Auriculocondylar syndrome 2 caused by a novel PLCB4 variant in a male Chinese neonate: A case report and review of the literature.

BACKGROUND: Auriculocondylar syndrome (ARCND) is a rare congenital craniofacial developmental malformation syndrome of the first and second pharyngeal arches with external ear malformation at the junction between the lobe and helix, micromaxillary malformation, and mandibular condylar hypoplasia. Four subtypes of ARCND have been described so far, that is, ARCND1 (OMIM # 602483), ARCND2 (ARCND2A, OMIM # 614669; ARCND2B, OMIM # 620458), ARCND3 (OMIM # 615706), and ARCND4 (OMIM # 620457). METHODS: This study reports a case of ARCND2 resulting from a novel pathogenic variant in the PLCB4 gene, and summarizes PLCB4 gene mutation sites and phenotypes of ARCND2. RESULTS: The proband, a 5-day-old male neonate, was referred to our hospital for respiratory distress. Micrognathia, microstomia, distinctive question mark ears, as well as mandibular condyle hypoplasia were identified. Trio-based whole-exome sequencing identified a novel missense variant of NM_001377142.1:c.1928C>T (NP_001364071.1:p.Ser643Phe) in the PLCB4 gene, which was predicted to impair the local structural stability with a result that the protein function might be affected. From a review of the literature, only 36 patients with PLCB4 gene mutations were retrieved. CONCLUSION: As with other studies examining familial cases of ARCND2, incomplete penetrance and variable expressivity were observed within different families' heterozygous mutations in PLCB4 gene. Although, motor and intellectual development are in the normal range in the vast majority of patients with ARCND2, long-term follow-up and assessment are still required.

Genotype-phenotype associations in microtia: a systematic review.

BACKGROUND: Microtia is a congenital ear malformation that can occur as isolated microtia or as part of a syndrome. The etiology is currently poorly understood, although there is strong evidence that genetics has a role in the occurrence of microtia. This systematic review aimed to determine the genes involved and the abnormalities in microtia patients' head and neck regions. METHODS: We used seven search engines to search all known literature on the genetic and phenotypic variables associated with the development or outcome of microtia. The identified publications were screened and selected based on inclusion and exclusion criteria and assessed for methodological quality using the Joanna Briggs Institute (JBI) critical appraisal tools. We found 40 papers in this systematic review with phenotypic data in microtia involving 1459 patients and 30 articles containing genetic data involved in microtia. RESULT: The most common accompanying phenotype of all microtia patients was external ear canal atresia, while the most common head and neck abnormalities were the auricular, mental, and oral regions. The most common syndrome found was craniofacial microsomia syndrome. In the syndromic microtia group, the most common genes were TCOF1 (43.75%), SIX2 (4.69%), and HSPA9 (4.69%), while in the non-syndromic microtia group, the most frequently found gene was GSC exon 2 (25%), FANCB (16.67%), HOXA2 (8.33%), GSC exon 3 (8.33%), MARS1 (8.33%), and CDT1 (8.33%). CONCLUSIONS: Our systematic review shows some genes involved in the microtia development, including TCOF1, SIX2, HSPA9, GSC exon 2, FANCB, HOXA2, GSC exon 3, MARS1, and CDT1 genes. We also reveal a genotype-phenotype association in microtia. In addition, further studies with more complete and comprehensive data are needed, including patients with complete data on syndromes, phenotypes, and genotypes.

Question Mark Ear: An Unusual Anomaly and a Novel Surgical Technique for Reconstruction.

The question mark ear is a rare abnormality characterized by a cleft between the helix and the earlobe, resulting in a protrusion of the upper part of the ear. The severity of this ear malformation can range from a minor notch in the helix to a complete separation of the helix and the earlobe. In this study, we present a case of a patient with a moderately severe right-sided unilateral question mark deformity. To address this issue, we utilized a novel technique that involves a combination of a Y-V flap with double opposing Z-plasty. Our clinical study demonstrates that using this technique for reconstructing the deformity yields excellent results in terms of the helical rim and fold contour, utilizing solely the local tissues.

Long-term results and quality of life after vibrant soundbridge implantation (VSBs) in children and adults with aural atresia.

PURPOSE: The aim of this study was to evaluate the long-term effectiveness and acceptance of the active middle ear implant system Vibrant Soundbridge (VSB®, MED-EL, Austria) in patients with aural atresia or aplasia (children and adults). METHODS: Data from 51 patients (mean age 13.9 ± 11.3 years), 42 (79.2%) children and adolescents, and 11 (20.8%) adults) who received a VSB implant between 2009 and 2019 at the Department of Otolaryngology at LMU Clinic Großhadern, Munich were included in the study. Pure-tone audiometry, speech recognition in a quiet environment and in a noisy environment were performed preoperatively, during the first fitting of the audio processor, after 1-3 years, after 3-5 years, and after 5 years (if possible). The follow-up period ranged from 11 to 157 months with a mean of 58.6 months (4.8 years). Furthermore, the benefit of the VSB was evaluated by self-assessment questionnaires (Speech, Spatial, and Qualities of Hearing Scale, respectively, for parents). RESULTS: Significant improvements were observed in hearing and speech comprehension immediately after the initial fitting of the VSB system (mean hearing gain 38.4 ± 9.4 dB HL) and at follow-up intervals (1-3, 3-5 and after 5 years) for children and adults (p < 0.01). The values remained stable over the long-term, indicating a sustained functional gain from the VSB (mean hearing gain 38.9 ± 9.2 dB HL). The results of the self-assessments affirm the positive influence on hearing and speech comprehension with the VSB. With the VSB, there was an improvement of 41.3 ± 13.7% in the Freiburg monosyllable test. CONCLUSION: These results (a stable hearing gain over the long term, a good tolerance of the implant and an improvement in quality of life) affirm the recommendation for using the active middle ear implant VSB as early as permitted for aural atresia and aplasia patients. This study represents the audiometric results with the (to date) largest collective of aural atresia patients and with a long follow-up period.

Comparison of Transcutaneous and Percutaneous Implantable Hearing Devices for the Management of Congenital Aural Atresia: A Systematic Review and Meta-Analysis.

OBJECTIVE: To compare audiometric outcomes, complications, and revisions required for percutaneous (pBCD) versus transcutaneous (tBCD) implantable bone-conduction devices for the treatment of hearing loss associated with congenital aural atresia (CAA).Databases Reviewed.PubMed, Scopus, CINAHL. METHODS: A systematic review was performed searching for English language articles from inception to December 14, 2022. Studies reporting audiometric outcomes or complications for either pBCDs or tBCDs for the treatment of CAA were selected for inclusion. A meta-analysis of single means and meta-analysis of proportions with comparison (Δ) of weighted proportions was conducted. RESULTS: A total of 56 articles with 756 patients were selected for inclusion. One hundred ninety patients were implanted with pBCDs, whereas the remaining 566 were implanted with tBCDs. Mean pure-tone audiometry improvement in the pBCD group (39.1 ± 1.1 dB) was significantly higher than in the tBCD group (34.6 ± 1.6 dB; Δ4.5 dB; 95% confidence interval, 4.2-4.7 dB; p < 0.0001). The average improvement in speech reception threshold was 38.6 ± 2.5 dB in the percutaneous group as compared with 32.7 ± 1.6 dB in the transcutaneous group (Δ5.9 dB [5.3-6.5 dB], p < 0.0001). Overall complication rates for patients implanted with pBCDs and tBCDs were 29.0% (15.7-44.4%) and 9.4% (6.5%-13.0%), respectively (Δ19.6% [12.0-27.7%], p < 0.0001). CONCLUSIONS: Patients with CAA implanted with pBCDs had significantly better audiometric outcomes than those implanted with tBCDs. However, complication rates were significantly higher among the pBCD group.

New strategies and methods for reconstruction of the outer ear canal (OEC).

Background: The incidence of re-stenosis or re-atresia after reconstruction of the Outer Ear Canal (OEC) in patients with Congenital Malformation of the Middle and Outer Ear (CMMOE) is very high (up to 48%), and it has been a difficult problem for otologists not being able to solve.Aims/Objectives: To explore new strategies and methods to improve re-stenosis or re-atresia after reconstruction of the OEC in patients with CMMOE.Material and Methods: According to the characteristics of reconstructed OEC (r-OEC) re-stenosis or re-atresia summarized by us, a number of new prevention strategies and methods have been proposed and related patent products have been designed, including the improvement of covering epithelium types and skin grafting methods (7 types), simulated drum ring function to prevent the formation of negative pressure in the cavity, and strengthen postoperative support to reduce skin shrinkage and bone hyperplasia. The postoperative effects of different ages and preoperative OEC malformations are statistically analyzed.Results: The incidence of re-stenosis/re-atresia is 14.3% (5/35) in the thin sectional skin of the temporal scalp overlap splicing skin grafting, which was significantly better than 45.5% (15/33) in the whole piece mosaic splicing and barrel skin grafting from the inner thin sectional thigh skin and overlay splicing other methods, including the inner thigh thin sectional skin, chest medium thick skin and subcutaneous pedicle + chest medium thick skin (p<0.05). The patent artificial drum ring and the model stent of the OEC have obvious effects. The mean operation age of postoperative atresia, stenosis, and good groups are 9.3, 13.1, and 12.5 years old, respectively. The proportion of preoperative atresia is 91.3%, 85.7%, and 57.7%, respectively. The total incidence of re-atresia and re-stenosis of r-OEC for two groups of atresia and stenosis of OEC before surgery is 40.5% (49/121) and 13.3% (8/60), respectively.Conclusions and Significance: The best result is found in overlapping the splicing thin sectional skin of the temporal scalp, combined with artificial drum ring implantation, effective support of postoperative model stent of OEC and post-pubertal surgery selection are new and effective strategies and methods to prevent re-stenosis or re-atresia of r-OEC. Atresia or stenosis of the OEC before the operation is the influence factor of the postoperative effect.

Relationship between congenital malformation of the outer ear and hearing.

Background: There is no report on the relationship between congenital malformation of the outer ear and hearing, which makes it possible to predict the hearing level just based on microtia grades.Aims/Objectives: To investigate the correlation between two types of congenital malformation of the outer ear [microtia and Outer Ear Canal Malformation (OECM)] and hearing, as well as the interrelationship among all three variables.Material and methods: A total of 535 cases (598 ears) of congenital malformation of the middle and outer ear (CMMOE) with hearing data, out of which 319 cases (349 ears) microtia with available images and graded by I-V, 449 cases (482 ears) OECM graded by atresia, stenosis and normal, and 87 cases (87 ears) OEC atresia graded I-IV, 301 cases (301 ears) with materials of microtia, OECM and hearing at the same time were carried out correlation analysis. The Average Air-Conduction Threshold of pure tone (AACT) at 0.5-4 KHz was calculated corresponding to the ears with different malformation grades. The differences in AACT among different malformation grades, the correlation between malformation severity and AACT, as well as the relationship among microtia, OECM and AACT were analyzed. The one-way analysis of variance (ANOVA) was employed to compare the differences in AACT, Kendall's tau-b rank correlation coefficient test was used for correlation analysis. A statistical significance level of p < 0 .05 was applied.Results: Among the 349 ears with microtia, the corresponding AACT values for grades I to V were 61.6, 63.0, 69.9, 75.4, and 75.0 (dB HL), respectively. Comparing grade III to grades II or IV, both p < 0 .05. However, p > 0 .05 between grade I and II or between grade IV and V. The correlation coefficient between microtia grades and AACT r = 0.219, p < 0.05. Among the 482 ears of OECM, the distribution was as follows: 73.6% atresia, 19.1% stenosis, and 7.3% normal, the corresponding AACT values were 64.1, 61.7, and 52.5 (dB HL), respectively. Comparing normal to stenosis or atresia, both p < 0.05, while between atresia and stenosis p > 0.05. The correlation between OECM and AACT was r = 0.104, p < 0.05. The AACT values corresponding to grades I to IV of OEC atresia in the 87 ears were 59.9, 65.1, 71.1, and 64.1 (dB HL), respectively. Comparing these grades, all p > 0.05. The correlation between the degree of atresia and AACT r = 0.23, p < 0 .05. The correlation coefficients for 301 ears microtia to OECM, microtia to AACT, OECM to AACT were r = 0.339, r = 0.163 and r = 0.128 respectively, with all p < 0 .05.Conclusion and significance: There are positive correlations among the degree of microtia, degree of OECM, and AACT values for each other, and so between the degree of OEC atresia and AACT, suggesting that as the severity of microtia or OECM increased, the AACT also tended to be higher, which make it possible to predict the hearing level and the degree of OECM based on microtia grades in clinical practice. Additionally, there are significant differences in AACT values in microtia grade III to grades II or IV, OEC normal to stenosis or atresia, while no differences in microtia grade I to II and grade IV to V, OEC stenosis to atresia, and among the grades I-IV of the OEC atresia.

Pediatric cholesteatoma associated with congenital aural atresia and stenosis.

OBJECTIVE: Investigate presenting features, associated surgical treatment, and outcomes in patients with cholesteatoma associated with congenital aural atresia (CAA) or stenosis (CAS). METHODS: Colorado Multiple Institution Review Board approval was obtained. A retrospective chart review was performed at a single tertiary care children's hospital of all pediatric patients with congenital aural atresia or stenosis with associated cholesteatoma from January 1, 2003, to October 15, 2018. RESULTS: Of the 278 patients identified with CAA or CAS, twelve (4.3 %) were found to have a canal cholesteatoma. There was a male predominance (8:4). Nine patients (75 %) had conductive loss and three (25 %) had mixed loss. Four patients (33.3 %) exhibited canal cholesteatomas extending into the middle ear or mastoid cavity. All patients underwent surgery, and 25 % of patients required revision canalplasty while 58 % of patients required revision surgery for cholesteatoma recidivism. The average age at the time of surgery was 11.3 ± 3.7 years. CONCLUSION: Fewer than 5 % of pediatric patients with congenital aural atresia or stenosis were diagnosed with an acquired canal cholesteatoma. The need for revision surgery was common, occurring in >50 % of cases. Screening patients with CAA/CAS for cholesteatoma with imaging is recommended to avoid the morbidity of delayed identification.

Complete Isolation of Left Innominate Artery in a Patient With CHARGE Syndrome: Case Presentation and Review of Reported Cases.

We report a rare case of complete isolation of the left innominate artery in a child with CHARGE (coloboma, heart defects, atresia choanae, growth retardation, genital abnormalities, and ear abnormalities) syndrome. This anatomical cluster had been undetected for a relatively large period of time and the patient was referred to us with an incomplete diagnosis even after multiple medical evaluations and a thoracic surgery during the neonatal period. In conclusion, to the best of our knowledge, this is the first case of a complete isolation of left innominate artery treated with a transcatheter approach.

Benefits of bone conduction hearing aid in children with unilateral aural atresia.

Objective: To assess the hearing benefit with a unilateral bone conduction hearing aid in a cohort of children with unilateral aural atresia. Methods: Cross-sectional case series pilot study involving 7 children (median age: 10 years, range 6-11). All patients underwent pure-tone, speech, aided sound field and aided speech audiometry and Simplified Italian Matrix Test (SIMT) with and without bone conduction hearing aid (Baha 5® CochlearTM). Cognitive abilities were assessed in 5 patients. Results: The mean air conduction pure-tone average (PTA) of the atretic ear was 63.2 ± 6.9 dB, while the bone conduction PTA was 12.6 ± 4.7 dB. Speech discrimination score of the atretic ear was 88.6 ± 3.8 dB, while with the hearing aid it was 52.8 ± 1.9 dB. In the contralateral ear, there was no significant air-bone gap, and PTAs for air and bone conduction thresholds were within normal range (PTA ≤ 25 dB). The mean aided air conduction hearing threshold was 26.2 ± 7.97. Mean speech recognition threshold without the hearing aid was -5.1 ± 1.9 dB, and -6.0 ± 1.7 dB with the hearing aid tested with the SIMT. The mean score of the cognitive test was 46.8 ± 42.8. Conclusions: These preliminary findings should encourage clinicians in proposing a unilateral bone conduction hearing aid in children with unilateral atresia.

Auriculocondylar syndrome: Pathogenesis, clinical manifestations and surgical therapies.

Auriculocondylar syndrome (ARCND) is a genetic and rare craniofacial condition caused by abnormal development of the first and second pharyngeal arches during the embryonic stage and is characterized by peculiar auricular malformations (question mark ears), mandibular condyle hypoplasia, micrognathia and other less-frequent features. GNAI3, PLCB4 and EDN1 have been identified as pathogenic genes in this syndrome so far, all of which are implicated in the EDN1-EDNRA signal pathway. Therefore, ARCND is genetically classified as ARCND1, ARCND2 and ARCND3 based on the mutations in GNAI3, PLCB4 and EDN1, respectively. ARCND is inherited in an autosomal dominant or recessive mode with significant intra- and interfamilial phenotypic variation and incomplete penetrance, rendering its diagnosis difficult and therapies individualized. To raise clinicians' awareness of the rare syndrome, we focused on the currently known pathogenesis, pathogenic genes, clinical manifestations and surgical therapies in this review.

Benefits of medially based perichondrio-adipo-dermal flap in cartilage sparing prominent ear surgery.

BACKGROUND: Cartilage-cutting and cartilage-sparing techniques are the two types of otoplasty procedures. Because of the significant risk of haematoma, skin necrosis, and ear deformity, cartilage-cutting techniques have been questioned. As a result; suture-based cartilage-sparing procedures such as Mustarde and Furnas suture procedures have grown in popularity. However, these techniques have a tendency for deformity recurrence due to cartilage memory and suture fatigue, as well as the possibility of suture extrusion and pinpricking sensation of the sutures. METHODS: In this study, we used a medially based adipo-dermal flap including perichondrium which is elevated from the back of the auricle to cover and support a cartilage-sparing otoplasty, thirty-four patients (14 female and 20 male) were operated using this technique. The medially based perichondrio-adipo-dermal flap is advanced anteriorly and fixed to the helical rim under cover of the distal skin flap. This procedure sought to cover the suture line preventing suture extrusion and support in the repair of the deformity preventing its recurrence. RESULTS: The average operative time was 80min, ranging from 65 to 110min. The patients passed the early postoperative period uneventfully except for 2 patients; one patient (2.9%) developed haematoma, and the other patient developed a small area of necrosis on the new antihelical fold. In late the postoperative period recurrence of the deformity developed in one patient. No patients developed suture extrusion or granuloma. CONCLUSION: The treatment to repair prominent ears is easy and safe, with benefits such as a natural-looking antihelical fold and minimal tissue stress. The medially or proximally based adipo-dermal flap may help to lower recurrence rates and suture extrusion.

The advantages of domestic ear molding system in molding bilateral neonatal congenital auricular deformities.

BACKGROUND: There are different types of ear molding devices on the market. However, due to high cost, the wide application of the ear molding is hindered, especially for children with bilateral congenital auricular deformities (CAD). This study is designed to correct the bilateral CAD with the flexible use of Chinese domestic ear molding system. METHODS: Newborns diagnosed with bilateral CAD were recruited in our hospital from September 2020 to October 2021. For each subject, one ear wore a set of domestic ear molding system, while the contralateral ear used only matching Retractor and Antihelix Former. Medical charts were reviewed to collect data on the types of CAD, the incidence of complications, the initiation and duration of treatment, as well as the satisfaction after treatment. Treatment outcomes were graded into three levels: excellent, good, and poor, according to the improvement of auricular morphology evaluated by both doctors and parents, respectively. RESULTS: A total of 16 infants (32 ears) were treated with the Chinese domestic ear molding system, which contains 4 cases with Stahl's ear (8 ears), 5 cases with Helical rim deformity (10 ears), 3 cases with Cup ear (6 ears), 4 cases with Lop ear (8 ears). All infants accomplished the correction completely. Both parents and doctors were satisfied with the outcomes. No obvious complication was observed. CONCLUSIONS: Ear molding is an effective nonsurgical treatment for CAD. Molding with Retractor and Antihelix Former is simple and effective. Domestic ear molding system can be flexibly used in correcting bilateral CAD. With this approach, infants with bilateral CAD will benefit more in the near future.

Cholesteatoma in Congenital Aural Atresia and External Auditory Canal Stenosis: A Systematic Review.

OBJECTIVE: Patients with congenital external auditory canal (EAC) abnormalities are at risk of developing cholesteatoma and often undergo surveillance imaging to detect it. The aims of this systematic review are to determine the incidence of cholesteatoma in patients with congenital aural atresia (CAA) and patients with congenital EAC stenosis and to investigate the most common age of cholesteatoma diagnosis. This information will help clinicians decide which patients require surveillance scanning, as well as the timing of imaging. DATA SOURCES: Ovid MEDLINE, Embase, CENTRAL, and Web of Science databases. REVIEW METHODS: A systematic literature review following the PRISMA guidelines was performed. The data sources were searched by 2 independent reviewers, and articles were included that reported on CAA or congenital EAC stenosis with a confirmed diagnosis of cholesteatoma. The selected articles were screened separately by 3 reviewers before reaching a consensus on the final articles to include. Data collection on the number of patients with cholesteatoma and the age of diagnosis was performed for these articles. RESULTS: Eight articles met the inclusion criteria. The incidence of cholesteatoma was 1.7% (4/238) in CAA and 43.0% (203/473) in congenital EAC stenosis. The majority of patients with congenital EAC stenosis that developed cholesteatoma were diagnosed at age <12 years. CONCLUSION: CAA is associated with a low risk of cholesteatoma formation, and surveillance imaging is unnecessary in asymptomatic patients. EAC stenosis is strongly associated with cholesteatoma, and a surveillance scan for these patients is recommended prior to 12 years of age with close follow-up into adulthood.

Congenital aural atresia: hearing rehabilitation using active middle-ear implants.

OBJECTIVE: To assess hearing rehabilitation in patients with congenital aural atresia using an active middle-ear implant (Vibrant Soundbridge). METHODS: Of a cohort of 70 microtia and atresia patients, 10 underwent Vibrant Soundbridge implantation between 2008 and 2021. Two of the 10 patients had binaural implantation, resulting in 12 ears for analysis. Pre- and post-operative audiometry data were analysed, and patient satisfaction was evaluated. Surgical issues regarding coupling sites and outcomes were analysed. RESULTS: Pure tone average (0.5, 1, 2 and 4 kHz) improved from a pre-operative mean (standard deviation) of 65.3 (8.7) dB HL to a post-operative mean of 26.8 (4.9) dB HL. This resulted in a mean pure tone average gain of 38.5 dB HL. The results indicate no obvious difference between stapes (n = 8) and incus (n = 4) coupling. The mean effective gain for 0.5, 1, 2 and 4 kHz was -17.8 dB HL (standard deviation = 4.3). Concerning effective gain, Vibrant Soundbridge performed best at 2 kHz. Patients reported high overall satisfaction, good sound quality and strongly improved directional hearing. CONCLUSION: An active middle-ear implant (Vibrant Soundbridge) allows hearing rehabilitation in selected atretic ears, and provides long-term hearing stability in children and adults.

Search for a genetic cause in children with unilateral isolated microtia and congenital aural atresia.

PURPOSE: Microtia describes a spectrum of auricular malformations ranging from mild dysplasia to anotia. A vast majority of microtia patients demonstrate congenital aural atresia (CAA). Isolated microtia has a right ear predominance (58-61%) and is more common in the male sex. Isolated microtia is a multifactorial condition involving genetic and environmental causes. The aim of this study is to describe the phenotype of children with unilateral isolated microtia and CAA, and to search for a common genetic cause trough DNA analysis. METHODS: Phenotyping included a complete clinical examination. Description on the degree of auricular malformation (Weerda classification-Weerda 1988), assessment for hemifacial microsomia and age-appropriate audiometric testing were documented. Computerized tomography of the temporal bone with 3-D rendering provided a histopathological classification (HEAR classification-Declau et al. 1999). Genetic testing was carried out by single nucleotide polymorphism (SNP) microarray. RESULTS: Complete data are available for 44 children (50% was younger than 33 days at presentation; 59.1% boys; 72.7% right ear). Type III microtia was present in 28 patients. Type 2b CAA existed in 32 patients. All patients had a normal hearing at the non-affected side. Genome wide deletion duplication analysis using microarray did not reveal any pathological copy number variant (CNV) that could explain the phenotype. CONCLUSIONS: Type III microtia (peanut-shell type) in combination with a type 2b CAA was the most common phenotype, present in 23 of 44 (52.3%) patients with isolated unilateral microtia. No abnormalities could be found by copy number variant (CNV) analysis. Whole exome sequencing in a larger sample with a similar phenotype may represent a future diagnostic approach.

Damaging variants in FOXI3 cause microtia and craniofacial microsomia.

PURPOSE: Craniofacial microsomia (CFM) represents a spectrum of craniofacial malformations, ranging from isolated microtia with or without aural atresia to underdevelopment of the mandible, maxilla, orbit, facial soft tissue, and/or facial nerve. The genetic causes of CFM remain largely unknown. METHODS: We performed genome sequencing and linkage analysis in patients and families with microtia and CFM of unknown genetic etiology. The functional consequences of damaging missense variants were evaluated through expression of wild-type and mutant proteins in vitro. RESULTS: We studied a 5-generation kindred with microtia, identifying a missense variant in FOXI3 (p.Arg236Trp) as the cause of disease (logarithm of the odds = 3.33). We subsequently identified 6 individuals from 3 additional kindreds with microtia-CFM spectrum phenotypes harboring damaging variants in FOXI3, a regulator of ectodermal and neural crest development. Missense variants in the nuclear localization sequence were identified in cases with isolated microtia with aural atresia and found to affect subcellular localization of FOXI3. Loss of function variants were found in patients with microtia and mandibular hypoplasia (CFM), suggesting dosage sensitivity of FOXI3. CONCLUSION: Damaging variants in FOXI3 are the second most frequent genetic cause of CFM, causing 1% of all cases, including 13% of familial cases in our cohort.

[A case report of the first and second branchial arch syndrome with torticollis].

A 54-month-old female patient presented to the department of ophthalmology with abnormal head posture and facial asymmetry for two years. The patient's facial development was asymmetrical, with the middle 1/3 of the left side shorter than the right side. The left ear is less malformed than the right. There was no obvious abnormality in corneal light reflex and eye movement. Head tilt test ( -). So, paralysis of the superior oblique muscle was excluded. In consultation with the department of maxillofacial surgery, the patient was confirmed as the first and second branchial arch syndrome and torticollis.