Biallelic truncating variants in VGLL2 cause syngnathia in humans.

BACKGROUND: Syngnathia is an ultrarare craniofacial malformation characterised by an inability to open the mouth due to congenital fusion of the upper and lower jaws. The genetic causes of isolated bony syngnathia are unknown. METHODS: We used whole exome and Sanger sequencing and microsatellite analysis in six patients (from four families) presenting with syngnathia. We used CRISPR/Cas9 genome editing to generate vgll2a and vgll4l germline mutant zebrafish, and performed craniofacial cartilage analysis in homozygous mutants. RESULTS: We identified homozygous truncating variants in vestigial-like family member 2 (VGLL2) in all six patients. Two alleles were identified: one in families of Turkish origin and the other in families of Moroccan origin, suggesting a founder effect for each. A shared haplotype was confirmed for the Turkish patients. The VGLL family of genes encode cofactors of TEAD transcriptional regulators. Vgll2 is regionally expressed in the pharyngeal arches of model vertebrate embryos, and morpholino-based knockdown of vgll2a in zebrafish has been reported to cause defects in development of pharyngeal arch cartilages. However, we did not observe craniofacial anomalies in vgll2a or vgll4l homozygous mutant zebrafish nor in fish with double knockout of vgll2a and vgll4l. In Vgll2 -/- mice, which are known to present a skeletal muscle phenotype, we did not identify defects of the craniofacial skeleton. CONCLUSION: Our results suggest that although loss of VGLL2 leads to a striking jaw phenotype in humans, other vertebrates may have the capacity to compensate for its absence during craniofacial development.

Management of sleep-disordered breathing in patients with syndromic hemifacial macrosomia.

PURPOSE: Patients with syndromic hemifacial microsomia (SHFM) are at risk of obstructive sleep apnea (OSA). The aim of the study was to describe the prevalence of OSA and its management, especially in patients with Goldenhar syndrome (GS). METHODS: The respiratory polygraphies and clinical management of 15 patients, aged 2 to 23 years, evaluated at a national reference center, were analyzed. RESULTS: Four (27%) patients had no OSA, 4 (27%) had mild OSA, and 7 (46%), of whom 5 were ≤ 2 years old, had severe OSA. None of the patients had central apneas. Only one patient had alveolar hypoventilation, and another one had nocturnal hypoxemia. Two patients had severe OSA despite prior adenoidectomy or mandibular distraction osteogenesis. Median duration of follow-up was 3.5 years (range 0.5-9 years). None of the patients without OSA or with mild OSA at baseline respiratory polygraphy developed OSA during the follow up. Among the 7 patients with severe OSA, 3 required continuous positive airway pressure or noninvasive ventilation, and one patient required a tracheostomy. CONCLUSION: In conclusion, patients with SHFM are at high risk of severe OSA at any age, underlining the importance of systematic sleep studies to diagnose and evaluate the severity of OSA. Individualized treatment should be privileged, based on a careful examination of the entire upper airway, taking in account potential associated risk factors. All patients with SHFM should be managed by a pediatric expert multidisciplinary medical/surgical team until the end of post pubertal growth.

Pediatric Nasal Reconstruction by Washio Procedure.

The use of the Washio retroauricular flap for nasal reconstruction has been infrequently covered in recent literature, particularly concerning the pediatric population. A retrospective study was conducted between 2014 and 2018 and included all pediatric patients who underwent a Washio retroauricular flap procedure for nasal reconstruction operated on by the same surgeon at a referral center for pediatric plastic and maxillofacial surgery. The mean age at the time of the first stage of the Washio procedure was just under 8 years of age (range: 6 years 3 months-8 years 10 months). The Washio retroauricular flap procedure was successfully employed in three patients with three different anatomical defects, including the nasal alae, nasal tip, and columella, without postoperative healing complications. Arguably, the Washio method is sufficiently versatile to be used in various defect types, allows space and planning for subsequent surgical corrections, avoids additional visible scarring of the face, and spares flaps that may be required at the end of the growth, such as the pedicled forehead flap. It is a safe procedure, provided that at least a two-stage procedure is performed, and a progressive postoperative verticalization is prescribed to limit venous drainage complications.

Next generation phenotyping for diagnosis and phenotype-genotype correlations in Kabuki syndrome.

The field of dysmorphology has been changed by the use Artificial Intelligence (AI) and the development of Next Generation Phenotyping (NGP). The aim of this study was to propose a new NGP model for predicting KS (Kabuki Syndrome) on 2D facial photographs and distinguish KS1 (KS type 1, KMT2D-related) from KS2 (KS type 2, KDM6A-related). We included retrospectively and prospectively, from 1998 to 2023, all frontal and lateral pictures of patients with a molecular confirmation of KS. After automatic preprocessing, we extracted geometric and textural features. After incorporation of age, gender, and ethnicity, we used XGboost (eXtreme Gradient Boosting), a supervised machine learning classifier. The model was tested on an independent validation set. Finally, we compared the performances of our model with DeepGestalt (Face2Gene). The study included 1448 frontal and lateral facial photographs from 6 centers, corresponding to 634 patients (527 controls, 107 KS); 82 (78%) of KS patients had a variation in the KMT2D gene (KS1) and 23 (22%) in the KDM6A gene (KS2). We were able to distinguish KS from controls in the independent validation group with an accuracy of 95.8% (78.9-99.9%, p < 0.001) and distinguish KS1 from KS2 with an empirical Area Under the Curve (AUC) of 0.805 (0.729-0.880, p < 0.001). We report an automatic detection model for KS with high performances (AUC 0.993 and accuracy 95.8%). We were able to distinguish patients with KS1 from KS2, with an AUC of 0.805. These results outperform the current commercial AI-based solutions and expert clinicians.

AI-based diagnosis in mandibulofacial dysostosis with microcephaly using external ear shapes.

Introduction: Mandibulo-Facial Dysostosis with Microcephaly (MFDM) is a rare disease with a broad spectrum of symptoms, characterized by zygomatic and mandibular hypoplasia, microcephaly, and ear abnormalities. Here, we aimed at describing the external ear phenotype of MFDM patients, and train an Artificial Intelligence (AI)-based model to differentiate MFDM ears from non-syndromic control ears (binary classification), and from ears of the main differential diagnoses of this condition (multi-class classification): Treacher Collins (TC), Nager (NAFD) and CHARGE syndromes. Methods: The training set contained 1,592 ear photographs, corresponding to 550 patients. We extracted 48 patients completely independent of the training set, with only one photograph per ear per patient. After a CNN-(Convolutional Neural Network) based ear detection, the images were automatically landmarked. Generalized Procrustes Analysis was then performed, along with a dimension reduction using PCA (Principal Component Analysis). The principal components were used as inputs in an eXtreme Gradient Boosting (XGBoost) model, optimized using a 5-fold cross-validation. Finally, the model was tested on an independent validation set. Results: We trained the model on 1,592 ear photographs, corresponding to 1,296 control ears, 105 MFDM, 33 NAFD, 70 TC and 88 CHARGE syndrome ears. The model detected MFDM with an accuracy of 0.969 [0.838-0.999] (p < 0.001) and an AUC (Area Under the Curve) of 0.975 within controls (binary classification). Balanced accuracies were 0.811 [0.648-0.920] (p = 0.002) in a first multiclass design (MFDM vs. controls and differential diagnoses) and 0.813 [0.544-0.960] (p = 0.003) in a second multiclass design (MFDM vs. differential diagnoses). Conclusion: This is the first AI-based syndrome detection model in dysmorphology based on the external ear, opening promising clinical applications both for local care and referral, and for expert centers.

Craniofacial phenotype in the branchio-oculo-facial syndrome: four case reports.

Branchio-oculo-facial syndrome represents a craniofacial disorder in which affected patients may develop a wide range of distinctive features that include cleft lip and/or palate, cervical aplastic skin defect, malformed pinna, and ocular anomalies. This study reports four new cases confirmed by the identification of mutations in the TFAP2A gene and describes in detail the findings in the craniofacial region. The four cases included two familial and two sporadic, and three have been followed since the birth. Two out of the four cases showed atypical features. One patient presented brainstem immaturity with dysregulation of sympathetic and parasympathetic systems, which have so far not been described in the literature and were associated with anxiety, panic attacks, and tiredness. Another patient had as an additional feature a hypoplastic thumb with distal implantation.

Mandibular magnetic distractor: preclinical validation.

The feasibility of magnetic activation for mandibular distraction has been demonstrated previously. In this study, we developed a biocompatible device to evaluate the feasibility of distraction in cadaveric subjects and the functionality of the device in bench tests. To confirm, considering the dimension of the distractor, that the torque applied on the internal magnet would be sufficient to activate distraction osteogenesis we measured, for different distances, the transmitted torque between a magnet (internal and external). We evaluated the friction force of the device, and the resilience of the magnet to the sterilisation process. To confirm the feasibility of distraction with this device, we proceeded to cadaveric tests, and evaluated the satisfaction of four surgeons. The force applied to the moving plate was greater than 50 Newtons (N) with a friction coefficient of η=0.2. We determined a friction torque of 65.10-3 N.mm in the distractor mechanism and demonstrated that sterilisation did not alter the magnet. Mandibular distraction had been successfully achieved in cadaveric trials, and surgeons were satisfied. This new device could be implanted in human subjects, for clinical assay, after approval by the regulatory agencies. The use of this fully internalised device should improve patients' comfort.

Facial, lingual, and pharyngeal electromyography in infants with Pierre Robin sequence.

INTRODUCTION: We evaluated the role of electromyography (EMG) in assessing orofacial neurological dysfunction in 81 infants with Pierre Robin sequence (PRS). METHODS: Needle EMG of muscles of the face, tongue, and soft palate, and blink responses were recorded. A two-channel EMG recorded sucking and swallowing during bottle feeding. RESULTS: Neurogenic EMG signs were detected in facial or oral muscles in 17 of 24 associated PRS and 1 of 57 isolated PRS cases (P < 0.0001). Soft palate muscles showed low-amplitude traces in 41.4% of patients who required two surgical steps for cleft palate repair and 18.5% of those who required only one step. Regarding EMG study during bottle feeding, patients with moderate or severe abnormalities of oral/pharyngeal coordination required more prolonged enteral feeding than patients with mild abnormalities or normal coordination (P = 0.002). CONCLUSION: Combined EMG methods were useful in the treatment of infants with PRS. EMG detection of cranial nerve involvement strongly suggests an associated form of PRS.

Prenatal evaluation of the middle ear and diagnosis of middle ear hypoplasia using MRI.

BACKGROUND: Analysis of the middle ear with fetal MRI has not been previously reported. OBJECTIVE: To show the contribution of fetal MRI to middle ear imaging. MATERIALS AND METHODS: The tympanic cavity was evaluated in 108 fetal cerebral MRI examinations (facial and/or cerebral malformation excluded) and in two cases, one of Treacher Collins syndrome (case 1) and the other of oculo-auriculo-vertebral (OUV) spectrum (case 2) with middle ear hypoplasia identified by MRI at 27 and 36 weeks' gestation, respectively. RESULTS: In all 108 fetuses (mean gestational age 32.5 weeks), the tympanic cavity and T2 hypointensity related to the ossicles were well visualised on both sides. Case 1 had micro/retrognathia and bilateral external ear deformity and case 2 had retrognathism with a left low-set and deformed ear. MRI made it possible to recognize the marked hypoplasia of the tympanic cavity, which was bilateral in case 1 and unilateral in case 2. Both syndromes are characterized by craniofacial abnormalities including middle ear hypoplasia, which cannot be diagnosed with US. CONCLUSION: The middle ear cavity can be visualized with fetal MRI. We emphasize the use of this imaging modality in the diagnosis of middle ear hypoplasia.

Conservative management is effective in unicystic ameloblastoma occurring from the neonatal period: A case report and a literature review.

Unicystic ameloblastoma (UA), a benign odontogenic tumor of the jaw, represents less than a third of all ameloblastomas and seems less aggressive than other types of ameloblastoma. We present here the first case of UA that developed prenatally and was successfully managed in the early neonatal period with marsupialization and curettage performed carefully to avoid injury to the tooth germ. BRAF and SMO mutations were not detected. After 2 years of follow-up, complete reossification and normal eruption of deciduous teeth were noted, and there was no recurrence of UA. We recommend conservative treatment of UA in the pediatric population to avoid loss of and/or injury to the tooth germ, provided close follow-up is carried out all through the individual's growth for early detection of potential recurrences, growth impairments, or tooth eruption disorders. The intratumoral somatic mutational status of BRAF, SMO, RAS family, and FGFR2 may help determine personalized targeted treatment, particularly in case of recurrence.

Sleep disordered breathing in Silver-Russell syndrome patients: a new outcome.

OBJECTIVE: Imprinting disorders (ID), such as Prader-Willi syndrome (PWS), are associated with sleep-disordered breathing (SDB). No data are available for Silver-Russell syndrome (SRS), another ID that shares clinical features with PWS, although many patients describe excessive daytime sleepiness, disturbed sleep, and snoring. The aim of this study was to characterize sleep in children with SRS and to evaluate the impact of recombinant growth hormone (rGH) therapy. METHODS: We performed a retrospective analysis of sleep recordings in 40 patients with molecularly proven SRS (methylation anomaly in 11p15 [n = 32] or maternal uniparental disomy of chromosome 7 [n = 16]). Sleep recordings were either by means of polygraphy or polysomnography (PSG) (n = 16). A total of 34 patients received rGH therapy. RESULTS: We collected 61 sleep recordings. The mean apnea-hypopnea index (AHI) was 3.4 events/h (0-12.4), with a mean central AHI of 0.5 events/h (0-2.4). SDB was identified in 73.8% (n = 45) of the recordings and was severe in 4.9%. SDB was present in 86.4% of patients before rGH therapy and was severe in 13.6%. AHI worsened for 5 of 12 patients with sleep recordings before and after rGH therapy initiation, reaching mild impairment. The mean rGH dose was 32.3 µg/kg/(12.9-51.4), with a mean insulin-like growth factor 1 plasma level of 1.7 SDS (-1.9 to 6.6). CONCLUSION: Most patients with SRS present with SDB with an obstructive profile, possibly explained by narrowing of the airways and lymphoid organ hypertrophy. We recommend systematic ear-nose-throat evaluation of SRS patients and PSG if there are clinical anomalies, preferably before initiating rGH therapy, to monitor and adapt the management of patients with SDB.

Mandibular symphyseal distraction osteogenesis: 20 years of experience treating transverse deficiencies with an internal hybrid device.

INTRODUCTION: Transverse mandibular deficiency has been traditionally managed by orthodontic compensation. However, without resolving the underlying skeletal hypoplasia it leads to high relapse rates. Few studies have reviewed the long-term experience and potential complications of mandibular symphyseal distraction osteogenesis (MSDO) as an alternative treatment method. MATERIALS AND METHOD: A retrospective review of 20 patients (range: 4-19 years; mean: 11.9 years) treated with a hybrid MSDO device over the period of 1996-2017 was conducted. Epidemiological data, medical and dental history as well as photographic and cephalometric analyses were carried out. Furthermore, pre-operative and long-term post-operative status including dental occlusion and tooth-jaw discrepancies were recorded. RESULTS: The distraction amount ranged from 3 mm to 15 mm (mean: 10 mm) with an average distraction period of 30.9 days. In long-term follow-up (mean: 7.3 years), 14 patients presented a class I and 6 patients presented a class II relationship. Correction of overjet, tooth jaw discrepancy and arch length discrepancy were obtained in 18, 20 and 17 cases respectively. A device malfunction was experienced in 6 patients. CONCLUSION: Mandibular widening using a hybrid MSDO device can be efficiently and safely performed in a paediatric population. Further studies confirming our results and analysing facial aesthetic outcomes are warranted.

Management of rare diseases of the Head, Neck and Teeth: results of a French population-based prospective 8-year study.

BACKGROUND: In the last ten years, national rare disease networks have been established in France, including national centres of expertise and regional ones, with storage of patient data in a bioinformatics tool. The aim was to contribute to the development and evaluation of health strategies to improve the management of patients with rare diseases. The objective of this study has been to provide the first national-level data concerning rare diseases of the head, neck and teeth and to assess the balance between demand and supply of care in France. METHODS: Centres of expertise for rare diseases record a minimum data set on their clinical cases, using a list of rare Head, Neck and Teeth diseases established in 2006. The present analysis focuses on 2008 to 2015 data based on the Orphanet nomenclature. Each rare disease RD "case" was defined by status "affected" and by the degree of diagnostic certainty, encoded as: confirmed, probable or non-classifiable. Analysed parameters, presented with their 95% confidence intervals using a Poisson model, were the following: time and age at diagnosis, proportions of crude and standardized RD prevalence by age, gender and geographical site. The criteria studied were the proportions of patients in Paris Region and the "included cases geography", in which these proportions were projected onto the other French Regions, adjusting for local populations. RESULTS: In Paris Region, estimated prevalence of these diseases was 5.58 per 10,000 inhabitants (95% CI 4.3-7.1). At December 31st 2015, 11,342 patients were referenced in total in France, of whom 7294 were in Paris Region. More than 580 individual clinical entities (ORPHA code) were identified with their respective frequencies. Most abnormalities were diagnosed antenatally. Nearly 80% of patients recorded come to Paris hospitals to obtain either diagnosis, care or follow up. We observed that the rarer the disease, the more patients were referred to Paris hospitals. CONCLUSIONS: A health network covering a range of aspects of the rare diseases problematic from diagnostics to research has been developed in France. Despite this, there is still a noticeable imbalance between health care supply and demand in this area.

Five years experience with a new intraoral maxillary distraction device (RID).

Maxillary distraction osteogenesis is well established for the treatment of severe retromaxilla. We report our experience since 2004 of the treatment of 19 patients using a new intraoral maxillary distraction device. Maxillary advancement was successful in all patients with mean advancement of 9.6mm (range 4-17) measured at a point in lateral cephalograms. The new device limited surgical exposure and the amount of materials implanted, and improved control in every phase of the distraction. It was psychologically accepted by patients and was more comfortable than existing devices.

Physiologic and clinical benefits of noninvasive ventilation in infants with Pierre Robin sequence.

OBJECTIVE: The objective of the study was to determine the clinical and physiologic benefits of noninvasive respiratory support (NRS) (continuous positive airway pressure or noninvasive positive pressure ventilation) for infants with a Pierre Robin sequence (PRS). METHODS: Breathing patterns, respiratory efforts, and gas exchange were analyzed for 7 infants with a PRS during spontaneous breathing and during NRS. Clinical outcomes with duration of NRS and need for a tracheotomy and/or nutritional support was evaluated. RESULTS: Compared with spontaneous breathing, breathing patterns, respiratory efforts, and transcutaneous carbon dioxide pressures improved during NRS; the mean respiratory rate decreased from 55 ± 9 to 37 ± 7 breaths per minute (P = .063), the mean inspiratory time/total duty cycle decreased from 59 ± 9% to 40 ± 7% (P = .018), the mean esophageal pressure swing decreased from 29 ± 13 to 9 ± 4 cm H(2)O (P = .017), the diaphragmatic pressure-time product decreased from 844 ± 308 to 245 ± 126 cm H(2)O-second per minute (P = .018), and the mean transcutaneous carbon dioxide pressure during sleep decreased from 57 ± 7 to 31 ± 7 mm Hg (P = .043). All of the patients could be discharged successfully from the hospital with NRS. The mean duration of NRS was 16.7 ± 12.2 months. Six patients could be weaned from nutritional support, and none required a tracheotomy. CONCLUSIONS: NRS is able to improve breathing patterns and respiratory outcomes for infants with severe upper airway obstruction attributable to a PRS, which supports its use as a first-line treatment.