-
Frontiers in Pediatrics 2023Mandibulo-Facial Dysostosis with Microcephaly (MFDM) is a rare disease with a broad spectrum of symptoms, characterized by zygomatic and mandibular hypoplasia,...
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] ( < 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] ( = 0.002) in a first multiclass design (MFDM vs. controls and differential diagnoses) and 0.813 [0.544-0.960] ( = 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.
PubMed: 37664547
DOI: 10.3389/fped.2023.1171277 -
European Journal of Paediatric Dentistry Dec 2023Mandibulofacial dysostosis Guion-Almeida Type (MFDGA; OMIM#610536) is a rare autosomal dominant genetic disorder caused by heterozygous pathogenic variants in the EFTUD2...
Mandibulofacial dysostosis Guion-Almeida Type (MFDGA; OMIM#610536) is a rare autosomal dominant genetic disorder caused by heterozygous pathogenic variants in the EFTUD2 gene. Mandibulofacial dysostoses are characterised by the core triad malar hypoplasia, maxillary hypoplasia and dysplastic ears, all derived by the impaired development of the first and second branchial arches. Differential diagnosis is often challenging. The early genetic diagnosis is extremely useful, not only for the correct management of cranial malformations, but also for the early diagnosis and treatment of the comorbidities associated to the disease, which greatly benefit from early treatment.
Topics: Humans; Branchial Region; Mandibulofacial Dysostosis; Diagnosis, Differential; Zygoma; Peptide Elongation Factors; Ribonucleoprotein, U5 Small Nuclear
PubMed: 38015115
DOI: 10.23804/ejpd.2023.24.04.03 -
Genes Dec 2023Nager syndrome is a rare human developmental disorder characterized by craniofacial defects including the downward slanting of the palpebral fissures, cleft palate, limb... (Review)
Review
Nager syndrome is a rare human developmental disorder characterized by craniofacial defects including the downward slanting of the palpebral fissures, cleft palate, limb deformities, mandibular hypoplasia, hypoplasia or absence of thumbs, microretrognathia, and ankylosis of the temporomandibular joint. The prevalence is very rare and the literature describes only about a hundred cases of Nager syndrome. There is evidence of autosomal dominant and autosomal recessive inheritance for Nager syndrome, suggesting genetic heterogeneity. The majority of the described causes of Nager syndrome include pathogenic variants in the gene, which encodes a component of the spliceosome; therefore, the syndrome belongs to the spliceosomopathy group of diseases. The diagnosis is made on the basis of physical and radiological examination and detection of mutations in the gene. Due to the diversity of defects associated with Nager syndrome, patients require multidisciplinary, complex, and long-lasting treatment. Usually, it starts from birth until the age of twenty years. The surgical procedures vary over a patient's lifetime and are related to the needed function. First, breathing and feeding must be facilitated; then, oral and facial clefts should be addressed, followed by correcting eyelid deformities and cheekbone reconstruction. In later age, a surgery of the nose and external ear is performed. Speech and hearing disorders require specialized logopedic treatment. A defect of the thumb is treated by transplanting a tendon and muscle or transferring the position of the index finger. In addition to surgery, in order to maximize a patient's benefit and to reduce functional insufficiency, complementary treatments such as rehabilitation and physiotherapy are recommended. In our study, we describe eight patients of different ages with various cases of Nager syndrome. The aim of our work was to present the actual genetic knowledge on this disease and its treatment procedures.
Topics: Child; Humans; Young Adult; Adult; Mandibulofacial Dysostosis; Cleft Palate; Micrognathism; Syndrome; RNA Splicing Factors
PubMed: 38254920
DOI: 10.3390/genes15010029 -
The Cleft Palate-craniofacial Journal :... Sep 2023This paper describes 20 years of microtia and craniofacial microsomia (CFM) psychosocial and healthcare studies and suggests directions for clinical care and research. A... (Review)
Review
This paper describes 20 years of microtia and craniofacial microsomia (CFM) psychosocial and healthcare studies and suggests directions for clinical care and research. A narrative review of papers January 2000 to July 2021 related to psychosocial and healthcare experiences of individuals with microtia and CFM and their families. Studies (N = 64) were mainly cross-sectional (69%), included a range of standardized measures (64%), and were with European (31%), American (27%), or multinational (23%) samples. Data were generally collected from both patients and caregivers (38%) or patient self-report (35%). Sample sizes were 11 to 25 (21%), 26 to 50 (19%), 51 to 100 (22%), or over 100 (38%). Studies addressed 5 primary topics: (1) Healthcare Experiences, including Medical Care, Hearing Loss/Amplification, Diagnostic Experiences, and Information Preferences; (2) Psychosocial Experiences, including Teasing, Behavioral Adjustment, Psychosocial Support, and Public Perception; (3) Neurocognitive Functioning and Academic Assistance; (4) Pre- and Post-Operative Psychosocial Outcomes of Ear Reconstruction/Canaloplasty; and (5) Quality of Life and Patient Satisfaction. Care involved multiple specialties and was often experienced as stressful starting at diagnosis. Psychosocial and neurocognitive functioning were generally in the average range, with possible risk for social and language concerns. Coping and resiliency were described into adulthood. Satisfaction and positive benefit of ear reconstruction/canaloplasty were high. Care recommendations include increasing: hearing amplification use, microtia and CFM knowledge among providers, efficient treatment coordination, psychosocial support, academic assistance, and advances to minimize surgical scarring. This broad literature overview informs clinical practice and research to improve psychosocial outcomes.
Topics: Humans; United States; Goldenhar Syndrome; Congenital Microtia; Quality of Life; Cross-Sectional Studies; Adaptation, Psychological
PubMed: 35382590
DOI: 10.1177/10556656221091699 -
The Journal of Craniofacial Surgery Sep 2023Characteristics of patients with craniofacial microsomia (CFM) vary in type and severity. The diagnosis is based on phenotypical assessment and no consensus on...
Characteristics of patients with craniofacial microsomia (CFM) vary in type and severity. The diagnosis is based on phenotypical assessment and no consensus on standardized clinical diagnostic criteria is available. The use of diagnostic criteria could improve research and communication among patients and healthcare professionals. Two sets of phenotypic criteria for research were independently developed and based on multidisciplinary consensus: the FACIAL and ICHOM criteria. This study aimed to assess the sensitivity of both criteria with an existing global multicenter database of patients with CFM and study the characteristics of patients that do not meet the criteria. A total of 730 patients with CFM from were included. Characteristics of the patients were extracted, and severity was graded using the O.M.E.N.S. and Pruzansky-Kaban classification. The sensitivity of the FACIAL and ICHOM was respectively 99.6% and 94.4%. The Cohen's kappa of 0.38 indicated a fair agreement between both criteria. Patients that did not fulfill the FACIAL criteria had facial asymmetry without additional features. It can be concluded that the FACIAL and ICHOM criteria are accurate criteria to describe patients with CFM. Both criteria could be useful for future studies on CFM to create comparable and reproducible outcomes.
Topics: Humans; Goldenhar Syndrome; Facial Asymmetry; Face; Health Personnel; Patients
PubMed: 37264504
DOI: 10.1097/SCS.0000000000009446 -
The British Journal of Oral &... Jan 2024This review provides a comprehensive overview of the literature on velopharyngeal insufficiency, associated anomalies, and speech/language impairment in patients with... (Review)
Review
This review provides a comprehensive overview of the literature on velopharyngeal insufficiency, associated anomalies, and speech/language impairment in patients with craniofacial microsomia (CFM). A systematic search of the literature was conducted to identify records on VPI and speech impairment in CFM from their inception until September 2022 within the databases Embase, PubMed, MEDLINE, Ovid, CINAHL EBSCO, Web of Science, Cochrane, and Google Scholar. Seventeen articles were included, analysing 1,253 patients. Velopharyngeal insufficiency results in hypernasality can lead to speech impairment. The reported prevalence of both velopharyngeal insufficiency and hypernasality ranged between 12.5% and 55%, while the reported prevalence of speech impairment in patients with CFM varied between 35.4% and 74%. Language problems were reported in 37% to 50% of patients. Speech therapy was documented in 45.5% to 59.6% of patients, while surgical treatment for velopharyngeal insufficiency consisted of pharyngeal flap surgery or pharyngoplasty and was reported in 31.6% to 100%. Cleft lip and/or palate was reported in 10% to 100% of patients with CFM; these patients were found to have worse speech results than those without cleft lip and/or palate. No consensus was found on patient characteristics associated with an increased risk of velopharyngeal insufficiency and speech/language impairment. Although velopharyngeal insufficiency is a less commonly reported characteristic of CFM than other malformations, it can cause speech impairment, which may contribute to delayed language development in patients with CFM. Therefore, timely recognition and treatment of speech impairment is essential.
Topics: Humans; Cleft Lip; Cleft Palate; Goldenhar Syndrome; Language Development Disorders; Retrospective Studies; Speech; Speech Disorders; Treatment Outcome; Velopharyngeal Insufficiency
PubMed: 38057178
DOI: 10.1016/j.bjoms.2023.09.008 -
The Cleft Palate-craniofacial Journal :... Sep 2023To (1) appraise current international classification and clinical management strategies for craniofacial microsomia (CFM) and microtia, and (2) to assess agreement with...
To (1) appraise current international classification and clinical management strategies for craniofacial microsomia (CFM) and microtia, and (2) to assess agreement with the European Reference Network "European Guideline Craniofacial Microsomia" recommendations on screening and monitoring. This was a cross-sectional online survey study. The survey consisted of 44 questions on demographics, diagnostics and classification, obstructive sleep apnea, feeding difficulties, speech and language development, hearing, ocular abnormalities, visual development, orthodontic screening, genetic counselling, psychological wellbeing, and extracraniofacial anomalies. Respondents were participants of 3 international cleft and craniofacial conferences, members of the American Cleft Palate and Craniofacial Association and members of the International Society for Auricular Reconstruction. Respondents were requested to complete 1 questionnaire per multidisciplinary team. Fifty-seven responses were received from 30 countries (response rate ∼3%).The International Consortium for Health Outcomes Measurement diagnostic criteria were used by 86% of respondents, though 65% considered isolated microtia a mild form of CFM. The Orbit, Mandible, Ear, Facial Nerve and Soft Tissue classification system was used by 74% of respondents. Agreement with standardized screening and monitoring recommendations was between 61% and 97%. A majority of respondents agreed with screening for extracraniofacial anomalies (63%-68%) and with genetic counselling (81%). This survey did not reveal consistent agreement on the diagnostic criteria for CFM. Respondents mostly supported management recommendations, but frequently disagreed with the standardization of care. Future studies could focus on working towards international consensus on diagnostic criteria, and exploring internationally feasible management strategies.
Topics: Humans; Goldenhar Syndrome; Congenital Microtia; Cross-Sectional Studies; Mandible; Surveys and Questionnaires
PubMed: 35469463
DOI: 10.1177/10556656221093912 -
Lin Chuang Er Bi Yan Hou Tou Jing Wai... Sep 2023By analyzing the clinical phenotypic characteristics and gene sequences of two patients with Treacher Collins syndrome(TCS), the biological causes of the disease...
By analyzing the clinical phenotypic characteristics and gene sequences of two patients with Treacher Collins syndrome(TCS), the biological causes of the disease were determined. Then discuss the therapeutic effect of hearing intervention after bone bridge implantation. All clinical data of the two family members were collected, and the patients signed the informed consent. The peripheral blood of the proband and family members was extracted, DNA was extracted for whole exome sequencing, and Sanger sequencing was performed on the family members for the mutation site.genetic mutations analysis was performed on the paitents. Then, the hearing threshold and speech recognition rate of family 2 proband were evaluated and compared under the sound field between bare ear and wearing bone bridge. In the two pedigrees, the probands of both families presented with auricle deformity, zygomatic and mandibular hypoplasia, micrognathia, hypotropia of the eye fissure, and hypoplasia of the medial eyelashes. The proband of Family 1 also presents with specific features including right-sided narrow anterior nasal aperture and dental hypoplasia, which were consistent with the clinical diagnosis of Treacher Collins syndrome. Genetic testing was conducted on both families, and two heterozygous mutations were identified in the gene: c. 1350_1351dupGG(p. A451Gfs*43) and c. 4362_4366del(p. K1457Efs*12), resulting in frameshift mutations in the amino acid sequence. Sanger sequencing validation of the gene in the parents of the proband in Family 1 did not detect any mutations. Proband 1 c. 1350_1351dupGG heterozygous variants have not been reported previously. The postoperative monosyllabic speech recognition rate of family 2 proband was 76%, the Categories of Auditory Performance(CAP) score was 6, and the Speech Intelligibility Rating(SIR) score was 4. Assessment using the Meaningful Auditory Integration Scale(MAIS) showed notable improvement in the patient's auditory perception, comprehension, and usage of hearing aids. Evaluation using the Glasgow Children's Benefit Inventory and quality of life assessment revealed significant improvements in the child's self care abilities, daily living and learning, social interactions, and psychological well being, as perceived by the parents. This study has elucidated the biological cause of Treacher Collins syndrome, enriched the spectrum of gene mutations in the Chinese population, and demonstrated that bone bridge implantation can improve the auditory and speech recognition rates in TCS patients.
Topics: Child; Humans; Mandibulofacial Dysostosis; Quality of Life; Speech; Parents; Mutation; Nuclear Proteins; Phosphoproteins
PubMed: 37640998
DOI: 10.13201/j.issn.2096-7993.2023.09.011 -
International Journal of Molecular... Apr 2024Hemifacial microsomia (HFM) is a rare congenital genetic syndrome primarily affecting the first and second pharyngeal arches, leading to defects in the mandible,...
Hemifacial microsomia (HFM) is a rare congenital genetic syndrome primarily affecting the first and second pharyngeal arches, leading to defects in the mandible, external ear, and middle ear. The pathogenic genes remain largely unidentified. Whole-exome sequencing (WES) was conducted on 12 HFM probands and their unaffected biological parents. Predictive structural analysis of the target gene was conducted using PSIPRED (v3.3) and SWISS-MODEL, while STRING facilitated protein-to-protein interaction predictions. CRISPR/Cas9 was applied for gene knockout in zebrafish. In situ hybridization (ISH) was employed to examine the spatiotemporal expression of the target gene and neural crest cell (NCC) markers. Immunofluorescence with PH3 and TUNEL assays were used to assess cell proliferation and apoptosis. RNA sequencing was performed on mutant and control embryos, with rescue experiments involving target mRNA injections and specific gene knockouts. was identified as a novel candidate gene for HFM, with four nonsynonymous de novo variants detected in three unrelated probands. Structural predictions indicated significant alterations in the secondary and tertiary structures of . knockout in zebrafish resulted in craniofacial malformation, spine deformity, and cardiac edema, mirroring typical HFM phenotypes. Abnormalities in somatic cell apoptosis, reduced NCC proliferation in pharyngeal arches, and chondrocyte differentiation issues were observed in mutants. mRNA injections and or knockout significantly rescued pharyngeal arch cartilage dysplasia, while mRNA administration partially restored the defective phenotypes. Our findings suggest a functional link between and HFM, primarily through the inhibition of proliferation and disruption of pharyngeal chondrocyte differentiation.
Topics: Animals; Zebrafish; Humans; Male; Female; Goldenhar Syndrome; Apoptosis; Neural Crest; Exome Sequencing; Cell Proliferation; Phenotype; Mutation; Gene Knockout Techniques
PubMed: 38731925
DOI: 10.3390/ijms25094707