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Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis

Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis
Literature review current through: Jan 2024.
This topic last updated: Sep 26, 2023.

INTRODUCTION — Autoimmune lymphoproliferative syndrome (ALPS) is an inborn error of immunity characterized by dysregulation of the immune system due to an inability to control lymphocyte homeostasis through the process of lymphocyte apoptosis (a form of programmed cell death) [1]. The consequences include lymphoproliferative disease, manifested by lymphadenopathy, hepatomegaly, splenomegaly, and an increased risk of lymphoma, as well as autoimmune disease, typically involving blood cells.

This topic reviews the clinical features and diagnosis of ALPS. The epidemiology, genetics, pathogenesis, management, and prognosis of ALPS are discussed separately. (See "Autoimmune lymphoproliferative syndrome (ALPS): Epidemiology and pathogenesis" and "Autoimmune lymphoproliferative syndrome (ALPS): Management and prognosis".)

CLINICAL MANIFESTATIONS OF ALPS-FAS — ALPS due to germline pathogenic variants in the Fas cell surface death receptor (FAS) gene that encodes an apoptosis-associated antigen (ALPS-FAS) is the most common and best-characterized type of ALPS, although it is nonetheless a rare condition. (See "Autoimmune lymphoproliferative syndrome (ALPS): Epidemiology and pathogenesis", section on 'Genetics'.)

Timing of onset and features — ALPS typically manifests in the first years of life. The most common presenting clinical manifestations are noninfectious, nonmalignant lymphoid expansion with lymphadenopathy, splenomegaly, and/or hepatomegaly and autoimmune cytopenias, including thrombocytopenia and hemolytic anemia. Lymphoma is a late complication. All disease manifestations appear to be more common in males than females [2,3].

In the two largest cohorts of patients with ALPS, a French cohort and a cohort from the National Institutes of Health (NIH), disease onset was most commonly marked by lymphoproliferation with generalized adenopathy and hepatosplenomegaly at a median age of 2.7 to 3 years [2,3]. Patients with later disease onset often presented with autoimmune manifestations rather than lymphoproliferative disease.

Chronic nonmalignant lymphoproliferation — Expansion and persistence of lymphocyte populations that are not eliminated through apoptosis result in chronic lymphadenopathy that typically fluctuates and most often involves the cervical, axillary, and inguinal nodal chains; splenomegaly with or without premature destruction of blood cells (hypersplenism); and, less frequently, hepatomegaly. The lymphoproliferation typically manifests in the first years of life in individuals with ALPS-FAS. In some persons, splenomegaly is the predominant or only manifestation of lymphoproliferation [4,5]. Lymphadenopathy tends to decrease in the second decade of life, whereas splenomegaly often does not. The overall prognosis of lymphoproliferation is relatively good, and few patients require long-term treatment with immunosuppressive agents. A frequent cause of death in patients treated with splenectomy is sepsis; therefore, splenectomy should be avoided.

In the French and NIH cohorts, chronic lymphadenopathy was present in 85 and 97 percent, respectively, while splenomegaly was present in approximately 95 percent in both cohorts (with 73 percent showing evidence of hypersplenism).

Long-term follow-up has shown that resolution of lymphadenopathy is not always accompanied by significant changes in the overall expansion of lymphocyte subsets in peripheral blood [6]. The lymphoproliferation waxes and wanes for reasons that are not entirely clear. Intercurrent viral and bacterial infections can influence lymphadenopathy, but both increased and decreased intensity of lymphoproliferative manifestations have been observed with infections, making it difficult to predict the effect of infection or to understand the mechanism responsible.

Autoimmunity — Autoimmunity is a common feature of ALPS [2,3]. It is typically limited to the hematopoietic system, but other organs (eg, liver, kidneys) are sometimes involved. Autoimmunity can be the first ALPS manifestation, although it is not always present at the time of diagnosis or at the time of the most extensive lymphoproliferation. Autoimmune manifestations wax and wane, although experience suggests that autoimmune disease poses a lifelong risk and burden. In many patients, the occurrence of autoimmunity signifies the transition from ALPS without the need for immunosuppressive and/or immunomodulating therapy into ALPS requiring long-term and/or intermittent therapy, which has a less favorable prognosis.

Combinations of cytopenias (also known as Evans syndrome) that occur concomitantly and/or sequentially are typical, with Coombs-positive autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) the most common combination, followed by ITP and autoimmune neutropenia (AIN). Autoimmune cytopenias may be difficult to distinguish from the effects of concomitant hypersplenism. Other types of autoimmunity are also seen. (See "Warm autoimmune hemolytic anemia (AIHA) in adults" and "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis" and "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis" and "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis" and "Immune neutropenia", section on 'Autoimmune neutropenia'.)

In both the French and NIH cohorts, there was roughly a two- to three-year delay between disease onset (lymphoproliferation) and clinically significant autoimmunity [2,3]. The reason for this delay is unclear but may be related to age-dependent acquisition of secondary pathogenic factors or sequential exposures to infectious agents during infancy and early childhood. In many persons, autoantibodies can be detected before clinical evidence of autoimmune disease, and it is possible that certain patients never develop overt autoimmune disease despite the presence of autoantibodies [4,5].

Autoimmune cytopenias were present in 52 percent of patients in the French cohort, and autoimmune disease of any variety was found in 61 percent, giving a risk of overall autoimmune disease development before the age of 30 years of 72 percent [2]. Approximately 69 percent of patients in the NIH cohort developed at least one episode of autoimmune cytopenia [3]. Conversely, ALPS is common in patients with Evans syndrome (presence of ≥2 cytopenias), even in those without significant lymphoproliferation, and was seen in approximately half of patients in one series [7,8]. Nearly all these patients had elevated numbers of double-negative T (DNT) cells.

Examination of blood smears for evidence of hemolysis, measurement of autoantibodies, and the degree of reticulocytosis may help in distinguishing autoimmune cytopenias from the effects of hypersplenism, as well as the fact that autoimmune cytopenias often manifest clinically (eg, with bleeding). This also helps in distinguishing ALPS-related ITP from idiopathic ITP, which can be experienced without significant bleeding issues.

Additional autoimmune features are seen in ALPS, often in patterns that appear to be family specific, suggesting the influence of other modifying genes [9-11]. These features include glomerulonephritis, autoimmune hepatitis, Guillain-Barré syndrome, uveitis, and iridocyclitis. Autoimmunity affecting endocrine systems or joints is not common in ALPS compared with other immunodeficiency disorders.

Lymphoma — Persons with ALPS-FAS are at an increased risk for both Hodgkin and non-Hodgkin lymphoma (HL and NHL), underscoring the role of FAS as a tumor-suppressor gene, although other malignancies are not more common. Lymphoma can develop at any age in ALPS-FAS but is rare as a presenting feature. Distinguishing a "good" node from a "bad" node is a diagnostic challenge because of the frequent concomitant presence of benign (ie, "typical") lymphadenopathy and splenomegaly seen with ALPS. Important clues for lymphoma are B type symptoms including fever, night sweats, itching, and weight loss. Lymphoma typically originates in the B cell lineage, but T cell lymphomas have also occurred. Lymphoma is infrequently related to Epstein-Barr virus (EBV) infection, based upon absence of EBV in tumor biopsies. (See "Autoimmune lymphoproliferative syndrome (ALPS): Management and prognosis", section on 'Evaluation for lymphoma'.)

In an earlier study, the calculated increased risk was 14-fold and 51-fold for NHL and HL, respectively [12]. The cumulative risk of lymphoma before the age of 30 years was 15 percent in the French cohort (three cases of HL and four cases of NHL out of a total of 90 patients) [2]. In the NIH cohort, 18 cases of lymphoma out of a total of 150 patients were identified with a median age of detection of 18 years [3]. The male-to-female ratio was 3.5 to 1. Sixteen of 18 cases were of B cell origin, and 17 of 18 cases occurred in patients with pathogenic variants affecting the death domain of Fas. Using published expected cases of HL and NHL in the general population, the 16 cases of B cell lymphoma conferred a significantly increased standardized incidence ratio (SIR) of 149 for HL and 61 for NHL, respectively [12].

A number of studies have looked at associations between Fas and neoplasms, including somatic variants in solid tumors, leukemias, and lymphomas [13-16]. However, there is no indication that there is an increased risk for malignancies other than lymphoma.

Other findings — Many patients report skin rashes, such as urticaria and eczema, as well as less frequent manifestations, such as vasculitis, panniculitis, arthritis/arthralgia, enteritis/enterocolitis, and recurrent oral ulcers. Constitutional signs, including fever, night sweats, and weight loss, are uncommon and should prompt evaluation for lymphoma.

CLINICAL FEATURES OF OTHER ALPS GENOTYPES — Much less can be said with certainty with respect to the other germline ALPS genotypes (ALPS due to variants in the genes for Fas ligand or caspase 10, ALPS-FASLG and ALPS-CASP10) and somatic ALPS-FAS since there are only a few cases.

ALPS-FASLG has features distinctly different from typical ALPS due to FAS variants [17-19]. ALPS-FASLG is inherited in an autosomal recessive manner. Fas-induced apoptosis is normal, although an increase in double-negative T (DNT) cells is reported [20]. In contrast, activation-induced cell death (AICD) is diminished, and, less consistently, cytotoxic T lymphocyte (CTL) function is abnormal.

ALPS-CASP10 has autosomal dominant inheritance [21,22]. The variant CASP10 has a dominant-negative interaction with multiple death receptor pathways. Patients have a wide array of autoimmune and inflammatory conditions and a significantly increased percentage of DNT cells. One patient had recurrent noninvasive skin infections, oral aphthous ulcers, arthralgia, and failure to thrive [22].

Patients with ALPS due to somatic variants in FAS (ALPS-sFAS) are relatively similar to ALPS-FAS patients. However, this needs further study and longer follow-up, particularly with respect to the development of autoimmune disease and lymphoma, since most (if not all or virtually all) B cells in these patients lack the pathogenic FAS variant. Persons with non-FAS forms of ALPS may also be at an increased risk for lymphoma; however, further data are needed to provide a detailed risk assessment.

LABORATORY FINDINGS — Patients with ALPS have a variety of laboratory findings, some of which are shared with other immunologic and hematologic disorders, but others that are unique to ALPS [4,6,23-32].

Key laboratory features — The signature laboratory abnormalities that facilitate diagnosis of ALPS include:

Presence of alpha beta double-negative T (DNT) cells (in peripheral blood and tissue specimens)

Elevated peripheral blood levels of the cytokine interleukin (IL) 10 and vitamin B12 (IL-18 and soluble Fas ligand [FasL] levels are also elevated, but these tests are not available at most laboratories)

Defective Fas-mediated apoptosis on in vitro assay (not available in most laboratories)

DNT cells and other lymphocyte subsets — In patients with ALPS, there is expansion of alpha beta double-negative T (DNT) cells in the peripheral blood and tissues. These cells express the alpha beta T cell receptor (TCR) CD3 complex but lack both CD4 and CD8 coreceptors. Detected by flow cytometric immunophenotyping, these terminally differentiated, in vivo-activated T cells are rare in healthy persons and those with other immune-mediated (lymphoproliferative) disorders, typically <1 percent of the lymphocyte pool compared with 2 to 23 percent DNT cells in patients with ALPS [33]. (See "Flow cytometry for the diagnosis of inborn errors of immunity", section on 'Autoimmune lymphoproliferative syndrome'.)

As part of the lymphoproliferative aspect of ALPS, other lymphocyte subsets are expanded as well. Immunophenotypically, these include gamma delta DNT cells, CD8+CD57+ T cells, as well as human leukocyte antigen (HLA) DR+ T cells and B cells that express CD5 and lack CD27. Not all lymphocyte subsets are expanded, however, as patients show decreased numbers of CD4+CD25+ T cells and decreased numbers of CD27+ B cells. In rare patients, lymphopenia is observed instead of the typical lymphocytosis (independent of immunosuppressive therapy).

Lymph node histology — Lymph node pathology in typical cases shows paracortical T cell expansion with immunoblasts/plasma cells and DNT cells in interfollicular areas, florid follicular hyperplasia, and progressive transformation of germinal centers. Sinus histiocytosis is also occasionally observed.

ALPS biomarkers and Fas-mediated apoptosis — Other immunologic laboratory findings, most of which are performed at specialized labs, that are typical and unique to ALPS include abnormal Fas-mediated apoptosis in vitro [6] and increased levels of vitamin B12, IL-10, and soluble FasL in serum/plasma (together referred to as "ALPS biomarkers") [30,31,34]. These biomarkers vary in their degree of ALPS specificity. As an example, IL-10 is ALPS specific, but IL-18 it not. These biomarkers seem to perform better when evaluated in combination and/or when other biomarkers (eg, IL-10 and IL-6) are absent. The Fas-mediated apoptosis assay is conducted on separated lymphocytes and measures the ability of stimulated T cells to undergo cell death by apoptosis upon ligation of cell surface Fas. There are also increased levels of soluble IL-18, CD25, CD27, and CD30, but these may not be specific for ALPS [35]. (See 'Testing and classification strategy' below.)

Lymphocyte function — The immune system is largely intact as far as T cell and natural killer (NK) cell functions are concerned. B cell function, as measured by antibody responses to infections and vaccinations, is relatively preserved, with normal responses to protein antigens but reduced responses to polysaccharide antigens [36], although this is not uniformly the case [2]. Immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin E (IgE) are increased, with normal or decreased concentrations of immunoglobulin M (IgM). (See "The adaptive humoral immune response", section on 'Natural antibodies'.)

Autoantibodies — A wide repertoire of autoantibodies can be present and most often includes a positive direct or indirect antiglobulin (Coombs) test; antiplatelet, antineutrophil, antiphospholipid, and antinuclear antibodies; and rheumatoid factor. Autoantibodies are typically of the IgG subclass and of high affinity, in contrast to naturally occurring autoantibodies of the same specificity that are low affinity and IgM derived. Hematologically, Coombs-positive hemolytic anemia with reticulocytosis, dyserythropoiesis, thrombocytopenia, neutropenia, and eosinophilia is observed in most patients, although often not at the time of ALPS diagnosis.

DIAGNOSIS

Whom to test — The diagnosis of ALPS should be suspected in patients with lymphoid expansion with lymphadenopathy, splenomegaly, and/or hepatomegaly; autoimmune disease with blood cytopenias including thrombocytopenia and hemolytic anemia; and/or lymphoma. (See 'Clinical manifestations of ALPS-FAS' above and 'Clinical features of other ALPS genotypes' above and 'Laboratory findings' above.)

Diagnostic criteria — A revised set of diagnostic criteria was published in 2010 [32]. A definitive diagnosis of ALPS is based upon the presence of both required criteria and one primary accessory criterion. A probable diagnosis is based upon the presence of both required criteria plus one secondary accessory criterion.

Required criteria — Evidence of lymphoproliferation is required for the diagnosis of ALPS.

Chronic (more than six months) nonmalignant, noninfectious lymphadenopathy, splenomegaly, or both. If only lymphadenopathy is present, it must affect two or more nodal chains. Hepatomegaly also may be present but is not required for diagnosis.

Elevated (>2 percent or >68 cells/microL) percent and/or number of peripheral blood CD3 positive T cells that express the alpha beta T cell receptor (TCR) but lack both CD4 and CD8 coreceptor (alpha beta double-negative T [DNT] cells) on flow cytometry in the context of normal or elevated total lymphocyte counts, keeping in mind that these values may vary depending upon the laboratory running this assay and/or the gating strategy used. Although many patients who otherwise meet the criteria for ALPS have T cell lymphopenia, this finding should prompt assessment for other disorders unless the patient was known to have received lymphocyte-depleting immunosuppressive therapy.

Primary accessory criteria

Defective lymphocyte apoptosis. If the assay is abnormal (≤50 percent of the cell death seen in a control sample assayed simultaneously), it is helpful, but not always practical, to repeat at least once for confirmation. This assay is typically normal in patients whose ALPS is due to a somatic FAS variant or germline FASLG variant.

Germline pathogenic variant in FAS, FASLG, or CASP10 or somatic pathogenic variant in FAS. (Deleterious somatic variants in FASLG and CASP10 have not been reported.)

Secondary accessory criteria

Elevated levels of any of the following ALPS biomarkers: plasma (or serum) levels of soluble Fas ligand (FasL; >200 pg/mL), interleukin (IL) 10 (>20 pg/mL), IL-18 (>500 pg/mL), and vitamin B12 (>1500 ng/L).

Autoimmune blood cytopenias (hemolytic anemia, thrombocytopenia, and/or neutropenia) with hypergammaglobulinemia (elevated polyclonal IgG levels).

Positive family history of confirmed ALPS or nonmalignant, noninfectious lymphoproliferation with or without autoimmunity.

Typical immunohistologic findings, including lymph node pathology (usually obtained for evaluation of possible lymphoma) and T cell studies (flow cytometry, immunohistochemical analysis, and polymerase chain reaction [PCR] assessing for TCR gene rearrangement), as determined by an experienced hematopathologist. (See 'Laboratory findings' above.)

Testing and classification strategy — A revised algorithm for testing and classification, derived from the diagnostic criteria for ALPS, starts with establishing the presence of chronic nonmalignant lymphoproliferation and elevated alpha beta DNT cells, and elevated ALPS biomarkers (algorithm 1). Caution should be used regarding interpretation of laboratory data if the patient is, or was recently, on immunosuppressive/immunomodulatory therapy.

If the three features listed above are present, the following next steps are recommended [30-32,34]:

The preferred approach is to sequence all ALPS-related genes concurrently. This can be done by ordering an ALPS gene panel testing, if available, or ordering testing for each gene separately. The ALPS panels typically include both ALPS genes (FAS, FASLG, and CASP10) as well as genes associated with ALPS-like conditions that are part of the differential diagnosis (most panels include CASP8, CTLA4, FADD, ITK, MAGT1, PIK3CD, PRKCD, STAT3, KRAS, LRBA, NRAS; additional genes that may be included are ADA2 [CECR1], SH2D1A, TNFRSF6, and XIAP). This testing determines the presence of a germline variant in unsorted cells obtained from blood or other tissues. The diagnosis of ALPS due to a specific genetic defect is established if a germline pathogenic variant is identified. With next-generation sequencing genetic testing modalities, somatic pathogenic variants in these genes may be detected if the level of mosaicism is high enough.

In the absence of a germline variant, the next step is to obtain sorted DNT cells for deoxyribonucleic acid (DNA) isolation and assessment of a somatic variant in FAS. The diagnosis of ALPS is established and classified as ALPS due to somatic variants in FAS (ALPS-sFAS) if a deleterious somatic FAS variant is found. Of note, the absence of a positive family history in a patient with typical clinical features is also suggestive of ALPS-sFAS.

If no genetic defects are identified in FAS, FASLG, or CASP10, perform Fas-mediated lymphocyte apoptosis assay (repeat to confirm an abnormal test, if possible). If abnormal, the diagnosis of ALPS is established and classified as ALPS-U since the genetic defect is unknown. This assay may be normal if the patient is on concomitant immunosuppressive therapy.

If Fas-mediated apoptosis is normal, consider examining CASP10 and/or FASLG for somatic variants using previously sorted DNT cells, keeping in mind that no patients with ALPS and somatic variants in these genes have been identified. Another option is to perform additional genetic testing (whole exome or whole genome sequencing). Alternative diagnoses should also be considered at this point. (See 'Differential diagnosis' below.)

Of note, the presence of a variant in FAS, FASLG, or CASP10 alone is not diagnostic of ALPS, while a definitive diagnosis of ALPS can be made without the need for genetic testing. Due to highly variable penetrance of ALPS, one can have a pathogenic variant in FAS and not meet diagnostic criteria. (See 'Diagnostic criteria' above.)

Impact of immunosuppressive therapy on testing — One question that frequently comes up regarding diagnostic testing has to do with the impact of immunosuppressive drugs. A rough rule of thumb is that the impact is related to the potency and duration of immunosuppressive therapy. As examples, a short burst of glucocorticoids, such as prednisone, may not alter the DNT cell compartment and/or ALPS biomarkers, while drugs that are often used chronically in ALPS therapy, particularly sirolimus and mycophenolate, can largely normalize laboratory values and/or interfere in Fas-mediated apoptosis assays. (See "Autoimmune lymphoproliferative syndrome (ALPS): Management and prognosis", section on 'Autoimmune manifestations'.)

Depending upon the particular situation, one can follow the abovementioned testing algorithm, keeping in mind that a lack of DNT cells or ALPS biomarkers may not be reliable. If the clinical condition permits discontinuation of immunosuppressive drugs, the diagnostic process can be delayed until that time. Conversely, FAS can be sequenced if continued immunosuppressive therapy is required and there is a strong suspicion of ALPS since this test will capture the vast majority of patients with ALPS. Confirmation of ALPS-sFAS, the second most common type of ALPS, requires sorting DNT cells, which may not be feasible if the DNT cell compartment is reduced by immunosuppressive drugs. In this case, testing may be performed at a later date if discontinuation of immunosuppressive medications in the future is possible.

Inheritance and prenatal diagnosis — Germline ALPS is inherited as an autosomal dominant trait, although rare cases of compound heterozygous or homozygous variants have been reported in patients with severe disease of early, even congenital, onset [37]. Thus, offspring of males or females affected with germline ALPS have a 50 percent chance of inheriting the condition, although penetrance and expressivity vary even in family members with the same variant. Somatic ALPS is generally not heritable, since it is restricted to hematopoietic cells.

Prenatal diagnosis for pregnancies at increased risk for a FAS, FASLG, or CASP10 variant is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis at approximately 15 to 18 weeks' gestation or chorionic villus sampling at approximately 10 to 12 weeks' gestation. The disease-causing allele(s) of an affected family member must be identified before prenatal testing can be performed.

Additional testing and diagnostic considerations — Performance of the Fas-mediated apoptosis assay, if available, is suggested only after ALPS-FAS, ALPS-sFAS, ALPS-CASP10, and ALPS-FASLG have been ruled out (algorithm 1). This is due to the complex and labor-intensive nature of the assay, which can take up several weeks of culturing. However, there is a novel Fas-mediated apoptosis assay based upon differential sensitivity of memory T cells versus naïve T cells that can be completed in one to two days instead of several weeks and can identify patients with ALPS who have germline or somatic defects [38]. This experimental assay shows promise and may precede genetic testing in the diagnostic evaluation if further studies confirm the utility of the test and it becomes available in clinical diagnostic laboratories.

A second area of investigational testing has grown out of the observation of cumulative genetic defects in ALPS patients, which lead to the presence of somatic loss of heterozygosity (LOH). Thus, measurement of Fas surface expression on T cells, particularly DNT cells, may allow detection of LOH. (See "Autoimmune lymphoproliferative syndrome (ALPS): Epidemiology and pathogenesis".)

DIFFERENTIAL DIAGNOSIS — The main considerations in the differential diagnosis are more common but self-limited viral infections, other immunodeficiency disorders characterized or complicated by lymphoproliferation, autoimmune disease (particularly autoimmune cytopenias), and lymphoma [39]. While a number of acquired viral infections such as Epstein-Barr virus (EBV) can be confused with ALPS, double-negative T (DNT) cells associated with infections predominantly express gamma delta rather than alpha beta T cell receptors (TCRs). Evans syndrome is sometimes considered a specific entity. However, it should be regarded as a descriptive term, meaning the presence of immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA), either concomitantly and/or sequentially. Even if a primary diagnosis cannot be made, Evans syndrome should be regarded as a constellation of manifestations of an underlying immunologic/hematologic disorder (such as ALPS). In that context, inborn errors of immunity can present with lymphoproliferation, including lymphoma, and autoimmune cytopenias. With this in mind, the differential diagnosis includes the following.

FADD deficiency — FAS-associated protein with death domain (FADD) deficiency is a rare, autosomal recessive condition that is not part of ALPS classification, mostly due to the fact that only seven patients have been reported [40-42]. However, one reported patient displayed key diagnostic findings that have come to define ALPS from a laboratory perspective. These include an expansion of DNT cells; increased levels of biomarkers (interleukin [IL] 10, soluble Fas ligand [FasL], and vitamin B12); and, importantly, abnormal in vitro Fas-mediated apoptosis. These patients may have a unique susceptibility to recurrent viral infections because FADD has a role in Toll-like receptor (TLR) independent innate immune responses [40]. The proper place of FADD deficiency in the classification and/or differential diagnosis of ALPS remains to be determined. Due to the proliferation of unbiased genetic testing, this requires careful characterization of clinical and laboratory parameters and cannot be based solely on in silico analyses.

Common variable immunodeficiency — Common variable immunodeficiency (CVID) is an inborn error of immunity characterized by impaired B cell differentiation or function with defective immunoglobulin production. It is the most prevalent form of severe antibody deficiency affecting both children and adults, hence the term "common." "Variable" refers to the heterogeneous clinical manifestations of this disorder, which include recurrent infections, chronic lung disease, autoimmune disorders, gastrointestinal disease, and a heightened susceptibility to lymphoma. The underlying causes of CVID are not known for most patients, although specific molecular defects are being identified in a growing subset of patients. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults" and "Pathogenesis of common variable immunodeficiency".)

From a clinical and immunologic standpoint, CVID can be roughly classified into two groups, depending upon the presence or absence of mature B cells in peripheral blood. Individuals with CVID who have mature 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 [43-45]. A reduction in memory B cells is also seen in some patients with ALPS [46]. CVID with preservation of B cells should be regarded in the differential diagnosis of ALPS [45], while CVID characterized by low or absent B cells and generally low serum concentrations of immunoglobulins should not.

CVID can be differentiated from ALPS based upon clinical manifestations, particularly the lack of infections in ALPS; laboratory features (eg, hypogammaglobulinemia in CVID contrasting with hypergammaglobulinemia in ALPS, lack of DNT cells, etc); and genetic testing (identification of an ALPS-related genotype or, conversely, identification of a CVID-associated genotype).

CTLA-4 haploinsufficiency with autoimmune infiltration (CHAI) disease — Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an inhibitory receptor expressed on regulatory T (Treg) cells. Haploinsufficiency of CTLA-4 causes dysregulation of forkhead box P3 positive (FoxP3+) Treg cells and hyperactivation of effector T cells, resulting in severe loss of tolerance and infiltrative autoimmune disease [47]. Clinical features include lymphoproliferation; lymphocytic infiltration of nonlymphoid organs (eg, brain, lungs, gastrointestinal tract); autoimmune cytopenias (eg, autoimmune hemolytic anemia [AIHA], autoimmune thrombocytopenia); CD4+ T cell lymphopenia; and B cell abnormalities with increased CD21lo B cells and hypogammaglobulinemia. Additional features include diffuse lymphadenopathy, hepatosplenomegaly, and EBV-associated Hodgkin lymphoma (HL).

CTLA-4 haploinsufficiency can be difficult to distinguish from ALPS. As with CVID (see 'Common variable immunodeficiency' above), reduced levels of serum immunoglobulins, lack of DNT cells, and targeted genetic testing should make this differentiation possible. In addition, lymphocytic infiltration of nonlymphoid organs appears to be more common in CTLA-4 haploinsufficiency. (In daily practice, the presence of pulmonary nodules, detected by imaging studies, points away from ALPS and towards CTLA-4 defects.)

STAT3 gain-of-function variants causing autoimmune disease — Loss-of-function dominant interfering variants in signal transducer and activator of transcription 3 (STAT3), a transducer of activating signals from cytokines at the cell surface to the nucleus of lymphocytes, are associated with immunodeficiency and the hyper-IgE recurrent infection syndrome. In contrast, STAT3 gain-of-function variants lead to a variety of clinical features, including lymphadenopathy, elevated alpha beta DNT cells, and autoimmune cytopenias that resemble ALPS [48]. Affected patients can also exhibit recurrent infections and short stature, as well as multiorgan autoimmunity affecting the lungs, gastrointestinal tract, liver, and endocrine organs. This condition may respond best to treatments targeting cytokine activation, such as the anti-IL-6 receptor monoclonal antibody tocilizumab.

Amongst the disorders that need to be differentiated from ALPS, gain-of-function variants in STAT3 can be particularly challenging. Although the origin of DNT cells may not be the same as in ALPS, this typically is not of practical use. Specific clinical manifestations (eg, short stature), in combination with laboratory and genetic testing (ruling out ALPS genes and/or ruling in an appropriate STAT3 genotype), should provide separation between these two entities.

LRBA deficiency disease — Defects in the lipopolysaccharide (LPS) responsive beige-like anchor protein (LRBA) gene were originally described in patients with both immunodeficiency and immune dysregulation, but the spectrum of this disorder includes individuals presenting with splenomegaly, adenopathy, elevated DNT cells, raised FasL serum levels, and autoimmune cytopenias [49]. In contrast to ALPS, LRBA deficiency is not characterized by defective apoptosis.

LRBA deficiency can be distinguished from ALPS by specific genetic testing and laboratory features, such as hypogammaglobulinemia. Importantly, LRBA defects are associated with type 1 diabetes mellitus (including early-onset diabetes), while this has not been described in ALPS.

CASP8 deficiency — Caspases are a family of proteases that play roles in signal transduction by inflammatory cytokine receptors (eg, IL-1 and IL-18), as well as in pathways leading to programmed cell death (apoptosis) [50]. Caspase 8 (CASP8) deficiency (MIM #697271) due to a pathogenic variant in the CASP8 gene have been described in several patients with a broad phenotypic spectrum [51-53]. CASP8 deficiency is also referred to as autoimmune lymphoproliferative syndrome type IIB (ALPS2B), although there is debate as to whether this disorder is a CID or a disease of immune dysregulation like ALPS [54]. Of note, it is classified as an ALPS in the 2022 International Union of Immunological Societies (IUIS) report.

In the original description, two siblings presented at 11 and 12 years of age with recurrent sinopulmonary bacterial infections and herpes simplex virus infections, poor growth, lymphadenopathy and splenomegaly, eczema, and asthma [51]. Two adult siblings subsequently were reported, one who presented with pulmonary hypertension and the other with a complex neurologic disease with cranial nerve palsies [52]. Both had severe lymphocytic infiltration of the lungs, liver, spleen, bone marrow, and central nervous system, granulomas, immunodeficiency, and immune dysregulation. Three children with very-early-onset inflammatory bowel disease (VEO-IBD), as well as increased susceptibility to bacterial and viral infections, were also identified [53]. One of the children died from complications due to sepsis.

In the first two patients described, immunoglobulin levels were normal, although in vivo antibody responses to Streptococcus pneumoniae and in vitro production of IgG and IgM were diminished [51]. All patients had a low CD4 T cell count, with decreased central regulatory, central memory, and T helper type 17 (Th17) cells in the two patients with VEO-IBD [51-53]. T cells showed decreased proliferation and IL-2 production in vitro with mitogens, and natural killer (NK) cell function was also impaired.

Management is directed toward infectious complications, which may include immune globulin replacement, and management of end-organ involvement [51-53]. The adult patient with pulmonary hypertension required lung transplantation [52]. She developed a fatal Nocardia asteroides meningoencephalitis while on immunosuppression to prevent graft rejection. Her brother with neurologic manifestations and immune dysregulation was treated with glucocorticoids and mycophenolate mofetil. CASP8 is ubiquitously expressed, and, therefore, one cannot predict that hematopoietic cell transplantation (HCT) would be curative.

Hyperimmunoglobulin M syndrome — Hyperimmunoglobulin M syndrome (HIGM) is a group of genetic defects that include impairment of B cell isotype switching, causing deficiency of IgG, IgA, and IgE while maintaining normal or elevated levels of IgM. HIGM can be X linked (due to a defect in CD40 ligand [CD40L] or due to NEMO syndrome) or autosomal recessive (due to defects in CD40, activation-induced cytidine deaminase [AICDA], or uracil DNA glycosylase [UNG]). The shared features caused by these defects 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. (See "Hyperimmunoglobulin M syndromes".)

The predominance of infections in the HIGM should facilitate differentiation of these entities from ALPS. As with CVID, distinct laboratory features and genetics that are present in ALPS but not in HIGM and vice versa further allow separation of ALPS from HIGM.

X-linked lymphoproliferative syndrome — X-linked lymphoproliferative (XLP) syndrome is associated with an inappropriate immune response to EBV infection resulting in unusually severe and often fatal infectious mononucleosis, dysgammaglobulinemia, and/or lymphoproliferative disorders that are typically of B cell origin. XLP is caused by hemizygous variants in the gene SH2 domain-containing 1A (SH2D1A). 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 often involve the intestine. (See "X-linked lymphoproliferative disease".)

XLP can be associated with lymphoproliferative diseases, including lymphoma. Genetic testing of SH2D1A allows for straightforward differentiation from ALPS.

Wiskott-Aldrich syndrome — Wiskott-Aldrich syndrome (WAS) is an X-linked disorder that typically manifests in early infancy with thrombocytopenia and petechiae, soon followed by eczema and recurrent bacterial and viral infections of variable severity, particularly recurrent ear infections. At least 40 percent of males who survive the early complications develop one or more autoimmune conditions such as hemolytic anemia, 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. (See "Wiskott-Aldrich syndrome".)

Genetic testing of the WAS gene, in combination with the presence of thrombocytopenia, eczema, and infections, should make differentiation from ALPS straightforward.

XLP and WAS are both X-linked diseases and would, under normal circumstances, not be expected in female patients.

Other rare disorders — There are a few case reports of patients with variants in the genes for NRAS proto-oncogene, GTPase (NRAS) [55] or KRAS proto-oncogene GTPase (KRAS) [56-58] that have clinical features similar to ALPS. As part of the revised diagnostic criteria, these disorders have been separated from ALPS [32].

In daily practice, current or past immunosuppressive and/or immunomodulatory therapy can make it challenging to determine the etiology of disease. As examples, DNT cells may no longer be detectable in patients treated with sirolimus, and B cells will be depleted on rituximab.

Lymphoma — 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 [15,59].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

Overview – Autoimmune lymphoproliferative syndrome (ALPS) is a rare disorder characterized by defective lymphocyte homeostasis, resulting from defective Fas-mediated apoptosis. (See 'Introduction' above and "Autoimmune lymphoproliferative syndrome (ALPS): Epidemiology and pathogenesis".)

Clinical features – ALPS typically manifests in the first years of life. The most common early clinical manifestations are lymphoid expansion with lymphadenopathy, splenomegaly, and hepatomegaly and autoimmune disease with blood cytopenias including thrombocytopenia and hemolytic anemia. A late complication is lymphoma. Patients who have undergone splenectomy are prone to life-threatening sepsis; thus, splenectomy is to be avoided in ALPS. (See 'Clinical manifestations of ALPS-FAS' above.)

Laboratory findings – The signature laboratory abnormality unique to ALPS is the presence of T cells that express the alpha beta T cell receptor (TCR) but lack both CD4 and CD8 coreceptors (alpha beta double-negative T [DNT] cells) in peripheral blood or tissue specimens. Other immunologic laboratory findings that are typical and unique to ALPS include abnormal Fas-mediated apoptosis in vitro, increased levels of interleukin (IL) 10 in serum/plasma, and increased blood levels of vitamin B12, IL-18, and soluble Fas ligand (FasL). Hematologic findings include Coombs-positive hemolytic anemia with reticulocytosis and hyperbilirubinemia, dyserythropoiesis, thrombocytopenia, neutropenia, and eosinophilia. (See 'Laboratory findings' above.)

Diagnosis – The diagnosis of ALPS is based upon strict criteria (algorithm 1) that include required clinical findings (lymphadenopathy and/or splenomegaly) and laboratory abnormalities including presence of alpha beta DNT cells, as well as accessory features such as elevated levels of ALPS biomarkers (vitamin B12, IL-10, IL-18, and soluble FasL), defective in vitro Fas-mediated apoptosis, and identification of variants in genes relevant for the Fas pathway of apoptosis including Fas, Fas ligand, and caspase 10 (FAS, FASLG, and CASP10). (See 'Diagnosis' above.)

Differential diagnosis – The main considerations in the differential diagnosis are more common but self-limited viral infections, other immunodeficiency disorders characterized or complicated by lymphoproliferation, autoimmune disease (particularly autoimmune cytopenias), and lymphoma. Inborn errors of immunity include common variable immunodeficiency (CVID), cytotoxic T lymphocyte antigen 4 (CTLA-4) haploinsufficiency, lipopolysaccharide (LPS) responsive beige-like anchor protein (LRBA) deficiency disease, signal transducer and activator of transcription 3 (STAT3) gain-of-function disease, hyperimmunoglobulin M syndrome (HIGM), X-linked lymphoproliferative (XLP) disease, Ras-associated lymphoproliferative disease, and Wiskott-Aldrich syndrome (WAS). Both B cell and T cell lymphoma should also be considered in the differential diagnosis of ALPS. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.

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Topic 16837 Version 21.0

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