Preliminary Genetic Analysis And Comprehensive Treatment Of Auriculocondylar Syndrome

Objective1.To explore the possible pathogenic genes of auriculo-condylar syndrome(ACS)with the application of whole exon sequencing and Sanger sequencing technologies and to discuss the pathogenesis of this disease preliminarily.2.To design precise surgery and individualized craniofacial treatment for ACS with the assist of preoperative simulation and navigation guide plate based on three-dimensional computerized design and manufacturing technology.3.To analyze the three-dimensional change of the airway by three-dimensional digitalmeasurement technology and to evaluate the improvement of mandibular deformity by cephalometrics of ACS patients after distraction osteogenesis.Methods1.Six members from a family of three affected generations and four patients with ACS who were treated between April 2012 and March 2017 were selected.Sequencing methods was determined according to family characteristics.Whole exon sequencing technologies and Sanger sequencing techniques was applied for gene sequencing analysis.2.Three cases with ACS who were treated with maxillofacial plastic surgery from April 2012 to March 2016 were selected.CT data were used for preoperative design and the surgical osteotomy simulation.The navigation guide plate was prefabricated and used in operation.Treatments for mandibular malformation was summarized for severe deformity and mild deformity respectively.3.Two cases with ACS who were treated with distraction osteogenesis from April 2012 to March 2016 were selected.Mimics software was used to remodel and measure airway parameters before and after distraction osteogenesis.Methods of cephalometrics was used to measure parameters of mandibular deformity before and after surgery.All the data were analyzed by paired sample T test method.Results1.In this study,one family of ACS was analyzed by using exome sequencing and Sanger sequencing techniques.The filtered sequencing results showed there were a total of 67 SNP candidate genes and 15 InDel candidate genes.Among those candidate genes,a novel mutation site PLCB4:c.1006 c>G was noticed,and the presence of this mutation in the family was verified by Sanger sequencing.This variant was absent from the public databases and might affect evolutionary conserved residues.2.For patients with severe deformity,surgeries by stages were performed.They underwent bilateral distraction osteogenesis,LeFort I osteotomy,genioplasty and Chin augmentation with porous polyethylene implant in multiple sessions.No complications were reported.Their mandibular contour improved greatly.For the patient with mild deformity,a single-stage face re-contouring operation improved his chin and facial contour a lot.3.Results of measurement presented the volume of airway was significantly enlarged,and the area of sagittal plane and the transverse section were significantly increased after distraction osteogenesis.The phenomenon of snoring and sleep apnea vanished.The postoperative SNB Angle,NP-FH Angle and ANS-Me/N-Me were also significantly improved.Conclusions1.Our analysis identified a novel pathogenic autosomal dominant mutation in an ACS family of PLCB4:c.1006 C>G p.(Gln336 Glu).It was possible that the amino acids changes might be mediated by a dominant negative mechanism.Our researches suggested that autosomal dominant PLCB4 mutations might be associated with the phenotype of ACS.Further study was required to elucidate the relationship between phenotypic variability and gene mutation in the EDNRA pathway2.Based on digital technology,preoperative design and simulation can be performed to produce navigational plate and to assist osteotomy.This procedure improved surgery accuracy and safety,and provided precise and individualized treatment for patients.All the patients and their families were satisfied with the postoperative results.The overall staging therapies were referable options for ACS patients.3.The airway analysis and surgical effect evaluation of distraction osteogenesis were performed through three-dimensional digital measurement and cephalometrics.Various indexes showed large improvement.Without the disorders of snoring and sleep apnea,living quality of patients also got improved.Distraction osteogenesis is a very safe and effective method to correct the mandible malformation of ACS.