DiagnosisClinical DiagnosisThe diagnosis of autoimmune lymphoproliferative syndrome (ALPS) is based on a constellation of clinical findings, laboratory abnormalities, and identification of mutations in genes relevant for the tumor necrosis factor receptor superfamily member 6 (Fas) pathway of apoptosis. Recently, a revised set of diagnostic criteria were proposed [Oliveira et al 2010]:A definitive diagnosis of ALPS is based on the presence of both required criteria and one primary accessory criterion below.A probable diagnosis is based on the presence of both required criteria plus one secondary accessory criterion.Required criteriaChronic (>6 months) non-malignant, noninfectious lymphadenopathy and/or splenomegaly Elevated α/β-DNT cells with normal or elevated lymphocyte counts Primary accessory criteria Defective lymphocyte apoptosis (repeated at least once)Germline or somatic pathogenic mutations in FAS, FASLG, or CASP10 Secondary accessory criteriaElevated plasma soluble FASL levels or elevated plasma interleukin-10 levels or elevated serum vitamin B₁₂ levels or elevated plasma interleukin-18 levelsTypical immunohistologic findings as determined by an experienced hematopathologist, Autoimmune cytopenias with elevated (polyclonal) immunoglobulin G levels Positive family historyALPS should be considered in individuals with (combinations of) the following [Bleesing 2003, Rieux-Laucat et al 2003]: See also Clinical Manifestations of ALPS.Chronic non-malignant lymphoproliferationChronic and/or recurrent lymphadenopathySplenomegaly with/without hypersplenismHepatomegalyLymphocytic interstitial pneumonia (LIP) (less common)Autoimmune diseaseCytopenia, particularly combinations of autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and autoimmune neutropenia
Note: The combination of AIHA and ITP is often referred to as Evans syndrome.Other, including autoimmune hepatitis, autoimmune glomerulonephritis, autoimmune thyroiditis and, less commonly, uveitis and Guillain Barré syndromeLymphoma, both Hodgkin lymphoma and non-Hodgkin lymphomaSkin rashes, often but not exclusively of an urticarial natureFamily history of ALPS or ALPS-like featuresTestingAlthough no specific laboratory abnormality alone is diagnostic of ALPS, the detection of the following facilitates the diagnosis [Bleesing 2003, Oliveira et al 2010]:Defective Fas-mediated apoptosis in vitroT cells that express the alpha/beta T-cell receptor but lack both CD4 and CD8 (so-called alpha/beta double-negative T cells [α/β-DNT cells] in peripheral blood or tissue specimens). Detected by flow cytometric immunophenotyping, these terminally differentiated in vivo-activated T cells are rare in healthy individuals and other immune-mediated (lymphoproliferative) disorders; typically they constitute less than 2% of the lymphocyte pool.Laboratory findings in ALPS [Lim et al 1998, Carter et al 2000, Bleesing et al 2001a, Bleesing et al 2001b, Lopatin et al 2001, Bleesing et al 2002, Bleesing 2003, Bleesing 2005, Maric et al 2005, Magerus-Chatinet et al 2009, Caminha et al 2010, Oliveira et al 2010]: HematologyLymphocytosis, lymphopenia (primary or secondary in response to treatment)Coombs-positive hemolytic anemiaDyserythropoiesisReticulocytosisThrombocytopeniaNeutropeniaEosinophiliaImmunologyExpansion of other lymphocyte subsetsGamma/delta-DNT cellsCD8+/CD57+ T cellsHLA-DR+ T cellsCD5+ B cellsDecreased numbers of CD4+/CD25+ T cellsDecreased numbers of CD27+ B cellsElevated concentration of IL-10 in serum/plasmaElevated concentrations of IgG, IgA, and IgE; normal or decreased concentrations of IgMAutoantibodies (most often positive direct or indirect antiglobulin test, antiplatelet antibody, antineutrophil antibody, antiphospholipid antibody, antinuclear antibody, rheumatoid factor)Lymph node pathology (paracortical expansion with immunoblasts/plasma cells and DNT cells in interfollicular areas, florid follicular hyperplasia, progressive transformation of germinal centers [PTGC])OtherIncreased soluble CD25 (sIL-2Ralpha), CD27, CD30, and Fas ligand(FasL)Monoclonal gammopathyDecreased antibody responses to polysaccharide antigensChemistryLiver function abnormalities (in case of autoimmune hepatitis)Proteinuria (in case of glomerulonephritis)Elevated serum concentration of vitamin B_{12Normal findings in ALPSNeutrophil functionComplement concentrations and functionIn vitro proliferative responses of T cells (e.g., in response to common mitogens and antigens)NK-cell and cytotoxic T-lymphocyte (CTL) function; possibly decreased CTL activity in ALPS on the basis of defective FasL (i.e., ALPS-FASL).Antibody responses to protein antigens (e.g., diphtheria, tetanus)Note: (1) The abnormal and normal laboratory findings listed have been most reliably established for individuals with ALPS caused by either germline or somatic mutations in FAS. (2) Cell surface expression of Fas (CD95) can be normal, increased, or decreased and is in general not helpful in the diagnosis of ALPS. (3) When interpreting laboratory data of individuals with (suspected) ALPS, the influence of concurrent immunosuppressive agents at the time of testing needs to be considered.Molecular Genetic TestingGenes. Germline mutations in the three following genes are known to be associated with ALPS: FAS (TNFRSF6), FASLG (TNFSF6), and CASP10.Additionally, FAS somatic mutations in selected cell populations, including α/β-DNT cells, produce a phenotype similar to that caused by FAS germline mutations.FAS (TNFRSF6)ALPS-FAS. Heterozygous FAS germline mutations account for approximately 75% of individuals with ALPS; homozygous/compound heterozygous FAS germline mutations are also observed [Rieux-Laucat et al 1995, Kasahara et al 1998, van der Burg et al 2000, Bleesing 2003, Rieux-Laucat et al 2003].ALPS -sFAS. FAS somatic mutations in selected cell populations, including α/β-DNT cells, have been identified in individuals with an ALPS phenotype similar to that caused by FAS heterozygous germline mutations [Holzelova et al 2004, Rössler et al 2005, Dowdell et al 2010]. Since the original publications, it has become clear that this group constitutes the second largest group of persons with ALPS. Somatic mutations are always identified in the α/β-DNT cells, but rarely in other lymphocyte subsets and not in non-lymphocytes. Note: The method of sorting cell populations can influence the detection level of mutations in rare cell populations. FASLG (FASL, TNFSF6)ALPS-FASLG is associated with germline mutations in FASLG, the gene encoding tumor necrosis factor ligand superfamily member 6 (FasL). Four affected individuals have been reported to date [Wu et al 1996, CIS 1999, Del-Rey et al 2006, Bi et al 2007].CASP10ALPS-CASP10 is associated with mutations in CASP10 (the gene encoding caspase-10) [Wang et al 1999]. Of the two affected individuals originally reported in 1999, the reported homozygous CASP10 alteration was determined subsequently not to cause ALPS. In a recent study, two of 32 probands with ALPS had heterozygous missense mutations in CASP10 [Zhu et al 2006].Evidence of further locus heterogeneity. Approximately 20%-25% of individuals with ALPS currently lack a genetic diagnosis. They are classified as having one of the following:ALPS-U if no mutations are detected in FAS, FASLG, or CASP10ALPS-non-FAS if only FAS mutations have been ruled out [Dianzani et al 1997, Ramenghi et al 2000, Hundt et al 2002, van der Werff Ten Bosch et al 2002, Bleesing 2003]Note: (1) Depending on the criteria used to define ALPS (e.g., with regard to presence of α/β-DNT cells or demonstration of defective Fas-mediated apoptosis), defects in other genes or gene products inside or outside the Fas/FasL pathway may be associated with ALPS features; these include CASP8 encoding caspase-8 and the gene encoding N-RAS [Chun et al 2002, Oliveira et al 2007]. Three of these disorders have recently been classified as ALPS-related disorders: caspase-8 deficiency state (CEDS), Ras-associated autoimmune leukoproliferative disorder (RALD), and Dianzani autoimmune lymphoproliferative disease (DALD) [Oliveira et al 2010]. (2) No independently confirmed and published information has associated other Fas pathway-related genes with ALPS. (3) Thus far, somatic mutations in FAS only have been reported to cause ALPS; however, it is possible that somatic mutations in FASLG and CASP10 can also be causative.TestingFAS. FAS germline mutations have been identified throughout the entire coding region and exon/intron boundaries. Sequencing of the entire coding region and intron/exon boundaries of FAS detects approximately 90% of all reported FAS mutations [NHGRI ALPS Database].FASLG. The mutation detection rate for sequence analysis of the entire coding region is not known. Only a few mutations in FASLG have been reported.CASP10. The mutation detection rate for sequence analysis of the entire coding region is not known. CASP10 mutations have been reported in only two families, one of which was later found to have another mutation in TNFRSF1A, consistent with a diagnosis of TNF receptor-associated periodic syndrome.In two recently described patients, ALPS was presumed to result from co-inherited mutations in FAS and CASP10 that were hypothesized to cooperate in causing ALPS [Cerutti et al 2007].Detection of FAS somatic mutations requires specialized genetic testing of α/β-DNT cells sorted by either flow cytometric immunophenotyping or by magnetic bead immunophenotyping. Table 1. Summary of Molecular Genetic Testing Used in ALPSView in own windowGene SymbolALPS TypeProportion of ALPS Attributed to Mutations in This GeneTest MethodMutation TypeTest AvailabilityFASALPS-FAS65%-70% ^{1Sequence analysisSequence variants 2ClinicalALPS-sFAS~15%-20% 3Research onlyFASLGALPS-FASLG<5% 4ClinicalCASP10ALPS-CASP10<5% 5Clinical1. Germline mutations [Rieux-Laucat et al 1995, Kasahara et al 1998, van der Burg et al 2000, Bleesing 2003, Rieux-Laucat et al 2003]2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Somatic mutations in selected cell populations, including α/β-DNT cells [Holzelova et al 2004, Rössler et al 2005, Dowdell et al 2010]4. To date, four affected individuals with germline mutations [Wu et al 1996, CIS 1999, Del-Rey et al 2006, Bi et al 2007]5. To date, two affected individuals [Wang et al 1999, Zhu et al 2006]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a proband. A recently proposed algorithm for diagnostic workup for patients with suspected ALPS based on the presence of required and accessory criteria is outlined in the revised diagnostic criteria for ALPS [Oliveira et al 2010]. The key components of this algorithm (keeping in mind that the presence of chronic non-malignant lymphoproliferation and α/β-DNT cells has already been established) are: Identification of a germline FAS mutation in unsorted cells; Measurement of plasma or serum biomarkers (interleukin-10, soluble FasL, vitamin B12); Identification of a somatic FAS mutation in sorted α/β-DNT cells;Identification of a germline mutation in FASLG or CASP10 and defective Fas-mediated apoptosis in vitro. The proposed algorithm recommends the following:1.Sequence analysis to determine presence of germline FAS mutation(s) in unsorted cells. If present, the diagnosis of ALPS is established and classified as ALPS-FAS.2.In the absence of a germline FAS mutation(s): determine if biomarkers (as listed above) are elevated. If so, obtain sorted α/β-DNT cells to assess somatic mutation in FAS. If present, the diagnosis of ALPS is established and classified as ALPS-sFAS.
Note: absence of a positive family history is suggestive of ALPS-sFAS as well.3.If neither a germline nor a somatic FAS mutation is identified, consider sequence analysis of CASP10 and FASLG.
Note: The presence of elevated biomarkers has not reliably been established in these ALPS genotypes.4.If germline mutations in either CASP10 or FASLG have been identified, the diagnosis of ALPS is established and classified as ALPS-CASP10 or ALPS-FASLG, respectively.5.If germline mutations in CASP10 or FASLG are not identified, perform Fas-mediated apoptosis assay (repeat if necessary, noting the influence of concomitant immunosuppressive therapy). If abnormal, the diagnosis of ALPS is established and classified as ALPS-U.6.If Fas-mediated apoptosis assay is normal, consider somatic mutations in CASP10 or FASLG (using previously sorted DNTCs), or consider an alternative diagnosis.Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersFAS. No phenotype other than ALPS is known to be associated with germline or somatic mutations in FAS.FASLG}, CASP10. Because only a few individuals with mutations in FASLG and CASP10 have been reported, it is currently unknown whether clinical phenotypes other than ALPS may be associated with mutations in these two genes; however, this possibility is considered unlikely.}

Natural HistoryAutoimmune lymphoproliferative syndrome (ALPS) can be considered a prototypic disorder of defective lymphocyte homeostasis [Sneller et al 1992, Fisher et al 1995, Rieux-Laucat et al 1995].The manifestations are lymphadenopathy, hepatosplenomegaly with or without hypersplenism, and autoimmune disease, mostly directed toward blood cells. In addition, the risk of lymphoma is increased.Summary of Clinical Manifestations of ALPSLymphoproliferation of non-malignant lymphoid cellsLymphadenopathySplenomegaly (+/- hypersplenism)HepatomegalyAutoimmunityAutoimmune hemolytic anemiaAutoimmune thrombocytopeniaAutoimmune neutropeniaGlomerulonephritisAutoimmune hepatitisGuillain Barré syndromeUveitis, iridocyclitisOther autoimmune disorders (in individual cases)Neoplasia (including benign tumors)Lymphoma (Hodgkin and non-Hodgkin lymphoma)Carcinoma (thyroid, breast, skin, tongue, liver)Multiple neoplastic lesions (thyroid/breast adenomas, gliomas)Other and/or infrequent findingsUrticaria and other skin rashesVasculitisPanniculitisArthritis and arthralgiaRecurrent oral ulcersHumoral immunodeficiencyPulmonary infiltratesPremature ovarian insufficiencyHydrops fetalisOrganic brain syndrome (mental status changes, seizures, headaches)Much remains to be learned about the natural history and prognosis of ALPS. While non-malignant lymphoproliferative manifestations often regress or improve over time, autoimmunity appears to show no permanent remission with advancing age. Moreover, the risk for development of lymphoma likely is lifelong. Thus, in the absence of curative treatment, the overall prognosis for ALPS remains guarded, necessitating long-term clinical studies to better understand its natural history [Rieux-Laucat et al 1999, Bleesing 2003, Rieux-Laucat et al 2003].ALPS-FAS. ALPS-FAS is the most common and best-characterized type of ALPS. The following are the main consequences of perturbed lymphocyte homeostasis in ALPS-FAS:Chronic non-malignant lymphoproliferation. Expansion of antigen-specific lymphocyte populations that are not eliminated through apoptosis leads to expansion of the lymphoid compartment, resulting in lymphadenopathy, splenomegaly, hypersplenism, and, less frequently, hepatomegaly. In most individuals with ALPS-FAS, this finding typically manifests in the first years of life. In some individuals, splenomegaly is the predominant or only manifestation of lymphoproliferation [Bleesing 2003, Rieux-Laucat et al 2003].
In many individuals, lymphadenopathy tends to decrease early in the second decade, whereas splenomegaly often does not. Furthermore, long-term follow up in several individuals has shown that diminution of lymphadenopathy is not accompanied by significant changes in the overall expansion of lymphocyte subsets in peripheral blood [Bleesing et al 2001b]. The lymphoproliferation waxes and wanes for reasons that are not entirely clear. Intercurrent viral and bacterial infections can influence lymphadenopathy, perhaps reflecting activation of other (intact) apoptosis pathways.
The overall prognosis of lymphoproliferation is relatively good and few individuals require long-term treatment with immunosuppressive agents to control lymphoproliferation [Bleesing 2003, Rieux-Laucat et al 2003].
Laboratory findings of lymphoproliferation are the expansion of most lymphocyte subsets including the pathognomonic α/β-DNT cells as well as other T- and B-cell subsets.Autoimmunity, a common feature of ALPS, is often not present at the time of diagnosis or at the time of the most extensive lymphoproliferation. The reason for the delay in onset is unclear but may be related to age-dependent acquisition of secondary pathogenic factors that interact with defective Fas-mediated apoptosis. In many individuals with ALPS autoantibodies can be detected years before the appearance of clinical manifestations of autoimmune disease [Bleesing 2003, Rieux-Laucat et al 2003].
Although autoimmune manifestations can also wax and wane, current knowledge suggests that autoimmune disease poses a lifelong burden.
Autoimmunity most often involves combinations of Coombs-positive hemolytic anemia and immune thrombocytopenia (together referred to as Evans syndrome); autoimmune neutropenia is less common. The observation of primary lymphopenia, contrasting with the typical presence of lymphocytosis, suggests the possibility of autoimmune lymphopenia (as seen in other autoimmune diseases).
The presence of Evans syndrome without significant lymphoproliferation can be consistent with ALPS, especially if α/β-DNT cells are present [Seif et al 2010].
Autoimmune cytopenias may be difficult to distinguish from the effects of concomitant hypersplenism; examination of blood smears for evidence of hemolysis and measurement of autoantibodies and the degree of reticulocytosis may help in establishing the distinction.
Additional autoimmune features can be found, often in patterns that appear to be family specific, suggesting the influence of other (background) genetic information [Rieux-Laucat et al 1999, Vaishnaw et al 1999, Kanegane et al 2003].
Laboratory findings include among others: autoantibodies detected by direct and indirect antiglobulin tests (Coombs' test), antiplatelet antibodies, antineutrophil antibodies, antinuclear antibodies (ANA), and antiphospholipid antibodies.Lymphoma. Individuals with ALPS-FAS are at an increased risk for both Hodgkin and non-Hodgkin lymphoma, underscoring the role of Fas as a tumor-suppressor gene. Based on calculations in one study, the increased risk is 14-fold and 51-fold for non-Hodgkin and Hodgkin lymphoma, respectively [Straus et al 2001].
Lymphoma typically originates in B cells, but has been found in T cells as well, although much less frequently. Lymphoma is not related to EBV infection (based on absence of EBV in tumor biopsies).
Current experience suggests that lymphomas can occur at any age in ALPS-FAS and do respond to conventional chemotherapeutic treatment. Individuals with other forms of ALPS may also be at an increased risk for lymphoma; however, further data are needed to provide a detailed risk assessment. Because of the frequent concomitant presence of benign (i.e., "typical") lymphadenopathy and splenomegaly, distinguishing a "good" node from a "bad" node is a diagnostic challenge. Important clues are B-type symptoms including fever, night sweats, itching, and weight loss. In addition, PET-based imaging may be helpful in distinguishing “good” from “bad” nodes on the basis of presumed higher metabolic activity of malignant lymphoid tissue [Rao et al 2006].
A number of studies have looked at associations between Fas and neoplasms, including somatic mutations in solid tumors, leukemias, and lymphomas. For further discussion, see Müschen et al [2002], Houston & O'Connell [2004], Poppema et al [2004], and Peter et al [2005].ALPS-FAS resulting from biallelic mutationsChronic non-malignant lymphoproliferation. Individuals with homozygous or compound heterozygous FAS mutations often present with severe lymphoproliferation at or shortly after birth [Rieux-Laucat et al 1995, Le Deist et al 1996, Kasahara et al 1998, van der Burg et al 2000].Autoimmunity. In several individuals reported, the delay between onset of autoimmunity and lymphoproliferation was minimal, while in others this was not the case. The rarity of and poor prognosis in ALPS -FAS resulting from biallelic mutations make it difficult to draw firm conclusions regarding autoimmunity in this type of ALPS [Rieux-Laucat et al 1995, Le Deist et al 1996, Kasahara et al 1998, van der Burg et al 2000].Lymphoma. Because of the severity of ALPS-FAS caused by biallelic mutations, affected individuals typically succumb to lymphoproliferation and/or autoimmunity at an early age.ALPS-sFAS. Somatic FAS mutations in selected cell populations (notably the α/β-DNT cells) have been identified in individuals with ALPS-sFAS. Individuals with somatic FAS mutations now constitute the second largest group of ALPS. Most of the clinical and laboratory features of ALPS-FAS are recapitulated in individuals with somatic FAS mutations, although no cases of lymphoma have yet been published. The population of α/β-DNT cells is expanded; however, as noted initially [Holzelova et al 2004, Rössler et al 2005], Fas-mediated apoptosis in vitro is typically not defective, although such apoptosis has been noted in some recently published cases [Dowdell et al 2010]. Pathogenesis of ALPS. The phenotype of ALPS results from defective apoptosis of lymphocytes mediated through the Fas/Fas ligand (FasL) pathway. This pathway normally limits the size of the lymphocyte compartment by eliminating/removing autoreactive lymphocytes; therefore, defects in this pathway lead to expansion of antigen-specific lymphocyte populations. Although Fas also appears to play a role in suppression of malignant transformation of lymphocytes, it remains to be firmly established whether this involves the Fas/FasL pathway in a similar way. It should be noted that the pathogenesis of ALPS remains an ongoing topic of research.Somatic FAS mutations are of particular interest in understanding the pathogenesis of ALPS, for example, with regard to the observed delay between lymphoproliferation and autoimmunity: the somatic mutation is mostly confined to the α/β-DNT cells and typically not found (at least not in large proportion) in other lymphocyte subsets such as B cells. Perhaps this observation will help to characterize the impact of the FAS mutation relative to other potential pathogenic factors.

Genotype-Phenotype CorrelationsALPS-FAS. Although the death domain (DD) of ALPS — the intracellular domain of Fas that connects cell surface-expressed Fas to the intracellular (death) signal transduction pathway — is a mutational hotspot, genotypes resulting from mutations in any domain of Fas lead to the same clinical lymphoproliferative and autoimmune phenotype of ALPS. Lymphomas, in contrast, seem thus far to be associated only with mutations affecting the intracellular domains of Fas, though independent confirmation is required [Straus et al 2001].Despite this similar clinical phenotype, in vitro Fas-mediated apoptosis is less defective in individuals with mutations affecting extracellular domains than in those with mutations affecting intracellular domains [Bleesing et al 2001b].In the majority of affected individuals, heterozygous FAS mutations are associated with ALPS-FAS by the mechanism of dominant-negative interference; however, with certain mutations affecting extracellular domain, the mechanism is haploinsufficiency. In the latter case, the ALPS clinical phenotype may be less severe, linked to less defective in vitro apoptosis [Kuehn et al 2011]. (For further discussion see Molecular Genetic Pathogenesis.)ALPS-FASLG and ALPS-CASP10. Because of their rarity, genotype-phenotype correlations are not established for FASLG and CASP10 mutations.

Differential DiagnosisThe main considerations in the differential diagnosis for autoimmune lymphoproliferative syndrome (ALPS) are other immunodeficiency disorders characterized or complicated by lymphoproliferation, autoimmune disease, and lymphoma. These include the following:Common variable immunodeficiency disease (CVID) has an estimated incidence of one in 50,000 and occurs equally in males and females. Findings include recurrent infections (especially of the respiratory tract) at any age. The genetic etiology of most CVID is currently unknown. From a clinical and immunologic standpoint, CVID can be roughly classified into two groups, depending on the presence or absence of mature B cells in peripheral blood. Individuals with CVID with B cells (but absent or decreased memory B cells) are at an increased risk for autoimmune disease that often targets blood cells and for chronic lymphoproliferation including lymphadenopathy, splenomegaly, and lymphoma [Warnatz et al 2002, Piqueras et al 2003]. CVID with present B cells should be regarded in the differential diagnosis of ALPS, while the variant characterized by low or absent B cells and generally low serum concentrations of immunoglobulins should not.
The overlap between ALPS and CVID is also illustrated by the report of two individuals with CVID who were found to have heterozygous mutations in CASP8 [Chun et al 2002].Hyper IgM (HIGM) syndrome. Several non-X-linked forms of hyper IgM syndrome have now been identified. In varying degrees, they share features with the X-linked form (see X-Linked Hyper IgM Syndrome), caused by mutations in TNFSF5 (CD40L) [Winkelstein et al 2003]. Shared features include recurrent bacterial infections such as otitis media, sinusitis, and pneumonias. Autoimmune hematologic disorders including neutropenia, thrombocytopenia, and hemolytic anemia are also found. Other complications may include lymphomas and other malignancies as well as gastrointestinal complications. Serum concentration of IgM is elevated while other immunoglobulin levels are normal; specific antibody responses are defective. In contrast to HIGM1, T-cell function in ALPS is typically within normal limits, reflected in an absence of opportunistic infections.
HIGM2 is caused by mutations in AICDA, encoding activation-induced cytidine deaminase. Inheritance is usually autosomal recessive, but in rare cases autosomal dominant [Revy et al 2000, Lee et al 2005]. Recurrent bacterial, respiratory, and gastrointestinal infections are typical; opportunistic infections are rare. Lymphoid hyperplasia, seen in ALPS, has been reported in HIGM2 [Revy et al 2000, Lee et al 2005]. AICDA mutations typically affect only B-cell differentiation.
HIGM3, HIGM4, and HIGM5 are other forms of non-X-linked hyper IgM syndrome. Their inclusion in the differential diagnosis of ALPS is less clear on the basis of known clinical presentation and inheritance pattern [Ferrari et al 2001, Imai et al 2003].X-linked lymphoproliferative disease (XLP) is associated with an inappropriate immune response to Epstein-Barr virus (EBV) infection resulting in unusually severe and often fatal infectious mononucleosis, dysgammaglobulinemia; and/or lymphoproliferative disorders (typically of B-cell origin). Clinical manifestations of XLP vary, even among affected family members. The most common presentation is a near-fatal or fatal EBV infection associated with an unregulated and exaggerated immune response with widespread proliferation of cytotoxic T cells, EBV-infected B cells, and macrophages. Mortality is greater than 90%. In approximately one third of males with XLP, hypogammaglobulinemia of one or more immunoglobulin subclasses is diagnosed prior to EBV infection or in rare survivors of EBV infection. The prognosis for males with this phenotype is more favorable if they are managed with regular intravenous immune globulin (IVIG). Lymphomas or other lymphoproliferative disease occur in approximately one third of males with XLP, some of whom have hypogammaglobulinemia or have survived an initial EBV infection. The lymphomas seen in individuals with XLP are typically high-grade B-cell lymphomas, non-Hodgkin type, often extranodal, and particularly involving the intestine. Demonstration of defective T-cell receptor restimulation apoptosis in persons with XLP suggests that altered lymphocyte homeostasis affects disease pathogenesis as well [Snow et al 2008]. Allogeneic bone marrow transplantation (BMT) is the only curative therapy for XLP. Average life expectancy without curative BMT has been estimated at less than ten years. XLP is caused by hemizygous mutations in SH2D1A.Wiskott-Aldrich syndrome (WAS) typically manifests in infancy with thrombocytopenia, eczema, and recurrent bacterial and viral infections, particularly recurrent ear infections. At least 40% of males who survive the early complications develop one or more autoimmune conditions including hemolytic anemia, immune thrombocytopenic purpura (ITP), immune-mediated neutropenia, arthritis, vasculitis of small and large vessels, and immune-mediated kidney and liver disease. Individuals with WAS, particularly those who have been exposed to EBV, have an increased risk of developing lymphomas, which often occur in unusual, extranodal locations such as the brain, lung, or gastrointestinal tract. Mutations in WAS are causative; inheritance is X-linked.Lymphoma without other manifestations of ALPS has been observed in families with ALPS-FAS. Thus, both B-cell and T-cell lymphoma should be considered in the differential diagnosis of ALPS [van der Werff Ten Bosch et al 1999, Poppema et al 2004].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo determine the presence and extent of lymphoproliferation and/or autoimmunity in an individual diagnosed with autoimmune lymphoproliferative syndrome (ALPS), the following evaluations are recommended:Complete blood counts and flow cytometric immunophenotyping of lymphocytes, especially with regard to α/β-DNT cells, in combination with physical examination and imaging studies to assess lymphadenopathy and hepatosplenomegalyComplete blood counts and measurement of autoantibodies to assess for autoimmunityIf significant lymphadenopathy is present, more extensive diagnostic procedures to detect lymphoma, especially if constitutional symptoms (e.g., fever, night sweats, weight loss) are presentTreatment of ManifestationsIn the absence of curative treatment, current management is focused on the control and/or treatment of manifestations of lymphoproliferation and/or autoimmunity and the treatment of lymphoma [Rieux-Laucat et al 1999, Van Der Werff Ten Bosch et al 2001, van der Werff Ten Bosch et al 2002, Bleesing 2003, Rieux-Laucat et al 2003, Rao et al 2005].Manifestations of lymphoproliferation typically can be suppressed with the use of immunosuppressive agents including corticosteroids, cyclosporine, sirolimus tacrolimus, and mycophenolate mofetil. The benefits of immunosuppression, however, are balanced by the side effects, as well as the need to monitor drug levels. Moreover, it has become clear that lymphadenopathy, as well as organomegaly, invariably return once immunosuppression is discontinued [Bleesing 2003]. Thus, one approach is to use immunosuppressive therapy only for severe complications of lymphoproliferation (e.g., airway obstruction) and/or autoimmune manifestations. Early experience with sirolimus suggests that this agent may affect lymphoproliferation in a more sustained manner [Teachey et al 2009].In severe cases, more potent – lymphodepleting – agents may be required to sufficiently control lymphoproliferative manifestations. Agents include cyclophosphamide, antithymocyte globulin (ATG) and select monoclonal antibodies such as alemtuzumab (Campath^®).Autoimmune manifestations typically respond to short courses of immunosuppressive agents.Mycophenolate mofetil cyclosporine, tacrolimus, and sirolimus are effective in chronic recalcitrant autoimmune cytopenias and may spare steroid usage [Rao et al 2005, Teachey et al 2009].Rituximab has been used successfully in the treatment of refractory cytopenias in ALPS, although it remains to be seen how long affected individuals remain in clinical remission [Wei & Cowie 2007, Rao et al 2009].Lymphoma is treated according to conventional protocols. The presence of defective Fas-mediated apoptosis does not appear to hinder the response to chemotherapeutic agents or radiation.Prevention of Primary ManifestationsBone marrow (hematopoietic stem cell) transplantation (BMT/HSCT) is currently the only curative treatment for ALPS. Because of the risks associated with BMT, it has so far been performed mostly in individuals with ALPS with severe clinical phenotypes, such as those with homozygous or compound heterozygous mutations in FAS. It is likely, however, that individuals with undiagnosed forms of ALPS, including ALPS-FAS, have been transplanted.Successful (reported) BMT in several individuals indicates that defective Fas-mediated apoptosis does not pose a barrier to this treatment option [Benkerrou et al 1997, Sleight et al 1998, Dowdell et al 2010].Prevention of Secondary ComplicationsVaccinations pre-splenectomy (with consideration of post-splenectomy boost vaccinations) and penicillin prophylaxis are strongly recommended for individuals who undergo splenectomy. SurveillanceClinical assessment, imaging, and laboratory studies outlined in Evaluations Following Initial Diagnosis can be used in surveillance for manifestations of lymphoproliferation and autoimmunity.Specialized imaging studies such as combined CT and PET scanning in combination with clinical and laboratory surveillance may be helpful in detection of malignant transformation [Rao et al 2006].Agents/Circumstances to AvoidSplenectomy to control autoimmune cytopenias is discouraged because it typically does not lead to permanent remission of autoimmunity and may be associated with an increased risk for infections [Author, unpublished observation, Price et al 2010]. The use of over-the-counter medications such as aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) should be discussed with a physician as some of these medications can interfere with platelet function.Evaluation of Relatives at RiskIt is appropriate to perform molecular genetic testing on relatives at risk for ALPS-FAS, ALPS-FASLG or ALPS-CASP10 if the disease-causing mutation has been identified in the proband.Relatives who have the family-specific mutation should:Be advised of their increased risk for ALPS or ALPS-related manifestations if the type and location of the FAS mutation (i.e., missense mutations affecting the intracellular domains) is predicted to have a high penetrance for clinical ALPS;Undergo ALPS-specific evaluations at initial diagnosis (e.g., enumeration of α/β-DNT cells, detection of autoantibodies, IL-10/soluble FasL measurement) (see Evaluations Following Initial Diagnosis);Be advised that ALPS-specific evaluations or other assessments may need to be repeated at regular intervals, particularly if the family member is young and/or if new health-related issues consistent with ALPS or ALPS-related complications (e.g., lymphoma) become apparent (see Surveillance).See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management No evidence suggests that C-section reduces the risk of morbidity and mortality in newborns with ALPS, though the possible presence of autoimmune cytopenias such as immune thrombocytopenia in a newborn with ALPS-FAS could pose a risk of increased bleeding in the neonate.Therapies Under InvestigationReduced-intensity transplants. The advent of less toxic BMT conditioning regimens (i.e., reduced-intensity transplants, or "mini-transplants") may make BMT a realistic treatment option for individuals with ALPS who are not considered candidates for conventional BMT because of the associated risks.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherHigh-dose intravenous immune globulin (IVIG) does not appear to be as effective in inducing permanent or long-term remission in ALPS as it is in isolated immune thrombocytopenia (ITP).Gene therapy. No studies regarding gene therapy to treat ALPS are ongoing; the highly regulated expression and activity of Fas pose substantial difficulties for gene therapy.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Autoimmune Lymphoproliferative Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFAS10q23​.31Tumor necrosis factor receptor superfamily member 6Autoimmune Lymphoproliferative Syndrome Database (ALPSbase)
CCHMC - Human Genetics Mutation DatabaseFASFASLG1q24​.3Tumor necrosis factor ligand superfamily member 6Resource of Asian Primary Immunodeficiency Diseases (RAPID)
CCHMC - Human Genetics Mutation DatabaseFASLGCASP102q33​.1Caspase-10Catalogue of Somatic Mutations in Cancer (COSMIC)
Resource of Asian Primary Immunodeficiency Diseases (RAPID)
CCHMC - Human Genetics Mutation DatabaseCASP10Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Autoimmune Lymphoproliferative Syndrome (View All in OMIM) View in own window 134637TUMOR NECROSIS FACTOR RECEPTOR SUPERFAMILY, MEMBER 6; TNFRSF6 134638TUMOR NECROSIS FACTOR LIGAND SUPERFAMILY, MEMBER 6; TNFSF6 601762CASPASE 10, APOPTOSIS-RELATED CYSTEINE PROTEASE; CASP10 601859AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; ALPS 603909AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IIA; ALPS2AMolecular Genetic PathogenesisAutoimmune lymphoproliferative syndrome (ALPS) can be considered a prototypic disorder of defective lymphocyte homeostasis [Sneller et al 1992, Fisher et al 1995, Rieux-Laucat et al 1995]. Although it appears that the full clinical spectrum of ALPS may depend on the interplay of several pathogenic factors, defective activation-induced cell death (also known as apoptosis or cellular suicide) through the Fas/FasL pathway is central in the etiology of ALPS [Lenardo et al 1999]. The two existing mouse models of lymphoproliferative disease show features similar (though not identical) to features of ALPS [Watanabe-Fukunaga et al 1992, Takahashi et al 1994].As in the mouse models, the genetic background may determine penetrance of the clinical manifestations of ALPS, as well as the age of onset and/or severity of these manifestations. The genetic background may concern detrimental (loss-of-function) mutations affecting other tumor necrosis factor receptor superfamily member 6 (Fas) pathway components, as demonstrated by individuals with tumor necrosis factor ligand superfamily member 6 (FasL) and caspase-10 defects. Alternatively, genes relevant to Fas-independent apoptosis pathways may be affected. It should be noted that the distinction between Fas-mediated apoptosis pathways (i.e., the extrinsic apoptosis pathway) and Fas-independent apoptosis pathways (i.e., the intrinsic apoptosis pathway) is largely artificial, as connections between the two pathways exist and both pathways can be engaged in vivo, depending on multiple variables that include (among others) levels of antigens and levels of growth factors [Snow et al 2008]. Case in point: a patient has been identified with a partial ALPS phenotype, associated with a gain-in-function mutation in the gene encoding N-RAS [Oliveira et al 2007].Finally, the genetic background may operate at the level of genes that encode regulators of other aspects of lymphocyte function and survival. The presence of clinical manifestations of ALPS at birth makes environmental influences less likely; the occurrence of murine ALPS in Fas-mutant mice kept in a germ-free environment is consistent with this assumption.The discovery of individuals with ALPS with somatic mutations in FAS may offer new insights as the presence of mutations in some, but not all, lymphocyte subsets could allow dissection of the molecular mechanisms of ALPS in a manner that cannot be achieved in individuals with germline mutations in FAS.FASNormal allelic variants. FAS comprises nine exons. Exons 1 and 2 encode a signal sequence that, upon trafficking of the Fas protein to the cell surface, is cleaved off. Exons 3, 4 and 5 encode three extracellular cysteine-rich domains (CRD). Exon 6 encodes the transmembrane domain (TM). The intracellular domains of Fas are encoded by exons 7-9, with exon 9 representing the death domain (DD) that interacts with the intracellular, apoptosis-inducing signal transduction pathway [Jackson et al 1999].Genomic DNA of FAS spans approximately 25 kb. To date, at least eight alternatively spliced transcript variants encoding seven distinct normal allele variants have been observed. These have been documented by biochemical and functional testing in vivo and are highly unlikely to have pathologic effects on FAS expression.Pathologic allelic variants. To date, approximately 70 pathologic variants have been identified. Mutations have been found throughout the entire coding region and exon/intron boundaries. These allele variants would lead to the absence of functional proteins or result in truncated proteins.Most of the (reported) FAS mutations affect the intracellular domains of Fas, with approximately 60% of those located in the death domain. Mutations include missense mutations, nonsense mutations, splicing defects, small deletions/insertions, gross deletions, and complex deletion/duplications.Normal gene product. FAS encodes a 16-amino acid signal sequence, followed by a mature protein of 319 amino acids with a single transmembrane domain and a molecular mass of approximately 36 kd.The protein encoded by FAS is a member of the TNF-receptor superfamily and contains a death domain; it has been shown to play a central role in the physiologic regulation of programmed cell death. The interaction of Fas with its ligand allows the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase-8, and caspase-10. The autoproteolytic processing of the inductor caspases in the complex triggers a downstream effector caspase cascade, leading to apoptosis. Fas has also been shown to activate NF-kappaβ, MAPK3/ERK1, and MAPK8/JNK, leading to the transduction of proliferating signals in normal diploid fibroblast and T cells.Abnormal gene product. The fact that heterozygous mutations lead to defective Fas-mediated apoptosis can be explained by dominant-negative interference by the abnormal Fas protein in many cases of ALPS-FAS. Because Fas and FasL form homotrimers, the contribution of the mutant FAS allele versus the normal FAS allele to these trimers results in a normal Fas trimer (consisting of three normal proteins) in only one out of eight, and an abnormal Fas trimer (in which at least one of the proteins is mutated) in seven out of eight possible configurations, assuming equal amounts of mutant and wild type Fas protein [Fisher et al 1995, Jackson et al 1999]. Dominant-negative interference by abnormal Fas chains has been demonstrated for mutations affecting the death domain as well as for other intracellular mutations [Jackson et al 1999, Martin et al 1999].Extracellular heterozygous mutations affecting the FasL-binding domain (CRD2 and CRD3) are also associated with dominant-negative interference because Fas proteins self-associate into trimers prior to FasL interaction. The result, as with intracellular mutations, is the assembly of faulty Fas trimers that dominantly interfere with Fas-mediated apoptosis in seven out of eight configurations [Siegel et al 2000]. For other extracellular heterozygous mutations, including mutations that affect the domain of the protein that regulates self-association into trimers, defective apoptosis can be explained by interference of truncated and/or soluble fragments of mutant Fas, or by haploinsufficiency, in which the total amount of Fas generated is below a threshold needed for physiologic induction of apoptosis [Roesler et al 2005, Kuehn et al 2011].In individuals with homozygous or compound heterozygous mutations, defective Fas-mediated apoptosis can be explained by loss of function [van der Burg et al 2000]. In contrast to those with heterozygous mutations, these individuals display absent or reduced surface expression of Fas on lymphocytes.FASLGNormal allelic variants. FASLG (FASL) spans approximately 8 kb and comprises four exons. No normal allelic variants have been reported to date.Pathologic allelic variants. See Table 3. To date, only three pathologic alleles have been reported. Wu et al [1996] described p.Met158_Glu185del resulting in a 28-amino acid in-frame deletion within exon 4 of FASLG in a person with lymphadenopathy. The second mutation, c.-844T>C, is in the promoter region of FASLG [Zhang et al 2005]. The third mutation, a homozygous p.Ala247Glu, was found in an individual with ALPS who demonstrated both defective FasL-mediated apoptosis and defective Fas-dependent cytotoxic function, while the fourth case concerns an individual with ALPS with a heterozygous mutation that leads to a substitution of p.Arg156Gly [Del-Rey et al 2006, Bi et al 2007].Table 3. Selected FASLG Pathologic Allelic VariantsView in own windowDNA Nucleotide Change
(Alias ¹)Protein Amino Acid Change
(Alias ¹)Reference Sequencesc.-844T>CNoneNM_000639​.1
NP_000630​.1c.472_555delp.Met158_Glu185del
(84-bp deletion)c.740C>Ap.Ala247Gluc. 466A>G
(530A>G)p.Arg156GlySee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. The FASLG cDNA codes a protein of 281 amino acids. Fas ligand (FasL) is a type II transmembrane protein that belongs to the tumor necrosis factor family. It is expressed in activated splenocytes and thymocytes, consistent with its involvement in T-cell mediated cytotoxicity and in several non-lymphoid tissues (e.g., testis, liver, lung, ovary, heart), where its function is unclear.Abnormal gene product. A study of peripheral blood mononuclear cells from the individual with the p.Met158_Glu185del mutation revealed decreased FasL activity, decreased activation-induced cell death, and increased T-cell proliferation after activation [Wu et al 1996]. The individual with the homozygous missense mutation (p.Ala247Glu) showed decreased Fas-mediated cell death and Fas-dependent cytotoxicity [Del-Rey et al 2006]. Compared to controls, the c.-844T>C mutation resulted in increased expression of FasL in many types of human cancers including lung cancer [Zhang et al 2005]. The heterozygous p.Arg156Gly mutation affects the extracellular Fas-binding region of FASL. The mutation produces a dominant interfering FasL protein that binds to wild-type FasL, preventing Fas-mediated apoptosis [Bi et al 2007].CASP10Normal allelic variants. See Table 4. CASP10 comprises 11 exons and spans approximately 48 kb [Hadano et al 2001]. There are two isoforms of CASP10 transcripts. The CASP10L isoform encodes an insertion of 43 amino acids at the end of the prodomain, but its C terminus is the same as the short CASP10 isoform. The two isoforms are expressed equally. In addition, one common polymorphic variant of CASP10 (p.Thr446Cys) was observed in 5% of normal controls and had no effect on apoptotic function of caspase-10 [Wang et al 1999].Pathologic allelic variants. See Table 4. To date, seven CASP10 mutations have been reported in eight individuals [Wang et al 1999, Park et al 2002, Shin et al 2002]. Two missense mutations, p.Leu285Phe and p.Ile406Leu, were identified in one and two kindreds, respectively, with ALPS-CASP10 characterized by abnormal lymphocyte and dendritic cell homeostasis and immune regulatory defects [Wang et al 1999, Zhu et al 2006]. The other five somatic mutations in CASP10 were suspected to be responsible for development of non-Hodgkin lymphoma (NHL) and gastric cancers [Park et al 2002, Shin et al 2002].Note: The previously reported homozygous p.Val367Ile mutation [Wang et al 1999] has subsequently been deemed not be associated with ALPS-CASP10 [Zhu et al 2006].Table 4. Selected CASP10 Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide Change
(Alias ¹)Protein Amino Acid Change
(Alias ¹)Reference SequencesNormalc.1337A>G
(1208A>G)p.Tyr446CysNM_032977​.3
NP_116759​.2Pathologicc.853C>T
(c.724C>T)p.Leu285Phe
(p.Leu242Phe)c.1216A>C
(c.1087A>C)p.Ile406Leu
(p.Ile363Leu)c.1228G>A
(c.1099G>A)p. Val410Ile
(p. Val367Ile) See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. The physiologic function of caspase-10 is poorly understood. Gene transfection assays verified its function as a death-inducing caspase [Chaudhary et al 1997, Pan et al 1997, Schneider et al 1997, Vincenz & Dixit 1997]. Moreover, Wang et al [2001] showed that caspase-10 can function independently of caspase-8 in initiating Fas and tumor necrosis factor-related apoptosis.Abnormal gene product. The p.Leu285Phe and p.Val410Ile mutations result in decreased caspase activity and dominantly interfere with death receptor-induced apoptosis, particularly that stimulated by FasL and TRAIL. Wang et al [1999] and Shin et al [2002] expressed some CASP10 mutants in 293 cells and found that apoptosis was suppressed, possibly contributing to the pathogenesis of some human non-Hodgkin lymphomas.