DOCSLIB.ORG

Development of Monocytosis in Patients with Primary Myelofibrosis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Development of Monocytosis in Patients with Primary Myelofibrosis Modern Pathology (2013) 26, 204–212 204 & 2013 USCAP, Inc All rights reserved 0893-3952/13 $32.00 Development of monocytosis in patients with primary myelofibrosis indicates an accelerated phase of the disease Leonardo Boiocchi1,3, Rosanny Espinal-Witter1, Julia Turbiner Geyer1, Julia Steinhilber2, Irina Bonzheim2, Daniel M Knowles1, Falko Fend2 and Attilio Orazi1 1Department of Pathology and Laboratory Medicine, Weill Cornell Medical College/New York Presbyterian Hospital, New York, NY, USA and 2Department of Pathology, University of Tubingen, Tubingen, Germany Primary myelofibrosis is a type of chronic myeloproliferative neoplasm characterized by progressive bone marrow failure with worsening cytopenia and in a subset of patients, progression to acute leukemia. Published data in patients with myelodysplastic syndromes have shown that the development of monocytosis in the course of myelodysplastic syndromes is associated with a poor prognosis. A similar occurrence has been only sporadically reported in patients with primary myelofibrosis. Over a period of four years we identified 10 out of 237 cases of primary myelofibrosis who developed persistent absolute monocytosis (41 Â 109/l) during the course of disease (5 men and 5 women; median age/range: 68 years/52–82). Monocytosis developed at a median interval of 42 months from diagnosis (range: 1–180) and persisted for a median period of 23 months (range: 2–57). Five patients died after developing monocytosis (range: 20–188 months) and two experienced worsening disease and became transfusion dependent. Monocytosis was associated with increased white blood cells, decreased hemoglobin, decreased platelet count, and the presence of circulating blasts. In three cases, bone marrow biopsies after the onset of monocytosis showed marked myelomonocytic proliferation with morpho- logical shifting from a typical primary myelofibrosis marrow appearance to aspects compatible with an overt ‘secondary’ chronic myelomonocytic leukemia. Before the development of monocytosis, 5 of 10 patients carried the JAK2V617F mutation; five patients showed karyotypic alterations. No change in JAK2 mutational status or cytogenetic evolution were associated with the development of monocytosis. Four of nine patients analyzed showed KRAS mutation in codon 12 or 13 with low allele burden. This is the first study correlating monocytosis developing in primary myelofibrosis patients with bone marrow morphology, laboratory data, molecular analysis and clinical follow-up. Development of monocytosis in patients with established primary myelofibrosis is associated with rapid disease progression and these patients should be considered as a high-risk group associated with short survival. Modern Pathology (2013) 26, 204–212; doi:10.1038/modpathol.2012.165; published online 28 September 2012 Keywords: accelerated phase; chronic myelomonocytic leukemia; disease progression; monocytosis; primary myelofibrosis; prognosis Primary myelofibrosis, one of the classic Phidalel- phia chromosome/BCR-ABL1-negative myeloproli- Correspondence: Dr Attilio Orazi, MD, FRCPath. (Engl.), Depart- ferative neoplasms, is characterized in its overt stage ment of Pathology and Laboratory Medicine, Weill Cornell by typical marrow changes such as cytoarchitectural Medical College/NYPH, Room ST-707, 525 East 68th Street, disarray and severe marrow fibrosis in association New York, NY 10065, USA. E-mail: [email protected] with splenomegaly due to extramedullary hemato- 1 3Current address: Pathology Unit, Department of Medicine, poiesis (also known as myeloid metaplasia). Surgery and Dentistry, University of Milan Medical School, Although its prognosis is highly variable, primary Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, myelofibrosis has the worst outcome among the Ph- Milan, Italy myeloproliferative neoplasms with a median survival This work has been presented in part at the 100th Annual Meeting of 5 years (range: 1–10 years). The disease has a of the United States and Canadian Academy of Pathology, San Antonio, TX, USA, February 26-March 4, 2011. strong tendency to progress towards marrow failure Received 8 May 2012; revised 8 August 2012; accepted 8 August and complications related to cytopenia are the most 2012; published online 28 September 2012 common cause of death. In addition, a significant www.modernpathology.org Monocytosis and disease progression in primary myelofibrosis L Boiocchi et al 205 subset of primary myelofibrosis patients (5–30%) and laboratory data, molecular analysis, cyto- tranform to acute myeloid leukemia. In a proportion genetics, and bone marrow morphology results in of the patients transformation to acute myeloid an attempt to facilitate the identification of a leukemia is heralded by a usually brief myelodys- previously unrecognized type of disease progression plastic syndrome-like progression termed acceler- in primary myelofibrosis associated with adverse ated phase, characterized by the presence of an prognosis. increased number of blasts and often multilineage dysplasia including numerous micromegakaryo- cytes. In these patients, the bone marrow, at least Materials and methods in part, resembles a high-grade myelodysplastic syndrome (eg, a refractory anemia with excess of Case Selection blasts).1 In others, transformation to acute leukemia We retrospectively identified in the files of the is more abrupt and is not preceded by a myelody- Department of Pathology and Laboratory Medicine splastic syndrome-like phase. of Weill Cornell Medical College/New York-Presby- The prognostic heterogeneity of primary myelofi- terian Hospital in New York City 237 consecutive brosis causes clinical challenges in, eg, deciding the patients diagnosed with primary myelofibrosis over type of therapy and when to start to treat a patient. a period spanning from 2008 to 2011. These bone Over time, multiple parameters have been evaluated marrow biopsies were taken during the normal to try to predict the speed of progression toward clinical follow-up of primary myelofibrosis patients marrow failure or the risk of developing acute in our institution: peripheral blood counts were leukemia. Clinical parameters that have been asso- reviewed to identify primary myelofibrosis patients ciated with worse outcome include older age, anemia, that at some point during their clinical history red blood cell transfusion dependency, presence developed absolute monocytosis (41 Â 109 /l) per- of leukopenia, leukocytosis or thrombocytopenia, sistent for 43 months. We then investigated the increased peripheral blast count, manifestation of clinical files of patients with monocytosis and systemic symptoms, detection of cytogenetic abnor- excluded those with any clinical condition known malities, and low JAK2V617F allele burden.2 However, to be possibly associated with reactive monocytosis. better prognostic parameters still need to be identi- Ten patients out of 237 with a previous diagnosis of fied for these patients. primary myelofibrosis and who had developed Chronic myelomonocytic leukemia is a de novo persistent monocytosis were selected. For these myelodysplastic/myelopoliferative neoplasm of vari- patients we looked for the first bone marrow biopsy able but usually unfavorable prognosis which is diagnostic for primary myelofibrosis: this was characterized by the present of absolute monocytosis available in 5 cases. When it was not available, for of 41 Â 109/l and usually 410% of the white blood example, when a case was an outside consult, we count (WBC), sustained for 43 months.3–5 Although carefully studied the reports and their clinical more often a ‘primary neoplasm’, rare cases of history to make sure the clinal diagnosis was also secondary chronic myelomonocytic leukemia have confirmed histologically both at the time of disease been sporadically reported. In a recent study,6 it was presentation and during the ensuing follow-up, noted that a subset of patients with myelodysplastic following the criteria published by the WHO in its syndrome developed monocytosis in the course of 2008 monograph.1 their disease. In these patients, the peripheral blood Thirteen additional bone marrow biopsies patho- monocyte counts reached levels similar to those logically and clinically classified as primary myelo- seen in patients with de novo chronic myelomono- fibrosis in fibrotic phase were also selected from the cytic leukemia and that this event portended a poor files of the Department of Pathology of the Uni- prognosis.6 In addition, monocytosis has also been versity of Tubingen, Germany, to be used as a control reported to indicate a worse prognosis in patients group in the comparison of the molecular results with adult T-cell leukemia/lymphoma7 and head 8 obtained from the primary myelofibrosis cases that and neck cancers. In patients with primary myelo- developed monocytosis. fibrosis, there is lack of information in relation to the The design of this study was approved by the development of monocytosis during the course of Institutional Review Board of Weill Cornell Medical the disease. One study, however, has reported that College and of University of Tubingen. the presence of absolute monocytosis at disease outset had a statistically significant, independent predictive value of inferior survival in younger Morphological Analysis patients with primary myelofibrosis.9 In this study, we describe a rare subset of primary All bone marrow biopsies were fixed in Bouin’s myelofibrosis patients who developed monocytosis solution and acid
Load more

Recommended publications
  • Updates in Mastocytosis
    Updates in Mastocytosis Tryptase PD-L1 Tracy I. George, M.D. Professor of Pathology 1 Disclosure: Tracy George, M.D. Research Support / Grants None Stock/Equity (any amount) None Consulting Blueprint Medicines Novartis Employment ARUP Laboratories Speakers Bureau / Honoraria None Other None Outline • Classification • Advanced mastocytosis • A case report • Clinical trials • Other potential therapies Outline • Classification • Advanced mastocytosis • A case report • Clinical trials • Other potential therapies Mastocytosis symposium and consensus meeting on classification and diagnostic criteria for mastocytosis Boston, October 25-28, 2012 2008 WHO Classification Scheme for Myeloid Neoplasms Acute Myeloid Leukemia Chronic Myelomonocytic Leukemia Atypical Chronic Myeloid Leukemia Juvenile Myelomonocytic Leukemia Myelodysplastic Syndromes MDS/MPN, unclassifiable Chronic Myelogenous Leukemia MDS/MPN Polycythemia Vera Essential Thrombocythemia Primary Myelofibrosis Myeloproliferative Neoplasms Chronic Neutrophilic Leukemia Chronic Eosinophilic Leukemia, NOS Hypereosinophilic Syndrome Mast Cell Disease MPNs, unclassifiable Myeloid or lymphoid neoplasms Myeloid neoplasms associated with PDGFRA rearrangement associated with eosinophilia and Myeloid neoplasms associated with PDGFRB abnormalities of PDGFRA, rearrangement PDGFRB, or FGFR1 Myeloid neoplasms associated with FGFR1 rearrangement (EMS) 2017 WHO Classification Scheme for Myeloid Neoplasms Chronic Myelomonocytic Leukemia Acute Myeloid Leukemia Atypical Chronic Myeloid Leukemia Juvenile Myelomonocytic
    [Show full text]
  • Mutation Analysis in Myeloproliferative Neoplasms AHS - M2101
    Corporate Medical Policy Mutation Analysis in Myeloproliferative Neoplasms AHS - M2101 File Name: mutation_analysis_in_myeloproliferative_neoplasms Origination: 1/1/2019 Last CAP review: 8/2021 Next CAP review: 8/2022 Last Review: 8/2021 Description of Procedure or Service Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal disorders characterized by overproduction of one or more differentiated myeloid lineages (Grinfeld, Nangalia, & Green, 2017). These include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The majority of MPN result from somatic mutations in the 3 driver genes, JAK2, CALR, and MPL, which represent major diagnostic criteria in combination with hematologic and morphological abnormalities (Rumi & Cazzola, 2017). Related Policies: BCR-ABL 1 Testing for Chronic Myeloid Leukemia AHS-M2027 ***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician. Policy BCBSNC will provide coverage for mutation analysis in myeloproliferative neoplasms when it is determined to be medically necessary because the medical criteria and guidelines shown below are met. Benefits Application This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy. When Mutation Analysis in Myeloproliferative Neoplasms is covered 1. JAK2, CALR or MPL mutation testing is considered medically necessary for the diagnosis of patients presenting with clinical, laboratory, or pathological findings suggesting classic forms of myeloproliferative neoplasms (MPN), that is, polycythemia vera (PV), essential thrombocythemia (ET), or primary myelofibrosis (PMF) when ordered by a hematology and/or oncology specialist in the following situations: A.
    [Show full text]
  • Acute Myeloid Leukemia Evolving from JAK 2-Positive Primary Myelofibrosis and Concomitant CD5-Negative Mantle Cell
    Hindawi Publishing Corporation Case Reports in Hematology Volume 2012, Article ID 875039, 6 pages doi:10.1155/2012/875039 Case Report Acute Myeloid Leukemia Evolving from JAK 2-Positive Primary Myelofibrosis and Concomitant CD5-Negative Mantle Cell Lymphoma: A Case Report and Review of the Literature Diana O. Treaba,1 Salwa Khedr,1 Shamlal Mangray,1 Cynthia Jackson,1 Jorge J. Castillo,2 and Eric S. Winer2 1 Department of Pathology and Laboratory Medicine, Rhode Island Hospital, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA 2 Division of Hematology/Oncology, The Miriam Hospital, The Warren Alpert Medical School, Brown University, Providence, RI 02904, USA Correspondence should be addressed to Diana O. Treaba, [email protected] Received 2 April 2012; Accepted 21 June 2012 Academic Editors: E. Arellano-Rodrigo, G. Damaj, and M. Gentile Copyright © 2012 Diana O. Treaba et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Primary myelofibrosis (formerly known as chronic idiopathic myelofibrosis), has the lowest incidence amongst the chronic myeloproliferative neoplasms and is characterized by a rather short median survival and a risk of progression to acute myeloid leukemia (AML) noted in a small subset of the cases, usually as a terminal event. As observed with other chronic myeloproliferative neoplasms, the bone marrow biopsy may harbor small lymphoid aggregates, often assumed reactive in nature. In our paper, we present a 70-year-old Caucasian male who was diagnosed with primary myelofibrosis, and after 8 years of followup and therapy developed an AML.
    [Show full text]
  • Mutations and Prognosis in Primary Myelofibrosis
    Leukemia (2013) 27, 1861–1869 & 2013 Macmillan Publishers Limited All rights reserved 0887-6924/13 www.nature.com/leu ORIGINAL ARTICLE Mutations and prognosis in primary myelofibrosis AM Vannucchi1, TL Lasho2, P Guglielmelli1, F Biamonte1, A Pardanani2, A Pereira3, C Finke2, J Score4, N Gangat2, C Mannarelli1, RP Ketterling5, G Rotunno1, RA Knudson5, MC Susini1, RR Laborde5, A Spolverini1, A Pancrazzi1, L Pieri1, R Manfredini6, E Tagliafico7, R Zini6, A Jones4, K Zoi8, A Reiter9, A Duncombe10, D Pietra11, E Rumi11, F Cervantes12, G Barosi13, M Cazzola11, NCP Cross4 and A Tefferi2 Patient outcome in primary myelofibrosis (PMF) is significantly influenced by karyotype. We studied 879 PMF patients to determine the individual and combinatorial prognostic relevance of somatic mutations. Analysis was performed in 483 European patients and the seminal observations were validated in 396 Mayo Clinic patients. Samples from the European cohort, collected at time of diagnosis, were analyzed for mutations in ASXL1, SRSF2, EZH2, TET2, DNMT3A, CBL, IDH1, IDH2, MPL and JAK2. Of these, ASXL1, SRSF2 and EZH2 mutations inter-independently predicted shortened survival. However, only ASXL1 mutations (HR: 2.02; Po0.001) remained significant in the context of the International Prognostic Scoring System (IPSS). These observations were validated in the Mayo Clinic cohort where mutation and survival analyses were performed from time of referral. ASXL1, SRSF2 and EZH2 mutations were independently associated with poor survival, but only ASXL1 mutations held their prognostic relevance (HR: 1.4; P ¼ 0.04) independent of the Dynamic IPSS (DIPSS)-plus model, which incorporates cytogenetic risk. In the European cohort, leukemia-free survival was negatively affected by IDH1/2, SRSF2 and ASXL1 mutations and in the Mayo cohort by IDH1 and SRSF2 mutations.
    [Show full text]
  • Myelofibrosis (MF)
    Myelofibrosis (MF) A Guide for Patients Introduction Being diagnosed with myelofibrosis (MF) can be a shock, particularly when you may have never heard of it. If you have questions about MF – what causes it, who it affects, how it affects your body, what symptoms to expect and likely treatments – this booklet covers the basics for you. You will also find useful advice Haematologist at University about how to get the best from Hospital of Wales, Cardiff. We your haematologist, plus practical are also grateful to Chris Rogers, advice on how to help important patient reviewer, for his valuable people in your life understand contribution. The rewrite was put such a rare condition. For together by Lisa Lovelidge and more information talk to your peer reviewed by Professor Claire haematologist or clinical nurse Harrison. This booklet has since specialist. been updated by our Patient Information Writer Isabelle Leach This booklet originally written and peer reviewed by Dr Sebastian by Professor Claire Harrison, Francis. We also appreciate Consultant Haematologist Norman Childs and Amy Cross for at Guy’s and St Thomas’ their input as patient reviewers NHS Foundation Trust, and as well as Samantha Robertson subsequently revised by Dr whose husband had MF. Steve Knapper, Consultant If you would like any information on the sources used for this booklet, please email [email protected] for a list of references. Version 4 Printed: 10/2020 2 www.leukaemiacare.org.uk Review date: 10/2022 In this booklet Introduction 2 In this booklet 3 About Leukaemia Care 4 What is myelofibrosis? 6 What are the signs and symptoms of MF? 9 How is MF diagnosed? 10 What is the treatment for MF? 12 Living with MF 26 Talking about MF 28 Glossary 31 Useful contacts and further support 39 Helpline freephone 08088 010 444 3 About Leukaemia Care Leukaemia Care is a national charity dedicated to ensuring that people affected by blood cancer have access to the right information, advice and support.
    [Show full text]
  • Acute Massive Myelofibrosis with Acute Lymphoblastic Leukemia Akut Masif Myelofibrozis Ve Akut Lenfoblastik Lösemi Birlikteliği
    204 Case Report Acute massive myelofibrosis with acute lymphoblastic leukemia Akut masif myelofibrozis ve akut lenfoblastik lösemi birlikteliği Zekai Avcı1, Barış Malbora1, Meltem Gülşan1, Feride Iffet Şahin2, Bülent Celasun3, Namık Özbek1 1Department of Pediatrics, Başkent University Faculty of Medicine, Ankara, Turkey 2Department of Medical Genetics, Başkent University Faculty of Medicine, Ankara, Turkey 3Department of Pathology, Başkent University Faculty of Medicine, Ankara, Turkey Abstract Acute myelofibrosis is characterized by pancytopenia of sudden onset, megakaryocytic hyperplasia, extensive bone mar- row fibrosis, and the absence of organomegaly. Acute myelofibrosis in patients with acute lymphoblastic leukemia is extremely rare. We report a 4-year-old boy who was diagnosed as having acute massive myelofibrosis and acute lym- phoblastic leukemia. Performing bone marrow aspiration in this patient was difficult (a “dry tap”), and the diagnosis was established by means of a bone marrow biopsy and immunohistopathologic analysis. The prognostic significance of acute myelofibrosis in patients with acute lymphoblastic leukemia is not clear. (Turk J Hematol 2009; 26: 204-6) Key words: Acute myelofibrosis, acute lymphoblastic leukemia, dry tap Received: April 9, 2008 Accepted: December 24, 2008 Özet Akut myelofibrozis ani gelişen pansitopeni, kemik iliğinde megakaryositik hiperplazi, belirgin fibrozis ve organomegali olmaması ile karakterize bir hastalıktır. Akut myelofibrozis ile akut lenfoblastik lösemi birlikteliği çok nadir görülmektedir.
    [Show full text]
  • The Evolving Understanding of Prognosis in Post–Essential Thrombocythemia Myelofibrosis and Post–Polycythemia Vera Myelofibrosis Vs Primary Myelofibrosis
    The Evolving Understanding of Prognosis in Post–Essential Thrombocythemia Myelofibrosis and Post–Polycythemia Vera Myelofibrosis vs Primary Myelofibrosis Lucia Masarova, MD, and Srdan Verstovsek, MD Dr Masarova is an assistant professor Abstract: Myelofibrosis (MF) is the most aggressive of the classic and Dr Verstovsek is a professor in Philadelphia chromosome–negative myeloproliferative neoplasms the Department of Leukemia at The (MPNs). In some patients with essential thrombocytopenia or poly- University of Texas MD Anderson cythemia vera, which are relatively benign MPNs, MF develops Cancer Center in Houston, Texas. as a natural evolution of their disease, resulting in post–essential thrombocythemia myelofibrosis (PET-MF) or post–polycythemia Corresponding author: vera myelofibrosis (PPV-MF). Presenting with the same clini- Srdan Verstovsek, MD, PhD cal features, including debilitating symptoms and signs of bone MD Anderson Cancer Center marrow failure, PET/PPV-MF has traditionally been considered Department of Leukemia akin to primary myelofibrosis (PMF). However, recent observa- 1515 Holcombe Blvd, Unit 428 Houston, TX 77030 tions that PET/PPV-MF may be a distinct clinical entity from PMF Tel: (713) 745-3429 have triggered efforts to improve prognostication in these diseases. E-mail: [email protected] Novel predictive models that incorporate rapidly emerging clini- cal and molecular data are being developed to improve outcomes in patients with PMF or PET/PPV-MF. This review focuses on the major clinical features and prognostic classification systems used in PMF and PET/PPV-MF. Introduction Myelofibrosis (MF) is one of the chronic Philadelphia chromosome– negative myeloproliferative neoplasms (MPNs). It is characterized by the clonal proliferation of myeloid cells, leading to extramedullary hematopoiesis, hepatosplenomegaly, constitutional symptoms (ie, fatigue, night sweats, weight loss, and fever), and cytopenia, along with bone marrow fibrosis and an increased risk for evolution into acute myeloid leukemia (AML).
    [Show full text]
  • Chronic Myeloid Leukemia Mimicking Primary Myelofibrosis: a Case Report
    ISSN: 2640-7914 DOI: https://dx.doi.org/10.17352/ahcrr CLINICAL GROUP Received: 02 November, 2020 Case Report Accepted: 01 February, 2021 Published: 02 February, 2021 *Corresponding author: Anju S, Junior Resident, Gov- Chronic myeloid leukemia ernment Medical College, Kottayam, Kerala, India, Tel: 91 9496057350; E-mail: mimicking primary Keywords: Chronic myeloid leukemia; Primary myelo- fi brosis; Blast crisis; Myeloproliferative neoplasms myelofi brosis: A case report https://www.peertechz.com Anju S*, Jayalakshmy PL and Sankar Sundaram Junior Resident, Government Medical College, Kottayam, Kerala, India Abstract Bone marrow fi brosis leading to dry tap aspiration and often associated with blast crisis has previously been reported in both Chronic myeloid leukemia and Primary myelofi brosis. The similarities between these two conditions in terms of clinical presentation and morphology can really create a diagnostic dilemma. Here we present a case of Chronic myeloid leukemia in fi brosis and blast crisis in a 32 year old lady which closely resembled Primary myelofi brosis in transformation. All myeloproliferative neoplasms can undergo blast transformation. In this case, the detection of Philadelphia chromosome helped to distinguish Chronic myeloid leukemia from other myeloproliferative neoplasms. Introduction diffi cult to distinguish the different MPNs especially those in blast crisis and fi brosis. The treatment of CML involves targeted Myeloproliferative Neoplasm (MPN) results from therapy namely, Imatinib mesylate, which is a tyrosine kinase unchecked proliferation of the cellular elements in the bone inhibitor. Also, JAK1/2 inhibitors administered in PMF patients marrow characterized by panmyelosis and accompanied by show clinical improvement [2]. So, it is Important to distinguish erythrocytosis, granulocytosis, and/or thrombocytosis in every MPNs even in their blastic phase as they have different the peripheral blood.
    [Show full text]
  • CDG and Immune Response: from Bedside to Bench and Back Authors
    CDG and immune response: From bedside to bench and back 1,2,3 1,2,3,* 2,3 1,2 Authors: Carlota Pascoal , Rita Francisco , Tiago Ferro , Vanessa dos Reis Ferreira , Jaak Jaeken2,4, Paula A. Videira1,2,3 *The authors equally contributed to this work. 1 Portuguese Association for CDG, Lisboa, Portugal 2 CDG & Allies – Professionals and Patient Associations International Network (CDG & Allies – PPAIN), Caparica, Portugal 3 UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal 4 Center for Metabolic Diseases, UZ and KU Leuven, Leuven, Belgium Word count: 7478 Number of figures: 2 Number of tables: 3 This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/jimd.12126 This article is protected by copyright. All rights reserved. Abstract Glycosylation is an essential biological process that adds structural and functional diversity to cells and molecules, participating in physiological processes such as immunity. The immune response is driven and modulated by protein-attached glycans that mediate cell-cell interactions, pathogen recognition and cell activation. Therefore, abnormal glycosylation can be associated with deranged immune responses. Within human diseases presenting immunological defects are Congenital Disorders of Glycosylation (CDG), a family of around 130 rare and complex genetic diseases. In this review, we have identified 23 CDG with immunological involvement, characterised by an increased propensity to – often life-threatening – infection.
    [Show full text]
  • Severe Congenital Neutropenia with Monocytosis and Non-Syndromic Sensorineural Hear
    Venugopal et al. BMC Medical Genetics (2020) 21:35 https://doi.org/10.1186/s12881-020-0971-z RESEARCH ARTICLE Open Access Two monogenic disorders masquerading as one: severe congenital neutropenia with monocytosis and non-syndromic sensorineural hearing loss Parvathy Venugopal1,2†, Lucia Gagliardi1,2,3,4,5†, Cecily Forsyth6†, Jinghua Feng7,8, Kerry Phillips9, Milena Babic1,2, Nicola K. Poplawski9, Hugh Young Rienhoff Jr10, Andreas W. Schreiber2,7,8,11, Christopher N. Hahn1,2,3,8†, Anna L. Brown1,2,8† and Hamish S. Scott1,2,3,7,8*† Abstract Background: We report a large family with four successive generations, presenting with a complex phenotype of severe congenital neutropenia (SCN), partially penetrant monocytosis, and hearing loss of varying severity. Methods: We performed whole exome sequencing to identify the causative variants. Sanger sequencing was used to perform segregation analyses on remaining family members. Results: We identified and classified a pathogenic GFI1 variant and a likely pathogenic variant in MYO6 which together explain the complex phenotypes seen in this family. Conclusions: We present a case illustrating the benefits of a broad screening approach that allows identification of oligogenic determinants of complex human phenotypes which may have been missed if the screening was limited to a targeted gene panel with the assumption of a syndromic disorder. This is important for correct genetic diagnosis of families and disentangling the range and severity of phenotypes associated with high impact variants. Keywords: Neutropenia, Congenital neutropenia, Leukemia predisposition, Polygenic inheritance, Hearing loss Background cases [2]. It may also occur as a part of a syndrome with Severe congenital neutropenia (SCN) was first described other developmental defects (e.g.
    [Show full text]
  • The Significance of Various Granulocytic Inclusions
    4/8/19 THE SIGNIFICANCE OF VARIOUS DISCLOSURES GRANULOCYTIC INCLUSIONS ¡ No relevant financial interests to disclose. KRISTLE HABERICHTER, DO, FCAP GRAND TRAVERSE PATHOLOGY, PLLC OBJECTIVES GRANULOCYTES ¡ Innate immune system ¡ Travel to sites of infection, recognize and phagocytose pathogens ¡ Recognize common and uncommon granulocytic inclusions, including those associated with certain ¡ Utilize numerous cytotoxic mechanisms to kill pathogens inherited disorders and infectious etiologies ¡ Granulopoiesis occurs in the bone marrow ¡ Sufficient stem cells, adequate microenvironment, and regulatory factors ¡ Identify newly described green neutrophilic inclusions ¡ Granulocyte colony stimulating factor (G-CSF) → Granulocytes ¡ Monocyte colony stimulating factor (M-CSF) → Monocytes ¡ Understand the clinical significance and implications of various inclusions ¡ Granulocyte-monocytes colony stimulating factor (GM-CSF) → Granulocytes & Monocytes ¡ 1-3 weeks for complete granulopoiesis to occur ¡ Neutrophils only circulate for a few hours before migrating to the tissues Photo by K. Haberichter (Giemsa, 1000x) GRANULOCYTES INCLUSION CATEGORIES ¡ Primary granules → Myeloperoxidase Reactive/Acquired Changes Congenital Abnormalities Infectious Etiologies ¡ “Late” myeloblasts and promyelocytes ¡ To x ic G r a n u la t io n ¡ Chédiak-Higashi Syndrome ¡ Anaplasma ¡ Secondary granules → Leukocyte alkaline phosphatase ¡ Döhle Bodies ¡ Alder-Reilly Anomaly ¡ Ehrlichia ¡ Myelocytes, metamyelocytes, band and segmented neutrophils ¡ Cytokine Effect ¡ May-Hegglin
    [Show full text]
  • Utility of JAK2 V617F Allelic Burden in Distinguishing Chronic Myelomonocytic Leukemia from Primary Myelofibrosis with Monocytosis☆ Zhihong Hu MD, Phd A, Carlos E
    Human Pathology (2019) 85,290–298 www.elsevier.com/locate/humpath Original contribution Utility of JAK2 V617F allelic burden in distinguishing chronic myelomonocytic Leukemia from Primary myelofibrosis with monocytosis☆ Zhihong Hu MD, PhD a, Carlos E. Bueso Ramos MD, PhD b, L. Jeffrey Medeiros MD b, Chong Zhao MD b, C. Cameron Yin MD, PhD b,ShaoyingLiMDb, Shimin Hu MD, PhD b, Wei Wang MD, PhD b, Beenu Thakral MD b, Jie Xu MD, PhD b, Srdan Verstovsek MD c, Pei Lin MD b,⁎ aDepartment of Pathology and Lab Medicine, The University of Texas Health Center at Houston, Houston, TX 77030, USA bDepartment of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA cDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Received 1 July 2018; revised 30 October 2018; accepted 31 October 2018 Keywords: Summary The concurrent presence of JAK2 V617F, monocytosis, and bone marrow fibrosis can be observed JAK2V617F; in both chronic myelomonocytic leukemia (CMML) and primary myelofibrosis (PMF). It can be challeng- SRSF2 mutation; ing to distinguish CMML with JAK2 mutation and fibrosis from other myeloid neoplasms, particularly Monoctyosis; PMF. To identify key features that may help distinguish these 2 entities, we retrospectively studied 21 cases Primary myelofibrosis; diagnosed as “CMML” with JAK2 V617F and bone marrow fibrosis that were identified from a cohort of Chronic myelomonocytic 610 cases of CMML diagnosed in 2006 to 2016. Upon further review, we confirmed the diagnosis of leukemia; CMML in 7 cases, 11 cases were reclassified as PMF, and 3 cases had features intermediate between CMML Gray zone and PMF (gray zone).
    [Show full text]