Otopalatodigital spectrum disorders (OPDSD), comprising otopalatodigital syndromes types 1 and 2 (OPD1, OPD2) and frontometaphyseal dysplasia (FMD), are rare X-linked disorders caused by FLNA gene variants, with phenotypes ranging from mild skeletal anomalies to severe multisystem malformations. We describe two unrelated cases: a 14-year-old male (P1, FMD) and an aborted fetus (P2, OPD2). Whole-exome sequencing identified hemizygous maternally inherited FLNA gene variants in P1 (c.733G>A; p.Glu245Lys) and P2 (c.3707G>A; p.Gly1236Asp, novel), expanding the OPD2 mutational spectrum (NM_001110556). P1 presented with facial dysmorphism, dental anomalies, flattened thumbs, and dermatoglyphic changes; P2 showed facial dysmorphism, skeletal and cardiac malformations, and omphalocele. These cases underscore the breadth of OPDSD phenotypic variability and add novel genetic data. Dental management demands multidisciplinary care from infancy through adolescence, including cleft repair, orthodontics for micrognathia and facial aesthetics, and treatment of dental anomalies. Early recognition, molecular diagnosis, and coordinated management are critical for improving outcomes in these complex disorders. The FLNA-related otopalatodigital (FLNA-OPD) spectrum disorders, characterized primarily by skeletal dysplasia, include the following allelic conditions: otopalatodigital syndrome type 1 (FLNA-OPD1), otopalatodigital syndrome type 2 (FLNA-OPD2), frontometaphyseal dysplasia (FLNA-FMD), Melnick-Needles syndrome (FLNA-MNS), and terminal osseous dysplasia (FLNA-TOD). In FLNA-OPD1, most manifestations are present at birth; females can present with severity similar to affected males, although some have only mild manifestations. In FLNA-OPD2, females are less severely affected than related affected males. Most males with FLNA-OPD2 die during the first year of life, usually from thoracic hypoplasia resulting in pulmonary insufficiency. Males who live beyond the first year of life are usually developmentally delayed and require respiratory support and assistance with feeding. In FLNA-FMD, females are less severely affected than related affected males who are hemizygous for the same allele. Males usually, but not always, demonstrate a skeletal dysplasia in association with hearing loss and, variably, joint contractures and hand and foot malformations. Progressive scoliosis is observed in both affected males and females. In females with FLNA-MNS, wide phenotypic variability is observed; some individuals are diagnosed in adulthood, while others require respiratory support and have reduced longevity. FLNA-MNS in males results in perinatal lethality in all known individuals. FLNA-TOD, seen only in females, is characterized by a skeletal dysplasia that is most prominent in the hand and feet, pigmentary defects of the skin, and recurrent digital fibromata. The diagnosis of an FLNA-OPD spectrum disorder is established in a male proband with characteristic clinical and radiographic features and a family history consistent with X-linked inheritance. Identification of a hemizygous pathogenic variant in FLNA by molecular genetic testing can confirm the diagnosis if clinical features, radiographic features, and/or family history are inconclusive. The diagnosis of an FLNA-OPD spectrum disorder is usually established in a female proband with characteristic clinical and radiographic features and a family history consistent with X-linked inheritance. Identification of a heterozygous pathogenic variant in FLNA by molecular genetic testing can confirm the diagnosis if clinical features, radiographic features, and/or family history are inconclusive. Treatment of manifestations: Surgical treatment may be required for hand and foot malformations. Monitoring, bracing, and surgical intervention as needed for scoliosis; physical therapy for contractures; cosmetic surgery may correct the fronto-orbital deformity; surgical correction for orthognathic deformities as needed; chest expansion surgery has been used to treat thoracic hypoplasia; continuous positive airway pressure and mandibular distraction can improve airway complications related to micrognathia; hearing aids for deafness; treatment of cardiac anomalies and cardiomyopathy per cardiologist and cardiac surgeon; treatment of oligohypodontia per orthodontist and/or dental surgeon; treatment of genitourinary anomalies per urologist; evaluation with anesthesiologist if intubation and ventilation are required due to laryngeal stenosis. Surveillance: Annual clinical evaluation for orthopedic complications including contractures and scoliosis; evaluation of bone mineral density in those with FLNA-FMD; monitor head size and shape with each clinical evaluation in infancy for craniosynostosis; annual clinical evaluation for apnea with polysomnography studies as indicated; annual audiology evaluation; dental evaluations every six to 12 months beginning with eruption of primary teeth. Evaluation of relatives at risk: Consider molecular genetic testing for the family-specific pathogenic variant in at-risk female relatives. FLNA-OPD spectrum disorders are inherited in an X-linked manner. If the mother of the proband has an FLNA pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected. Penetrance in males with an FLNA pathogenic variant leading to an FLNA-OPD spectrum disorder is complete (male sibs of a proband with FLNA-MNS or FLNA-TOD who inherit the pathogenic variant will be affected and generally die prenatally or perinatally). Females who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations. If the father of the proband has an FLNA pathogenic variant, he will transmit it to all his daughters and none of his sons. Once the FLNA pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for FLNA-OPD spectrum disorders are possible.

Objective: To explore the perioperative precautions, rehabilitation effect, and affecting factors in cochlear implantation (CI) among patients with hereditary syndromic hearing loss. Methods: This was a retrospective cohort study. 47 patients diagnosed as hereditary syndromic deafness were treated in the Department of Otolaryngology-Head and Neck Surgery of the Chinese PLA General Hospital from 2010 to 2021, including 26 males and 21 females, aged 0.9-25 years. All patients received unilateral or bilateral CI. Clinical manifestation combined with genetic testing was used to diagnose syndromic hearing loss. The risks and precautions of CI in these patients were summarized from preoperative imaging, intraoperative observations, and postoperative complications. Single factor linear regression and multiple linear regression models in SPSS 26.0 software were used to evaluate the effects of various factors on auditory and speech rehabilitation after CI for syndromic hearing loss. The postoperative outcomes were analyzed through aided hearing thresholds, categories of auditory performance (CAP) scale, and speech intelligibility rate (SIR) scale. Results: Thirteen kinds of syndromes, totally 47 cases, including CHARGE (20 cases), Waardenburg (9 cases), Autosomal dominant deafness-onychodystrophy (DDOD, 4 cases), Pendred (3 cases), Noonan Syndrome with Multiple Lentigines (NSML, 2 cases), Branchio-Oto-Renal (BOR, 2 cases), Bart-Pumphery (1 case), Perrault (1 case), Kabuki (1 case), Frontometaphyseal dysplasia type 2 (FMD 2, 1 case), Mandibulofacial dysostosis Guion-Almeida type (MFDGA, 1 case), Coffin-Siris (1 case), and 10q26.12-q26.3 del (1 case), were enrolled. The perioperative special management included the following measures. For patients with cardiac and/or cartilage development issues, preoperative assessments of cardiac function and/or laryngeal cartilage development were performed to minimize anesthetic risks. For patients with mild intellectual disability and/or an auditory neuropathy phenotype, preoperative communication with the patients' families was conducted to explain the limitations of CI and assist in setting reasonable expectations. For syndromic hearing loss patients who commonly present with inner ear malformations, facial nerve anomalies, and/or intraoperative cerebrospinal fluid leakage, appropriate electrodes were selected prior to surgery, intraoperative facial nerve monitoring and careful cerebrospinal fluid leak repair were conducted, respectively. For patients with NSML accompanied by coagulation issues, the postoperative compression bandaging duration was extended to reduce the risk of hematoma formation. The daily duration of cochlear implant use, the presence of cochlear malformation, and developmental delay were independent factors influencing postoperative CAP scores. The daily duration of cochlear implant use, developmental delay, and unilateral or bilateral CI were independent factors influencing postoperative SIR scores. Conclusions: Hereditary syndrome deafness is a rare disease that affects multiple organs and causes extensive functional impairment. Before CI, a comprehensive evaluation of major affected organ functions is required to assess anesthetic and surgical risks. Genetic diagnosis not only identifies the molecular etiology of patients with syndromic hearing loss and reveals rare phenotypes, but also aids in prognostic evaluation. The main factors affecting CI outcomes in patients with syndromic hearing loss include the presence of cochlear malformations, developmental delays, daily duration of cochlear implant use, and bilateral implantation status. 目的： 分析遗传性综合征型聋患者人工耳蜗植入的围手术期注意事项、术后效果及其影响因素。 方法： 本研究为回顾性队列研究，研究对象为2010—2021年间在中国人民解放军总医院耳鼻咽喉头颈外科就诊的综合征型聋患者47例，其中男26例、女21例，年龄0.9~25岁。所有患者均接受单侧或双侧人工耳蜗植入。通过表型评估结合基因检测进行综合征型聋的诊断；从术前影像、术中所见及并发症处理等方面总结综合征型聋患者人工耳蜗植入的风险及注意事项；用助听听阈、听觉行为分级（Categories of Auditory Performance，CAP）量表和言语可懂度分级（Speech Intelligibility Rating，SIR）量表评价术后效果。应用SPSS 26.0软件通过单因素线性回归和多重线性回归模型评估各因素对综合征型聋患者人工耳蜗植入术后效果的影响。 结果： 47例综合征型聋患者中CHARGE综合征20例，Waardenburg综合征9例，耳聋甲发育不全综合征4例，Pendred综合征3例，多痣Noonan综合征2例，鳃耳（肾）综合征2例，Bart-Pumphrey综合征、Perrault综合征、Kabuki综合征、额骨骺发育不良2型、Guion-Almeida型下颌面骨发育不全、Coffin-Siris综合征、10号染色体12.7 Mb区带缺失各1例。围手术期特殊处理包括：对累及心脏和/或软骨发育的患者，术前行心功能和/或喉软骨发育评估以减低麻醉风险；对伴有轻度智力障碍和/或听神经病表型的患者，术前与患者家属沟通人工耳蜗植入效果的局限性以帮助其建立合理预期；针对综合征型聋患者进行人工耳蜗植入术较常遇到的内耳畸形、面神经畸形、脑脊液漏等情况，在术前选择合适的电极，术中进行面神经监测、妥善修补脑脊液漏；对累及凝血功能的多痣Noonan综合征患者，延长术后加压包扎时间以减少血肿发生。人工耳蜗每日佩戴时长、是否有耳蜗畸形、是否有发育迟缓是术后CAP分级的独立影响因素；人工耳蜗每日佩戴时长、是否有发育迟缓、单双侧植入是术后SIR分级的独立影响因素。 结论： 遗传性综合征型聋属于罕见病，累及多器官，功能损伤广泛。人工耳蜗植入前需要全面评估主要受累脏器功能以明确麻醉和手术风险。基因诊断除了明确综合征型聋患者的分子病因、提示罕见表型，还能辅助预后判断。是否伴耳蜗畸形、是否伴发育迟缓、人工耳蜗每日佩戴时长、单双侧植入是影响综合征型聋患者人工耳蜗植入效果的主要因素。.

Pathogenic variants in FLNA cause a diversity of X-linked developmental disorders associated with either preserved or diminished levels of filamin A protein and are conceptualized dichotomously as relating to underlying gain- or loss-of-function pathogenic mechanisms. Hemizygosity for germline deletions or truncating variants in FLNA is generally considered to result in embryonic lethality. Structurally, filamin A is composed of an N-terminal actin-binding region, followed by 24 immunoglobulin-like repeat units. The repeat domains are separated into distinct segments by two regions of low-complexity known as hinge-1 and hinge-2. Hinge-1 is proposed to confer flexibility to the otherwise rigid protein and is a target for cleavage by calpain with the resultant filamin fragments mediating crucial cellular signaling processes. Here, three families with pathogenic variants in FLNA that impair the function of hinge-1 in males are described, leading to distinct clinical phenotypes. One large in-frame deletion that includes the hinge leads to frontometaphyseal dysplasia in affected males and females, while two germline truncating variants located within the exon encoding hinge 1 result in phenotypes in males that are explained by exon skipping and under-expression of a transcript that deletes hinge-1 from the resultant protein. These three variants affecting hinge-1 indicate that this domain does not mediate cellular functions that, when deficientresult in embryonic lethality in males and that germline truncating variants in this region of FLNA can result in viable phenotypes in males.

Here we present the case of a patient with a novel de novo, likely pathogenic, heterozygous MAP3K7 variant (c.528dupT, p.G177WfsX5) causing cardiospondylocarpofacial syndrome (CSCFS). The variant, which falls in exon 6, is the first frameshift or non-sense mutation to be connected to CSCFS and presents with a phenotype that shares features with other MAP3K7-linked pathologies, including frontometaphyseal dysplasia 2 (FMD2) and the syndrome arising from an interstitial 6q15 deletions which envelop the gene. Other known mutations associated with CSCFS are plotted in black text (1,2,3).

Frontometaphyseal dysplasia 2 (FMD2) is a rare disease caused by MAP3K7 gene mutation. We report a 7-year-old sporadic patient with FMD2 due to a de novo splicing variant in MAP3K7. He has the common characteristics of FMD2 but also has some characteristics that have never been reported, which increases the clinical phenotype of FMD2. Moreover, no systematic description of the imaging characteristics of FMD2 in computed tomography (CT) is available. In the present work, we found some different features of FMD2, reviewed previous literature, and summarized the general imaging manifestations of FMD2. This case emphasizes the important clinical value of CT and VR in the diagnosis of FMD2. We can clearly find the characteristics of FMD2 by CT examination, indicating its great significance for the prompt diagnosis and treatment of FMD2 patients. La displasia frontometafisaria 2 (DFM2) es una enfermedad rara causada por una mutación en el gen MAP3K7. En este artículo, se informa sobre un paciente de 7 años con DFM2 causada por una variante nueva de corte y empalme en MAP3K7. El paciente presenta las características frecuentes de la DFM2, pero algunas nunca antes informadas. No se dispone de una descripción sistemática de las características de las imágenes tomográficas de la DFM2. Describimos ciertas diferencias en las características de la DFM2, la bibliografía publicada y las manifestaciones imagenológicas generales de la DFM2. Este caso resalta la importancia del valor clínico de la tomografía computada (TC) y la renderización de volúmenes (VR) en el diagnóstico de la DFM2. Las características de la DFM2 pueden observarse claramente en los estudios tomográficos, lo que señala la gran importancia de la TC para el diagnóstico y el tratamiento precoces de los pacientes con DFM2.