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Autoimmune lymphoproliferative syndrome type 4(ALPS4; RALD)

MedGen UID:
382434
Concept ID:
C2674723
Disease or Syndrome
Synonyms: AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IV; RAS-associated autoimmune leukoproliferative disorder
SNOMED CT: RAS-associated autoimmune leukoproliferative disease (723508002); Autoimmune lymphoproliferative syndrome type 4 (723508002); Autoimmune lymphoproliferative syndrome type IV (723508002); RALD - RAS-associated autoimmune leukoproliferative disease (723508002)
Modes of inheritance:
Unknown inheritance
MedGen UID:
989040
Concept ID:
CN307042
Finding
Source: Orphanet
Hereditary clinical entity whose mode of inheritance is unknown.
 
Genes (locations): KRAS (12p12.1); NRAS (1p13.2)
 
Monarch Initiative: MONDO:0013767
OMIM®: 614470
Orphanet: ORPHA268114

Definition

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. [from OMIM]

Clinical features

From HPO
Leukemia
MedGen UID:
9725
Concept ID:
C0023418
Neoplastic Process
A cancer of the blood and bone marrow characterized by an abnormal proliferation of leukocytes.
Lymphoma
MedGen UID:
44223
Concept ID:
C0024299
Neoplastic Process
A cancer originating in lymphocytes and presenting as a solid tumor of lymhpoid cells.
Lymphoproliferative disorder
MedGen UID:
6162
Concept ID:
C0024314
Neoplastic Process
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).
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Hemolytic anemia
MedGen UID:
1916
Concept ID:
C0002878
Disease or Syndrome
A type of anemia caused by premature destruction of red blood cells (hemolysis).
Pancytopenia
MedGen UID:
18281
Concept ID:
C0030312
Disease or Syndrome
An abnormal reduction in numbers of all blood cell types (red blood cells, white blood cells, and platelets).
Recurrent respiratory infections
MedGen UID:
812812
Concept ID:
C3806482
Finding
An increased susceptibility to respiratory infections as manifested by a history of recurrent respiratory infections.
Autoimmunity
MedGen UID:
2136
Concept ID:
C0004368
Pathologic Function
The occurrence of an immune reaction against the organism's own cells or tissues.
Lymphocytosis
MedGen UID:
9834
Concept ID:
C0024282
Disease or Syndrome
Increase in the number or proportion of lymphocytes in the blood.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Monocytosis
MedGen UID:
39091
Concept ID:
C0085702
Disease or Syndrome
An increased number of circulating monocytes.
Recurrent infections
MedGen UID:
65998
Concept ID:
C0239998
Finding
Increased susceptibility to infections.
Autoimmune thrombocytopenia
MedGen UID:
116621
Concept ID:
C0242584
Disease or Syndrome
The presence of thrombocytopenia in combination with detection of antiplatelet antibodies.
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
An abnormally low number of neutrophils in the peripheral blood.
Decreased lymphocyte apoptosis
MedGen UID:
349066
Concept ID:
C1858969
Finding
A reduction in the rate of apoptosis in lymphocytes.
Follicular hyperplasia
MedGen UID:
863170
Concept ID:
C4014733
Finding
Lymphadenopathy (enlargement of lymph nodes) owing to hyperplasia of follicular (germinal) centers.
Increased circulating antibody concentration
MedGen UID:
1713383
Concept ID:
C5397581
Finding
An increased level of gamma globulin (immunoglobulin) in the blood.

Professional guidelines

PubMed

Fattizzo B, Marchetti M, Michel M, Cantoni S, Frederiksen H, Giordano G, Glenthøj A, González-López TJ, Murakhovskaya I, Napolitano M, Mingot ME, Arguello M, Patriarca A, Raso S, Vianelli N, Barcellini W
Lancet Haematol 2024 Aug;11(8):e617-e628. Epub 2024 Jul 2 doi: 10.1016/S2352-3026(24)00144-3. PMID: 38968944
Jackson CE, Fischer RE, Hsu AP, Anderson SM, Choi Y, Wang J, Dale JK, Fleisher TA, Middelton LA, Sneller MC, Lenardo MJ, Straus SE, Puck JM
Am J Hum Genet 1999 Apr;64(4):1002-14. doi: 10.1086/302333. PMID: 10090885Free PMC Article

Recent clinical studies

Etiology

Andrews A, Maharaj A, Cottrell E, Chatterjee S, Shah P, Denvir L, Dumic K, Bossowski A, Mushtaq T, Vukovic R, Didi M, Shaw N, Metherell LA, Savage MO, Storr HL
J Clin Endocrinol Metab 2021 Oct 21;106(11):e4716-e4733. doi: 10.1210/clinem/dgab437. PMID: 34136918Free PMC Article
Slade CA, Bosco JJ, Binh Giang T, Kruse E, Stirling RG, Cameron PU, Hore-Lacy F, Sutherland MF, Barnes SL, Holdsworth S, Ojaimi S, Unglik GA, De Luca J, Patel M, McComish J, Spriggs K, Tran Y, Auyeung P, Nicholls K, O'Hehir RE, Hodgkin PD, Douglass JA, Bryant VL, van Zelm MC
Front Immunol 2018;9:694. Epub 2018 May 14 doi: 10.3389/fimmu.2018.00694. PMID: 29867917Free PMC Article
Stanciu AE, Sava F, Toldi G
Gynecol Endocrinol 2018 Apr;34(4):283-285. Epub 2017 Oct 18 doi: 10.1080/09513590.2017.1391775. PMID: 29043872
Monti G, Saccardo F, Castelnovo L, Novati P, Sollima S, Riva A, Sarzi-Puttini P, Quartuccio L, De Vita S, Galli M
Autoimmun Rev 2014 Jun;13(6):609-14. Epub 2014 Jan 10 doi: 10.1016/j.autrev.2013.11.005. PMID: 24418294
Aricò M, Boggio E, Cetica V, Melensi M, Orilieri E, Clemente N, Cappellano G, Buttini S, Soluri MF, Comi C, Dufour C, Pende D, Dianzani I, Ellis SR, Pagliano S, Marcenaro S, Ramenghi U, Chiocchetti A, Dianzani U
PLoS One 2013;8(7):e68045. Epub 2013 Jul 1 doi: 10.1371/journal.pone.0068045. PMID: 23840885Free PMC Article

Diagnosis

Taki E, Wirtshafter S, Geara AS
Clin Nephrol 2024 Oct;102(4):244-247. doi: 10.5414/CN111383. PMID: 38994595
Fattizzo B, Marchetti M, Michel M, Cantoni S, Frederiksen H, Giordano G, Glenthøj A, González-López TJ, Murakhovskaya I, Napolitano M, Mingot ME, Arguello M, Patriarca A, Raso S, Vianelli N, Barcellini W
Lancet Haematol 2024 Aug;11(8):e617-e628. Epub 2024 Jul 2 doi: 10.1016/S2352-3026(24)00144-3. PMID: 38968944
Andrews A, Maharaj A, Cottrell E, Chatterjee S, Shah P, Denvir L, Dumic K, Bossowski A, Mushtaq T, Vukovic R, Didi M, Shaw N, Metherell LA, Savage MO, Storr HL
J Clin Endocrinol Metab 2021 Oct 21;106(11):e4716-e4733. doi: 10.1210/clinem/dgab437. PMID: 34136918Free PMC Article
Monti G, Saccardo F, Castelnovo L, Novati P, Sollima S, Riva A, Sarzi-Puttini P, Quartuccio L, De Vita S, Galli M
Autoimmun Rev 2014 Jun;13(6):609-14. Epub 2014 Jan 10 doi: 10.1016/j.autrev.2013.11.005. PMID: 24418294
Gehrs BC, Friedberg RC
Am J Hematol 2002 Apr;69(4):258-71. doi: 10.1002/ajh.10062. PMID: 11921020

Therapy

Taki E, Wirtshafter S, Geara AS
Clin Nephrol 2024 Oct;102(4):244-247. doi: 10.5414/CN111383. PMID: 38994595
Fattizzo B, Marchetti M, Michel M, Cantoni S, Frederiksen H, Giordano G, Glenthøj A, González-López TJ, Murakhovskaya I, Napolitano M, Mingot ME, Arguello M, Patriarca A, Raso S, Vianelli N, Barcellini W
Lancet Haematol 2024 Aug;11(8):e617-e628. Epub 2024 Jul 2 doi: 10.1016/S2352-3026(24)00144-3. PMID: 38968944
Gu H, Chen Z, Ma J, Wang J, Zhang R, Wu R, Wang T
Int J Immunopathol Pharmacol 2021 Jan-Dec;35:20587384211025934. doi: 10.1177/20587384211025934. PMID: 34187243Free PMC Article
Stanciu AE, Sava F, Toldi G
Gynecol Endocrinol 2018 Apr;34(4):283-285. Epub 2017 Oct 18 doi: 10.1080/09513590.2017.1391775. PMID: 29043872
Monti G, Saccardo F, Castelnovo L, Novati P, Sollima S, Riva A, Sarzi-Puttini P, Quartuccio L, De Vita S, Galli M
Autoimmun Rev 2014 Jun;13(6):609-14. Epub 2014 Jan 10 doi: 10.1016/j.autrev.2013.11.005. PMID: 24418294

Prognosis

Fattizzo B, Marchetti M, Michel M, Cantoni S, Frederiksen H, Giordano G, Glenthøj A, González-López TJ, Murakhovskaya I, Napolitano M, Mingot ME, Arguello M, Patriarca A, Raso S, Vianelli N, Barcellini W
Lancet Haematol 2024 Aug;11(8):e617-e628. Epub 2024 Jul 2 doi: 10.1016/S2352-3026(24)00144-3. PMID: 38968944
Andrews A, Maharaj A, Cottrell E, Chatterjee S, Shah P, Denvir L, Dumic K, Bossowski A, Mushtaq T, Vukovic R, Didi M, Shaw N, Metherell LA, Savage MO, Storr HL
J Clin Endocrinol Metab 2021 Oct 21;106(11):e4716-e4733. doi: 10.1210/clinem/dgab437. PMID: 34136918Free PMC Article
Johnson MB, De Franco E, Lango Allen H, Al Senani A, Elbarbary N, Siklar Z, Berberoglu M, Imane Z, Haghighi A, Razavi Z, Ullah I, Alyaarubi S, Gardner D, Ellard S, Hattersley AT, Flanagan SE
Diabetes 2017 Aug;66(8):2316-2322. Epub 2017 May 4 doi: 10.2337/db17-0040. PMID: 28473463Free PMC Article
Papiris SA, Tsonis IA, Moutsopoulos HM
Semin Respir Crit Care Med 2007 Aug;28(4):459-71. doi: 10.1055/s-2007-985667. PMID: 17764063
Bryce AH, Dispenzieri A, Kyle RA, Lacy MQ, Rajkumar SV, Inwards DJ, Yasenchak CA, Kumar SK, Gertz MA
Clin Lymphoma Myeloma 2006 Sep;7(2):140-4. doi: 10.3816/CLM.2006.n.052. PMID: 17026826

Clinical prediction guides

LeBlanc RE, Lansigan F
J Cutan Pathol 2021 Apr;48(4):572-577. Epub 2020 Oct 9 doi: 10.1111/cup.13863. PMID: 32894575
Galli M, Oreni L, Saccardo F, Castelnovo L, Filippini D, Marson P, Mascia MT, Mazzaro C, Origgi L, Ossi E, Pietrogrande M, Pioltelli P, Quartuccio L, Scarpato S, Sollima S, Riva A, Fraticelli P, Zani R, Giuggioli D, Sebastiani M, Sarzi Puttini P, Gabrielli A, Zignego AL, Scaini P, Ferri C, De Vita S, Monti G
Clin Exp Rheumatol 2017 Mar-Apr;35 Suppl 103(1):67-76. Epub 2017 Apr 19 PMID: 28466806
Maric I, Pittaluga S, Dale JK, Niemela JE, Delsol G, Diment J, Rosai J, Raffeld M, Puck JM, Straus SE, Jaffe ES
Am J Surg Pathol 2005 Jul;29(7):903-11. doi: 10.1097/01.pas.0000157997.61177.08. PMID: 15958855
Bertolo F, De Vita S, Dolcetti R, Carbone A, Ferraccioli GF, Bartoli E, Boiocchi M
Clin Exp Rheumatol 1999 May-Jun;17(3):339-42. PMID: 10410268
Pensati L, Costanzo A, Ianni A, Accapezzato D, Iorio R, Natoli G, Nisini R, Almerighi C, Balsano C, Vajro P, Vegnente A, Levrero M
Gastroenterology 1997 Oct;113(4):1384-9. doi: 10.1053/gast.1997.v113.pm9322534. PMID: 9322534

Recent systematic reviews

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