KMT2D regulates activation, localization, and integrin expression by T-cells.

Individuals with Kabuki syndrome present with immunodeficiency; however, how pathogenic variants in the gene encoding the histone-modifying enzyme lysine methyltransferase 2D (KMT2D) lead to immune alterations remain poorly understood. Following up on our prior report of KMT2D-altered integrin expression in B-cells, we performed targeted analyses of KMT2D's influence on integrin expression in T-cells throughout development (thymocytes through peripheral T-cells) in murine cells with constitutive- and conditional-targeted Kmt2d deletion. Using high-throughput RNA-sequencing and flow cytometry, we reveal decreased expression (both at the transcriptional and translational levels) of a cluster of leukocyte-specific integrins, which perturb aspects of T-cell activation, maturation, adhesion/localization, and effector function. H3K4me3 ChIP-PCR suggests that these evolutionary similar integrins are under direct control of KMT2D. KMT2D loss also alters multiple downstream programming/signaling pathways, including integrin-based localization, which can influence T-cell populations. We further demonstrated that KMT2D deficiency is associated with the accumulation of murine CD8+ single-positive (SP) thymocytes and shifts in both human and murine peripheral T-cell populations, including the reduction of the CD4+ recent thymic emigrant (RTE) population. Together, these data show that the targeted loss of Kmt2d in the T-cell lineage recapitulates several distinct features of Kabuki syndrome-associated immune deficiency and implicates epigenetic mechanisms in the regulation of integrin signaling.

Immunological Aspects of Kabuki Syndrome: A Retrospective Multicenter Study of the Italian Primary Immunodeficiency Network (IPINet).

Kabuki Syndrome (KS) is a multisystemic genetic disorder. A portion of patients has immunological manifestations characterized by increased susceptibility to infections and autoimmunity. Aiming to describe the clinical and laboratory immunological aspects of KS, we conducted a retrospective multicenter observational study on patients with KS treated in centers affiliated to the Italian Primary Immunodeficiency Network.Thirty-nine patients were enrolled, with a median age at evaluation of 10 years (range: 3 m-21y). All individuals had organ malformations of variable severity. Congenital heart defect (CHD) was present in 19/39 patients (49%) and required surgical correction in 9/39 (23%), with associated thymectomy in 7/39 (18%). Autoimmune cytopenia occurred in 6/39 patients (15%) and was significantly correlated with thymectomy (p < 0.002), but not CHD. Individuals with cytopenia treated with mycophenolate as long-term immunomodulatory treatment (n = 4) showed complete response. Increased susceptibility to infections was observed in 22/32 patients (69%). IgG, IgA, and IgM were low in 13/29 (45%), 13/30 (43%) and 4/29 (14%) patients, respectively. Immunoglobulin substitution was required in three patients. Lymphocyte subsets were normal in all patients except for reduced naïve T-cells in 3/15 patients (20%) and reduced memory switched B-cells in 3/17 patients (18%). Elevated CD3 + TCRαß + CD4-CD8-T-cells were present in 5/17 individuals (23%) and were correlated with hematological and overall autoimmunity (p < 0.05).In conclusion, immunological manifestations of KS in our cohort include susceptibility to infections, antibody deficiency, and autoimmunity. Autoimmune cytopenia is correlated with thymectomy and elevated CD3 + TCRαß + CD4-CD8-T-cells, and benefits from treatment with mycophenolate.

Autoimmune Cytopenias and Dysregulated Immunophenotype Act as Warning Signs of Inborn Errors of Immunity: Results From a Prospective Study.

Inborn errors of immunity (IEI) are genetic disorders characterized by a wide spectrum of clinical manifestations, ranging from increased susceptibility to infections to significant immune dysregulation. Among these, primary immune regulatory disorders (PIRDs) are mainly presenting with autoimmune manifestations, and autoimmune cytopenias (AICs) can be the first clinical sign. Significantly, AICs in patients with IEI often fail to respond to first-line therapy. In pediatric patients, autoimmune cytopenias can be red flags for IEI. However, for these cases precise indicators or parameters useful to suspect and screen for a hidden congenital immune defect are lacking. Therefore, we focused on chronic/refractory AIC patients to perform an extensive clinical evaluation and multiparametric flow cytometry analysis to select patients in whom PIRD was strongly suspected as candidates for genetic analysis. Key IEI-associated alterations causative of STAT3 GOF disease, IKAROS haploinsufficiency, activated PI3Kδ syndrome (APDS), Kabuki syndrome and autoimmune lymphoproliferative syndrome (ALPS) were identified. In this scenario, a dysregulated immunophenotype acted as a potential screening tool for an early IEI diagnosis, pivotal for appropriate clinical management and for the identification of new therapeutic targets.

Autoimmune Vestibulocerebellar Syndromes.

Autoimmune disorders affecting the vestibular end organs, vestibular pathways, vestibular nuclei, and vestibulocerebellum are often underrecognized as a cause of chronic dizziness and ataxia. Autoantibodies specific for cell-surface, synaptic, and intracellular neural antigens serve as biomarkers of these disorders. This article describes the epidemiology, clinical presentation, diagnostic considerations, imaging findings, treatment, and prognosis of autoimmune disorders, in which the vestibulocerebellar syndrome is the main or presenting clinical presentation. Antibodies specific for intracellular antigenic targets described in the article are PCA-1 (Purkinje cell cytoplasmic antibody type 1, also known as anti-Yo), ANNA-1 (antinuclear neuronal antibody type 1, also known as anti-Hu), ANNA-2 (antinuclear neuronal antibody type 2, also known as anti-Ri), Ma1/2 (anti-Kelch-like 11/12 antibody), Kelch-like 11, amphiphysin, CV2 (collapsin response 2, also known as collapsin response mediator protein-5 [CRMP5]), VGCC (voltage-gated calcium channel), GAD65 (glutamic acid decarboxylase 65-kDa isoform), AP3B2 (adaptor protein 3B2, also known as anti-Nb), MAP1B (microtubule-associated protein 1B antibody, also known as anti-PCA-2), and neurochondrin antibodies. Antibodies targeting cell-surface or synaptic antigenic targets described in the article include DNER (delta/notchlike epidermal growth factor related receptor; antigen to anti-Tr), CASPR2 (contactin-associated proteinlike 2), septin-5, Homer-3, and mGluR1 (metabotropic glutamate receptor 1). The vestibulocerebellar presentation is largely indistinguishable among these conditions and is characterized by subacute onset of cerebellar symptoms over weeks to months. The diagnosis of autoimmune vestibulocerebellar syndromes is based on a combination of clinical and serological features, with a limited role for neuroimaging. Subtle eye movement abnormalities can be an early feature in many of these disorders, and therefore a meticulous vestibulo-ocular examination is essential for early and correct identification. Cancer occurrence and its type are variable and depend on the autoantibody detected and other cancer risk factors. Treatment comprises immunotherapy and cancer-directed therapy. Acute immunotherapies such as intravenous immunoglobulin, plasma exchange, and steroids are used in the initial phase, and the use of long-term immunosuppression such as rituximab may be necessary in relapsing cases. Outcomes are better if immunotherapy is started early. The neurologic prognosis depends on multiple factors.

Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals.

PURPOSE: Kabuki syndrome (KS) (OMIM 147920 and 300867) is a rare genetic disorder characterized by specific facial features, intellectual disability, and various malformations. Immunopathological manifestations seem prevalent and increase the morbimortality. To assess the frequency and severity of the manifestations, we measured the prevalence of immunopathological manifestations as well as genotype-phenotype correlations in KS individuals from a registry. METHODS: Data were for 177 KS individuals with KDM6A or KMT2D pathogenic variants. Questionnaires to clinicians were used to assess the presence of immunodeficiency and autoimmune diseases both on a clinical and biological basis. RESULTS: Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively; 13.6% (24/177) had autoimmune disease (AID; 25.6% [11/43] in adults), 5.6% (10/177) with ≥2 AID manifestations. The most frequent AID manifestations were immune thrombocytopenic purpura (7.3% [13/177]) and autoimmune hemolytic anemia (4.0% [7/177]). Among nonhematological manifestations, vitiligo was frequent. Immune thrombocytopenic purpura was frequent with missense versus other types of variants (p = 0.027). CONCLUSION: The high prevalence of immunopathological manifestations in KS demonstrates the importance of systematic screening and efficient preventive management of these treatable and sometimes life-threatening conditions.

Abnormal Peyer patch development and B-cell gut homing drive IgA deficiency in Kabuki syndrome.

BACKGROUND: Kabuki syndrome (KS) is commonly caused by mutations in the histone-modifying enzyme lysine methyltransferase 2D (KMT2D). Immune dysfunction is frequently observed in individuals with KS, but the role of KMT2D in immune system function has not been identified. OBJECTIVE: We sought to understand the mechanisms driving KS-associated immune deficiency (hypogammaglobulinemia [low IgA], splenomegaly, and diminished immunization responses). METHODS: We performed a comprehensive evaluation of humoral immunity and secondary lymphoid tissues in an established KS (Kmt2d+/ßGeo) mouse model and validated select findings in a patient with KS. RESULTS: Compared with wild-type littermates, Kmt2d+/ßGeo mice demonstrated deficiencies in multiple B-cell lineages and reduced serum IgA and elevated IgM levels across multiple ages. The bone marrow, spleen, and intestine of Kmt2d+/ßGeo mice contained diminished numbers of IgA-secreting cells, while elevated germinal center B cells were found in the mesenteric lymph node and Peyer patches. Kmt2d+/ßGeo mice have decreased size and numbers of Peyer patches, a finding confirmed in human samples. We identified deficiency of Itgb7 RNA and protein expression, a gene encoding an adhesion protein that mediates intestinal homing, and we demonstrated KMT2D-dependent control of ITGB7 expression in a human cell line. CONCLUSIONS: Kmt2d haploinsufficiency has broad deleterious effects on B-cell differentiation, specifically hampering gut lymphocyte homing and IgA+ plasma cell differentiation. Intestinal lymphoid defects caused by ITGB7 deficiency have not previously been recognized in KS, and these results provide new mechanistic insights into the pathogenesis of KS-associated immune deficiency.

Diabetes in the practice of otolaryngology.

Diabetes mellitus is the most common endocrine disease, characterized by chronic hyperglycemia. The hyperglycemic milieu leads to endothelial injury in blood vessels of variant size, which results in microangiopathy and macroangiopathy (atherosclerosis). Consequential ischemia of nerves and hyperglycemia by itself lead to nerve degeneration and generalized neuropathy, affecting most often the sensory peripheral nerves and the autonomic nervous system. Auditory, vestibular and olfactory sensorium may be compromised by DM. People with DM have an increased susceptibility to infection, as a result of neutrophil dysfunction and impaired humoral immunity. Therefore DM predisposes to certain infectious diseases, such as fungal sinusitis or malignant otitis externa, which are rare in general population. Recovery from infections or from injuries may be compromised by coexisting DM. In this review we discuss complications of DM in the head and neck region. Otolaryngologists and general practitioners should be alert to specific conditions related to DM and be minded of the relevant complications and consequences.

Autoimmune vertigo: an update on vestibular disorders associated with autoimmune mechanisms.

The role of the immune system in mediating cochleovestibular pathologies has received increasing attention in recent years. Autoimmune vertigo may be an invalidating condition and may worsen the quality of life of affected patients, especially in the cases of delayed diagnosis. Since the etiopathogenesis is still not clear, also the treatment is not yet completely delineated. According to the clinical presentation, autoimmune vertigo can present as an isolated disorder or in association with systemic autoimmune diseases. The main feature in autoimmune vertigo is the presence of an abnormal immune response, in either absence or presence of systemic autoimmune disease, directed against delicate components of the inner ear. This may determine a functional or anatomical alteration, with an inflammatory reaction often devastating for hearing and balance. Being the exact pathogenesis unknown, the diagnosis of autoimmune vertigo is based either on clinical criteria or on a positive response to steroids. The earlier the diagnosis is made, the sooner the therapy can be installed, giving a chance to the recovery of inner ear damages. Corticosteroids represent the most effective and universally accepted treatment, even if other immunomodulatory drugs are now having a more extensive use. HIGHLIGHTS: Vertigo is relatively frequent in autoimmune diseases; however, it is often misdiagnosed or attributed to central nervous system alterations rather to specific inner ear involvement. Vertigo and other audiovestibular symptoms may be the first manifestation of an autoimmune disease and if correctly addressed could significantly contribute to early diagnosis of the underlying autoimmune disease. Early diagnosis of immune-related vertigo can lead to prompt initiation of targeted therapy with elevate chances of preventing irreversible damages to the inner ear. The presence of alternating phases of well-being and disabling symptoms in patients with vertigo should always been considered, as they could suggest an underlying autoimmune condition.

Sirolimus as an alternative treatment in patients with granulomatous-lymphocytic lung disease and humoral immunodeficiency with impaired regulatory T cells.

BACKGROUND: One of the most frequent non-infectious complications of humoral immunodeficiencies with a CVID-like pattern is a particular form of inflammatory lung disease which is called granulomatous-lymphocytic interstitial lung disease (GLILD). Its development worsens patient prognosis, with a significant decrease in survival. Currently, there are no unified guidelines regarding its management, and different combinations of immunosuppressants have been used with variable success. METHODS: Clinical and radiological data were collected from patient's medical charts. Flow cytometry was performed to characterize the immunological features with special focus in regulatory T cells (Tregs). RESULTS: A 16-year-old girl with Kabuki syndrome and a 12-year-old boy, both with a CVID-like humoral immunodeficiency on immunoglobulin replacement treatment, developed during follow-up an inflammatory complication radiologically, clinically, and histologically compatible with GLILD. They required treatment, and sirolimus was started, with very good response and no serious side effects. CONCLUSIONS: These 2 cases provide insight into the underlying local and systemic immune anomalies involved in the development of GLILD, including the possible role of Tregs. Combined chemotherapy is commonly used as treatment for GLILD when steroids fail, but there have been some reports of successful monotherapy. As far as we know, these are the first 2 GLILD patients treated successfully with sirolimus, suggesting the advisability of further study of mTOR inhibitors as a more targeted treatment for GLILD, if impairment in Tregs is demonstrated.

HASHIMOTO THYROIDITIS AND VESTIBULAR DYSFUNCTION.

OBJECTIVE: The aim of this review was to analyze the existing literature concerning the relationship between Hashimoto thyroiditis (HT) and vestibular dysfunction. METHODS: We used electronic databases (PubMed, EMBASE, Cochrane Library) to search and collect all published articles about the association between HT and vestibular disorders. RESULTS: Several observational and retrospective studies have postulated a relationship between thyroid autoimmunity and vestibular disorders. In most cases, an appropriate control group was lacking, and the impact of thyroid functional status could not precisely be established. In recent years, two well-designed prospective studies have provided convincing evidence that the association is not random. One article reported that patients with Ménière disease (MD) had a significantly higher prevalence of positive anti-thyroid autoantibody as compared to healthy controls. Moreover, more than half of MD patients had either positive anti-thyroid or non-organ-specific autoantibody titers, compared to less than 30% of both patients with unilateral vestibular paresis without cochlear involvement and healthy controls. Another study found that patients with benign paroxysmal positional vertigo (BPPV) had significantly higher serum thyroid-stimulating hormone and antithyroid autoantibody levels than healthy controls. Additionally, almost one-fifth of euthyroid patients with HT had signs of BPPV. CONCLUSION: The published results indicate that patients with MD or BPPV are potential candidates to also develop HT. Thus, in HT patients, the presence of even slight symptoms or signs potentially related to vestibular lesions should be carefully investigated. ABBREVIATIONS: AITD = autoimmune thyroid disease; BPPV = benign paroxysmal positional vertigo; EH = endolymphatic hydrops; HT = Hashimoto thyroiditis; L-T4 = L-thyroxine; MD = Ménière disease; PS = Pendred syndrome; Tg = thyroglobulin; TPO = thyroid peroxidase; TSH = thyroid-stimulating hormone.

Humoral deficiency in three paediatric patients with genetic diseases.

BACKGROUND: Primary immunodeficiencies (PID) represent a heterogeneous group of genetic disorders characterised by poor or absent function in one or more components of the immune system. Humoral or antibody immunodeficiencies are the most common form of PID, of which common variable immunodeficiency (CVID) is the most frequent symptomatic form. CVID is usually characterised by hypogammaglobulinaemia with poor antibody specificity, and an increased susceptibility to infections, autoimmunity and lymphoproliferation. Fewer than 10% of CVID patients have a known monogenic basis. Several chromosomal abnormalities (chromosome 18q-syndrome, monosomy 22, trisomy 8 and trisomy 21) are currently identified as causes of hypogammaglobulinaemia, and can manifest with recurrent infections and mimic CVID. METHODS: Review of clinical charts and laboratory results of paediatric patients followed in the outpatient clinic of PID with a diagnosis of genetic disease and humoral immunodeficiency. RESULTS: Three patients with different genetic diseases (19p13.3 deletion, a ring 18 chromosome and Kabuki syndrome), were identified. During follow-up, they developed signs and symptoms suggestive of humoral deficiency mimicking CVID, despite which immunoglobulin levels were quantified with considerable delay with respect to symptoms onset, and specific management was subsequently delayed. CONCLUSIONS: Patients with genetic abnormalities and recurrent infections should be evaluated for hypogammaglobulinaemia. An early diagnosis of humoral deficiency can allow treatment optimisation to prevent complications and sequelae.

Defects of B-cell terminal differentiation in patients with type-1 Kabuki syndrome.

BACKGROUND: Kabuki syndrome (KS) is a complex multisystem developmental disorder associated with mutation of genes encoding histone-modifying proteins. In addition to craniofacial, intellectual, and cardiac defects, KS is also characterized by humoral immune deficiency and autoimmune disease, yet no detailed molecular characterization of the KS-associated immune phenotype has been reported. OBJECTIVE: We sought to characterize the humoral immune defects found in patients with KS with lysine methyltransferase 2D (KMT2D) mutations. METHODS: We comprehensively characterized B-cell function in a cohort (n = 13) of patients with KS (age, 4 months to 27 years). RESULTS: Three quarters (77%) of the cohort had a detectable heterozygous KMT2D mutation (50% nonsense, 20% splice site, and 30% missense mutations), and 70% of the reported mutations are novel. Among the patients with KMT2D mutations (KMT2D(Mut/+)), hypogammaglobulinemia was detected in all but 1 patient, with IgA deficiency affecting 90% of patients and a deficiency in at least 1 other isoform seen in 40% of patients. Numbers of total memory (CD27(+)) and class-switched memory B cells (IgM(-)) were significantly reduced in patients with KMT2D(Mut/+) mutations compared with numbers in control subjects (P < .001). Patients with KMT2D(Mut/+) mutations also had significantly reduced rates of somatic hypermutation in IgG (P = .003) but not IgA or IgM heavy chain sequences. Impaired terminal differentiation was noted in primary B cells from patients with KMT2D(Mut/+) mutations. Autoimmune pathology was observed in patients with missense mutations affecting the SET domain and its adjacent domains. CONCLUSIONS: In patients with KS, autosomal dominant KMT2D mutations are associated with dysregulation of terminal B-cell differentiation, leading to humoral immune deficiency and, in some cases, autoimmunity. All patients with KS should undergo serial clinical immune evaluations.

Epigenetic control of the immune system: a lesson from Kabuki syndrome.

Kabuki syndrome (KS) is a rare multi-systemic disorder characterized by a distinct face, postnatal growth deficiency, mild-to-moderate intellectual disability, skeletal and visceral (mainly cardiovascular, renal, and skeletal) malformations, dermatoglyphic abnormalities. Its cause is related to mutations of two genes: KMT2D (histone-lysine N-methyltransferase 2D) and KDM6A (lysine-specific demethylase 6A), both functioning as epigenetic modulators through histone modifications in the course of embryogenesis and in several biological processes. Epigenetic regulation is defined as the complex of hereditable modifications to DNA and histone proteins that modulates gene expression in the absence of DNA nucleotide sequence changes. Different human disorders are caused by mutations of genes involved in the epigenetic regulation, and not surprisingly, all these share developmental defects, disturbed growth (in excess or defect), multiple congenital organ malformations, and also hematological and immunological defects. In particular, most KS patients show increased susceptibility to infections and have reduced serum immunoglobulin levels, while some suffer also from autoimmune manifestations, such as idiopathic thrombocytopenic purpura, hemolytic anemia, autoimmune thyroiditis, and vitiligo. Herein we review the immunological aspects of KS and propose a novel model to account for the immune dysfunction observed in this condition.

Immunologic assessment and KMT2D mutation detection in Kabuki syndrome.

Kabuki or Niikawa-Kuroki syndrome (KS) is a rare disorder with multiple malformations and recurrent infections, especially otitis media. This study aimed to investigate the genetic defects in Kabuki syndrome and determine if immune status is related to recurrent otitis media. Fourteen patients from 12 unrelated families were enrolled in the 9-year study period (2005-2013). All had Kabuki faces, cleft palate, developmental delay, mental retardation, and the short fifth finger. Recurrent otitis media (12/14) and hearing impairment (8/14) were also more common features. Immunologic analysis revealed lower memory CD19+ cells (11/13), lower memory CD4+ cells (8/13), undetectable anti-HBs antibodies (7/13), and antibody deficiency (7/13), including lower IgA (4), IgG (2), and IgG2 (1). Naïve emigrant lymphocytes, lymphocyte proliferation function, complement activity, and superoxide production in polymorphonuclear cells were all normal. All the patients had KMT2D mutations and 10 novel mutations of R1252X, R1757X,Y1998C, P2550R fs2604X, Q4013X, G5379X, E5425K, R5432X, R5432W, and R5500W. Resembling the phenotype of common variable immunodeficiency, KS patients with antibody deficiency, decreased memory cells, and poor vaccine response increased susceptibility to recurrent otitis media. Large-scale prospective studies are warranted to determine if regular immunoglobulin supplementation decreases the frequency of otitis media and severity of hearing impairment.

Idiopathic bilateral vestibulopathy: an autoimmune disease?

Bilateral vestibulopathy (BV) is the loss of function of both peripheral labyrinths or of the eighth nerves. Its etiology remains obscure in approximately 20% to 50% of cases (so-called idiopathic bilateral vestibulopathy, IBV). Alternatively, the cause could be viral or vascular; to date, causative gene mutations have not been identified. Other potential disease mechanisms include autoimmune disorders. Antibodies have been detected against inner ear tissue (primarily against vestibular membranous labyrinth). The data suggest that the bulk of anti-labyrinthine autoantibodies may be an epiphenomenon, but a small subgroup of organ-specific autoantibodies may synergize with a cellular response to develop vestibular lesions. The two key symptoms of BV are the following: 1. unsteadiness of gait, particularly in the dark or on uneven ground, and 2. oscillopsia associated with head movements. Episodes of vertigo are reported by patients with IBV, particularly early in the development of vestibular loss. Associated hearing loss seldom occurs in the idiopathic type of this condition. Post-mortem examinations revealed a remarkably selective loss of vestibular hair cells in the vestibular end organs but normal hair cells in the cochlea. The diagnosis is made with a simple bedside test for defective vestibular function. The diagnosis can be confirmed by bithermal caloric testing and pendular body rotation. The therapy is based on steroid treatment, and the early initiation of immunosuppression appears to be essential for therapeutic success.

Bilateral progressive hearing loss and vestibular dysfunction with inner ear antibodies.

Autoimmune inner ear disease (AIED) is a clinical syndrome of uncertain etiology. We present the neuro-otological findings of 2 cases of bilateral hearing loss, dizziness and the antibody profiles of the inner ears. Case 1 had bilateral progressive hearing loss, vestibular dysfunction and abnormal eye movement as the disease progressed. She had inner ear antibodies against 42 and 58kDa protein antigency on Western blot immune assay, and responded to glycocorticosteroid but not to immunosuppressant treatment. Intratympanic steroid injection temporally eliminated her symptoms. However, she developed idiopathic Cushing's syndrome and underwent labyrinthectomy. Case 2 became deaf as a teenager and experienced dizziness 10 years after becoming deaf. He reacted strongly to 68kDa protein and was a good responder to immunosuppressant with steroid. As we still lack a definitive diagnostic test for AIED, careful observation of the clinical course is critical for differential diagnosis regarding the bilateral progressive hearing loss.

The diagnosis of autoimmune inner ear disease: evidence and critical pitfalls.

The purpose of this paper is to review the current diagnostic work-up for patients with suspected Autoimmune Inner Ear Disease (AIED). AIED is a rare disease accounting for less than 1% of all cases of hearing impairment or dizziness, characterized by a rapidly progressive, often fluctuating, bilateral SNHL over a period of weeks to months. While specific tests for autoimmunity to the inner ear would be valuable, at the time of writing, there are none that are both commercially available and proven to be useful. Thus far, most of the identified antigens lack a clear association with localized inner ear pathology and the diagnosis of AIED is based either on clinical criteria and/or on a positive response to steroids. For clinical practice, we recommend an antigen-non-specific test battery including blood test for autoimmune disorders and for conditions that resemble autoimmune disorders. Nevertheless, if financial resources are limited, a very restricted work-up study may have a similar efficiency.

Immune-mediated audiovestibular disorders in the paediatric population: a review.

Recent studies show that several audiovestibular pathologies in the paediatric population may be immune-mediated. This is even more probable if the pathology is associated with a coexisting systemic autoimmune disorder. At this time, however, the current literature is limited to a few case reports, and little is known with regard to prevalence, diagnosis, and management of immune-mediated inner-ear disorders in children. This review aims to shed some light on clinical presentation, diagnosis, and treatment of paediatric immune-mediated inner-ear disorders. Sudden and progressive sensorineural hearing loss is discussed, in addition to some of the systemic autoimmune disorders commonly associated with immune-mediated audiovestibular pathology such as Cogan's syndrome, systemic lupus erythematosus, Behcet's disease, Sjogren's syndrome, and juvenile idiopathic arthritis.