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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. See: This record Unknown inheritance (Orphanet)

Genes (locations): Gene(s) directly associated with this condition or phenotype.	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.

See: Feature record | Search on this feature

Lymphoma

MedGen UID:: 44223
•Concept ID:: C0024299
•: Neoplastic Process

A cancer originating in lymphocytes and presenting as a solid tumor of lymhpoid cells.

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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).

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Hepatomegaly

MedGen UID:: 42428
•Concept ID:: C0019209
•: Finding

Abnormally increased size of the liver.

See: Feature record | Search on this feature

Hemolytic anemia

MedGen UID:: 1916
•Concept ID:: C0002878
•: Disease or Syndrome

A type of anemia caused by premature destruction of red blood cells (hemolysis).

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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).

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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.

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Autoimmunity

MedGen UID:: 2136
•Concept ID:: C0004368
•: Pathologic Function

The occurrence of an immune reaction against the organism's own cells or tissues.

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Lymphocytosis

MedGen UID:: 9834
•Concept ID:: C0024282
•: Disease or Syndrome

Increase in the number or proportion of lymphocytes in the blood.

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Splenomegaly

MedGen UID:: 52469
•Concept ID:: C0038002
•: Finding

Abnormal increased size of the spleen.

See: Feature record | Search on this feature

Monocytosis

MedGen UID:: 39091
•Concept ID:: C0085702
•: Disease or Syndrome

An increased number of circulating monocytes.

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Recurrent infections

MedGen UID:: 65998
•Concept ID:: C0239998
•: Finding

Increased susceptibility to infections.

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Autoimmune thrombocytopenia

MedGen UID:: 116621
•Concept ID:: C0242584
•: Disease or Syndrome

The presence of thrombocytopenia in combination with detection of antiplatelet antibodies.

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Neutropenia

MedGen UID:: 163121
•Concept ID:: C0853697
•: Finding

An abnormally low number of neutrophils in the peripheral blood.

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Decreased lymphocyte apoptosis

MedGen UID:: 349066
•Concept ID:: C1858969
•: Finding

A reduction in the rate of apoptosis in lymphocytes.

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Follicular hyperplasia

MedGen UID:: 863170
•Concept ID:: C4014733
•: Finding

Lymphadenopathy (enlargement of lymph nodes) owing to hyperplasia of follicular (germinal) centers.

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Increased circulating antibody level

MedGen UID:: 1713383
•Concept ID:: C5397581
•: Finding

An increased level of gamma globulin (immunoglobulin) in the blood.

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Abnormality of blood and blood-forming tissues
- Hemolytic anemia
- Pancytopenia
Abnormality of the digestive system
- Hepatomegaly
Abnormality of the immune system
Abnormality of the respiratory system
- Recurrent respiratory infections
Neoplasm

Term Hierarchy

GTR
MeSH
Orphanet

CClinical test, RResearch test, OOMIM, GGeneReviews, VClinVar

Immunodeficiency syndrome with autoimmunity
- Autoimmune lymphoproliferative syndrome
  - Autoimmune lymphoproliferative syndrome type 4

Follow this link to review classifications for Autoimmune lymphoproliferative syndrome type 4 in Orphanet.

Professional guidelines

PubMed

Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance.

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: 10090885 Free PMC Article

See all (1)

Recent clinical studies

Etiology

Genetic Characterization of Short Stature Patients With Overlapping Features of Growth Hormone Insensitivity Syndromes.

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: 34136918 Free PMC Article

Delayed Diagnosis and Complications of Predominantly Antibody Deficiencies in a Cohort of Australian Adults.

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: 29867917 Free PMC Article

A rare case of polyglandular autoimmune syndrome type IIIc with primary antibody failure.

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

Prevalence of mixed cryoglobulinaemia syndrome and circulating cryoglobulins in a population-based survey: the Origgio study.

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

Variations of the UNC13D gene in patients with autoimmune lymphoproliferative syndrome.

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: 23840885 Free PMC Article

See all (16)

Diagnosis

Genetic Characterization of Short Stature Patients With Overlapping Features of Growth Hormone Insensitivity Syndromes.

Delayed Diagnosis and Complications of Predominantly Antibody Deficiencies in a Cohort of Australian Adults.

A rare case of polyglandular autoimmune syndrome type IIIc with primary antibody failure.

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

Prevalence of mixed cryoglobulinaemia syndrome and circulating cryoglobulins in a population-based survey: the Origgio study.

Autoimmune hemolytic anemia.

Gehrs BC, Friedberg RC
Am J Hematol 2002 Apr;69(4):258-71. doi: 10.1002/ajh.10062. PMID: 11921020

See all (21)

Therapy

Drug rash with eosinophilia and systemic symptoms syndrome masquerading as a lymphoproliferative disorder in a young adult on immunosuppressive therapy for rheumatoid arthritis: a case report.

Hyser E
J Med Case Rep 2022 Sep 5;16(1):336. doi: 10.1186/s13256-022-03526-0. PMID: 36059007 Free PMC Article

Sirolimus is effective in autoimmune lymphoproliferative syndrome-type III: A pedigree case report with homozygous variation PRKCD.

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: 34187243 Free PMC Article

A rare case of polyglandular autoimmune syndrome type IIIc with primary antibody failure.

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

Prevalence of mixed cryoglobulinaemia syndrome and circulating cryoglobulins in a population-based survey: the Origgio study.

Response to rituximab in patients with type II cryoglobulinemia.

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

See all (7)

Prognosis

Genetic Characterization of Short Stature Patients With Overlapping Features of Growth Hormone Insensitivity Syndromes.

30 Years of Experience with Non-Hodgkin Lymphoma in Children and Adolescents: a retrospective cohort study.

Oliveira MCL, Sampaio KC, Brito AC, Campos MK, Murao M, Gusmão R, Fernandes AAL, Viana MB
Rev Assoc Med Bras (1992) 2020;66(1):25-30. Epub 2020 Feb 27 doi: 10.1590/1806-9282.66.1.25. PMID: 32130377

Recessively Inherited LRBA Mutations Cause Autoimmunity Presenting as Neonatal Diabetes.

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: 28473463 Free PMC Article

Sjögren's Syndrome.

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

Response to rituximab in patients with type II cryoglobulinemia.

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

See all (10)

Clinical prediction guides

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

A homozygous Fas ligand gene mutation in a patient causes a new type of autoimmune lymphoproliferative syndrome.

Del-Rey M, Ruiz-Contreras J, Bosque A, Calleja S, Gomez-Rial J, Roldan E, Morales P, Serrano A, Anel A, Paz-Artal E, Allende LM
Blood 2006 Aug 15;108(4):1306-12. Epub 2006 Apr 20 doi: 10.1182/blood-2006-04-015776. PMID: 16627752

Histologic features of sinus histiocytosis with massive lymphadenopathy in patients with autoimmune lymphoproliferative syndrome.

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

Lack of Fas and Fas-L mutations in patients with lymphoproliferative disorders associated with Sjögren's syndrome and type II mixed cryoglobulinemia.

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

Fas/Apo1 mutations and autoimmune lymphoproliferative syndrome in a patient with type 2 autoimmune hepatitis.

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

See all (8)

Recent systematic reviews

A Systematic Review on Predisposition to Lymphoid (B and T cell) Neoplasias in Patients With Primary Immunodeficiencies and Immune Dysregulatory Disorders (Inborn Errors of Immunity).

Riaz IB, Faridi W, Patnaik MM, Abraham RS
Front Immunol 2019;10:777. Epub 2019 Apr 16 doi: 10.3389/fimmu.2019.00777. PMID: 31057537 Free PMC Article

See all (1)

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Autoimmune lymphoproliferative syndrome type 4(ALPS4; RALD)

Definition

Clinical features

Term Hierarchy

Professional guidelines

PubMed

Recent clinical studies

Etiology

Diagnosis

Therapy

Prognosis

Clinical prediction guides

Recent systematic reviews

Supplemental Content

Table of contents

Genetic Testing Registry

Clinical resources

Practice guidelines

Molecular resources

Consumer resources

Reviews

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