HYPERGAMMAGLOBULINEMIA AND MYELOMA IN FIVE TIGERS (PANTHERA TIGRIS): CLINICOPATHOLOGICAL FINDINGS.

Five adult tigers (Panthera tigris) presented with a range of clinical signs, including paresis (2/5), lameness (2/5), ataxia (3/5), anorexia (5/5), and lethargy (5/5). Each tiger demonstrated elevated plasma globulin levels (7.8-14.8 g/dl; [reference interval 2-5.1 g/dl]) on routine biochemistry, confirmed as a monoclonal gammopathy using protein electrophoresis. Serum gammaglobulin concentration ranged from 5 to 7.5 g/dl, or 45.1-63.4% of total protein concentration. Azotemia was present in three tigers. Diagnostics and management varied with the presenting signs but included magnetic resonance imaging, radiography, chemotherapy, supportive care, and euthanasia. In each case, necropsy revealed a neoplastic plasma cell proliferation in the bone marrow and one or more extramedullary sites. Lytic lesions in the thoraco-lumbar spine were found in three animals, and one lesion was associated with spinal cord compression. Splenomegaly was present in 4/5 cases. Histopathology confirmed a plasma cell neoplasm in each case, and immunohistochemistry staining with multiple myeloma oncogene 1 (MUM1) was positive in each case. CD20 staining was performed in two cases and was positive in one. CD3 staining was performed in the same two cases, and was negative in each. Based on the clinical, gross, microscopic, and immunohistochemical findings, myeloma was diagnosed in all five tigers.

Acute hyperviscosity: syndromes and management.

Plasma hyperviscosity is a rare complication of both monoclonal and polyclonal disorders associated with elevation of immunoglobulins. Asymptomatic patients with an elevation in the serum viscosity do not require plasma exchange, and the majority will have other indications for therapeutic intervention. For patients with hemorrhagic or central nervous system manifestations, plasma exchange is the therapy of choice and is relatively safe. Viscosity measurements are not required to initiate therapy if the index of suspicion is high and the clinical presentation is typical. However, patients should have a sample sent for confirmation of the diagnosis. Whole-blood hyperviscosity is seen in patients with extreme elevation of the red cell and white cell count. Phlebotomy of patients with primary and secondary elevation of the red cell count is a well-established therapy.

[Rosai-Dorfman disease: Sinusal histiocytosis with massive lymphadenopathy]. / Histiocytose sinusale de Rosai­Dorfman.

Rosai-Dorfman sinusal histiocytosis is a benign histiocytic disorder presenting as large lymphadenopathies, mostly in the cervical area. Visceral involvement is not unusual. The diagnosis is based on histologic findings, showing intrasinusoidal histiocytic infiltration with pathognomonic emperipolesis features. Histiocytes display a normal activated phenotype. It probably represents a heterogeneous group of diseases with some common histopathologic findings. An association with immunologic abnormalities or auto-immune diseases, mostly auto-immunes cytopenias is possible. This is a criterion of poor prognosis. The evolution can sometimes be spontaneously favorable. Nonetheless, there is a risk of compression, due to the huge volume of tumoral masses, especially in case of orbital or epidural involvement. Therapeutic abstention is usually justified. Treatments are discussed in threatening forms, evolving forms or in case of poor prognosis factors. Treatment, when indicated, is not codified. Surgery, corticosteroids, immunosuppressive agents and/or alpha interferon can be used.

Síndrome de hiperinmunoglobulinemia E: revisión de la casuística con énfasis en las manifestaciones orofaciales / Hyperimmunoglobulinemia E syndrome: a review of the literature with emphasis on orofacial manifestations

El síndrome de Hiper EgE (SHIE) es una rara inmunodeficiencia caracterizada por abscesos cutáneos, neumonías recurrentes, conformación de neumatoceles y elevados niveles de IgE en suero. Se ha reconocido la asociación de rasgos faciales, esqueléticos y dentales, pero su frecuencia es poco conocida. Objetivo: describir la epidemiología, presentación clínica, hallazgos de laboratorio y tratamiento de este síndrome desde el punto de vista médico y odontológico, con énfasis en las manifestaciones estomatológicas y dentales. Métodos. Métodos: realizamos una revisión científica sistemática de todos los reporte y series de casos de SHIE en las bases de datos Lilacs, Medline, SciELO y Biblioteca Cochrane, utilizando como descriptores DeCS/MeSH las palabras claves: hyper IgE AND immunodeficiency, hypereosinophilia, Job´s syndrome, hiperinmunoglobulinemia E. Resultados: revisamos 31 publicaciones con 328 pacientes. Los abscesos cutáneos se encontraron en 89 pior ciento de los casos, la neumonía en el 87 por ciento y la IgE sérica dio una mediana de 3.417 Ul/mL. Los rasgos faciales característicos estuvieron en el 69 por ciento, las alteraciones dentarias en 58 por ciento y la candidiasis oral fue reportada en 53 por ciento de los pacientes. Conclusión: el síndrome de IgE es un desorden multisistémico que afecta a la dentición, el esqueleto, el tejido conectivo y el sistema inmune. Por esto, el odontopediatra debe ser capaz de reconocer el fenotipo orofacial para mejorar la calidad del diagnóstico y brindar el abordaje terapéutico apropiado...

Monoclonal hyperglobulinemia in lymphosarcoma in a cockatiel (Nymphicus hollandicus) and a blue and gold macaw (Ara ararauna).

A 15-yr-old cockatiel (Nymphicus hollandicus) presented with decreased activity and appetite. A presumptive diagnosis of lymphoproliferative disease was made because of a monoclonal band observed on plasma protein electrophoresis. The owner declined further diagnostics or treatment, and the bird died 2 yr later. In a second case, a 4-yr-old blue and gold macaw (Ara ararauna) presented with lethargy and anorexia. Despite supportive treatment, the bird died 7 days later. Blood studies also demonstrated a monoclonal band on plasma protein electrophoresis. The histologic review of tissues from both birds found extensive neoplastic lymphoplasmocytic cells in the liver and supported a diagnosis of lymphosarcoma.

The challenge of systemic immunoglobulin light-chain amyloidosis (Al).

The cardiac involvement and associated mortality that occur in systemic AL amyloidosis remain among the most challenging aspects of the systemic amyloid-related diseases. Monoclonal immunoglobulin light chains produced by a clone of plasma cells are usually the cause of symptoms and organ dysfunction via both poorly understood toxic effects of misfolded species and accumulation of interstitial amyloid fibrils in key viscera. Treatment is aimed at eliminating the clonal cells in order to eliminate toxic light chain production. Recent advances in therapy have helped many patients with AL achieve complete hematologic responses and significant reversal of organ damage but these benefits do not extend to that 10-15 % who present with advanced cardiac involvement. Even with cardiac transplant followed by effective therapy such as stem cell transplant, outcomes for these patients remain promising at best.

Granulomatous skin lesions, severe scrotal and lower limb edema due to mycobacterial infections in a child with complete IFN-γ receptor-1 deficiency.

Interferon-γ receptor-1 (IFNγR1) deficiency is caused by mutations in the IFNγR1 gene and is characterized mainly by susceptibility to mycobacterial disease. Herein, we report an 8-month-old boy with complete recessive IFNγR1 deficiency, afflicted by recurrent mycobacterial diseases with Mycobacterium bovis, Mycobacterium tuberculosis, Mycobacterium avium intracellulare and Mycobacterium fortuitum. Genetic analysis showed a homozygous mutation (106insT) in the IFNγR1 gene leading to complete IFNγR1 deficiency. In addition, he had atypical mycobacterial skin lesions caused by M. avium intracellulare and developed scrotal and lower limb lymphedema secondary to compression of large and fixed inguinal lymphadenopathies. Hematopoietic stem cell transplantation was performed from a matched unrelated donor at 5 years of age; however, he died at 9 months post-transplant. To our knowledge, the patient is the first case with IL-12/IFN-γ pathway defect and severe lymphedema. We have also reviewed and summarized the literature related with IFNγR1 deficiency.

Síndrome de hipergammaglobulinemia IgE con infecciones recurrentes: patogénesis, diagnóstico y aproximación terapéutica / Hyper-IgE recurrent infection syndrome: pathogenesis, diagnosis and therapeutic management

El síndrome de la hipergammaglobulinemia IgE con infecciones recurrentes es una inmunodeficiencia primaria poco frecuente, que se caracteriza por niveles elevados de IgE, dermatitis eccematoide, infecciones recurrentes de piel y pulmón por Staphylococcus aureus, y formación de abscesos con escasos signos inflamatorios. También produce alteraciones dentarias, esqueléticas y del tejido conjuntivo. La forma clásica (tipo 1) está causada por mutaciones dominantes del gen de la proteína transductora de señal y activadora de la transcripción 3. Se ha descrito una forma incompleta (tipo 2) solo con las manifestaciones de la inmunodeficiencia, pero sin manifestaciones mesenquimales. Esta forma incompleta se debe a la mutación recesiva del gen de la tirosin-cinasa 2. Ambas mutaciones condicionan un déficit en la generación de células Th17 a partir de células T CD4+. Estos avances en el conocimiento genético e inmunológico del síndrome de hipergammaglobulinemia IgE han permitido la mejor comprensión de los fenómenos clínicos de la enfermedad(AU)

Hyper-IgE recurrent infection syndrome is an uncommon primary immunodeficiency characterized by high serum levels of total IgE, eczema-like dermatitis, recurrent skin abscesses and staphylococci pneumonias, which can produce abscesses with mild inflammatory signs. It also causes dental, musculoskeletal and connective tissue abnormalities. The classical (type 1) variation is caused by autosomal-dominant mutations in signal transducer and activator of transcription 3. An incomplete form (type 2) has been described with only the immunological manifestations, but without the mesenchymal manifestations, has been described. This incomplete form is caused by recessive mutations in the tyrosine kinase 2 gene. Both kinds of mutations produce deficient formation of Th17-cells. These advances in the genetic and immunologic knowledge of hyper-IgE recurrent infection syndrome have allowed a better clinical comprehension of the clinical phenomena of the disease(AU)

Síndrome de hiper IgE (HIES): criterios de atención odontológica / Hiper IgE syndrome (HIES): criteria for dental care

El síndrome de Hiper IgE o hiperinmunoglobulinemia E por infección recurrente es una enfermedad rara, descripta inicialmente por JOb Buckey en 1966. Su diagnóstico se realiza a través de la tríada: *)eosinofilia y elevados niveles de IgE, *) eczema e infecciones recurrentes de piel y *) aparato respiratorio (pulmones). Tiene dos variantes: tipo 1 o autosómica y tipo 2 o autosómica recesiva. PUedepresentar facies características y alteraciones óseas y dentales. Son pacientes que requieren terapias prolongadas con antibióticos para evitar las infecciones respiratorias. La importancia de la atención odontológica radica en mantener una boca saludable para evitar focos sépticos que pongan en riesgo la vida del paciente.

IgA orbital plasmacytoma in multiple myeloma.

The authors report a case of orbital plasmacytoma in a 48-year-old man with known multiple myeloma. He presented with proptosis, diplopia, and decreased vision of the left eye for several weeks. He had been previously treated for IgA lambda multiple myeloma with chemotherapy, radiation, and autologous stem cell transplant. After a left orbitotomy, flow cytometry revealed a tumor rich in plasma cells expressing CD138 with equivocal lambda light chain expression. The patient underwent orbital radiation, with improvement of vision and disc edema OS. The patient is currently undergoing salvage chemotherapy for relapse of multiple myeloma. This is the third reported case of IgA myeloma involving the orbit.

Ocular adnexal mucosa-associated lymphoid tissue lymphoma with polyclonal hypergammaglobulinemia.

PURPOSE: To determine the characteristics of patients with primary ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma associated with polyclonal hypergammaglobulinemia. DESIGN: Case series study. METHODS: Among 81 Japanese patients with primary ocular adnexal MALT lymphoma, seven patients (9%) were diagnosed with polyclonal hypergammaglobulinemia. Patient clinical data included a history of autoimmune disease and dissemination. Peripheral blood collected from all patients was analyzed for serum levels of rheumatoid factor, soluble interleukin-2 receptor (sIL-2R), and immunoglobulins at the time of diagnosis and after each treatment. RESULTS: Seven patients with polyclonal hypergammaglobulinemia had elevated serum levels of rheumatoid factor, sIL-2R, immunoglobulin G (IgG), and immunoglobulin E (IgE) at the time of diagnosis. One patient had Sjogren syndrome. Six patients (86%) had a dissemination of the MALT lymphoma or lymphadenopathy at the time of diagnosis. Histopathologic examination of the patients with lymphadenopathy revealed not only MALT lymphoma but also secondary follicles. None of the seven patients showed improvement in serum levels of IgG, rheumatoid factor, or sIL-2R in spite of complete regression of the ocular lesions after radiotherapy. After administration of cyclophosphamide/doxorubicin/vincristine/prednisone and/or rituximab to three patients, all three showed improved serum levels of IgG, rheumatoid factor, and sIL-2R. CONCLUSIONS: Patients with ocular adnexal MALT lymphoma and polyclonal hypergammaglobulinemia have elevated serum levels of rheumatoid factor, sIL-2R, and IgE, and high dissemination or lymphadenopathy. These unique characteristics may correlate with the systemic immunologic imbalances.

Effect of plasmapheresis on hyperviscosity-related retinopathy and retinal hemodynamics in patients with Waldenstrom's macroglobulinemia.

PURPOSE: Waldenström's macroglobulinemia (WM) is characterized by an overproduction of immunoglobulin M (IgM), which can lead to a hyperviscosity syndrome (HVS) and HVS-related retinopathy. Plasmapheresis is known to reduce serum viscosity (SV) and IgM levels. The purpose of this study was to investigate the effects of plasmapheresis on HVS-related retinopathy and retinal hemodynamic parameters in patients with WM. METHODS: Nine patients with HVS due to WM were studied. SV and plasma IgM levels were measured before and after plasmapheresis treatment. The patients were evaluated for HVS-related retinopathy, and hemodynamic changes in a major temporal retinal vein by laser Doppler, before and after plasmapheresis. RESULTS: Plasmapheresis resulted in significant reductions in serum IgM (46.5% +/- 18.0%, mean +/- SD; P = 0.0009) and SV (44.7% +/- 17.3%, P = 0.002). HVS-related retinopathy improved in all patients after plasmapheresis. After treatment, the venous diameter decreased in each patient by an average of 15.3% +/- 5.8% (P = 0.0001). A significant (P = 0.0004) 55.2% +/- 22.5% increase in retinal venous blood speed accompanied the decreases in diameter. There was no significant change in the retinal blood flow rate after treatment. The percentage decreases in SV in the patients were significantly correlated with the percentage decreases in venous blood column diameter (P = 0.031, R(2) = 0.51). CONCLUSIONS: HVS triggers a distinctive retinopathy with a central retinal vein occlusion (CRVO)-like appearance. However, the retinal blood flow is not decreased as in CRVO, but remains at normal levels. Plasmapheresis is effective in reversing HVS-related retinopathy and in reducing abnormal venous dilatation.

[Renal disease in multiple myeloma].

Renal involvement is common in multiple myeloma. Although several types of renal disease are observed, most of them are considered to be specifically related to monoclonal immunoglobulin light chains. Myeloma cast nephropathy is the most frequent and sometimes associated with acute renal failure. AL amyloidosis and monoclonal immunoglobulin deposit disease are often presented as a nephrotic syndrome. In this review, we describe the pathogenesis and diagnosis of these three renal diseases. We also focus on the treatment of renal disease in multiple myeloma, in the view points of the chemotherapy to reduce M-protein and the prevention to reduce the risks of promoting renal injury.

Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem-cell transplantation.

Long-term survival and outcome were determined for 80 patients with immunoglobulin light chain (AL) amyloidosis treated with high-dose melphalan and stem cell transplantation (HDM/SCT) more than 10 years ago. Seventeen (21%) patients died within the first year of treatment, of treatment-related complications (14%) or progressive disease (8%). Of the 63 surviving evaluable patients at one year, 32 (51%) achieved a complete hematologic response (CR). For all 80 patients, the median survival was 57 months (4.75 yrs). The median survival exceeds 10 years for patients achieving a CR after HDM/SCT, compared with 50 months for those not achieving a CR (P < .001). In conclusion, HDM/SCT leads to durable remissions and prolonged survival, particularly for those patients who achieve a hematologic CR.

Anakinra is safe and effective in controlling hyperimmunoglobulinaemia D syndrome-associated febrile crisis.

Hyper-IgD and periodic fever syndrome (HIDS) is a hereditary autoinflammatory syndrome, characterized by recurrent inflammatory attacks. Treatment of HIDS is difficult. Recently, the IL-1ra analogue anakinra was reported to be successful in aborting the IgD inflammatory attacks in a vaccination model. We report a clinical case of spectacular reduction of febrile attacks in a severe HIDS patient.