A homozygous missense variant in the PLCB4 gene causes severe phenotype of auriculocondylar syndrome type 2.

Auriculocondylar syndrome (ARCND) is a rare craniofacial birth defect characterized by malformations in the mandible and external ear (Question Mark Ear). Genetically, three distinct subtypes of ARCND (ARCND1, ARCND2, and ARCND3) have been identified. ARCND2 is linked to pathogenic variants in the PLCB4 gene (phospholipase C ß4). PLCB4 is a key effector of the EDN1-EDNRA pathway involved in craniofacial development via the induction, migration, and maintenance of neural crest cells. ARCND2 is typically inherited in an autosomal dominant pattern, with recessive inheritance pattern being rare. In this study, we report the first homozygous missense variant (NM_000933.4: c.2050G>A: p.(Gly684Arg)) in the PLCB4 gene causing ARCND in a 3-year-old patient with a severe clinical phenotype of the syndrome. The patient presented with typical craniofacial ARCND features, in addition to intestinal transit defect, macropenis, and hearing loss. These findings further delineate the phenotypic spectrum of ARCND associated with autosomal recessive PLCB4 loss of function variants. Notably, our results provide further evidence that these variants can result in a more severe and diverse manifestations of the syndrome. Clinicians should consider the rare features of this condition for better management of patients.

New locus underlying auriculocondylar syndrome (ARCND): 430 kb duplication involving TWIST1 regulatory elements.

BACKGROUND: Auriculocondylar syndrome (ARCND) is a rare genetic disease that affects structures derived from the first and second pharyngeal arches, mainly resulting in micrognathia and auricular malformations. To date, pathogenic variants have been identified in three genes involved in the EDN1-DLX5/6 pathway (PLCB4, GNAI3 and EDN1) and some cases remain unsolved. Here we studied a large unsolved four-generation family. METHODS: We performed linkage analysis, resequencing and Capture-C to investigate the causative variant of this family. To test the pathogenicity of the CNV found, we modelled the disease in patient craniofacial progenitor cells, including induced pluripotent cell (iPSC)-derived neural crest and mesenchymal cells. RESULTS: This study highlights a fourth locus causative of ARCND, represented by a tandem duplication of 430 kb in a candidate region on chromosome 7 defined by linkage analysis. This duplication segregates with the disease in the family (LOD score=2.88) and includes HDAC9, which is located over 200 kb telomeric to the top candidate gene TWIST1. Notably, Capture-C analysis revealed multiple cis interactions between the TWIST1 promoter and possible regulatory elements within the duplicated region. Modelling of the disease revealed an increased expression of HDAC9 and its neighbouring gene, TWIST1, in neural crest cells. We also identified decreased migration of iPSC-derived neural crest cells together with dysregulation of osteogenic differentiation in iPSC-affected mesenchymal stem cells. CONCLUSION: Our findings support the hypothesis that the 430 kb duplication is causative of the ARCND phenotype in this family and that deregulation of TWIST1 expression during craniofacial development can contribute to the phenotype.

Taste Alteration in External Auditory Canal Cholesteatoma: Indicator of Impending N VII Affection.

INTRODUCTION: External auditory canal cholesteatoma (EACC) is a rare disease, with an estimated incidence of approximately 1:1,000 adult and 1.6:1,000 pediatric otologic patients. Systematic studies of chronic ear disease and taste alteration prior to surgery are rare; in fact, there are no such studies for EACCs. Therefore, we describe chorda tympani nerve (CTN) dysfunction and the related clinical consequences in EACC patients. METHODS/STUDY DESIGN: Between 1992 and 2021, we retrospectively analyzed the symptoms, signs, and radiological and intraoperative descriptions of CTN involvement in 73 patients. Liquid taste tests and, since 2009, Taste StripsTM as well as an olfactory screening test (Smell DiskettesTM) have been performed for all symptomatic patients and, when feasible, all other EACC patients. RESULTS: Ten of 73 patients complained subjectively of dysfunction, and 8 showed abnormal taste test results. Four patients complained of olfactory dysfunction (3 cases with pathological taste tests). Gustatory dysfunction was most frequent in radiogenic EACC cases (n = 4), followed by postoperative EACC (n = 3). Two postoperative patients were asymptomatic despite abnormal test results. Rarely, patients with idiopathic (n = 2) and posttraumatic (n = 1) EACC showed acute taste dysfunction that was confirmed in each with abnormal test results. DISCUSSION/CONCLUSION: CTN dysfunction often developed asymptomatically in chronic ears, except for idiopathic and posttraumatic EACCs under previous healthy middle ear conditions. Taste disturbance is not a cardinal symptom of EACC, but objective testing suggests that up to one out of 10 EACC patients with advanced disease may experience regional gustatory dysfunction prior to surgery. Especially in context of a new and acute presentation, regional taste dysfunction may alert the clinician of potential progressive EACC invasion and danger to the facial nerve.

Chondrodermatitis Nodularis Nasi: A Case Report of a Rare Variant of Chondrodermatitis Nodularis Helicis.

ABSTRACT: Chondrodermatitis nodularis helicis is an inflammatory condition affecting the helix or antihelix of the ear. It is commonly described as a solitary, painful, ulcerated nodule affecting the cartilage or skin because of continuous pressure, trauma, sun exposure, or ischemic changes. In this case report, we present a rare variant of chondrodermatitis, named chondrodermatitis nodularis nasi, which affects the skin and cartilage of the nose. Clinical resemblance to neoplasms of the skin such as squamous cell carcinoma and basal cell carcinoma requires that a biopsy be performed for definitive diagnosis. On histopathological examination, chondrodermatitis presents as a central ulcer bordered by epidermal hyperplasia, hypergranulosis, hyperkeratosis, and parakeratosis with fibrin deposits in the papillary dermis admixed with sparse inflammatory cells. Included in this case report is a discussion of the clinical and histopathology of chondrodermatitis nodularis nasi. With increased frequency of diagnosing this rare variant, better management and treatments can be explored.

Patulous eustachian tube after balloon eustachian tuboplasty in a post-radiation patient.

BACKGROUND: Balloon eustachian tuboplasty (BET) is a minimally invasive surgical treatment that is effective and safe for obstructive eustachian tube dysfunction. However, BET complications include excessive widening of the eustachian tube, causing a patulous eustachian tube (PET). Herein, we report a case of PET following BET in a patient who underwent radiation therapy and reviewed the literature on considerations for reducing complications after BET. CASE PRESENTATION: A 63-year-old woman complained of bilateral ear fullness after concurrent chemoradiation therapy for nasopharyngeal lymphoma. BET was performed on the left side because the left-sided serous otitis media persisted. A left-sided PET was performed two weeks after the BET, along with eustachian tube silicone plug insertion on the left side. The patient became asymptomatic immediately after the surgery, with no recurrence reported after a 12-month follow-up period. CONCLUSIONS: To our knowledge, there has been no report of PET following BET in a post-radiation patient, and it was successfully treated via ET silicone plug insertion.

Merocel compression dressing: a novel modified surgical technique for treating auricular pseudocyst.

PURPOSE: Auricular pseudocyst (AP) is a benign, noninflammatory swelling to the ear, located on either the front or side surface. Deroofing surgery with variable compression methods is considered the most effective method. However, post-operative wound pain is the main drawback following compression. We are introducing a novel painless surgical procedure which involves deroofing technique followed by Merocel® compression dressing. METHODS: From 2015 to 2020, thirty-one patients with AP received this new surgical compression method in our university-affiliated tertiary hospital. Retrospective chart review and the analysis of the results were conducted. RESULTS: All patients had unilateral lesions, with left side lesions (58.1%) predominant. The concha cymba (38.7%) and concha cavum (35.8%) were the most common sites. Previous aspiration or drainage had been performed for the cysts in eight patients (25.8%). Only one patient had the recurrence after post-operative 3 months and received the revised surgery without following recurrence and discomfort. Among all patients, 29 (93.5%) patients claimed minimal pain around 0 or 1 in numeric rating scale of pain score. Three patients had mild ecchymosis but recovered after conservative treatment. One patient had mild auricular deformity after surgery due to pre-treatment partial cartilage necrosis. All patients had follow-up for at least 6 months. CONCLUSION: This novel Merocel® compression dressing technique to treat AP after deroofing is an effective procedure. Minimal pain, simple to do and easily acquired materials were the advantages of this novel procedure.

Mast Cells Are Activated in the Giant Earlobe Keloids: A Case Series.

Mast cells and inflammatory cells are abundant in keloid and hypertrophic scar tissues. Even if the cause of physical injury is similar, such as piercing or scratching with hands, clinical findings show differences in the size of keloids in the same area. Hence, we performed histological studies on giant keloids larger than the earlobe, and other smaller keloids. We also examined the risk factors associated with the formation of giant lesions. No statistically significant differences in the association of the risk factors were observed. However, histological observations clearly showed a high number of degranulated or active mast cells with a trend towards a greater number of degranulated mast cells in the giant keloid tissues. Collagen production also tended to increase. Two patients with giant keloids were severely obese, suggesting that the persistent inflammatory state of obesity may also be involved in the growth of keloid lesions.

A novel missense variant of the GNAI3 gene and recognisable morphological characteristics of the mandibula in ARCND1.

Auriculocondylar syndrome (ARCND) is an autosomal monogenic disorder characterised by external ear abnormalities and micrognathia due to hypoplasia of the mandibular rami, condyle and coronoid process. Genetically, three subtypes of ARCND (ARCND1, ARCND2 and ARCND3) have been reported. To date, five pathogenic variants of GNAI3 have been reported in ARCND1 patients. Here, we report a novel variant of GNAI3 (NM_006496:c.807C>A:p.(Asn269Lys)) in a Japanese girl with micrognathia using trio-based whole exome sequencing analysis. The GNAI3 gene encodes a heterotrimeric guanine nucleotide-binding protein. The novel variant locates the guanine nucleotide-binding site, and the substitution was predicted to interfere with guanine nucleotide-binding by in silico structural analysis. Three-dimensional computer tomography scan, or cephalogram, displayed severely hypoplastic mandibular rami and fusion to the medial and lateral pterygoid plates, which have been recognised in other ARCND1 patients, but have not been described in ARCND2 and ARCND3, suggesting that these may be distinguishable features in ARCND1.

An unexpected cyst of the ear lobule.

Branchial cleft anomalies (BCA) are among the most common congenital anomalies found in the pediatric head and neck. The embryology of these congenital anomalies is well understood, which allows clinicians to anticipate their diagnosis when a pediatric patient presents with a head or neck mass. The predictable anatomy of the various types of BCA allows for improved surgical planning to prevent recurrence and ensure complete resection. This report details an unusual location of a first BCA located in the ear lobule of a 10-month old male. There has been no documented first BCA at the ear lobule in the literature.

Screening Anti-Inflammatory Effects of Flavanones Solutions.

There are a large number of remedies in traditional medicine focused on relieving pain and inflammation. Flavanones have been a potential source in the search for leading compounds and biologically active components, and they have been the focus of much research and development in recent years. Eysenhardtia platycarpa is used in traditional medicine for the treatment of kidney diseases, bladder infections, and diabetes mellitus. Many compounds have been isolated from this plant, such as flavones, flavanones, phenolic compounds, triterpenoid acids, chalcones, sugars, and fatty acids, among others. In this paper, natural flavanone 1 (extracted from Eysenhardtia platycarpa) as lead compound and flavanones 1a-1d as its structural analogues were screened for anti-inflammatory activity using Molinspiration® and PASS Online in a computational study. The hydro alcoholic solutions (FS) of flavanones 1, 1a-1d (FS1, FS1a-FS1d) were also assayed to investigate their in vivo anti-inflammatory cutaneous effect using two experimental models, a rat ear edema induced by arachidonic acid (AA) and a mouse ear edema induced by 12-O-tetradecanoylphorbol acetate (TPA). Histological studies and analysis of pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6 were also assessed in AA-inflamed rat ear tissue. The results showed that the flavanone hydro alcoholic solutions (FS) caused edema inhibition in both evaluated models. This study suggests that the evaluated flavanones will be effective when used in the future in skin pathologies with inflammation, with the results showing 1b and 1d to be the best.

Sarcoidosis of the ear, nose and throat: A review of the literature.

OBJECTIVES: Sarcoidosis is a multisystemic inflammatory disease with extrathoracic manifestations, most commonly affecting the young and middle-aged, female and Black populations. Diagnosis usually requires evidence of non-caseating granulomata and, when treated, prognosis is usually favourable. We aim to establish the incidence, clinical features and optimal treatment of ENT manifestations of this disease. DESIGN: We performed a PubMed literature review to determine the evidence base supporting this. RESULTS: ENT manifestations are present in 5%-15% of patients with sarcoidosis, often as a presenting feature, and require vigilance for swift recognition and coordinated additional treatment specific to the organ. Laryngeal sarcoidosis presents with difficulty in breathing, dysphonia and cough, and may be treated by speech and language therapy (SLT) or intralesional injection, dilatation or tissue reduction. Nasal disease presents with crusting, rhinitis, nasal obstruction and anosmia, usually without sinus involvement. It is treated by topical nasal or intralesional treatments but may also require endoscopic sinus surgery, laser treatment or even nasal reconstruction. Otological disease is uncommon but includes audiovestibular symptoms, both sensorineural and conductive hearing loss, and skin lesions. CONCLUSIONS: The consequences of ENT manifestations of sarcoidosis can be uncomfortable, disabling and even life-threatening. Effective management strategies require good diagnostic skills and use of specific therapies combined with established treatments such as corticosteroids. Comparisons of treatment outcomes are needed to establish best practice in this area.

Primrose syndrome: Characterization of the phenotype in 42 patients.

Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down-slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha-fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype-phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.

Primrose syndrome associated with unclassified immunodeficiency and a novel ZBTB20 mutation.

Primrose syndrome is a congenital malformation syndrome characterized by intellectual disability, developmental delay, progressive muscle wasting, and ear lobe calcification. Mutations in the ZBTB20 gene have been established as being accountable for this syndrome. In this study, a novel de novo ZBTB20 mutation, NM_001164342.2:c.1945C>T (p.Leu649Phe), has been identified through whole exome sequencing (WES) in a female patient presenting a typical Primrose phenotype. Because the present patient exhibited recurrent otitis media, detailed immunological examinations were performed in this study and subnormal immunoglobulin levels were firstly identified in a Primrose patient. Anatomical anomaly of the inner ear has never been reported in this patient and WES data did not include any relevant variants causally linked with the immunologic defect. Thus, there is a possibility of a relation between an unclassified immunodeficiency with selective IgG2 deficiency and Primrose syndrome and this may be the reason of recurrent otitis media frequently observed in Primrose patients. Because subnormal levels of IgG2 in this patient might be caused by an unrelated and still uncharacterized genetic cause, further studies are required to prove the causal link between aberrant ZBTB20 function and immunodeficiency.

Mast Cells Limit Ear Swelling Independently of the Chymase Mouse Mast Cell Protease 4 in an MC903-Induced Atopic Dermatitis-Like Mouse Model.

Atopic dermatitis (AD) is a complex, often lifelong allergic disease with severe pruritus affecting around 10% of both humans and dogs. To investigate the role of mast cells (MCs) and MC-specific proteases on the immunopathogenesis of AD, a vitamin D3-analog (MC903) was used to induce clinical AD-like symptoms in c-kit-dependent MC-deficient Wsh-/- and the MC protease-deficient mMCP-4-/-, mMCP-6-/-, and CPA3-/- mouse strains. MC903-treatment on the ear lobe increased clinical scores and ear-thickening, along with increased MC and granulocyte infiltration and activity, as well as increased levels of interleukin 33 (IL-33) locally and thymic stromal lymphopoietin (TSLP) both locally and systemically. The MC-deficient Wsh-/- mice showed significantly increased clinical score and ear thickening albeit having lower ear tissue levels of IL-33 and TSLP as well as lower serum levels of TSLP as compared to the WT mice. In contrast, although having significantly increased IL-33 ear tissue levels the chymase-deficient mMCP-4-/- mice showed similar clinical score, ear thickening, and TSLP levels in ear tissue and serum as the WT mice, whereas mMCP-6 and CPA3 -deficient mice showed a slightly reduced ear thickening and granulocyte infiltration. Our results suggest that MCs promote and control the level of MC903-induced AD-like inflammation.

Effect of Terpenoids and Flavonoids Isolated from Baccharis conferta Kunth on TPA-Induced Ear Edema in Mice.

In this study, we isolated from the aerial parts of Baccharis conferta Kunth (i) a new neoclerodane, denominated "bacchofertone"; (ii) four known terpenes: schensianol A, bacchofertin, kingidiol and oleanolic acid; and (iii) two flavonoids: cirsimaritin and hispidulin. All structures were identified by an exhaustive analysis of nuclear magnetic resonance (NMR) and mass spectroscopy (MS). Extracts from aerial parts were screened for anti-inflammatory activity in the mice ear edema model of 12-O-tetradecanoylforbol-13-acetate mice. Dichloromethane extract (BcD) exhibited 78.5 ± 0.72% inhibition of edema, followed by the BcD2 and BcD3 fractions of 71.4% and 82.9% respectively, at a dose of 1 mg/ear. Kingidiol and cirsimaritin were the most potent compounds identified, with a median effective dose of 0.12 and 0.16 mg/ear, respectively. A histological analysis showed that the topical application of TPA promoted intense cell infiltration, and this inflammatory parameter was reduced with the topical application of isolated compounds.

Recurrent angiolymphoid hyperplasia with eosinophilia during several pregnancies.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare, benign vascular tumor. Although its etiology is not clearly known, infection, hormonal factors, and trauma are the suspected reasons. There are few cases considered to be related to pregnancy described in the literature. Granulomas are rarely seen in the histopathology and only four patients with granulomas have been described. Herein, we will present a 28-year-old woman who has been pregnant three times; in every pregnancy, she developed pink nodular lesions on the back of her ear. In the first two pregnancies, the lesions had appeared during the pregnancy and regressed completely in the postpartum period. In her third pregnancy, the condition emerged again and lasted 1.5 years after birth of her child. Histopathology exhibited ALHE with granulomas. Although the relationship between ALHE and pregnancy is already known, there are few cutaneous ALHE cases associated with pregnancy reported in the literature. This association is further supported by this case having recurrent ALHE during each pregnancy period. Also, the presence of naked granuloma in histopathology, unlike most of the cases, contributes to the current histopathological data.

Tophaceous Gout of the Middle Ear: Case Reports and Review of the Literature.

Tophaceous gout of the middle ear is a rare occurrence that presents as a granular white-colored mass. It is frequently misdiagnosed as cholesteatoma or tympanosclerosis in patients who otherwise may not manifest any clinical or biochemical signs of gout. While uncommon, it can lead to clinically significant disease such as conductive hearing loss. The present report describes 2 cases of middle ear gouty tophi initially mistaken for another entity. Both patients underwent surgery, and the diagnosis of gout was revealed after final histopathological analysis. A review of the literature is also presented.

Pediatric chondrodermatitis nodularis helicis (CNH) in a child with Beckwith-Wiedemann syndrome (BWS).

Chondrodermatitis nodularis helicis is an idiopathic degenerative process that presents as a painful nodule, papule, or ulcer on the helix or antihelix. It predominantly affects adults and is thought to be associated with trauma to the ear. We describe a case of pediatric chondrodermatitis nodularis helicis occurring in a child with a history of Beckwith-Wiedemann syndrome that was successfully treated with an excisional biopsy and relief from a recurrent source of pressure on the ear.

Angiolymphoid hyperplasia with eosinophilia of the external ear.

Herein we present the rare case of angiolymphoid hyperplasia with eosinophilia of the external ear treated by surgical resection and full-thickness skin graft. Current diagnosis and management options are reviewed.