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1.
Int J Mol Sci ; 22(16)2021 Aug 18.
Article En | MEDLINE | ID: mdl-34445584

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.


Anti-Inflammatory Agents/pharmacology , Ear Diseases/drug therapy , Edema/drug therapy , Fabaceae/chemistry , Flavanones/pharmacology , Inflammation/drug therapy , Plant Extracts/pharmacology , Animals , Ear Diseases/pathology , Edema/pathology , High-Throughput Screening Assays , Inflammation/pathology , Mice , Rats , Rats, Wistar
2.
Sci Rep ; 11(1): 10839, 2021 05 25.
Article En | MEDLINE | ID: mdl-34035389

Early detection and appropriate medical treatment are of great use for ear disease. However, a new diagnostic strategy is necessary for the absence of experts and relatively low diagnostic accuracy, in which deep learning plays an important role. This paper puts forward a mechanic learning model which uses abundant otoscope image data gained in clinical cases to achieve an automatic diagnosis of ear diseases in real time. A total of 20,542 endoscopic images were employed to train nine common deep convolution neural networks. According to the characteristics of the eardrum and external auditory canal, eight kinds of ear diseases were classified, involving the majority of ear diseases, such as normal, Cholestestoma of the middle ear, Chronic suppurative otitis media, External auditory cana bleeding, Impacted cerumen, Otomycosis external, Secretory otitis media, Tympanic membrane calcification. After we evaluate these optimization schemes, two best performance models are selected to combine the ensemble classifiers with real-time automatic classification. Based on accuracy and training time, we choose a transferring learning model based on DensNet-BC169 and DensNet-BC1615, getting a result that each model has obvious improvement by using these two ensemble classifiers, and has an average accuracy of 95.59%. Considering the dependence of classifier performance on data size in transfer learning, we evaluate the high accuracy of the current model that can be attributed to large databases. Current studies are unparalleled regarding disease diversity and diagnostic precision. The real-time classifier trains the data under different acquisition conditions, which is suitable for real cases. According to this study, in the clinical case, the deep learning model is of great use in the early detection and remedy of ear diseases.


Ear Diseases/diagnosis , Image Interpretation, Computer-Assisted/methods , Adult , Deep Learning , Ear Diseases/pathology , Early Diagnosis , Endoscopy , Female , Humans , Male , Neural Networks, Computer , Sensitivity and Specificity , Severity of Illness Index , Young Adult
3.
PLoS One ; 16(3): e0247708, 2021.
Article En | MEDLINE | ID: mdl-33651800

Chronic obstructive Eustachian tube dysfunction (ETD) is a common disorder of the middle ear. In recent years, two main diagnostic tools have become available: Eustachian tube score (ETS-7) and computed tomography (CT) combined with Valsalva maneuver. The aim of this study is to evaluate the outcomes of ETS-7 and CT in a group of patients affected by middle ear atelectasis with a strong suspicion of ETD. Three males and nine females, affected by middle ear atelectasis with retraction of the TM were enrolled. Each patient underwent to Eustachian tube dysfunction evaluation adopting the ETS-7 score and a temporal bone CT with Valsalva maneuver. The ears analyzed at steady state were divided into 2 groups: ETS<7 group and ETS≥ 7 group. The same division was applied for the ears analyzed after the Valsalva maneuver: ETS<7 group and ETS≥ 7 group. ETs were categorized as "well defined" (WD) and "not defined" (ND). The results of the analysis of the ETS-7 score in all 24 ears showed that 42% presented ETS ≥7, while 58% had ETS <7, indicating a diagnosis of ETD. In the ETS<7 group after Valsalva, ET was visualized in 33% of patients. In the ETS≥7 group it was WD in 29% after the Valsalva manoeuver. In both groups the comparison between the visualization of the ET before and after the Valsalva manoeuver did not present a statistical difference. No correlation emerged between ET evaluation with CT scan during Valsalva maneuver and ETS-7 score. It confirms that there is not a gold standard for the study of ET dysfunction.


Ear Diseases/pathology , Eustachian Tube/pathology , Valsalva Maneuver/physiology , Adolescent , Adult , Aged , Ear Diseases/diagnostic imaging , Ear Diseases/therapy , Eustachian Tube/diagnostic imaging , Female , Humans , Male , Middle Aged , Prospective Studies , Research Design , Tomography, X-Ray Computed
5.
Am J Otolaryngol ; 42(4): 102976, 2021.
Article En | MEDLINE | ID: mdl-33610922

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.


Branchial Region/abnormalities , Craniofacial Abnormalities/surgery , Cysts/surgery , Ear Diseases/surgery , Ear/surgery , Otorhinolaryngologic Surgical Procedures/methods , Pharyngeal Diseases/surgery , Branchial Region/physiology , Branchial Region/surgery , Craniofacial Abnormalities/complications , Cysts/etiology , Cysts/pathology , Ear Diseases/pathology , Ear Diseases/therapy , Hematoma/therapy , Humans , Infant , Male , Paracentesis , Pharyngeal Diseases/complications , Postoperative Complications/therapy , Therapeutic Irrigation , Treatment Outcome
6.
Laryngoscope ; 131(4): E1315-E1321, 2021 04.
Article En | MEDLINE | ID: mdl-32888356

OBJECTIVES: The post-traumatic ear deformity, known today as cauliflower ear, has been described since antiquity. It has long been associated with pugilistic sports (wrestling, boxing) as well as among the mentally ill. The aim of this study is to present the various terms used since antiquity to describe these traumatic deformations of the auricle and to trace the origin of the modern moniker "cauliflower ear." METHODS: Historical study, only based on original documentation accessed through personal libraries and universities repositories, completed with online sources and etymological dictionaries. RESULTS: We were able to identify no fewer than 39 names for the deformity. The term cauliflower ear is of relatively recent origin. It was coined in the first decade of the 20th century, initially in the popular press and subsequently adopted by the medical profession. CONCLUSION: Ironically, the deformity has only superficial resemblance to a cauliflower. The vegetable, which is part of the cabbage family, has a symmetrical and highly ordered fractal geometry with well-circumscribed excrescences. Cauliflower ear, by contrast, notably lacks symmetry and its rounded protuberances flow into one another. Although somewhat a misnomer, the term is deeply rooted in both popular and medical culture. LEVEL OF EVIDENCE: N/A Laryngoscope, 131:E1315-E1321, 2021.


Athletic Injuries/complications , Ear Auricle/abnormalities , Ear Auricle/injuries , Ear Deformities, Acquired/etiology , Ear Auricle/blood supply , Ear Auricle/pathology , Ear Deformities, Acquired/diagnosis , Ear Deformities, Acquired/history , Ear Deformities, Acquired/pathology , Ear Diseases/etiology , Ear Diseases/history , Ear Diseases/pathology , Hematoma/complications , History, 18th Century , History, 19th Century , History, 20th Century , History, Ancient , History, Medieval , Humans , Sports/trends , Terminology as Topic
8.
Int J Immunopathol Pharmacol ; 34: 2058738420959554, 2020.
Article En | MEDLINE | ID: mdl-33084473

AIM: The present review aimed to consolidate and analyze the recent information about the use of zebrafish in studies concerning cisplatin-induced ototoxicity and otoprotection. MATERIAL AND METHODS: The PubMed, Web of Science, and Scopus databanks were searched using the following MESH terms: zebrafish, cisplatin, ototoxicity. The identified publications were screened according to inclusion and exclusion criteria and the 26 qualifying manuscripts were included in the full-text analysis. The experimental protocols, including cisplatin concentrations, the exposure duration and the outcome measurements used in zebrafish larvae studies, were evaluated and the reported knowledge was summarized. RESULTS: Twenty-six substances protecting from cisplatin-induced toxicity were identified with the use of zebrafish larvae. These substances include quinine, salvianolic acid B, berbamine 6, benzamil, quercetin, dexmedetomidine, dexamethsanone, quinoxaline, edaravone, apocynin, dimethyl sulfoxide, KR-22335, SRT1720, ORC-13661, 3-MA, D-methionine, mdivi-1, FUT-175, rapamycin, Z-LLF-CHO, ATX, NAC, CYM-5478, CHCP1, CHCP2 and leupeptin. The otoprotective effects of compounds were attributed to their anti-ROS, anti-apoptotic and cisplatin uptake-blocking properties. The broadest range of protection was achieved when the experimental flow used preconditioning with an otoprotective compound and later a co-incubation with cisplatin. Protection against a high concentration of cisplatin was observed only in protocols using short exposure times (4 and 6 h). CONCLUSIONS: The data extracted from the selected papers confirm that despite the differences between the human and the zebra fish hearing thresholds (as affected by cisplatin), the sensory cells of zebrafish and larval zebrafish are a valuable tool which could be used: (i) for the discovery of novel otoprotective substances and compounds; (ii) to screen their side effects and (iii) to extend the knowledge on the mechanisms of cisplatin-induced inner ear damage. For future studies, the development of a consensus experimental protocol is highly recommended.


Cisplatin , Ear Diseases/prevention & control , Lateral Line System/drug effects , Protective Agents/pharmacology , Zebrafish , Animals , Apoptosis/drug effects , Cytoprotection , Disease Models, Animal , Ear Diseases/chemically induced , Ear Diseases/metabolism , Ear Diseases/pathology , Lateral Line System/metabolism , Lateral Line System/pathology , Ototoxicity , Reactive Oxygen Species/metabolism , Species Specificity , Zebrafish/embryology
9.
Dermatol Online J ; 26(8)2020 Aug 15.
Article En | MEDLINE | ID: mdl-32941719

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.


Angiolymphoid Hyperplasia with Eosinophilia/pathology , Ear Auricle/pathology , Laser Therapy , Pregnancy Complications/pathology , Adult , Angiolymphoid Hyperplasia with Eosinophilia/surgery , Biopsy , Ear Auricle/surgery , Ear Diseases/pathology , Ear Diseases/surgery , Female , Humans , Pregnancy , Recurrence
10.
Int J Mol Sci ; 21(17)2020 Aug 31.
Article En | MEDLINE | ID: mdl-32878208

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.


Calcitriol/analogs & derivatives , Dermatitis, Atopic/immunology , Ear Diseases/prevention & control , Hypersensitivity/prevention & control , Inflammation/prevention & control , Mast Cells/immunology , Serine Endopeptidases/physiology , Animals , Calcitriol/toxicity , Dermatitis, Atopic/chemically induced , Dermatitis, Atopic/metabolism , Dermatitis, Atopic/pathology , Dermatologic Agents/toxicity , Ear Diseases/etiology , Ear Diseases/metabolism , Ear Diseases/pathology , Female , Hypersensitivity/etiology , Hypersensitivity/metabolism , Hypersensitivity/pathology , Inflammation/etiology , Inflammation/metabolism , Inflammation/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout
11.
Eur J Med Genet ; 63(8): 103967, 2020 Aug.
Article En | MEDLINE | ID: mdl-32473227

Primrose syndrome (OMIM 259050) is a rare disorder characterised by macrocephaly with developmental delay, a recognisable facial phenotype, altered glucose metabolism, and other features such as sensorineural hearing loss, short stature, and calcification of the ear cartilage. It is caused by heterozygous variants in ZBTB20, a member of the POK family of transcription repressors. Recently, this gene was shown to have a role in skeletal development through its action on chondrocyte differentiation by repression of SOX9. We describe five unrelated patients with Primrose syndrome and distinct skeletal features including multiple Wormian bones, platybasia, bitemporal bossing, bathrocephaly, slender bones, epiphyseal and spondylar dysplasia. The radiological abnormalities of the skull and the epiphyseal dysplasia were the most consistent findings. This novel constellation of skeletal features expands the phenotypic spectrum of the disorder.


Abnormalities, Multiple/pathology , Bone and Bones/abnormalities , Calcinosis/pathology , Ear Diseases/pathology , Intellectual Disability/pathology , Muscular Atrophy/pathology , Phenotype , Abnormalities, Multiple/genetics , Adolescent , Bone and Bones/diagnostic imaging , Calcinosis/genetics , Child , Child, Preschool , Ear Diseases/genetics , Female , Humans , Intellectual Disability/genetics , Male , Muscular Atrophy/genetics , Nerve Tissue Proteins/genetics , SOXB1 Transcription Factors/genetics , Transcription Factors/genetics , Young Adult
12.
Clin Genet ; 97(6): 890-901, 2020 06.
Article En | MEDLINE | ID: mdl-32266967

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.


Abnormalities, Multiple/genetics , Calcinosis/genetics , Ear Diseases/genetics , Genetic Predisposition to Disease , Intellectual Disability/genetics , Megalencephaly/genetics , Muscular Atrophy/genetics , Nerve Tissue Proteins/genetics , Transcription Factors/genetics , 3-Hydroxyacyl CoA Dehydrogenases/genetics , Abnormalities, Multiple/pathology , Acetyl-CoA C-Acyltransferase/genetics , Adolescent , Adult , Calcinosis/pathology , Carbon-Carbon Double Bond Isomerases/genetics , Child , Child, Preschool , Ear Diseases/pathology , Enoyl-CoA Hydratase/genetics , Face/abnormalities , Female , Genetic Association Studies , Heterozygote , Humans , Infant , Intellectual Disability/pathology , Male , Megalencephaly/pathology , Middle Aged , Mitochondria/genetics , Mitochondria/pathology , Muscular Atrophy/pathology , Mutation , Mutation, Missense/genetics , Phenotype , Racemases and Epimerases/genetics , Testicular Neoplasms , Young Adult
13.
Diagn Cytopathol ; 48(7): 666-669, 2020 Jul.
Article En | MEDLINE | ID: mdl-32275346

Juvenile xanthogranulomas (JXG) are the most common type of self-limiting non-Langerhans cell histiocytosis (LCH) usually presenting in infancy and early childhood. Clinically, they present as solitary to multiple rounded cutaneous nodules which resolve over time. Adult type xanthogranulomas (AXG), though histologically similar to JXG, are usually single and do not regress spontaneously. AXG arising in the external auditory canal (EAC) is a rare occurrence with very few cases reported in literature. We present a case of AXG in a 48-year-old man, arising from the right EAC. This case is unique as it is the only case to be described with both cytology and histology correlation. On cytology, smears showed scattered foamy histiocytes, inflammatory cells and thick stromal fragments. Cytology differential diagnoses of xanthomatous lesion, benign fibrous histiocytoma (BFH) and ceruminous adenoma were given; final diagnosis was deferred to histopathology which confirmed it to be an AXG. Thus, it is important to keep the diagnosis of AXG in mind while dealing with solitary polypoidal lesions in EAC showing prominent foam cell component. Lipidised BFH forms a close differential diagnosis, however can be excluded by subtle points on cytology and on histopathology.


Ear Canal/pathology , Ear Diseases/pathology , Histiocytosis, Non-Langerhans-Cell/pathology , Humans , Male , Middle Aged
14.
Molecules ; 25(6)2020 Mar 18.
Article En | MEDLINE | ID: mdl-32197377

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.


Anti-Inflammatory Agents , Baccharis/chemistry , Ear Diseases , Edema , Flavones , Terpenes , Tetradecanoylphorbol Acetate/toxicity , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , Anti-Inflammatory Agents/pharmacology , Disease Models, Animal , Ear Diseases/chemically induced , Ear Diseases/drug therapy , Ear Diseases/metabolism , Ear Diseases/pathology , Edema/chemically induced , Edema/drug therapy , Edema/metabolism , Edema/pathology , Flavones/chemistry , Flavones/isolation & purification , Flavones/pharmacology , Male , Mice , Mice, Inbred ICR , Terpenes/chemistry , Terpenes/isolation & purification , Terpenes/pharmacology
15.
Eur J Med Genet ; 63(6): 103917, 2020 Jun.
Article En | MEDLINE | ID: mdl-32201334

Auriculocondylar syndrome (ARCND, MIM #614669, #602483, and #615706); also known as ''question-mark ear syndrome'' or ''dysgnathia complex'', is a rare craniofacial malformation of first and second branchial arches with a prevalence of <1/1,000,000. It is characterized by a distinctive auricular malformation (question mark ear (QME)) and highly variable mandibular anomalies. Variants found in PLCB4, GNAI3, and in EDN1 genes are responsible for >90% of tested ARCND patients. Whole exome sequencing in a multigenerational Egyptian kindred with high intrafamilial variability revealed a known heterozygous missense variant in PLCB4 (NM_000933.3:c.1862G>A:p.(Arg621His)). This report increases the number of molecularly characterized ARCND patients to 29 and emphasizes the highly variable clinical presentation within families.


Ear Diseases/genetics , Ear/abnormalities , Mutation , Phenotype , Phospholipase C beta/genetics , Adolescent , Adult , Child , Ear/pathology , Ear Diseases/pathology , Endothelin-1/genetics , Female , GTP-Binding Protein alpha Subunits, Gi-Go/genetics , Humans , Male , Pedigree
16.
Eur J Hum Genet ; 28(8): 1044-1055, 2020 08.
Article En | MEDLINE | ID: mdl-32071410

Primrose syndrome is characterized by variable intellectual deficiency, behavior disorders, facial features with macrocephaly, and a progressive phenotype with hearing loss and ectopic calcifications, distal muscle wasting, and contractures. In 2014, ZBTB20 variants were identified as responsible for this syndrome. Indeed, ZBTB20 plays an important role in cognition, memory, learning processes, and has a transcription repressive effect on numerous genes. A more severe phenotype was discussed in patients with missense single nucleotide variants than in those with large deletions. Here, we report on the clinical and molecular results of 14 patients: 6 carrying ZBTB20 missense SNVs, 1 carrying an early truncating indel, and 7 carrying 3q13.31 deletions, recruited through the AnDDI-Rares network. We compared their phenotypes and reviewed the data of the literature, in order to establish more powerful phenotype-genotype correlations. All 57 patients presented mild-to-severe ID and/or a psychomotor delay. Facial features were similar with macrocephaly, prominent forehead, downslanting palpebral fissures, ptosis, and large ears. Hearing loss was far more frequent in patients with missense SNVs (p = 0.002), ectopic calcification, progressive muscular wasting, and contractures were observed only in patients with missense SNVs (p nonsignificant). Corpus callosum dysgenesis (p = 0.00004), hypothyroidism (p = 0.047), and diabetes were also more frequent in this group. However, the median age was 9.4 years in patients with deletions and truncating variant compared with 15.1 years in those with missense SNVs. Longer follow-up will be necessary to determine whether the phenotype of patients with deletions is also progressive.


Abnormalities, Multiple/genetics , Calcinosis/genetics , Ear Diseases/genetics , Intellectual Disability/genetics , Muscular Atrophy/genetics , Nerve Tissue Proteins/genetics , Phenotype , Transcription Factors/genetics , Abnormalities, Multiple/pathology , Adolescent , Calcinosis/pathology , Child , Child, Preschool , Chromosome Deletion , Chromosomes, Human, Pair 3/genetics , Corpus Callosum/diagnostic imaging , Ear Diseases/pathology , Humans , Intellectual Disability/pathology , Muscular Atrophy/pathology , Mutation, Missense
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