Objective:To explore the clinical diagnosis, otological treatment and molecular etiology in a rare syndromic hearing loss case characterized by mandibulofacial dysostosis with microcephaly（MFDM）. Methods: The proband underwent detailed history collection, systematic physical examination and phenotypic analysis, as well as audiological examination, chest X-ray, temporal bone CT and brain MRI and other imaging examinations. The blood DNA of the proband and his parents was extracted and tested by the whole exom sequencing. The EFTUD2-related-MFDM literatures published by the end of 2020 were searched and sifted in PubMed and CNKI databases,the clinical characteristics of MFDM were summarized. Results:In this study, the patient presented with hypoplasia of auricle, micrognathia, microcephaly, developmental retardation, severe sensorineural hearing loss in both ears, and developmental malformation of middle and inner ear. Genetic analysis revealed a de novo deletion c.623_624delAT in EFTUD2 gene. According to the clinical features and genetic test results, the patient was diagnosed as MFDM. In order to solve the problem of hearing loss, the patient was further performed bilateral cochlear implantation, and part of the electrodes responded well during and after operation. Conclusion:This is the first domestic reported case of MFDM caused by EFTUD2 gene mutation. The key problem of cochlear implantation for this kind of patient is to avoid damaging the malformed facial nerve during the operation.The effect of speech rehabilitation after cochlear implant operation is related to many factors such as intelligence development of the patients.
目的：分析探讨罕见的下颌骨颜面发育不全伴小头畸形（MFDM）的临床诊断、耳科学治疗以及分子病因学特征。 方法：对先证者进行详细的病史采集，系统查体及表型特征分析，以及听力学检查，胸部X线、颞骨CT和颅脑MRI等影像学检查。同时提取先证者及其父母血液DNA进行全外显子组测序，并检索PubMed、中国知网数据库，对截止2020年底前报道的由EFTUD2基因突变导致的MFDM临床特征进行筛选、归纳和总结。 结果：患儿表现为耳廓发育不良、小下颌、小头畸形，同时合并发育迟缓、双耳极重度感音神经性聋，中耳及内耳发育畸形，基因学检测发现EFTUD2基因的新生缺失变异c.623_624delAT。根据临床特征及基因学检测结果诊断为MFDM。行双侧人工耳蜗植入手术，术中及开机后部分电极反应良好。 结论：这是国内首次报道的EFTUD2基因突变导致的MFDM，对该患儿进行人工耳蜗植入术的关键在于术中避免损伤畸形的面神经，术后言语康复效果与患儿智力发育等多因素相关。.

OBJECTIVE: Facial dysostosis is a group of rare craniofacial congenital disabilities requiring multidisciplinary long-term care. This report presents the phenotypic and genotypic information from South India.
METHODS: The study is a case series.
METHODS: This was an international collaborative study involving a tertiary craniofacial clinic and medical genetics unit.
METHODS: The participants were 9 families with 17 affected individuals of facial dysostosis.
METHODS: Exome analysis focused on known genes associated with acrofacial and mandibulofacial syndromes.
METHODS: The outcome measure was to report phenotyptic and genetic heterogeneity in affected individuals.
RESULTS: A Tessier cleft was seen in 7 (41%), lower eyelid coloboma in 12 (65%), ear anomalies in 10 (59%), uniolateral or bilateral aural atresia in 4 (24%), and deafness in 6 (35%). The facial gestalt of Treacher Collins syndrome (TCS) showed extensive phenotypic variations. Pathogenic variants in TCOF1 (Treacher Collins syndrome) were seen in six families, POLR1A (acrofacial dysostosis, Cincinnati type) and EFTUD2 (mandibulofacial dysostosis with microcephaly) in one each. One family (11.1%) had no detectable variation. Five out of six probands with Treacher Collins syndrome had other affected family members (83.3%), including a non-penetrant mother, identified after sequencing.
CONCLUSIONS: Our report illustrates the molecular heterogeneity of mandibulofacial dysostosis in India.

Mandibulofacial dysostosis with microcephaly (MFDM) is a rare autosomal dominant genetic disease characterized by intellectual and growth retardations, as well as major microcephaly, induced by missense and splice site variants or microdeletions in the EFTUD2 gene.
Here, we investigate the case of a young girl with symptoms of MFDM and a normal karyotype. Whole-exome sequencing of the family was performed to identify genetic alterations responsible for this phenotype. We identified a de novo synonymous variant in the EFTUD2 gene. We demonstrated that this synonymous variant disrupts the donor splice-site in intron 9 resulting in the skipping of exon 9 and a frameshift that leads to a premature stop codon.
We present the first case of MFDM caused by a synonymous variant disrupting the donor splice site, leading to exon skipping.

We report a case of mandibulofacial dysostosis with microcephaly presenting with seizures. The proband, a 6-year-old Korean boy, had microcephaly, malar and mandibular hypoplasia, and deafness. He showed developmental delay and had suffered recurrent seizures beginning at 21months of age. Electroencephalography revealed occasional spike discharges from the right frontal area. Head magnetic resonance imaging revealed dilatation of the lateral ventricles and a small frontal lobe volume. Whole exome sequencing revealed a de novo frame shift mutation, c.2698_2701 del, of EFTUD2. The epileptic focus was consistent with the reduced frontal lobe volume on head magnetic resonance imaging. Seizures are thus a main feature of mandibulofacial dysostosis with microcephaly, which results from an embryonic development defect due to the EFTUD2 mutation.