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Lymphoproliferative disorder

MedGen UID:
6162
Concept ID:
C0024314
Neoplastic Process
Synonym: Lymphoproliferative syndrome
SNOMED CT: Lymphoproliferative disorder (414629003); Lymphoproliferative disorder (277466009)
 
HPO: HP:0005523
Monarch Initiative: MONDO:0016537
OMIM® Phenotypic series: PS308240
Orphanet: ORPHA238510

Definition

A disorder characterized by proliferation of lymphocytes at various stages of differentiation. Lymphoproliferative disorders can be neoplastic (clonal, as in lymphomas and leukemias) or reactive (polyclonal, as in infectious mononucleosis). [from NCI]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVLymphoproliferative disorder

Conditions with this feature

Wiskott-Aldrich syndrome
MedGen UID:
21921
Concept ID:
C0043194
Disease or Syndrome
The WAS-related disorders, which include Wiskott-Aldrich syndrome, X-linked thrombocytopenia (XLT), and X-linked congenital neutropenia (XLN), are a spectrum of disorders of hematopoietic cells, with predominant defects of platelets and lymphocytes caused by pathogenic variants in WAS. WAS-related disorders usually present in infancy. Affected males have thrombocytopenia with intermittent mucosal bleeding, bloody diarrhea, and intermittent or chronic petechiae and purpura; eczema; and recurrent bacterial and viral infections, particularly of the ear. At least 40% of those who survive the early complications develop one or more autoimmune conditions including hemolytic anemia, immune thrombocytopenic purpura, immune-mediated neutropenia, rheumatoid arthritis, vasculitis, and immune-mediated damage to the kidneys and liver. Individuals with a WAS-related disorder, particularly those who have been exposed to Epstein-Barr virus (EBV), are at increased risk of developing lymphomas, which often occur in unusual, extranodal locations including the brain, lung, or gastrointestinal tract. Males with XLT have thrombocytopenia with small platelets; other complications of Wiskott-Aldrich syndrome, including eczema and immune dysfunction, are usually mild or absent. Males with XLN have congenital neutropenia, myeloid dysplasia, and lymphoid cell abnormalities.
Reticular dysgenesis
MedGen UID:
124417
Concept ID:
C0272167
Disease or Syndrome
Reticular dysgenesis, the most severe form of inborn severe combined immunodeficiency (SCID), is characterized by absence of granulocytes and almost complete deficiency of lymphocytes in peripheral blood, hypoplasia of the thymus and secondary lymphoid organs, and lack of innate and adaptive humoral and cellular immune functions, leading to fatal septicemia within days after birth (summary by Pannicke et al., 2009).
Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency
MedGen UID:
351256
Concept ID:
C1864947
Disease or Syndrome
Immunodeficiency-54 is an autosomal recessive primary immunodeficiency characterized by severe intra- and extrauterine growth retardation, microcephaly, decreased numbers of natural killer (NK) cells, and recurrent viral infections, most often affecting the respiratory tract and leading to respiratory failure. Affected individuals also have adrenal insufficiency requiring corticosteroid replacement therapy and may have an increased susceptibility to cancer. Laboratory studies of patient cells showed a DNA repair defect (summary by Gineau et al., 2012).
Autoimmune lymphoproliferative syndrome type 4
MedGen UID:
382434
Concept ID:
C2674723
Disease or Syndrome
RAS-associated leukoproliferative disorder is characterized by lymphadenopathy, splenomegaly, and variable autoimmune phenomena, including autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, and neutropenia. Laboratory studies show an expansion of lymphocytes due to defective apoptosis, as well as significant autoantibodies. Some patients have recurrent infections, and there may be an increased risk of hematologic malignancy (summary by Oliveira, 2013 and Niemela et al., 2010). The disorder shows significant overlap with autoimmune lymphoproliferative syndrome (ALPS; 601859) and was originally designated ALPS IV.
X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia
MedGen UID:
477076
Concept ID:
C3275445
Disease or Syndrome
XMEN is an X-linked recessive immunodeficiency characterized by CD4 (186940) lymphopenia, severe chronic viral infections, and defective T-lymphocyte activation (Li et al., 2011). Affected individuals have chronic Epstein-Barr virus (EBV) infection and are susceptible to the development of EBV-associated B-cell lymphoproliferative disorders. Magnesium supplementation may be therapeutic (summary by Li et al., 2014).
Lymphoproliferative syndrome 1
MedGen UID:
765548
Concept ID:
C3552634
Disease or Syndrome
Lymphoproliferative syndrome-1 is an autosomal recessive primary immunodeficiency characterized by onset in early childhood of Epstein-Barr virus (EBV)-associated immune dysregulation, manifest as lymphoma, lymphomatoid granulomatosis, hemophagocytic lymphohistiocytosis, Hodgkin disease, and/or hypogammaglobulinemia. Autoimmune disorders, such as autoimmune hemolytic anemia or renal disease, may also occur. Patients show a high EBV viral load and decreased invariant natural killer T cells. It is unknown whether patients with ITK mutations are intrinsically susceptible to development of lymphoma or dysgammaglobulinemia in the absence of EBV infection (summary by Stepensky et al., 2011; Linka et al., 2012). For a discussion of genetic heterogeneity of lymphoproliferative syndrome, see XLP1 (308240).
Combined immunodeficiency due to LRBA deficiency
MedGen UID:
766426
Concept ID:
C3553512
Disease or Syndrome
Common variable immunodeficiency-8 with autoimmunity is an autosomal recessive disorder of immune dysregulation. Affected individuals have early childhood onset of recurrent infections, particularly respiratory infections, and also develop variable autoimmune disorders, including idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and inflammatory bowel disease. The presentation and phenotype are highly variable, even within families (summary by Lopez-Herrera et al., 2012 and Alangari et al., 2012). Immunologic findings are also variable and may include decreased B cells, hypogammaglobulinemia, and deficiency of CD4+ T regulatory (Treg) cells (Charbonnier et al., 2015). For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (607594).
Combined immunodeficiency due to STK4 deficiency
MedGen UID:
766857
Concept ID:
C3553943
Disease or Syndrome
Immunodeficiency-110 (IMD110) is an autosomal recessive primary T-cell immunodeficiency syndrome characterized by progressive loss of naive T cells, recurrent bacterial, viral, and fungal infections, warts, and abscesses, and autoimmune manifestations. Patients are at risk for developing lymphoproliferative disorders or lymphoma, particularly associated with EBV. Some patients may show cardiac malformations, including atrial septal defect (Abdollahpour et al., 2012; Nehme et al., 2012).
Lymphoproliferative syndrome 2
MedGen UID:
767454
Concept ID:
C3554540
Disease or Syndrome
Lymphoproliferative syndrome-2, also known as CD27 deficiency, is an autosomal recessive immunodeficiency disorder associated with persistent symptomatic EBV viremia, hypogammaglobulinemia, and impairment in specific antibody function resulting from impaired T cell-dependent B-cell responses and T-cell dysfunction (summary by van Montfrans et al., 2012). The phenotype can vary significantly, from asymptomatic borderline-low hypogammaglobulinemia, to a full-blown symptomatic systemic inflammatory response with life-threatening EBV-related complications, including hemophagocytic lymphohistiocytosis, a lymphoproliferative disorder, and malignant lymphoma requiring stem cell transplantation (summary by Salzer et al., 2013). For a discussion of genetic heterogeneity of lymphoproliferative syndrome, see XLP1 (308240).
Autoimmune lymphoproliferative syndrome, type III caused by mutation in PRKCD
MedGen UID:
816258
Concept ID:
C3809928
Disease or Syndrome
Autoimmune lymphoproliferative syndrome type III is an autosomal recessive disorder of immune dysregulation. The phenotype is variable, but most patients have significant lymphadenopathy associated with variable autoimmune manifestations. Some patients may have recurrent infections. Lymphocyte accumulation results from a combination of impaired apoptosis and excessive proliferation (summary by Oliveira, 2013). For a general description and a discussion of genetic heterogeneity of ALPS, see 601859.
Vasculitis due to ADA2 deficiency
MedGen UID:
854497
Concept ID:
C3887654
Disease or Syndrome
Adenosine deaminase 2 deficiency (DADA2) is a complex systemic autoinflammatory disorder in which vasculopathy/vasculitis, dysregulated immune function, and/or hematologic abnormalities may predominate. Inflammatory features include intermittent fevers, rash (often livedo racemosa/reticularis), and musculoskeletal involvement (myalgia/arthralgia, arthritis, myositis). Vasculitis, which usually begins before age ten years, may manifest as early-onset ischemic (lacunar) and/or hemorrhagic strokes, or as cutaneous or systemic polyarteritis nodosa. Hypertension and hepatosplenomegaly are often found. More severe involvement may lead to progressive central neurologic deficits (dysarthria, ataxia, cranial nerve palsies, cognitive impairment) or to ischemic injury to the kidney, intestine, and/or digits. Dysregulation of immune function can lead to immunodeficiency or autoimmunity of varying severity; lymphadenopathy may be present and some affected individuals have had lymphoproliferative disease. Hematologic disorders may begin early in life or in late adulthood, and can include lymphopenia, neutropenia, pure red cell aplasia, thrombocytopenia, or pancytopenia. Of note, both interfamilial and intrafamilial phenotypic variability (e.g., in age of onset, frequency and severity of manifestations) can be observed; also, individuals with biallelic ADA2 pathogenic variants may remain asymptomatic until adulthood or may never develop clinical manifestations of DADA2.
Severe combined immunodeficiency due to CTPS1 deficiency
MedGen UID:
863054
Concept ID:
C4014617
Disease or Syndrome
IMD24 is an autosomal recessive immunodeficiency characterized by the impaired capacity of activated T and B cells to proliferate in response to antigen receptor-mediated activation. Patients have early onset of severe chronic viral infections, mostly caused by herpesviruses, including Epstein-Barr virus (EBV) and varicella zoster virus (VZV); they also suffer from recurrent encapsulated bacterial infections, a spectrum typical of a combined deficiency of adaptive immunity (CID) (summary by Martin et al., 2014).
Severe combined immunodeficiency due to CD70 deficiency
MedGen UID:
1799982
Concept ID:
C5568559
Disease or Syndrome
Lymphoproliferative syndrome-3 (LPFS3) is an autosomal recessive early-onset immunologic disorder characterized by increased susceptibility to Epstein-Barr virus (EBV) infection in B cells, resulting in abnormal B-cell proliferation and increased susceptibility to B-cell malignancies, including Hodgkin lymphoma. Patients usually have hypogammaglobulinemia without lymphopenia, although some subsets of immune cells may be low and some patients may have recurrent infections. The disorder results from impaired signaling from proliferating B cells to effector T cells that provide immune surveillance. There may be an increased risk of solid tumors in heterozygous carriers (summary by Abolhassani et al., 2017). For a discussion of genetic heterogeneity of lymphoproliferative syndrome, see XLP1 (308240).

Professional guidelines

PubMed

Atallah-Yunes SA, Salman O, Robertson MJ
Br J Haematol 2023 May;201(3):383-395. Epub 2023 Mar 22 doi: 10.1111/bjh.18763. PMID: 36946218
Jacobsen E
Am J Hematol 2022 Dec;97(12):1638-1651. Epub 2022 Oct 18 doi: 10.1002/ajh.26737. PMID: 36255040
Freedman A, Jacobsen E
Am J Hematol 2020 Mar;95(3):316-327. Epub 2019 Dec 22 doi: 10.1002/ajh.25696. PMID: 31814159

Recent clinical studies

Etiology

Amengual JE, Pro B
Blood 2023 Oct 26;142(17):1426-1437. doi: 10.1182/blood.2023020075. PMID: 37540819Free PMC Article
Atallah-Yunes SA, Salman O, Robertson MJ
Br J Haematol 2023 May;201(3):383-395. Epub 2023 Mar 22 doi: 10.1111/bjh.18763. PMID: 36946218
Goodlad JR, Cerroni L, Swerdlow SH
Virchows Arch 2023 Jan;482(1):281-298. Epub 2022 Oct 24 doi: 10.1007/s00428-022-03421-5. PMID: 36278991Free PMC Article
Sprangers B, Riella LV, Dierickx D
Am J Kidney Dis 2021 Aug;78(2):272-281. Epub 2021 Mar 25 doi: 10.1053/j.ajkd.2021.01.015. PMID: 33774079
Robinson C, Chanchlani R, Kitchlu A
Pediatr Nephrol 2021 Aug;36(8):2279-2291. Epub 2020 Oct 15 doi: 10.1007/s00467-020-04790-2. PMID: 33057766

Diagnosis

Goodlad JR, Cerroni L, Swerdlow SH
Virchows Arch 2023 Jan;482(1):281-298. Epub 2022 Oct 24 doi: 10.1007/s00428-022-03421-5. PMID: 36278991Free PMC Article
Weindorf SC, Smith LB, Owens SR
Arch Pathol Lab Med 2018 Nov;142(11):1347-1351. doi: 10.5858/arpa.2018-0275-RA. PMID: 30407861
Jeudy J, Burke AP, Frazier AA
Radiol Clin North Am 2016 Jul;54(4):689-710. doi: 10.1016/j.rcl.2016.03.006. PMID: 27265603
Salem PA, Estephan FF
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Ionescu DN, Pierson DM, Qing G, Li M, Colby TV, Leslie KO
Arch Pathol Lab Med 2005 Sep;129(9):1159-63. doi: 10.5858/2005-129-1159-PCH. PMID: 16119991

Therapy

Amengual JE, Pro B
Blood 2023 Oct 26;142(17):1426-1437. doi: 10.1182/blood.2023020075. PMID: 37540819Free PMC Article
Atallah-Yunes SA, Salman O, Robertson MJ
Br J Haematol 2023 May;201(3):383-395. Epub 2023 Mar 22 doi: 10.1111/bjh.18763. PMID: 36946218
Budde K, Prashar R, Haller H, Rial MC, Kamar N, Agarwal A, de Fijter JW, Rostaing L, Berger SP, Djamali A, Leca N, Allamassey L, Gao S, Polinsky M, Vincenti F
J Am Soc Nephrol 2021 Dec 1;32(12):3252-3264. doi: 10.1681/ASN.2021050628. PMID: 34706967Free PMC Article
Freedman A, Jacobsen E
Am J Hematol 2020 Mar;95(3):316-327. Epub 2019 Dec 22 doi: 10.1002/ajh.25696. PMID: 31814159
Johnson SA, Oscier DG, Leblond V
Blood Rev 2002 Sep;16(3):175-84. doi: 10.1016/s0268-960x(02)00016-4. PMID: 12163003

Prognosis

Robinson C, Chanchlani R, Kitchlu A
Pediatr Nephrol 2021 Aug;36(8):2279-2291. Epub 2020 Oct 15 doi: 10.1007/s00467-020-04790-2. PMID: 33057766
Berentsen S, Barcellini W, D'Sa S, Randen U, Tvedt THA, Fattizzo B, Haukås E, Kell M, Brudevold R, Dahm AEA, Dalgaard J, Frøen H, Hallstensen RF, Jæger PH, Hjorth-Hansen H, Małecka A, Oksman M, Rolke J, Sekhar M, Sørbø JH, Tjønnfjord E, Tsykunova G, Tjønnfjord GE
Blood 2020 Jul 23;136(4):480-488. doi: 10.1182/blood.2020005674. PMID: 32374875
Cacoub P, Comarmond C, Domont F, Savey L, Saadoun D
Am J Med 2015 Sep;128(9):950-5. Epub 2015 Mar 30 doi: 10.1016/j.amjmed.2015.02.017. PMID: 25837517
van Rhee F, Wong RS, Munshi N, Rossi JF, Ke XY, Fosså A, Simpson D, Capra M, Liu T, Hsieh RK, Goh YT, Zhu J, Cho SG, Ren H, Cavet J, Bandekar R, Rothman M, Puchalski TA, Reddy M, van de Velde H, Vermeulen J, Casper C
Lancet Oncol 2014 Aug;15(9):966-74. Epub 2014 Jul 17 doi: 10.1016/S1470-2045(14)70319-5. PMID: 25042199
Vincenti F, Charpentier B, Vanrenterghem Y, Rostaing L, Bresnahan B, Darji P, Massari P, Mondragon-Ramirez GA, Agarwal M, Di Russo G, Lin CS, Garg P, Larsen CP
Am J Transplant 2010 Mar;10(3):535-46. doi: 10.1111/j.1600-6143.2009.03005.x. PMID: 20415897

Clinical prediction guides

Jacobsen E
Am J Hematol 2022 Dec;97(12):1638-1651. Epub 2022 Oct 18 doi: 10.1002/ajh.26737. PMID: 36255040
Yeo WS, Ng QX
Pediatr Nephrol 2022 Mar;37(3):489-498. Epub 2021 Mar 12 doi: 10.1007/s00467-021-05023-w. PMID: 33712863
Kwapisz D
Clin Transplant 2021 Jun;35(6):e14286. Epub 2021 Mar 23 doi: 10.1111/ctr.14286. PMID: 33715217
Freedman A, Jacobsen E
Am J Hematol 2020 Mar;95(3):316-327. Epub 2019 Dec 22 doi: 10.1002/ajh.25696. PMID: 31814159
Scarfò L, Ferreri AJ, Ghia P
Crit Rev Oncol Hematol 2016 Aug;104:169-82. Epub 2016 Jun 16 doi: 10.1016/j.critrevonc.2016.06.003. PMID: 27370174

Recent systematic reviews

Honar N, Shahramian I, Imanieh MH, Ataollahi M, Tahani M, Rakhshaninasab S, Javadifar A
Hum Antibodies 2022;30(4):183-194. doi: 10.3233/HAB-220016. PMID: 37005883
Zanelli M, Zizzo M, Bisagni A, Froio E, De Marco L, Valli R, Filosa A, Luminari S, Martino G, Massaro F, Fratoni S, Ascani S
Ann Hematol 2020 Oct;99(10):2243-2253. Epub 2020 Apr 19 doi: 10.1007/s00277-020-04024-3. PMID: 32307569
Wieser I, Wohlmuth C, Nunez CA, Duvic M
Am J Clin Dermatol 2016 Aug;17(4):319-27. doi: 10.1007/s40257-016-0192-6. PMID: 27138554
Rezk E, Nofal YH, Hamzeh A, Aboujaib MF, AlKheder MA, Al Hammad MF
Cochrane Database Syst Rev 2015 Nov 8;2015(11):CD004402. doi: 10.1002/14651858.CD004402.pub3. PMID: 26558642Free PMC Article
Yang K, Tan J, Wu T
Cochrane Database Syst Rev 2009 Jan 21;(1):CD006719. doi: 10.1002/14651858.CD006719.pub3. PMID: 19160296

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