A novel de novo MYH9 mutation in MYH9-related disease

Abstract Objectives In IgG4-related disease (IgG4-RD), relapse including recurrent organ involvement (ROI) and de novo organ involvement (DNOI) occurs frequently during the clinical course. This study aimed to clarify the differences between the risk factors underlying ROI and DNOI in IgG4-RD. Methods We retrospectively investigated factors related to ROI and DNOI in 86 IgG4-RD patients. For assessment of factors related to ROI and DNOI, we performed uni- and multivariate Cox regression analyses. On stepwise multivariate analysis, we applied the variables with P < 0.1 in the univariate analysis and the predictors of relapse suggested in past reports. Results During the mean follow-up period of 63.1 months, ROI was detected at 1.0–120 months after diagnosis in 20 patients, 4 of whom were not receiving glucocorticoid (GC) at the time of ROI. In contrast, DNOI was detected at 5.0–120 months after diagnosis in 15 patients, 8 of whom were not receiving GC at the time of DNOI. In the multivariate analysis, blood eosinophil counts at diagnosis [per 100/μl; hazard ratio (HR) 1.072 (95% CI 1.018, 1.129)] and continuation of GC [vs discontinuation or observation without GC; HR 0.245 (95% CI 0.076, 0.793)] had a significant impact on the time to DNOI, whereas age [HR 0.942 (95% CI 0.899, 0.986)] and ANA positivity [vs negativity; HR 6.632 (95% CI 1.892, 23.255)] had a significant impact on the time to ROI. Conclusion The present study suggests that the risk factors of ROI and DNOI are different in IgG4-RD, highlighting the need for different preventative strategies.

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Heavy chain myosin 9-related disease (MYH9-RD): Neutrophil inclusions of myosin-9 as a pathognomonic sign of the disorder

Thrombosis and Haemostasis ◽

10.1160/th09-08-0593 ◽

2010 ◽

Vol 103 (04) ◽

pp. 826-832 ◽

Cited By ~ 56

Author(s):

Daniela De Rocco ◽

Emanuele Panza ◽

Valeria Bozzi ◽

Raffaella Scandellari ◽

Giuseppe Loffredo ◽

...

Keyword(s):

Sensitivity And Specificity ◽

Heavy Chain ◽

Molecular Genetic Analysis ◽

Immunofluorescence Assay ◽

Giant Platelets ◽

Cytoplasmic Inclusions ◽

Related Disease ◽

Significant Difference ◽

Pathognomonic Sign ◽

Myh9 Mutation

Summary MYH9-related disease (MYH9-RD) is an autosomal dominant thrombocytopenia with giant platelets variably associated with young-adult onset of progressive sensorineural hearing loss, presenile cataract, and renal damage. MYH9-RD is caused by mutations of MYH9, the gene encoding for non-muscle heavy-chain myosin-9. Wild-type and mutant myosin-9 aggregate as cytoplasmic inclusions in patients’ leukocytes, the identification of which by immunofluorescence has been proposed as a suitable tool for the diagnosis of MYH9-RD. Since the predictive value of this assay, in terms of sensitivity and specificity, is unknown, we investigated 118 consecutive unrelated patients with a clinical presentation strongly consistent with MYH9-RD. All patients prospectively underwent both the immunofluorescence assay for myosin-9 aggregate detection and molecular genetic analysis of the MYH9 gene. Myosin-9 aggregates were identified in 82 patients, 80 of which (98%) had also a MYH9 mutation. In the remaining 36 patients neither myosin-9 aggregates nor MYH9 mutations were found. Sensitivity and specificity of the immunofluorescence assay was evaluated to be 100% and 95%, respectively. Except for the presence of aggregates, we did not find any other significant difference between patients with or without aggregates, demonstrating that the myosin-9 inclusions in neutrophils are a pathognomonic sign of the disease. However, the identification of the specific MYH9 mutation is still of importance for prognostic aspects of MYH9-RD.

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Acute myeloid leukemia following exposure to benzene more closely resembles de novo than therapy related-disease

Genes Chromosomes and Cancer ◽

10.1002/gcc.22084 ◽

2013 ◽

Vol 52 (10) ◽

pp. 887-894 ◽

Cited By ~ 20

Author(s):

Richard D. Irons ◽

Yan Chen ◽

Xiaoqin Wang ◽

John Ryder ◽

Patrick J. Kerzic

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

De Novo ◽

Related Disease ◽

Acute Myeloid

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POS1356 PERSISTENCE OF TFH CELLS AFTER RITUXIMAB IS ASSOCIATED WITH IGG4-RELATED DISEASE RELAPSE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2715 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 960.2-960

Author(s):

G. Mancuso ◽

T. Jofra ◽

M. Lanzillotta ◽

J. Gerosa ◽

G. DI Colo ◽

...

Keyword(s):

B Cell ◽

Germinal Center ◽

Peripheral Blood ◽

De Novo ◽

Cell Depletion ◽

P Value ◽

B Cell Depletion ◽

Related Disease ◽

Tfh Cells ◽

Igg4 Related Disease

Background:Clinical improvement after B-cell depletion with rituxmab suggests a prominent pathogenic role of B-lymphcytes in IgG4-related disease (IgG4-RD). IgG4-RD, however, relapses in most cases together with re-expansion of clonally divergent plasmablasts indicating that treatment with rituximab does not completely abrogates T follicular helper (Tfh)-cells dependent germinal center reactions leading to de-novo plasmablast differentiation.Objectives:In the present work we aim to study the effects of B-cell depletion therapy with rituximab on circulating Tfh cells and on the levels of CXCL13 - a chemotactic factor for B-lymphocytes produced by Tfh cells - in patients with IgG4-RD.Methods:Thirty patients with IgG4-RD, diagnosed according to the “Consensus Statement on the Pathology of IgG4-RD” and fulfilling the “2019 ACR/EULAR Classification Criteria” were included in the present study. Ten patients with relapsing disease were treated with the anti-CD20 monoclonal antibody rituximab (two 1g infuxions 15 days apart). Peripheral blood mononuclear cells and serum were collected before rituximab and three months after infusion. Tfh cells subsets in the peripheral blood were measured by flow cytometry and CXCL13 plasma levels were measured by ELISA assay.Results:No changes in total Tfh cells and Tfh cells subsets were observed three months after rituximab neither in absolute counts nor in percentage of CD4+ T cells. In particular, no difference in Tfh1, Tfh2, Tfh17, T follicular regulatory and highly functional Tfh cells counts was observed before and after treatment. The serum level of CXCL13 was significantly higher in active untreated IgG4-RD patients compared to healthy controls (151.94 pg/ml vs 66.98 pg/ml, p value = 0.0026), but was not affected by rituximab treatment (p value = 0.41).Conclusion:In relapsing patients with IgG4-RD rituximab does not affect circulating Tfh cells numbers and serum levels of CXCL13. Persistence of Tfh cells after rituximab and reconstitution of germinal center reactions likely drives IgG4-RD flare.References:[1]Lanzillotta M, Mancuso G, Della-Torre E. Advances in the diagnosis and management of IgG4 related disease. BMJ. 2020 Jun 16;369:m1067. doi: 10.1136/bmj.m1067. PMID: 32546500.[2]Lanzillotta M, Della-Torre E, Stone JH. Roles of Plasmablasts and B Cells in IgG4-Related Disease: Implications for Therapy and Early Treatment Outcomes. Curr Top Microbiol Immunol. 2017;401:85-92. doi: 10.1007/82_2016_58. PMID: 28091934.[3]Campochiaro C, Ramirez GA, Bozzolo EP, Lanzillotta M, Berti A, Baldissera E, Dagna L, Praderio L, Scotti R, Tresoldi M, Roveri L, Mariani A, Balzano G, Castoldi R, Doglioni C, Sabbadini MG, Della-Torre E. IgG4-related disease in Italy: clinical features and outcomes of a large cohort of patients. Scand J Rheumatol. 2016;45(2):135-45. doi: 10.3109/03009742.2015.1055796. Epub 2015 Sep 23. PMID: 26398142.[4]Mattoo H, Mahajan VS, Della-Torre E, Sekigami Y, Carruthers M, Wallace ZS, Deshpande V, Stone JH, Pillai S. De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease. J Allergy Clin Immunol. 2014 Sep;134(3):679-87. doi: 10.1016/j.jaci.2014.03.034. Epub 2014 May 6. PMID: 24815737; PMCID: PMC4149918.Disclosure of Interests:None declared

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De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease

immuneACCESS ◽

10.21417/b7rp4t ◽

2018 ◽

Author(s):

H Mattoo ◽

VS Mahajan ◽

E Della-Torre ◽

Y Sekigami ◽

M Carruthers ◽

...

Keyword(s):

De Novo ◽

Related Disease ◽

Igg4 Related Disease

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Macrothrombocytopenia, renal dysfunction and nephrotic syndrome in a young male patient: a case report of MYH9-related disease

Brazilian Journal of Nephrology ◽

10.1590/2175-8239-jbn-3879 ◽

2018 ◽

Vol 40 (2) ◽

pp. 198-200 ◽

Cited By ~ 2

Author(s):

Gabriela Sevignani ◽

Giovana Memari Pavanelli ◽

Sibele Sauzem Milano ◽

Bianca Ramos Ferronato ◽

Maria Aparecida Pachaly ◽

...

Keyword(s):

Male Patient ◽

De Novo ◽

Young Male ◽

Renin Angiotensin System ◽

Bleeding Tendency ◽

Autosomal Dominant Disorder ◽

Related Disease ◽

Myh9 Gene ◽

Stage Renal Disease ◽

End Stage

ABSTRACT MYH9-related disease is an autosomal dominant disorder caused by mutations of the MYH9 gene, which encodes the non-muscle myosin heavy chain IIA on chromosome 22q12. It is characterized by congenital macrothrombocytopenia, bleeding tendency, hearing loss, and cataracts. Nephropathy occurs in approximately 30% of MYH9-related disease in a male patient carrier of a de novo missense mutation in exon 1 of the MYH9 gene [c.287C > T; p.Ser(TCG)96(TTG)Leu]. He presented all phenotypic manifestations of the disease, but cataracts. Renal alterations were microhematuria, nephrotic-range proteinuria (up to 7.5 g/24h), and rapid loss of renal function. The decline per year of the glomerular filtration rate was 20 mL/min/1.73m2 for five years. Blockade of the renin-angiotensin system, the only recommended therapy for slowing the progression of this nephropathy, was prescribed. Although MYH9-related disease is a rare cause of glomerulopathy and end-stage renal disease, awareness of rare genetic kidney disorders is essential to ensure accurate diagnosis and proper management of orphan disease patients.

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De novo MYH9 mutation in congenital scalp hemangioma

Molecular Case Studies ◽

10.1101/mcs.a002998 ◽

2018 ◽

Vol 4 (4) ◽

pp. a002998 ◽

Cited By ~ 2

Author(s):

Elena I. Fomchenko ◽

Daniel Duran ◽

Sheng Chih Jin ◽

Weilai Dong ◽

E. Zeynep Erson-Omay ◽

...

Keyword(s):

De Novo ◽

Myh9 Mutation

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Impact of Cytogenetics and Prior Therapy on Outcome of AML and MDS after Allogeneic Transplantation.

Blood ◽

10.1182/blood.v108.11.259.259 ◽

2006 ◽

Vol 108 (11) ◽

pp. 259-259 ◽

Cited By ~ 1

Author(s):

Philippe Armand ◽

Haesook T. Kim ◽

Daniel J. DeAngelo ◽

Vincent T. Ho ◽

Corey S. Cutler ◽

...

Keyword(s):

Overall Survival ◽

Prognostic Factor ◽

De Novo ◽

Risk Group ◽

Significant Prognostic Factor ◽

Prognostic Impact ◽

Complex Karyotype ◽

Prior Therapy ◽

Related Disease ◽

Risk Patients

Abstract Cytogenetics is an important determinant of outcome for patients with AML or MDS. However, the prognostic impact of cytogenetics in patients undergoing allogeneic stem cell transplantation (alloSCT) is less clear. Moreover, the existing cytogenetic risk groups were established on cohorts of patients treated mostly with chemotherapy, and thus may not be optimal for patients undergoing alloSCT. We retrospectively studied 556 consecutive patients with AML or MDS who received an alloSCT at our institution. Using Cox proportional hazards modeling, taking into account cytogenetics and other known prognostic factors (age, disease type and stage, HLA match, conditioning regimen, GVHD prophylaxis regimen, graft source, CMV serostatus, gender, and year of transplantation), we established a three-group cytogenetic classification scheme based on the 476 patients with de novo disease. In this system, patients with AML and t(15;17), t(8;21) alone, or inv(16)/t(16;16) were classified as favorable risk; patients with AML and complex karyotype, t(9;22), or t(6;9), as well as patients with MDS and complex karyotype or abnormality of 7, were classified as adverse risk. Cytogenetics for all other AML and MDS patients were classified as intermediate risk. Patients with AML and abnormal 3q, and patients with MDS and 5q- or 20q-, could not be assigned to a risk group due to inadequate representation in our study. The figure below shows the overall survival of all de novo AML and MDS patients when stratified according to this cytogenetic grouping scheme. Figure Figure In our cohort, this grouping scheme was the strongest prognostic factor (after age) for overall and disease-free survival. It applied to patients regardless of disease (AML, MDS, or AML arising from MDS) and of stage (AML in CR1 versus advanced leukemia). Furthermore, it outperformed the existing grouping schemes for AML (from MRC, CALGB and SWOG/ECOG) and the IPSS grouping scheme for MDS. Using competing risks regression analysis, we found that cytogenetics influences the risk of relapse but not the non-relapse mortality. The group of 80 patients with therapy-related MDS or AML had a higher frequency of adverse cytogenetics. In this population, cytogenetics remained a significant prognostic factor for overall survival. However, in multivariate models that accounted for cytogenetics, prior therapy by itself did not confer an additional adverse prognosis. This conclusion held true regardless of the grouping scheme used. Conclusion: cytogenetics is a key determinant of outcome for patients with AML or MDS undergoing alloSCT, whether with de novo disease or therapy-related disease. For patients with therapy-related disease, prior therapy has no additional prognostic importance after considering cytogenetic risk group. We also propose a new cytogenetic risk grouping scheme specifically applicable to this patient population, that can be validated in a multi-institutional database. Our results argue that patients entering clinical trials of transplantation should be stratified by cytogenetic risk group, and provide a means of doing so.

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Assessment of MYH9-Related Syndromes among a Series of Patients with Constitutional Macrothrombocytopenia (MT).

Blood ◽

10.1182/blood.v108.11.700.700 ◽

2006 ◽

Vol 108 (11) ◽

pp. 700-700

Author(s):

Nicole Schlegel ◽

Beatrice Saposnik ◽

Sylvie Binard ◽

Sandrine Elbaz ◽

Odile Fenneteau ◽

...

Keyword(s):

Renal Failure ◽

De Novo ◽

Direct Sequencing ◽

Phenotypic Variability ◽

Somatic Mosaicism ◽

Phenotypic Expression ◽

Unknown Etiology ◽

Myh9 Gene ◽

Uncertain Etiology ◽

Myh9 Mutation

Abstract MYH9-related disorders are autosomal dominant giant platelet syndromes with a wide phenotypic variability known under the following names: May Hegglin Anomaly (MHA), Fechtner Syndrome (FTNS), Epstein Syndrome (EPS), Sebastian Syndrome (SBS) and Alport-like Syndrome with MT. The aim of the study was to identify MYH9-related syndromes in a series of 43 propositi with constitutional MT. In this group, 26 have a characteristic MYH9-syndrome phenotype. The 17 other patients have a constitutional MT of uncertain etiology, 8 of them presenting a partial MYH9 syndrome phenotype. The leukocyte repartition of the Non-Muscle Myosin Heavy Chain IIa (NMMHC-IIA) encoded by the MYH9 gene was explored by May-Grunwald-Giemsa staining of blood smears or by immunofluorescence, while platelets were also examined by electron microscopy (EM). The MYH9 gene was studied by genomic DNA amplification and direct sequencing of the 8 exons in which mutations have been published (Dong, 2005). The results are the following: of the 17 patients with constitutional MT of unknown etiology, no MYH9 mutations were found; in contrast, 24/26 (92.3%) patients with a characteristic MYH9-syndrome phenotype were heterozygous for a MYH9 mutation. Among their 29 family members, 5 were heterozygous for the mutated allele. In 4 families, the mutations were found only in the propositus but not in the parents, suggesting that they might be either de novo mutations or the results of somatic mosaicism, as already published ( Kunishima et al, 2005). Six mutations are novel: F1446L, K1937X, A44P, D1424E in 4 MHA patients, W33C in 1 patient with MHA/SBS, and, interestingly, D1447V was associated with 2 different phenotypes, MHA and FTNS. As already published, the majority of the mutations in the C-terminus of the NMMHC-IIA are associated with a pure hematologic disorder. In contrast, the N-terminus mutations were more generally associated with a more severe phenotype with renal manifestations. However the same mutation can be associated with different phenotypes: S96L with FTNS, EPS and SBS/MHA, D1447V with MHA and FTNS. In addition the R702C mutation, which has been identifed in 2 cases with an identical FTNS phenotype, is associated with 2 different leukocyte NMMHC-IIA distributions. No MYH9 mutation could be detected in 2 patients with FTNS. These results, as a whole, are in agreement with the hypothesis that mutations in other genes than MYH9 might be involved in defining the phenotypes of such syndromes. The genotype of the 17 patients with uncertain etiology remains to be identified. The interest to diagnose MYH9 mutations is: to avoid misdiagnosis and inadequate therapy for patients with thrombocytopenia (2 patients initially diagnosed as ITP patients underwent splenectomy); to detect as early as possible the risk and occurrence of renal failure, deafness and cataracts (1 patient initially diagnosed as a SBS patient developed a renal failure characteristic of FTNS). A long-term follow-up of the patients with MYH9 mutations is of a high interest for a better knowledge of the relationship between the mutation and the phenotypic expression.

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