How is autoimmune lymphoproliferative syndrome (ALPS) classified?

Updated: Jul 29, 2019
  • Author: Akaluck Thatayatikom, MD, RhMSUS; Chief Editor: Harumi Jyonouchi, MD  more...
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The nomenclature for the various types of ALPS is determined based on the genetic mutation present in an individual. Patients meeting diagnostic criteria for ALPS in whom no genetic mutation can be identified and classified as ALPS–undetermined.

ALPS-like disorders or ALPS-related syndromes are diseases which have similar features of those with ALPS but are missing required diagnostic features such as elevated DNT cells or have additional manifestations such as immunodeficiency features (Table 1). ALPS-like disorders should be considered and evaluated in any patients with clinical features of ALPS.

Table 1. ALPS-like disorders or ALPS-related syndromes [6, 17] (Open Table in a new window)

Disease Mutation Clinical Features
Caspase-8 deficiency state (CEDS) Autosomal recessive/ LOF mutation in CASP8 gene (2q33.1) Recurrent sinopulmonary infections, severe mucocutaneous herpes simplex viral infection with defects in activation of T, B and NK cells, hypogammaglobulinemia, low pneumococcal antibodies, low T cell function (lymphocyte mitogen stimulation), low NK function [18]
FADD deficiency Autosomal recessive/ LOF mutation in FADD gene (11q13.3) Susceptibility to bacterial and viral infections related to functional hyposplenism and impaired interferon immunity, congenital heart disease, recurrent fever, liver dysfunction, seizures [19]
Ras-associated autoimmune leukoproliferative disorder Germline or somatic mutations/ GOF mutation in NRAS gene (1p13.2) and KRAS gene (12p12.1) Lymphadenopathy, massive splenomegaly, increased circulating B cells, hypergammaglobulinemia, autoimmunity [20, 21, 22]
Dianzani autoimmune lymphoproliferative disease N252S and A91B perforin gene variations, osteopontin polymorphism No increased DNT, defective Fas, lymphadenopathy, splenomegaly, autoimmunity [23, 24]
Activated phosphoinositide 3-kinase δ syndrome (APDS) Autosomal dominant/ gain of function mutations in PIK3CD (1p36.22), PIK3R1(5q13.1) Combined immunodeficiency with recurrent sinopulmonary infections, lymphadenopathy, herpesvirus infection, autoinflammatory disease, lymphoma and neurodevelopmental delay [25]
Protein kinase C delta (PRKCD) deficiency Autosomal recessive/ loss of function mutation in PRKCD gene (3p21.1) Hypogammaglobinemia, recurrent infections, lymphadenopathy, hepatosplenomegaly, autoimmunity and NK cell dysfunction [26, 27]
Lipopolysaccharide responsive and beige like anchor protein (LABA) deficiency with autoantibodies, regulatory T cell defects, autoimmune infiltration and enteropathy (LATAIE) Autosomal recessive/ loss of function mutation in LPS-responsive and beige-like anchor protein (LABA) gene  (4q31.3) Autoimmunity, chronic diarrhea, enteropathy or IBD–like disease, splenomegaly, pneumonia, reduction in number of regulatory T cell, CD4 T cells, class-switched memory B cell and hypogammaglobinemia [28]
CTLA4 haloinsufficiency with autoimmune infiltration (CHAI) Autosomal dominant/ LOF in CTLA4 gene (2q33.2) Hypogammaglobulinemia, lymphoproliferation, autoimmune cytopenia, and respiratory, gastrointestinal, or neurological symptoms [29]
GOF mutations in STAT1 Autosomal dominant/ GOF mutation in STAT1 gene (2q32.2) Recurrent infections including chronic mucocutaneous candidiasis (CMC), recurrent Staphylococcus aureus, recurrent herpes, Mycobacterium, autoimmunity, cytopenia and aneurysm [30]
GOF mutations in STAT3

Autosomal dominant/ GOF mutation in STAT3 gene (17q21.2)

Hypogammaglobulinemia, autoimmunity, cytopenia, lymphadenopathy, splenomegaly, enteropathy, interstitial lung disease, endocrinopathy, postnatal growth failure [31, 32]

Deficiency of adenosine deaminase 2 (DADA2)

Autosomal recessive adenosine deaminase-2 (ADA2) gene (22q11.1) Recurrent fever, vasculitis, aneurysms, hypertension, ischemic or hemorrhagic stroke, livedo reticularis, lymphadenopathy, hepatosplenomegaly,hypogammaglobulinemia, cytopenia, lymphopenia [33, 34]
B cell expansion with NF-B and T cell anergy disease (BENTA) Autosomal dominant, GOF mutation in CARD11 gene (7p22.2) Lymphadenopathy, splenomegaly, autoimmunity, cytopenia, low antibodies, recurrent bacterial infections, chronic viral (EBV, molluscum) infections, B cell lymphoma [35, 36]

Deregulation of Fas ligand expression caused by IL-12RB1 mutation

Autosomal recess, LOF mutation in IL12RB1 gene (19p13.11) Lymphadenopathy, splenomegaly, hepatomegaly, elevated numbers of double-negative T cells, autoimmune cytopenias, and increased levels of vitamin B12 and interleukin-10 [37]
X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia” (XMEN) LOF mutation in MAGT1 gene (Xq21.1) Persistent Epstein–Barr virus (EBV) viremia, history of EBV+ lymphoma, a CD4:CD8 T-cell ratio of 1 or less with a normal lymphocyte count or mild to moderate lymphopenia, recurrent sinopulmonary and viral infections, hypogammaglobulinemia, variable antibody response to vaccinations, neutropenia, autoimmunity [38, 39]

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