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Autoimmune Lymphoproliferative Syndrome

Synonyms: ALPS, Canale-Smith Syndrome

, MD, PhD, , MS, CGC, and , MD, MBA.

Author Information
, MD, PhD
Associate Professor of Pediatrics, Division of Bone Marrow Transplantation & Immune Deficiency
Cincinnati Children's Hospital
Cincinnati, Ohio
, MS, CGC
Project Manager, Division of Human Genetics
Cincinnati Children's Hospital
Cincinnati, Ohio
, MD, MBA
Associate Professor of Pediatrics, Division of Human Genetics
Cincinnati Children's Hospital
Cincinnati, Ohio

Initial Posting: ; Last Update: September 11, 2014.

Summary

Disease characteristics. Autoimmune lymphoproliferative syndrome (ALPS), caused by defective lymphocyte homeostasis, is characterized by:

  • Non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age;
  • Autoimmune disease, mostly directed toward blood cells; and
  • Lifelong increased risk for both Hodgkin and non-Hodgkin lymphoma.

In ALPS-FAS (the most common and best-characterized type of ALPS, associated with heterozygous germline mutations in FAS), non-malignant lymphoproliferation typically manifests in the first years of life, inexplicably waxes and wanes, and then often decreases without treatment in the second decade of life; however, neither splenomegaly nor the overall expansion of lymphocyte subsets in peripheral blood decreases in many affected individuals. Although autoimmunity is often not present at the time of diagnosis or at the time of the most extensive lymphoproliferation, autoantibodies can be detected before autoimmune disease manifests clinically. ALPS-FAS caused by homozygous or compound heterozygous (biallelic) mutations in FAS is characterized by severe lymphoproliferation before, at, or shortly after birth, and usually results in death at an early age. ALPS-sFAS, resulting from somatic FAS mutations in selected cell populations, notably the alpha/beta double-negative T cells (α/β-DNT cells), appears to be similar to ALPS-FAS resulting from heterozygous germline mutations in FAS, keeping in mind that those with somatic mutations need to be better characterized, particularly with regard to the risk for lymphoma.

Diagnosis/testing. The diagnosis of ALPS is based on the following:

  • Clinical findings
  • Laboratory abnormalities including:
    • Abnormal biomarker testing (soluble interleukin-10 [IL-10], Fas Ligand [FasL], IL-18, and vitamin B12)
    • Defective in vitro tumor necrosis factor receptor superfamily member 6 (Fas)-mediated apoptosis
    • T cells that express the alpha/beta T-cell receptor but lack both CD4 and CD8 (so-called α/β-DNT cells)
  • Identification of mutations in genes relevant for the Fas pathway of apoptosis

Mutations in FAS (TNFRSF6) are known to cause ALPS-FAS and ALPS-sFAS. Mutations in FASLG (previously known as FASL, TNFSF6) and CASP10 have been identified in a few individuals with ALPS.

Management. Treatment of manifestations: Lymphoproliferation can be suppressed with corticosteroids; in severe cases cyclophosphamide, sirolimus, antithymocyte globulin and alemtuzumab may be required. Because lymphadenopathy and organomegaly often return once these agents are discontinued, immunosuppressive therapy is generally reserved for severe complications of lymphoproliferation (e.g., airway obstruction, significant hypersplenism associated with splenomegaly) and/or autoimmune manifestations. Early experience with sirolimus suggests that it can reverse both proliferative and autoimmune features in a more sustained manner, including maintenance of remission following discontinuation of sirolimus; however, sirolimus is not without side effects. Lymphoma is treated with conventional protocols. Autoimmue cytopenias and other autoimmue diseases are treated with corticosteroids; mycophenolate mofetil (MMF) is generally introduced as steroids are tapered; those non-responsive to MMF may be treated with sirolimus. Splenectomy is reserved as an option of last resort in the treatment of life-thretening refractory cytopenias and/or severe hypersplenia because of the high risk of recurrence of cytopenias and sepsis post-splenectomy in people with ALPS.

Prevention of primary manifestations: Bone marrow (hematopoietic stem cell) transplantation (BMT/HSCT), the only curative treatment for ALPS, has to date mostly been performed on those with severe clinical phenotypes such as ALPS-FAS caused by biallelic mutations, those with severe and/or refractory autoimmune cytopenias, those with lymphoma, and those who developed complications from (often long-term) immunosuppressive therapy.

Prevention of secondary complications: Vaccinations pre-splenectomy (with consideration of post-splenectomy boost vaccinations) and penicillin prophylaxis are strongly recommended for individuals who undergo splenectomy.

Surveillance: Clinical assessment, imaging and laboratory studies for manifestations of lymphoproliferation and autoimmunity, and specialized imaging studies to detect malignant transformation.

Agents/circumstances to avoid: Splenectomy typically does not lead to permanent remission of autoimmunity and is associated with increased risk of infections. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) should be used with caution in individuals with immune thrombocytopenia (ITP) as they can interfere with platelet function.

Evaluation of relatives at risk: If the disease-causing mutation has been identified in a family member with ALPS, it is appropriate to perform molecular genetic testing on at-risk relatives to allow for early diagnosis and treatment.

Pregnancy management: Assessment of the risks and benefits of treating a woman who has ALPS with corticosteroids or mycophenylate mofitil during pregnancy must take into consideration the potential teratogenic risks to the fetus.

Genetic counseling. ALPS-FAS is generally inherited in an autosomal dominant manner. Most individuals diagnosed with ALPS-FAS have a parent with a FAS mutation; the proportion of ALPS-FAS caused by either somatic mosaicism or de novo mutations is currently unknown. Each child of an individual with ALPS-FAS has a 50% chance of inheriting the FAS mutation. ALPS-FAS can also be inherited in an autosomal recessive manner, i.e., the consequence of homozygous or compound heterozygous (biallelic) FAS mutations. The parents of such an individual are likely to be heterozygotes, in which case each has one FAS mutant allele; these parents may have ALPS-related findings or may be clinically asymptomatic. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation(s) have been identified in an affected family member.

Diagnosis

Suggestive Findings

The 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.

ALPS should be considered in individuals with combinations of the following [Bleesing 2003, Rieux-Laucat et al 2003] (see also Clinical Description, Clinical Manifestations of ALPS):

  • Chronic non-malignant lymphoproliferation
    • Chronic and/or recurrent lymphadenopathy
    • Splenomegaly with/without hypersplenism
    • Hepatomegaly
    • Lymphocytic interstitial pneumonia (LIP) (less common)
  • Autoimmune disease
    • Cytopenia, 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 syndrome
  • Lymphoma, both Hodgkin lymphoma and non-Hodgkin lymphoma
  • Skin rashes, often but not exclusively of an urticarial nature
  • Family history of ALPS or ALPS-like features

Establishing the Diagnosis

A revised set of diagnostic criteria have been 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 criteria

  • Chronic (>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 criteria

  • Elevated levels of one of the following:
    • Plasma soluble FASL
    • Plasma interleukin-10
    • Serum vitamin B12
    • Plasma interleukin-18
  • Typical immunohistologic findings as determined by an experienced hematopathologist
  • Autoimmune cytopenias with elevated (polyclonal) immunoglobulin G levels

Testing

Although no specific laboratory abnormality alone is diagnostic of ALPS, the detection of the following facilitates the diagnosis [Bleesing 2003, Magerus-Chatinet et al 2009, Caminha et al 2010, Oliveira et al 2010, Rensing-Ehl et al 2013]:

  • Defective Fas-mediated apoptosis in vitro
  • T 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.
  • Increased levels of the ALPS-specific biomarkers: soluble IL-10, IL-18, FasL, and vitamin B12 in plasma/serum [Bowen et al 2012]

Secondary 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, Bowen et al 2012, Neven et al 2014]:

  • Hematology
    • Lymphocytosis, lymphopenia (primary or secondary in response to treatment)
    • Coombs-positive hemolytic anemia
    • Dyserythropoiesis
    • Reticulocytosis
    • Thrombocytopenia
    • Neutropenia
    • Eosinophilia
  • Immunology
    • Expansion of other lymphocyte subsets
      • Gamma/delta-DNT cells
      • CD8+/CD57+ T cells
      • HLA-DR+ T cells
      • CD5+ B cells
    • Decreased numbers of CD4+/CD25+ T cells
    • Decreased numbers of CD27+ B cells
    • Elevated concentration of IL-10 and IL-18 in serum/plasma
    • Elevated concentrations of IgG, IgA, and IgE; normal or decreased concentrations of IgM
    • Autoantibodies (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])
  • Other
    • Increased soluble CD25 (sIL-2R alpha), CD27, CD30, and Fas ligand (FasL)
    • Monoclonal gammopathy
    • Decreased antibody responses to polysaccharide antigens [Neven et al 2014]
  • Chemistry
    • Liver function abnormalities (in case of autoimmune hepatitis)
    • Proteinuria (in case of glomerulonephritis)
    • Elevated serum concentration of vitamin B12

Normal findings in (typical) ALPS

  • Neutrophil function
  • Complement factors concentrations and function
  • In 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-FASLG).
  • 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 Testing

Genes. Germline mutations in three genes are known to cause ALPS: FAS (TNFRSF6), FASLG (TNFSF6), and CASP10.

  • FAS somatic mutations in selected cell populations, including α/β-DNT cells, produce a phenotype similar to that caused by FAS germline mutations.
  • Thus far, somatic mutations in only FAS have been reported to cause ALPS; however, it is theoretically possible that somatic mutations in FASLG and CASP10 may also be causative.

Clinical Testing

Table 1. Summary of Molecular Genetic Testing Used in ALPS

Gene 1ALPS TypeProportion of ALPS Attributed to Mutation of This GeneTest Method
FAS 2ALPS-FAS65%-70% 3, 4Sequence analysis 5
ALPS-sFAS~15%-20% 6, 7
FASLGALPS-FASLG<1% 8, 9
CASP10ALPS-CASP103%-6% 10, 11
UnknownALPS-U 12 and ALPS-non-FAS 13Unknown 14Not applicable

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2. Sequencing of the entire coding region and intron/exon boundaries of FAS detects approximately 90% of all reported FAS mutations [NHGRI ALPS Database].

3. Heterozygous germline mutations. Homozygous/compound heterozygous FAS germline mutations are also observed and are typically associated with a severe phenotype [Rieux-Laucat et al 1995, Kasahara et al 1998, van der Burg et al 2000, Bleesing 2003, Rieux-Laucat et al 2003].

4. Individuals with an inherited germline mutation in addition to a second acquired mutation [Magerus-Chatinet et al 2011], as well as individuals exhibiting somatic loss of heterozygosity [Magerus-Chatinet et al 2011, Hauck et al 2013], have been also described.

5. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. Somatic mutations in selected cell populations, including α/β-DNT cells [Holzelova et al 2004, Rössler et al 2005, Dowdell et al 2010], but rarely in other lymphocyte subsets and not in non-lymphocytes

7. 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.

8. Homozygous or heterozygous (biallelic) germline mutations in FASLG: to date only three affected individuals have been reported [Del-Rey et al 2006, Bi et al 2007, Magerus-Chatinet et al 2013].

9. Individuals with biallelic homozygous mutations have especially severe disease [Magerus-Chatinet et al 2013].

10. Of the two affected individuals originally reported in 1999, the reported homozygous CASP10 alteration was determined subsequently not to cause ALPS [Wang et al 1999].

11. In two individuals, ALPS was presumed to result from coinherited mutations in FAS and CASP10 that were hypothesized to cooperate in causing ALPS [Cerutti et al 2007].

12. No pathogenic variants are detected in FAS, FASLG, or CASP10.

13. Only FAS pathogenic variants 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].

14. Approximately 20%-25% of individuals with ALPS currently lack a genetic diagnosis.

Testing Strategy

To confirm/establish the diagnosis in a proband

One proposed algorithm for diagnostic evaluation of individuals with suspected ALPS based on the presence of required and accessory criteria involves combining measurements of α/β-DNT cells with biomarkers and molecular genetic testing, as outlined in Figure 1.

Figure 1

Figure

Figure 1. One proposed algorithm for the diagnostic evaluation of an individual suspected of having ALPS

Another proposed algorithm for diagnosis 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 elevated 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 for 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 been reliably 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.

Clinical Description

Natural History

Autoimmune 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 ALPS

Lymphoproliferation of non-malignant lymphoid cells

  • Lymphadenopathy
  • Splenomegaly (+/- hypersplenism)
  • Hepatomegaly

Autoimmunity

  • Autoimmune hemolytic anemia
  • Autoimmune thrombocytopenia
  • Autoimmune neutropenia
  • Glomerulonephritis
  • Autoimmune hepatitis
  • Guillain Barré syndrome
  • Uveitis, iridocyclitis
  • Other 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 findings

  • Urticaria and other skin rashes
  • Vasculitis
  • Panniculitis
  • Arthritis and arthralgia
  • Recurrent oral ulcers
  • Humoral immunodeficiency
  • Pulmonary infiltrates
  • Premature ovarian insufficiency
  • Hydrops fetalis
  • Organic brain syndrome (mental status changes, seizures, headaches)

Much remains to be learned. 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 life long. 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. Two recent publications have provided significant new insights into the features, complications, natural history, and prognosis of ALPS. These studies subsequently will be referred to in this GeneReview as the “French cohort” and the “NIH cohort” [Neven et al 2011, Price et al 2014].

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].

    The median age of onset was three years in the French cohort and 2.7 years in the NIH cohort. Lymphadenopathy was present in 85% in the French cohort and 97% in the NIH cohort, while splenomegaly was present in 94% in the French cohort (with 73% showing hypersplenism) and 95% in the NIH cohort [Neven et al 2011, Price et al 2014].

    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, Neven et al 2011, Price et al 2014].

    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].

    The French cohort and NIH cohort revealed that, in general, affected individuals with later disease onset often presented with autoimmune disease, while younger individuals typically presented with lymphoproliferative disease, followed by autoimmune disease, with a two- to three-year delay between lymphoproliferative disease onset and autoimmune disease onset. However, many affected individuals in both age groups presented with autoimmune disease as their first manifestation of ALPS [Neven et al 2011, Price et al 2014].

    Although autoimmune manifestations can also wax and wane, current knowledge suggests that autoimmune disease poses a lifelong burden. In fact, in the NIH cohort, 37% of affected individuals were described as having a severe autoimmune disease phenotype (as determined by the presence of grade 3 or 4 cytopenias) within two years of disease onset [Price et al 2014].

    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 lymphoma (NHL) and Hodgkin lymphoma (HL), respectively [Straus et al 2001].

    More recently, updated risk calculations were provided through the French cohort and the NIH cohort. The French cohort provided a 15% cumulative risk of lymphoma before age 30 years. This represented seven cases of lymphoma (3 cases of HL and 4 cases of NHL) out of a total of 90 affected individuals [Neven et al 2011].

    In the NIH cohort, 18 cases of lymphoma out of a total of 150 affected individuals were identified with a median age of detection of 18 years and a male-to-female ratio of 3.5 to 1. Sixteen (89%) of 18 cases were of B-cell origin. It was determined that 17/18 cases occurred in individuals with mutations 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 standardized incidence ratio (SIR) of 149 for HL and 61 for NHL. These numbers are significantly different from those previously published by the NIH group [Straus et al 2001, Price et al 2014].

    Lymphoma typically originates in B cells, but has been found in T cells as well, although much less frequently (2/18 cases in the NIH Cohort) [Price et al 2014]. 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 mutations

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, Magerus-Chatinet et al 2011], Fas-mediated apoptosis in vitro is typically not defective, although such defective 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 Correlations

ALPS-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 mostly with mutations affecting the intracellular domains of Fas, though independent confirmation is required [Straus et al 2001, Price et al 2014].

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 proposed 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 Genetics, Molecular Genetic Pathogenesis.)

ALPS-FASLG and ALPS-CASP10. Because of their rarity, genotype-phenotype correlations are not established for FASLG and CASP10 mutations.

Penetrance

ALPS-FAS. A distinction needs to be made between the penetrance of the cellular phenotype (defective Fas-mediated apoptosis) and the penetrance of the clinical phenotype (i.e., ALPS).

Family studies to date suggest that penetrance for the defective Fas-mediated apoptosis cellular phenotype approximates 100% (i.e., every individual heterozygous for an inherited [germline] disease-causing mutation has defective apoptosis) whereas the penetrance for the clinical phenotype is reduced because a significant proportion of relatives heterozygous for the disease-causing mutation have no clinical findings of ALPS. In addition, other relatives display laboratory features of ALPS (e.g., expansion of lymphocyte subsets and/or autoantibodies) without clinical evidence of either lymphoproliferation or autoimmunity [Infante et al 1998, Jackson et al 1999, Bleesing et al 2001b].

The factors that determine the penetrance of clinical ALPS are not entirely understood. It appears that penetrance is determined by the location and type of mutation [Rieux-Laucat et al 1999, Le Deist 2004]. In initial studies, the highest penetrance (70%-90%) for the clinical phenotype occured with missense mutations affecting the intracellular domains (ICD), followed by mutations leading to truncation of the ICDs. For pathogenic variants affecting the extracellular domains (ECD) the highest penetrance was estimated at approximately 30% [Jackson et al 1999].

In the French cohort ECD mutations had a penetrance of 52% (higher than previous data) and ICD mutations had a 63% penetrance, which is lower than previously reported. The penetrance of missense mutations affecting the death domain (part of the ICD) was 73% [Jackson et al 1999, Neven et al 2011].

The reduced penetrance for ALPS in some families suggests that one or more additional pathogenic factors interact with defective Fas-mediated apoptosis. However, the high penetrance for the clinical phenotype in certain families associated with specific types of FAS mutations (e.g., missense mutations affecting the death domain) casts doubt on that assumption, suggesting that under certain conditions a single defect in Fas-mediated apoptosis is sufficient to cause ALPS [Infante et al 1998, Jackson et al 1999, Le Deist 2004].

A recent observation may shed more light on the issue of penetrance, particularly as it relates to mutations affecting intracellular versus extracellular domains (as well as on pathogenesis and natural history of ALPS): in a small subset of affected individuals, clinical disease appeared to develop as a consequence of both an inherited heterozygous (germline) FAS mutation and a somatic genetic event in the second FAS allele [Magerus-Chatinet et al 2011]. Analysis of α/β-DNT cells revealed that the second genetic event involved either a somatic missense or nonsense mutation in the second FAS allele or loss of heterozygosity by telomeric uniparental disomy of chromosome 10. These observations were recently confirmed in a family with ALPS in which affected individuals had a heterozygous germline FAS start codon mutation with somatic loss of heterozygosity [Hauck et al 2013].

Anticipation

Anticipation has not been documented in ALPS.

Nomenclature

Table 2. Revised Classification of ALPS

Previously Used TermCurrent Term
ALPS0ALPS-FAS (caused by biallelic germline FAS mutations)
ALPSIaALPS-FAS (caused by heterozygous germline FAS mutations)
ALPSImALPS-sFAS (caused by somatic FAS mutations)
ALPSIbALPS-FASLG
ALPSIIaALPS-CASP10
ALPSIIIALPS-U (no mutation in FAS, FASLG or CASP10 identified)

Prevalence

The prevalence of ALPS is unknown. It is likely as rare as other primary immunodeficiency disorders that cause disease in a heterozygous state.

ALPS has a worldwide distribution and no racial or ethnic predilection.

A gender inequality in ALPS has been observed. In the French cohort, the likelihood of a male with a heterozygous germline FAS mutation developing ALPS was about 75%, compared to 51% for females. In the NIH cohort the likelihood of developing ALPS for males and females was 69% and 46%, respectively. The ratio of affected males to affected females was 2.2 (French cohort) and 1.6 (NIH cohort). Lastly, in the French cohort, the ratio of affected males to affected females increased from 2.2. to 2.9 if autoimmune disease was present and to 4.2 if autoimmune disease included autoimmune cytopenias [Neven et al 2011, Price et al 2014].

Differential Diagnosis

ALPS-like disorders. 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), other disorders caused by mutations in genes inside or outside the Fas/FasL pathway may be associated with ALPS features. These include:

  • Dianzani autoimmune lymphoproliferative disease (DALD) (OMIM 605233). Individuals with DALD present with autoimmunity, lymphoproliferation, splenomegaly, and defective Fas function without expansion of DNT cells. A genetic basis for this disorder is suspected, but no causative genes have been identified to date [Oliveira et al 2010, Boggio et al 2014].
  • Ras-associated autoimmune leukoproliferative disorder (RALD) secondary to somatic mutations in NRAS and KRAS. Similar to autoimmune lymphoproliferative syndrome (ALPS), RALD is a primary immunodeficiency disorder of defective apoptosis. Abnormal apoptosis in RALD results from a defect in a secondary apoptosis pathway, rather than the FAS-mediated apoptosis pathway in ALPS. RALD is characterized by mild peripheral lymphadenopathy, (hepato)splenomegaly, and autoimmunity. Recurrent respiratory tract infections are reported in some affected individuals. Because of the rarity of this condition, the risk for lymphoma is not known [Chun et al 2002, Oliveira et al 2007, Niemela et al 2011, Takagi et al 2011, Lanzarotti et al 2014].
  • Caspase-8 deficiency state (CEDS) (OMIM 607271). CEDS is a rare, autosomal recessive immunodeficiency syndrome resulting in lymphadenopathy, splenomegaly, marginal elevation of double-negative T cells, and defective FAS-mediated apoptosis, in addition to frequent bacterial and viral infections secondary to defective activation of T and B lymphocytes and NK cells. Autoimmunity has not been reported to date in individulas with CEDS. The risk of lymphoma in people with CASP8 mutations is not known, nor has the full spectrum of the disease been elucidated given the rarity of individuals with known mutations [Chun et al 2002, Oliveira 2013].
  • Fas-associated via death domain (FADD) deficiency (OMIM 613759). FADD deficiency is a rare, autosomal recessive primary immunodeficiency syndrome characterized by severe bacterial and viral infections, congenital heart defects and recurrent episodes of fever, liver dysfunction and seizures. Biochemical markers are consistent with ALPS, but the affected individuals described to date do not have the characteristic clinical features of ALPS, including lymphadenopathy and splenomegaly [Bolze et al 2010, Oliveira 2013]. FADD deficiency is caused by biallelic mutations in FADD.
  • Common variable immunodeficiency 9 (PRKCD deficiency) (OMIM 615559). PRKCD deficiency is a recently described autosomal recessive primary immunodeficiency characterized by recurrent infections, lymphadenopathy, [hepato]splenomegaly, autoimmunity and NK cell dysfunction. The full spectrum of the disease has not been elucidated given the small number of individuals with known mutations in PRKCD [Kuehn et al 2013, Salzer et al 2013].

Within the differential diagnosis for ALPS are other immunodeficiency disorders characterized or complicated by lymphoproliferation, autoimmune disease, and lymphoma. These include the following:

  • Common variable immune deficiency (CVID) has an estimated incidence of one in 50,000 and occurs equally in males and females. CVID is characterized by humoral immune deficiency with onset after age 24 months and usually in young adulthood, resulting in increased susceptibility to infections and diminished responses to protein and polysaccharide vaccines. 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, Rensing-Ehl et al 2010]. Furthermore, biomarkers have confirmed the overlap between ALPS and CVID [Roberts et al 2013].
  • 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) caused by hemizygous mutation in SH2D1A 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) administration. Lymphomas or other lymphoproliferative diseases 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), are often extranodal, and particularly involve 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. Note: XLP cause by mutation in XIAP has not been associated with lymphoproliferation or lymphoma to date.
  • WAS-related disorders, which include Wiskott-Aldrich syndrome, X-linked thrombocytopenia (XLT), and X-linked congenital neutropenia (XLN), are a spectrum of disorders of hematopoietic cells, with predominant defects of platelets and lymphocytes caused by mutation of WAS. WAS-related disorders usually present in infancy. Affected males have thrombocytopenia with intermittent mucosal bleeding, bloody diarrhea, and intermittent or chronic petechiae and purpura; eczema; and recurrent bacterial and viral infections, particularly recurrent ear infections. At least 40% of those 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 damage to the kidneys and liver. Individuals with a WAS-related disorder, particularly those who have been exposed to Epstein-Barr virus (EBV), are at increased risk of developing lymphomas, which often occur in unusual, extranodal locations such as the brain, lung, or gastrointestinal tract. Males with XLT have thrombocytopenia with small platelets; other complications of Wiskott-Aldrich syndrome, including eczema and immune dysfunction, are mild or absent.
  • 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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To determine the presence and extent of disease and needs 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 hepatosplenomegaly
  • Complete blood counts and measurement of autoantibodies to assess for autoimmunity
  • If significant lymphadenopathy is present, more extensive diagnostic procedures to detect lymphoma, especially if constitutional symptoms (e.g., fever, night sweats, weight loss) are present
  • Medical genetics consultation

Treatment of Manifestations

In the absence of curative treatment, current management is focused on:

Monitoring for and treatment of lymphoproliferation and hypersplenism

  • Manifestations of lymphoproliferation require close clinical observation, as well as serial CT and PET scans every two to three years.
  • Biopsy is indicated whenever there is a clinical suspicion of lymphoma.
  • Corticosteroids and immunosuppressive drugs do not decrease lymphadenopathy long term in individuals with ALPS, and are generally reserved for severe complications of lymphoproliferation (e.g., airway obstruction, significant hypersplenism associated with splenomegaly) and/or autoimmune manifestations.
  • Early experience with sirolimus suggests that this agent may affect lymphoproliferation in a more sustained manner, including maintenance of remission following discontinuation of sirolimus [Teachey et al 2009]. However, sirolimus is not without side effects.
  • In severe cases, more potent (lympho-depleting) agents may be required to sufficiently control lymphoproliferative manifestations. Agents include cyclophosphamide, antithymocyte globulin (ATG) and select monoclonal antibodies such as alemtuzumab (Campath®).

Treatment of lymphoma is according to conventional protocols. The presence of defective Fas-mediated apoptosis does not appear to hinder the response to chemotherapeutic agents or radiation.

Treatment of autoimmune cytopenias and other autoimmune diseases

  • Autoimmune cytopenias are typically treated by immune suppression with corticosteroids.
    • Mycophenolate mofetil (MMF) is generally introduced as steroids are tapered following the initial presentation and is continued long-term.
    • Those who are non-responsive to MMF may be treated with sirolimus, in conjunction with careful monitoring for toxic side effects.
  • Individuals with severe autoimmune hemolytic anemia may benefit from IVIG in combination with corticosteroids.
  • Rituximab has been used successfully in the treatment of refractory cytopenias in ALPS. However, because of its immune toxicity, its use is generally avoided until other immunosuppression therapies have failed [Rao et al 2009, Rao & Oliveira 2011].
  • Splenectomy is reserved as an option of last resort in the treatment of life-threatening refractory cytopenias and/or severe hypersplenia because of the high risk of recurrence of cytopenias and sepsis post-splenectomy in those with ALPS [Rao & Oliveira 2011, Price et al 2014].
  • Individuals with isolated chronic neutropenia may improve on low-dose G-CSF [Rao & Oliveira 2011].

Prevention of Primary Manifestations

Bone 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, those with severe and/or refractory autoimmune cytopenias, those with lymphoma, and those who developed complications from (often long-term) immunosuppressive therapy. 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 Complications

Vaccinations pre-splenectomy (with consideration of post-splenectomy boost vaccinations) and penicillin prophylaxis are strongly recommended for individuals who undergo splenectomy.

Surveillance

Clinical 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 & Oliveira 2011].

Agents/Circumstances to Avoid

Splenectomy to control autoimmune cytopenias and/or massive splenomagaly is discouraged because it typically does not lead to permanent remission of autoimmunity and may be associated with an increased risk for infections. The two recent cohort studies reveal clear-cut consequences of splenectomy. In the French cohort, nine (30%) of 30 affected individuals who underwent splenectomy suffered 17 cases of severe invasive bacterial infection with four deaths after splenectomy; in the NIH cohort, 27 (41%) of 66 affected individuals suffered one or more episodes of sepsis with seven deaths. Of note: Anti-microbial prophylaxis and appropriate vaccinations did not prevent the majority of episodes of sepsis, although poor compliance was found to be a risk factor in the French cohort [Neven et al 2011, Price et al 2014].

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 Risk

It 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.

In addition to the risks and benefits to a woman who has ALPS of treatment with corticosteroids or mycophenylate mofitil during pregnancy, the potential teratogenic risks of these exposures to the fetus must be weighed as well.

Therapies Under Investigation

Reduced-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 [Dimopoulou et al 2007].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

High-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), but should be considered in the management of autoimmune cytopenias [Rao & Oliveira 2011].

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

ALPS-FAS, ALPS-FASLG, and ALPS-CASP10 are generally inherited in an autosomal dominant manner.

ALPS-FAS and ALPS-FASLG caused by biallelic mutations are inherited in an autosomal recessive manner.

Risk to Family Members — Autosomal Dominant ALPS-FAS, ALPS-FASLG, ALPS-CASP10

Parents of a proband

  • Most individuals diagnosed with ALPS-FAS have a parent who has a FAS mutation. Individuals who are heterozygous for a FAS mutation all have defective Fas-mediated apoptosis but may have no clinical findings of ALPS (see Penetrance).
  • An insufficient number of cases of ALPS-FASLG and ALPS-CASP10 are available to determine risks to family members.

    A proband with ALPS-FAS, ALPS-FASLG, or ALPS-CASP10 may have the disorder as the result of somatic mosaicism. Somatic mutations have not been reported in ALPS-FASLG or ALPS-CASP10 to date.
  • A proband with ALPS-FAS, ALPS-FASLG, or ALPS-CASP10 may have the disorder as the result of a new germline mutation. The proportion of cases caused by de novo germline mutations is small.

Note: Although most individuals diagnosed with ALPS have a parent with a FAS mutation, the family history may appear to be negative because of reduced penetrance of the clinical symptoms of ALPS (as opposed to the nearly complete penetrance of defective in vitro apoptosis in individuals with a FAS mutation), failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, molecular genetic testing is the most accurate means of determining the genetic status of at-risk individuals.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband has a FAS, FASLG, or CASP10 mutation, each sib has a 50% chance of inheriting the FAS, FASLG, or CASP10 mutation. The risk of developing ALPS-related complications, however, depends on the nature of the mutation, as well as the presence of other as-yet incompletely understood genetic or environmental factors.
  • If the FAS, FASLG, or CASP10 mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with ALPS-FAS, ALPS-FASLG, or ALPS-CASP10 has a 50% chance of inheriting the FAS, FASLG, or CASP10 mutation. The risk of that child developing ALPS-related complications depends on the nature of the mutation as well as the presence of other as-yet incompletely understood genetic or environmental factors.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent has a FAS, FASLG, or CASP10 mutation, his or her family members may have inherited the same mutation and are potentially at some increased risk of developing ALPS-related complications.

Risk to Family Members —ALPS-FAS and ALPS-FASLG Resulting from Biallelic Mutations

Parents of a proband

  • The parents of a child with ALPS-FAS or ALPS-FASLG resulting from biallelic mutations are likely to be heterozygotes, in which case each parent would have one FAS or FASLG pathogenic variant.
  • Heterozygotes may present with ALPS-related findings or may be clinically asymptomatic.

Sibs of a proband

  • At conception, each sib of a child with ALPS-FAS or ALPS-FASLG resulting from biallelic mutations has an overall 75% chance of having one or two FAS/FASLG mutations; a 25% chance of inheriting two FAS/FASLG mutations, which would most likely result in a severe ALPS phenotype; a 50% chance of inheriting a single FAS/FASLG mutation, which could result in clinical manifestations of ALPS; and a 25% chance of inheriting one normal FAS/FASLG allele from each parent and having no clinical manifestations of ALPS.
  • Once an at-risk sib is known to be unaffected with ALPS-FAS or ALPS-FASLG resulting from biallelic mutations, the risk of his/her being a heterozygote for a mutation is 2/3.
  • Heterozygotes may present with ALPS-related symptoms or may be clinically asymptomatic.

Offspring of a proband. Individuals with ALPS resulting from biallelic mutations are more likely to die at an early age and thus are not as likely to reproduce.

Other family members of a proband. If a parent of the proband has a FAS mutation, his/her sibs are at a 50% risk of having the mutation.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Testing of at-risk asymptomatic family members for FAS, FASLG, or CASP10 mutations is possible once the disease-causing mutation(s) are identified in the proband. Although the factors that determine the penetrance of clinical ALPS are not entirely understood, penetrance appears to be determined by the location and type of mutation. Results of testing of at-risk asymptomatic family members may be helpful in predicting phenotype.

Molecular genetic testing of asymptomatic individuals should in general be undertaken following thorough genetic counseling and assessment of family-specific risks.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the FAS, FASLG, or CASP10 pathogenic variant(s) have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Institute of Allergy and Infectious Diseases (NIAID)
    NIAID Office of Communications and Government Relations
    6610 Rockledge Drive
    MSC 6612
    Bethesda MD 20892-6612
    Phone: 866-284-4107 (toll-free); 301-496-5717; 800-877-8339 (toll-free TDD)
    Fax: 301-402-3573
    Email: ocpostoffice@niaid.nih.gov
  • American Autoimmune Related Diseases Association, Inc. (AARDA)
    22100 Gratiot Avenue
    East Detroit MI 48021
    Phone: 800-598-4668 (toll-free); 586-776-3900
    Fax: 586-776-3903
    Email: aarda@aarda.org
  • Canadian Immunodeficiencies Patient Organization (CIPO)
    362 Concession Road 12
    RR #2
    Hastings Ontario K0L 1Y0
    Canada
    Phone: 877-262-2476 (toll-free)
    Fax: 866-942-7651 (toll-free)
    Email: info@cipo.ca
  • Immune Deficiency Foundation (IDF)
    40 West Chesapeake Avenue
    Suite 308
    Towson MD 21204
    Phone: 800-296-4433 (toll-free)
    Email: idf@primaryimmune.org
  • Jeffrey Modell Foundation/National Primary Immunodeficiency Resource Center
    747 Third Avenue
    New York NY 10017
    Phone: 866-463-6474 (toll-free); 212-819-0200
    Fax: 212-764-4180
    Email: info@jmfworld.org
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    UFK, Hugstetter Strasse 55
    79106 Freiburg
    Germany
    Phone: 49-761-270-34450
    Email: registry@esid.org
  • Primary Immunodeficiency Diseases Registry at USIDNET
    40 West Chesapeake Avenue
    Suite 308
    Towson MD 21204-4803
    Phone: 866-939-7568
    Fax: 410-321-0293
    Email: contact@usidnet.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table B. OMIM Entries for Autoimmune Lymphoproliferative Syndrome (View All in OMIM)

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; ALPS2A

Molecular Genetic Pathogenesis

Autoimmune 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-of-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.

FAS

Gene structure. 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. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. 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 unlikely to have pathologic effects on FAS expression.

Pathogenic allelic variants. To date, approximately 70 pathogenic 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 3 normal proteins) in only one out of eight, and an abnormal Fas trimer (in which at least 1 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.

FASLG

Gene structure. FASLG (FASL) spans approximately 8 kb and comprises four exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. No normal variants have been reported to date.

Pathogenic allelic variants. See Table 3. To date, only three pathogenic alleles have been reported in FASLG in association with an ALPS phenotype.

1.

Bi et al [2007] described p.Arg156Gly in a patient with ALPS and demonstrated that its protein interfered with apoptosis.

2.

A homozygous mutation, p.Ala247Glu, was found in an individual with ALPS who demonstrated both defective FasL-mediated apoptosis and defective Fas-dependent cytotoxic function [Del-Rey et al 2006].

3.

A heterozygous mutation leading to deletion of a single base pair, c.263delT, was identified in an individual with ALPS [Magerus-Chatinet et al 2013].

Several other variants in FASLG have been reported in association with other autoimmune phenotypes.

Table 3. Selected FASLG Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.263delTp.Phe88SerfsTer8NM_000639​.1
NP_000630​.1
c.466A>G
(530A>G)
p.Arg156Gly
c.740C>Ap.Ala247Glu

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal 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. 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].

CASP10

Gene structure. CASP10 comprises 11 exons and spans approximately 48 kb [Hadano et al 2001]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. 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.

Pathogenic allelic variants. See Table 4. To date, four CASP10 mutations have been reported in individuals with ALPS [Wang et al 1999, Zhu et al 2006, Cerutti et al 2007]. 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]. Cerutti et al [2007] described two patients who demonstrated coinheritance of both a FAS and a CASP10 mutation. FAS expression and CASP10 activity were decreased in both patients. Additionally, a common variant of CASP10 (p.Thr446Cys) originally thought to be benign [Wang et al 1999] has been associated with ALPS [Zhu et al 2006].

The other two 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 Val367Ile mutation [Wang et al 1999] has subsequently been deemed not be associated with ALPS-CASP10 [Zhu et al 2006].

Table 4. Selected CASP10 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
c.1337A>G 2
(1208A>G)
p.Tyr446CysNM_032977​.3
NP_116759​.2
c.853C>T
(724C>T)
p.Leu285Phe
(Leu242Phe)
c.1216A>C
(1087A>C)
p.Ile406Leu
(Ile363Leu)

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Zhu et al [2006]

Normal 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 mutation results 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.

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Suggested Reading

  1. Chronic lymphoproliferative diseases. Atlas of Genetics and Cytogenetics in Oncology and Haematology. Available online. 2000. Accessed 9-1-11.
  2. Dianzani U, Ramenghi U. Autoimmune lymphoproliferative syndrome. Atlas of Genetics and Cytogenetics Oncology and Haematology. Available online. 2006. Accessed 4-13-12.
  3. Hsu AP, Dowdell KC, Davis J, Niemela JE, Anderson SM, Shaw PA, Rao VK, Puck JM. Autoimmune lymphoproliferative syndrome due to FAS mutations outside the signal-transducing death domain: molecular mechanisms and clinical penetrance. Genet Med. 2012;14:81–9. [PubMed: 22237435]
  4. Janić MD, Brasanac CD, Janković JS, Dokmanović BL, Krstovski RN, Kraguljac Kurtović JN. Rapid regression of lymphadenopathy upon rapamycin treatment in a child with autoimmune lymphoproliferative syndrome. Pediatr Blood Cancer. 2009;53:1117–9. [PubMed: 19588524]
  5. Wang L, Yang JK, Kabaleeswaran V, Rice AJ, Cruz AC, Park AY, Yin Q, Damko E, Jang SB, Raunser S, Robinson CV, Siegel RM, Walz T, Wu H. The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations. Nat Struct Mol Biol. 2010;17:1324–9. [PMC free article: PMC2988912] [PubMed: 20935634]

Chapter Notes

Revision History

  • 11 September 2014 (me) Comprehensive update posted live
  • 8 September 2011 (me) Comprehensive update posted live
  • 7 April 2009 (me) Comprehensive update posted live
  • 9 July 2007 (cd) Revision: sequence analysis and prenatal diagnosis available clinically for CASP10
  • 14 September 2006 (me) Review posted to live Web site
  • 2 December 2005 (jj) Original submission
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