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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. [ABSTRACT FROM AUTHOR]

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 length 2 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Andries, Deschrevel, Maes, De Beukelaer, Corvelyn, Staut, De Houwer, Costamagna, Nijs, Metsemakers, Nijs, Hens, De Wachter, Prinsen, Desloovere, Van Campenhout and Gayan-Ramirez.)

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., (© 2023 Royal College of Speech and Language Therapists.)

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.

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., (© 2023 Royal College of Speech and Language Therapists.)

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., (© 2023 Royal College of Speech and Language Therapists.)

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., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).)

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., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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 (X 2 (1) = 4.38, p < 0.05). Furthermore, this group needed significantly more ventilation tube reinsertions (X 2 (2) = 12.22, p < 0.05) and was found to have a significantly higher incidence of oronasal fistula (53.5% vs. 17.2%, X 2 (1) = 14.75, p < 0.05). The latter was significantly associated with a higher need for ventilation tube reinsertion (X 2 (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., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Boonen, Hens, Meulemans, Hermans, Delaere and Vander Poorten.)

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., Competing Interests: The authors have declared that no competing interests exist.