Mediterranean Fever gene variants modify clinical phenotypes of idiopathic multicentric Castleman disease

Abstract Objective While the aetiology of idiopathic multicentric Castleman disease (iMCD) remains unclear, the involvement of autoinflammatory mechanisms has been suggested. Herein we report a Japanese patient with iMCD with a novel heterozygous Ile729Met mutation in exon 10 of the Mediterranean fever (MEFV) gene. Methods We performed genetic analysis via targeted next-generation sequencing analysis and Sanger sequencing and conducted molecular dynamics simulations to investigate the hydrophobic interactions around the 729th amino acid in human pyrin. Results In February 2011, a 59-year-old man was diagnosed with IgG4-related disease at our department based on the findings of cervical and hilar lymphadenopathies, typical lung lesions and cervical lymph node biopsy. The patient was followed up without treatment, as he was asymptomatic. However, he had been experiencing prolonged fatigue and fever with high levels of CRP since June 2017. Axillary lymph node biopsy findings led to the diagnosis of iMCD. He was successfully treated with an IL-6 inhibitor and has been in remission for 12 months. Genetic analyses for hereditary autoinflammatory disease–related genes were performed, revealing a novel heterozygous Ile729Met mutation in exon 10 of the MEFV gene. We identified that this novel mutation significantly altered the local interaction of the human pyrin B30.2 domain by molecular dynamics simulation analysis and experimentally had the potential for inflammasome activation with increased inflammatory cytokines. Conclusion The abnormal function of pyrin due to a mutation in the MEFV gene in this patient may have contributed to the development of MCD by inducing IL-6 production via inflammasome signalling.

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AIDS-Related Diffuse Large B-Cell Lymphoma Arising in HHV8-Positive Multicentric Castleman Disease

10.32388/zomqvh ◽

2020 ◽

Author(s):

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Castleman Disease ◽

Multicentric Castleman Disease ◽

Large B Cell Lymphoma ◽

Large B Cell

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Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease

Case Medical Research ◽

10.31525/ct1-nct03933904 ◽

2019 ◽

Author(s):

Keyword(s):

Castleman Disease ◽

Multicentric Castleman Disease ◽

Previously Treated

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Toll-like receptor-4 gene variations in Egyptian children with familial Mediterranean fever

Egyptian Rheumatology and Rehabilitation ◽

10.1186/s43166-020-00053-y ◽

2021 ◽

Vol 48 (1) ◽

Author(s):

Yomna Farag ◽

Samia Salah ◽

Hanan Tawfik ◽

Mai Hamed ◽

Huda Marzouk

Keyword(s):

Familial Mediterranean Fever ◽

Disease Severity ◽

Gene Mutation ◽

Rflp Analysis ◽

Gene Variants ◽

Gene Variant ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Egyptian Children ◽

Mediterranean Fever

Abstract Background Familial Mediterranean fever (FMF) is an autosomal recessive disorder affecting people in the region of the Mediterranean Sea. It is usually associated with mutation in Mediterranean fever (MEFV) gene that encodes the pyrin protein, which affects the innate inflammatory response. Toll-like receptors (TLR) are a family of pattern recognition receptors that recognize pathogenic microbes and activate antimicrobial defense mechanisms. Toll-like receptor 4 (TLR-4) is concerned with recognition of gram-negative organisms. There is growing clinical evidence suggesting a role for expression of TLRs in the immune pathogenesis of FMF. Thus, the aim of the current study was to evaluate the presence of TLR-4 (p.Asp299Gly) and TLR-4 (p.Thr399Ile) gene variants in association with Egyptian children having FMF, furthermore, its effect on disease course and severity. Results Seventy Egyptian children diagnosed as having FMF, together with 50 age and gender-matched controls were enrolled in the study. The TLR-4 (p.Asp299Gly) and (Thr399Ile) gene variants were determined by PCR-RFLP analysis for all studied patients and controls. TLR-4 p.Asp299Gly gene variant was detected in 1 (1.4%) of the patients and p.Thr399Ile gene variant was detected in 2 (2%). None of the controls had any of the two tested gene variants. All found variations were heterozygous. We could not find a statistically significant association with disease severity in cases with or without TLR-4 gene variants (P = 0.568). Patients with M694V gene mutation showed a higher disease severity (P = 0.035). Conclusion TLR-4 (p.Asp299Gly) and (p.Thr399Ile) gene variants were not found to have a link with the occurrence, the clinical picture of FMF, its severity, and response to colchicine treatment in Egyptian children. M694V gene mutation seems to be associated with higher disease severity. Further larger studies are needed to verify these results.

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“Chronic Disseminated Aspergillosis,” a Novel Fungal Immune Reconstitution Inflammatory Syndrome

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa175 ◽

2020 ◽

Vol 7 (11) ◽

Author(s):

Annabelle Pourbaix ◽

Romain Guery ◽

Julie Bruneau ◽

Estelle Blanc ◽

Gregory Jouvion ◽

...

Keyword(s):

Immune Reconstitution Inflammatory Syndrome ◽

Immune Reconstitution ◽

Clinical Presentation ◽

Castleman Disease ◽

Disease Symptoms ◽

Disseminated Candidiasis ◽

Multicentric Castleman Disease ◽

Chronic Disseminated Candidiasis ◽

Disseminated Aspergillosis ◽

Inflammatory Syndrome

Abstract We report a case of chronic hepatosplenic aspergillosis following immune reconstitution complicating colic aspergillosis in an AIDS patient with multicentric Castleman disease. Symptoms mimicked the clinical presentation of chronic disseminated candidiasis and responded to corticosteroid. This emerging entity enlarges the spectrum of fungal immune reconstitution inflammatory syndrome in the HIV setting.

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Validated International Definition of the TAFRO clinical subtype of idiopathic multicentric Castleman disease

American Journal of Hematology ◽

10.1002/ajh.26292 ◽

2021 ◽

Author(s):

Yoshito Nishimura ◽

David C. Fajgenbaum ◽

Sheila K. Pierson ◽

Noriko Iwaki ◽

Asami Nishikori ◽

...

Keyword(s):

Castleman Disease ◽

Multicentric Castleman Disease ◽

Definition Of ◽

Clinical Subtype

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Coexistence of disseminated Kaposi sarcoma and multicentric Castleman disease in an HIV-infected patient under viral suppression

International Journal of STD & AIDS ◽

10.1177/0956462420968385 ◽

2021 ◽

Vol 32 (3) ◽

pp. 286-289

Author(s):

I-Fan Lin ◽

Jiun-Nong Lin ◽

Tsung-Heng Tsai ◽

Chao-Tien Hsu ◽

Yu-Ying Wu ◽

...

Keyword(s):

Viral Load ◽

Viral Suppression ◽

Liposomal Doxorubicin ◽

Kaposi Sarcoma ◽

Castleman Disease ◽

Severe Thrombocytopenia ◽

Multicentric Castleman Disease ◽

Progressive Pancytopenia ◽

One Year ◽

Cd4 T Cell Count

Coexistence of multicentric Castleman disease and Kaposi sarcoma is rare and might be missed without an experienced pathologists’ interpretation. A 46-year-old man had been diagnosed with HIV infection and treated with combination antiretroviral therapy of dolutegravir/abacavir/lamivudine (Triumeq) for one year. The latest viral load was 49 copies/mL and CD4 T-cell count was 192 cells/uL. He was admitted due to fever off and on, splenomegaly, general lymphadenopathy, and severe thrombocytopenia for two months. Biopsy of a purplish skin lesion and gastric tissue showed Kaposi sarcoma. The pathology of inguinal lymph nodes revealed coexistence of Kaposi sarcoma and multicentric Castleman disease. The plasma Kaposi sarcoma herpesvirus viral load was 365,000 copies/mL. During hospitalization, progressive pancytopenia and spiking fever persisted, and he died of multi-organ failure before completion of chemotherapeutic treatments with rituximab plus liposomal doxorubicin.

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A Review of Genetic Abnormalities in Unicentric and Multicentric Castleman Disease

Biology ◽

10.3390/biology10040251 ◽

2021 ◽

Vol 10 (4) ◽

pp. 251

Author(s):

Alexandra Butzmann ◽

Jyoti Kumar ◽

Kaushik Sridhar ◽

Sumanth Gollapudi ◽

Robert S. Ohgami

Keyword(s):

Plasma Cells ◽

Treatment Options ◽

Disease Process ◽

Castleman Disease ◽

Mitogen Activated Protein Kinase ◽

Human Herpes Virus 8 ◽

Multicentric Castleman Disease ◽

Molecular Abnormalities ◽

Genetic Abnormalities ◽

Mitogen Activated Protein

Castleman disease (CD) is a rare lymphoproliferative disorder known to represent at least four distinct clinicopathologic subtypes. Large advancements in our clinical and histopathologic description of these diverse diseases have been made, resulting in subtyping based on number of enlarged lymph nodes (unicentric versus multicentric), according to viral infection by human herpes virus 8 (HHV-8) and human immunodeficiency virus (HIV), and with relation to clonal plasma cells (POEMS). In recent years, significant molecular and genetic abnormalities associated with CD have been described. However, we continue to lack a foundational understanding of the biological mechanisms driving this disease process. Here, we review all cases of CD with molecular abnormalities described in the literature to date, and correlate cytogenetic, molecular, and genetic abnormalities with disease subtypes and phenotypes. Our review notes complex karyotypes in subsets of cases, specific mutations in PDGFRB N666S in 10% of unicentric CD (UCD) and NCOA4 L261F in 23% of idiopathic multicentric CD (iMCD) cases. Genes affecting chromatin organization and abnormalities in methylation are seen more commonly in iMCD while abnormalities within the mitogen-activated protein kinase (MAPK) and interleukin signaling pathways are more frequent in UCD. Interestingly, there is a paucity of genetic studies evaluating HHV-8 positive multicentric CD (HHV-8+ MCD) and POEMS-associated CD. Our comprehensive review of genetic and molecular abnormalities in CD identifies subtype-specific and novel pathways which may allow for more targeted treatment options and unique biologic therapies.

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HHV8-Positive Castleman Disease and In Situ Mantle Cell Neoplasia within Dermatopathic Lymphadenitis, in Longstanding Psoriasis

Diagnostics ◽

10.3390/diagnostics11071150 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1150

Author(s):

Magda Zanelli ◽

Luca Stingeni ◽

Maurizio Zizzo ◽

Giovanni Martino ◽

Francesca Sanguedolce ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Rare Event ◽

Castleman Disease ◽

Axillary Lymph ◽

Tnf Inhibitor ◽

Dermatopathic Lymphadenitis ◽

Multicentric Castleman Disease ◽

Mantle Cell

A 73-year-old man presented with multiple lymphadenopathy. He had a 20-year history of palmoplantar psoriasis evolved to a diffuse erythrodermic picture in the last two years. Topic and systemic medications including prednisolone, acitretin, anti-IL17 (ixekizumab), TNF inhibitor (adalimumab), anti-IL23 (guselkumab), methotrexate, cyclosporine, and phosphodiesterase 4 inhibitor (apremilast) were ineffective. Repeated skin biopsies excluded mycosis fungoides, confirming psoriasis; molecular analysis of T-cell receptor genes ruled out clonality. The axillary lymph node histology documented a dermatopathic lymphadenitis, often associated with chronic cutaneous inflammatory diseases. At an accurate morphological evaluation, features of HHV8-positive multicentric Castleman disease were observed. Moreover, in a few follicles, in situ mantle cell neoplasia was identified. The translocation t(11;14)(q13;q32), characteristic of mantle cell lymphoma, and the monoclonal IGH gene rearrangement were present. HHV8 DNA was identified on plasma sample. Multicentric Castleman disease in psoriatic patients is a rare event and it might be favored by the immunomodulatory treatment in longstanding psoriasis. Multicentric Castleman disease patients are predisposed to developing simultaneous or subsequent lymphoma. In situ mantle cell neoplasia often behaves indolently, although it may progress to overt mantle cell lymphoma. Rituximab achieved a good control of psoriasis. Unfortunately, the patient developed Staphylococcus aureus sepsis for which he is currently on antibiotic therapy.

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