n = 2) and resection of teratoma (n = 7) or branchiogenic pathology (n = 3). All patients do well at long-term (minimum 54 months) follow-up. CONCLUSIONS: Combining prenatal imaging and perinatal fetoscopy, EXIT-procedure and neonatal surgery yields an optimal long-term outcome in these complex patients. Fetoscopy can dramatically reduce the number of EXIT-procedures.

Three-dimensional Morphing and Its Added Value in the Rhinoplasty Consult.

BACKGROUND: The evolving literature on 3D surface imaging demonstrates that this technology is becoming the preferred simulation technique in hospitals and research centers. However, no study has demonstrated before the superiority of this facility over standard 2D simulation during preoperative evaluation in rhinoplasty. METHODS: One hundred seventy-two consecutive patients requesting rhinoplasty were included. Patients answered a questionnaire following a 2D simulation and subsequently experienced 3D morphing. A single question was answered regarding the added value of the latter by patients and surgeons, respectively. RESULTS: In our survey, satisfaction with 2D morphing reached 61%. Ninety-five percentage of the same group considered 3D simulation an added value over 2D. Additionally, 84% of patients requesting revision rhinoplasty admitted that 3D computer simulation has helped them understand the aims of surgery, in contrast to 61% of patients from the primary group. Furthermore, patients unsatisfied with their 2D simulation got reassured following 3D simulation to undergo surgery at a higher percentage (67%), compared with the group initially satisfied with 2D (48%). Women appeared reassured by 3D imaging in higher percentage (63%) compared with men (42%). The 2 surgeons, however, found 3D simulations to be an added value in 66% and 74% of all patients. CONCLUSIONS: The overwhelming majority of our patients considered 3D simulation an added value over 2D. Patients initially unsatisfied with 2D morphing, revision rhinoplasty patients, and women seemed to be the groups that appreciated more 3D than 2D computer simulation. In contrast, surgeons considered the facility of 3D an added value in two-thirds of the patients.

Deletions and loss-of-function variants in TP63 associated with orofacial clefting.

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.

Vestibular dysfunction is a manifestation of 22q11.2 deletion syndrome.

The 22q11.2 deletion syndrome (22q11.2DS) is the second most common cause of developmental delay after Down syndrome. Impaired cognitive development is highly prevalent, but also motor abnormalities such as hypotonia and delays in achieving motor milestones are described. Instability is frequently detected in children, adolescents, and adults and is mostly attributed to their limited motor performance. Until now, vestibular function has not been investigated in these patients, despite the growing evidence that they often have inner ear malformations. The aim of this prospective study was to identify the presence and character of vestibular dysfunction in 22q11.2DS. We investigated 23 subjects with proven 22q11.2DS, older than the age of 12. We performed caloric testing and pendular rotation chair tests with videonystagmography, cervical vestibular-evoked myogenic potential (c-VEMP)-testing, and posturography. Additional otoscopy and audiometry were performed on all subjects. We found a unilateral caloric hypofunction in 55% of patients, a certain absent c-VEMP response in 15% of ears, an inconclusive c-VEMP response in 33% of ears, and abnormal posturography in 68% of patients, of whom 42% displayed a typical vestibular pattern. Remarkably, 90% revealed uni- or bilateral weak caloric responses, independent of caloric symmetry. Vestibular dysfunction is frequent in subjects with 22q11.2DS. This knowledge should be taken into account when assessing motor performance in these patients. Additional larger studies are needed to determine whether this dysfunction implicates a therapeutic potential.