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GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. The diagnosis of ALPS is based on clinical findings, laboratory abnormalities including defective in vitro tumor necrosis factor receptor superfamily member 6 (Fas)-mediated apoptosis and T cells that express the alpha/beta T-cell receptor but lack both CD4 and CD8 (so-called α/β-DNT cells), and identification of mutations in genes relevant for the Fas pathway of apoptosis. Mutations in FAS (TNFRSF6) are associated with ALPS 0, ALPS Ia, and ALPS Ia-SM. Mutations in FASLG (FASL, TNFSF6) and CASP10 have been identified in a few individuals with ALPS. Molecular genetic testing of FAS, FASLG, and CASP10 is available clinically.
Management. Treatment of manifestations: Lymphoproliferation can be suppressed with corticosteroids, cyclosporine, tacrolimus, sirolimus, and mycophenolate mofetil. Because lymphadenopathy and organomegaly invariably return once these agents are discontinued, one approach is to use immunosuppressive therapy only for severe complications of lymphoproliferation (e.g., airway obstruction) and/or autoimmune manifestations. Lymphoma is treated with conventional protocols. 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 0. Prevention of secondary complications: Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) should be used with caution as they can interfere with platelet function. 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 because it typically does not lead to permanent remission of autoimmunity and may be associated with increased risk of infections. Testing 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 early diagnosis and treatment.
Genetic counseling. ALPS Ia is inherited in an autosomal dominant manner. Most individuals diagnosed with ALPS Ia have a parent with a FAS mutation; the proportion of ALPS Ia caused by either somatic mosaicism or de novo mutations is currently unknown. Each child of an individual with ALPS Ia has a 50% chance of inheriting the FAS mutation. ALPS 0 is thought to be the consequence of homozygous (or compound heterozygous) FAS mutations. The parents of a child with ALPS 0 are likely to be heterozygotes and, in that case, would have one FAS mutant allele. Prenatal diagnosis for pregnancies at increased risk for a FAS, FASLG, or CASP10 mutation is possible if the disease-causing mutation(s) has/have been identified in an affected family member.
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 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
Although no specific laboratory abnormality alone is diagnostic of ALPS, the detection of the following facilitates the diagnosis [Bleesing 2003]:
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.
Note: The finding of α/β-DNT cells in individuals with clinical evidence of ALPS and somatic mutations in FAS who did not display defective in vitro Fas-mediated apoptosis suggests that the presence of α/β-DNT cells is the only consistent laboratory finding shared by individuals with ALPS [Rössler et al 2005].
[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]
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 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, CD27, CD30, and tumor necrosis factor ligand superfamily member 6 (Fas ligand, or FasL)
Monoclonal gammopathy
Decreased antibody responses to polysaccharide antigens
Chemistry
Liver function abnormalities (in case of autoimmune hepatitis)
Proteinuria (in case of glomerulonephritis)
Elevated serum concentration of vitamin B12
Neutrophil function
Complement concentrations and function
In vitro proliferative responses of T-cells (e.g., in response to common mitogens or antigens)
NK-cell and cytotoxic T-lymphocyte (CTL) function; possibly decreased CTL activity in ALPS on the basis of defective FasL (i.e., ALPS Ib)
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 mutations in FAS (ALPS Ia). (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.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genes. Germline mutations in the three following genes are known to be associated with ALPS. Additionally, somatic mutations in FAS in selected cell populations, including α/β-DNT cells, produce a phenotype similar to that caused by FAS germline mutations.
FAS (TNFRSF6)
ALPS 0 is associated with homozygous (or rarely compound heterozygous germline mutations) in FAS [Rieux-Laucat et al 1995, Kasahara et al 1998, van der Burg et al 2000].
ALPS Ia is associated with heterozygous FAS germline mutations; it accounts for approximately 75% of individuals with ALPS [Bleesing 2003, Rieux-Laucat et al 2003].
ALPS Ia-SM. Somatic mutations in selected cell populations, including α/β-DNT cells, have been identified in individuals with ALPS with a phenotype similar to that caused by FAS heterozygous germline mutations [Holzelova et al 2004, Rössler et al 2005].
FASLG (FASL, TNFSF6)
ALPS Ib is associated with germline mutations in FASLG, the gene encoding tumor necrosis factor ligand superfamily member 6 (FasL). Four affected individuals have been reported to date [Wu et al 1996, CIS 1999, Del-Rey et al 2006, Bi et al 2007].
CASP10
ALPS II is associated with mutations in CASP10 (the gene encoding caspase-10) [Wang et al 1999]. Of the two affected individuals originally reported in 1999, the reported homozygous CASP10 alteration was determined subsequently not be to causal of ALPS. In a recent study, two of 32 probands with ALPS had heterozygous missense mutations in CASP10 [Zhu et al 2006].
Other loci. Approximately 20%-25% of individuals with ALPS currently lack a genetic diagnosis. They are classified as having one of the following:
ALPS III if no mutations are detected in FAS, FASLG, or CASP10
ALPS non-Ia if only FAS mutations have been ruled out [Dianzani et al 1997, Ramenghi et al 2000, Hundt et al 2002, van der Werff Ten Bosch et al 2002, Bleesing 2003]
Note: (1) Depending on the criteria used to define ALPS (e.g., with regard to presence of α/β-DNT cells, or demonstration of defective Fas-mediated apoptosis), defects in other genes or gene products inside or outside the Fas/FasL pathway may be associated with ALPS features. This includes the CASP8 gene encoding caspase-8 and the gene encoding N-RAS [Chun et al 2002, Oliveira et al 2007]. No independently confirmed and published information has associated other Fas pathway-related genes with ALPS. (2) In two recently described patients, ALPS was presumed to be the result of co-inherited mutations in FAS and CASP10 that were hypothesized to cooperate in causing ALPS [Cerutti et al 2007]. (3) Thus far, only somatic mutations in FAS have been described, although it is possible that somatic mutations in FASLG and CASP10 exist.
Clinical testing
FAS. FAS germline mutations have been identified throughout the entire coding region and exon/intron boundaries. Sequencing of the entire coding region and intron/exon boundaries of the FAS gene detects approximately 90% of all reported mutations [NHGRI ALPS Database].
FASLG. Sequence analysis of the entire coding region of the FASLG gene is available clinically. The mutation detection rate is not known. Only a few mutations in the FASLG gene have been reported.
CASP10. Sequence analysis of the entire coding region of the CASP10 gene is available clinically. The mutation detection rate is not known. Furthermore, CASP10 mutations have been reported in only two families; one was later found to have another mutation in the TNFRSF1A gene, consistent with a diagnosis of TNF receptor-associated periodic syndrome.
Research testing
Detection of FAS somatic mutations requires specialized genetic testing of α/β-DNT cells sorted by flow cytometric immunophenotyping. Currently, such testing is not routinely available.
| Gene Symbol | Proportion of ALPS Attributed to Mutations in This Gene | Test Method | ALPS Type | Mutation Detection Frequency by Gene and Test Method | Test Availability |
|---|---|---|---|---|---|
| FAS | 75% | Sequence analysis | ALPS Ia | 90% | Clinical
 |
| FASLG | 1% | ALPS Ib | Unknown | Clinical
| |
| CASP10 | 2% | ALPS II | Unknown | Clinical
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Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Confirming the diagnosis in a proband
Confirm the presence of chronic non-malignant lymphoproliferation.
Identify the presence of T cells that express the alpha/beta T-cell receptor but lack both CD4 and CD8 (alpha/beta double-negative T cells [α/β-DNT cells]) in peripheral blood or tissue specimens.
Identify defective Fas-mediated apoptosis in vitro.
Perform molecular genetic testing of FAS.
If chronic non-malignant lymphoproliferation and α/β-DNT cells are present, defective Fas-mediated apoptosis in vitro is absent, and a germline mutation in FAS is not detectable, consider the possibility of a somatic mutation in FAS.
If a mutation in FAS is not identified, consider molecular genetic testing of FASLG and CASP10.
Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.
FAS. No phenotype other than ALPS is known to be associated with germline or somatic mutations in FAS.
FASLG, CASP10. Only a few individuals with mutations in FASLG and CASP10 have been reported; thus, it is currently unknown whether clinical phenotypes other than ALPS may be associated with mutations in FASLG or CASP10.
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.
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
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 failure
Hydrops fetalis
Organic brain syndrome (mental status changes, seizures, headaches)
Much remains to be learned about the natural history and prognosis of ALPS. While non-malignant lymphoproliferative manifestations often regress or improve over time, autoimmunity shows no permanent remission with advancing age. Moreover, the risk for development of lymphoma likely appears to be lifelong. Thus, in the absence of curative treatment, the overall prognosis for ALPS remains guarded, necessitating long-term clinical studies to better understand its natural history [Rieux-Laucat et al 1999, Bleesing 2003, Rieux-Laucat et al 2003].
ALPS Ia. ALPS Ia is the most common and best characterized type of ALPS. The following are the main consequences of perturbed lymphocyte homeostasis in ALPS Ia:
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 Ia, 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].
For many individuals with ALPS Ia, lymphadenopathy tends to decrease early in the second decade, while 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, reflecting activation of other (intact) apoptosis pathways.
The overall prognosis of lymphoproliferation is relatively good and few individuals require long-term treatment with immunosuppressive agents to control lymphoproliferation [Bleesing 2003, Rieux-Laucat et al 2003].
Laboratory findings of lymphoproliferation are the expansion of most lymphocyte subsets including the pathognomonic α/β-DNT cells as well as other T- and B-cell subsets.
Autoimmunity, a common feature of ALPS, is often not present at the time of diagnosis or at the time of the most extensive lymphoproliferation. The reason for the delay in onset is unclear but may be related to age-dependent acquisition of secondary pathogenic factors that interact with defective Fas-mediated apoptosis. In many individuals with ALPS, autoantibodies can be detected years before the appearance of clinical manifestations of autoimmune disease [Bleesing 2003, Rieux-Laucat et al 2003].
Although autoimmune manifestations can also wax and wane, current knowledge suggests that autoimmune disease poses a lifelong burden.
Autoimmunity most often involves combinations of Coombs-positive hemolytic anemia and immune thrombocytopenia (together referred to as Evans syndrome); autoimmune neutropenia is less common. The observation of primary lymphopenia, contrasting with the typical presence of lymphocytosis, suggests the possibility of autoimmune lymphopenia (as seen in other autoimmune diseases).
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) genes [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 Ia are at an increased risk for both Hodgkin and non-Hodgkin lymphoma, underscoring the role of Fas as a tumor-suppressor gene. Based on calculations in one study, the increased risk is 14-fold and 51-fold for non-Hodgkin and Hodgkin lymphoma, respectively [Straus et al 2001].
Lymphoma can originate from B and T cells and does not appear to be related to EBV infection (based on absence of EBV in tumor biopsies).
Current experience suggests that lymphomas can occur at any age in ALPS Ia 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 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 Muschen et al [2002], Houston & O'Connell [2004], Poppema et al [2004], and Peter et al [2005].
ALPS 0
Chronic non-malignant lymphoproliferation. Individuals with homozygous or compound heterozygous FAS mutations often present with severe lymphoproliferation before, at, or shortly after birth [Rieux-Laucat et al 1995, Le Deist et al 1996, Kasahara et al 1998, van der Burg et al 2000].
Autoimmunity. In several individuals reported, the delay between onset of autoimmunity and lymphoproliferation was minimal, while in others this was not the case. The rarity of and poor prognosis in ALPS 0 make it difficult to draw firm conclusions regarding autoimmunity in this type of ALPS [Rieux-Laucat et al 1995, Le Deist et al 1996, Kasahara et al 1998, van der Burg et al 2000].
Lymphoma. Because of the severity of ALPS 0, affected individuals typically succumb to lymphoproliferation and/or autoimmunity at an early age.
ALPS Ia-SM (provisional classification). Somatic FAS mutations in selected cell populations, notably the α/β-DNT cells, have been identified in individuals with ALPS. The clinical phenotype is similar to that caused by FAS germline mutations. The population of α/β-DNT cells is expanded; however, as a consequence of technical aspects of the assay, Fas-mediated apoptosis of lymphocytes in vitro is not defective [Holzelova et al 2004, Rössler et al 2005].
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. Fas also appears to play a role in suppression of malignant transformation of lymphocytes, although it remains to be firmly established whether this involves the Fas/FasL pathway in a similar way.
ALPS Ia. 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 phenotype of ALPS, as far as lymphoproliferation and autoimmunity are concerned. Lymphomas, in contrast, seem thus far to be associated only with mutations affecting the intracellular domains of Fas, though independent confirmation is required [Straus et al 2001].
Despite this similar clinical phenotype, in vitro Fas-mediated apoptosis is less defective in individuals with mutations affecting extracellular domains than in those with mutations affecting intracellular domains [Bleesing et al 2001b].
In the majority of affected individuals, heterozygous FAS mutations are associated with ALPS I by the mechanism of dominant negative interference; however, with certain mutations affecting extracellular domain, the mechanism is presumed to be haploinsufficiency. In these cases, it is possible that the ALPS clinical phenotype is less severe. (For further discussion see Molecular Genetic Pathogenesis.)
ALPS Ib and ALPS II. Genotype-phenotype correlations are not established for FASLG and CASP10 mutations.
ALPS Ia. 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 show 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 symptoms 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, but it appears that penetrance is determined by the location and type of mutation; however, further study and independent confirmation are needed [Rieux-Laucat et al 1999, Le Deist & Fischer 2001]. The highest penetrance (70%-90%) for the clinical phenotype occurs with missense mutations affecting the intracellular domains, followed by mutations leading to truncation of the intracellular domains [Jackson et al 1999]. The penetrance for the clinical phenotype with extracellular mutations is approximately 30%.
The reduced penetrance for ALPS in some families suggests that one or more additional pathogenic factors interact with defective Fas-mediated apoptosis. On the other hand, 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) cast doubt on that assumption by 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 & Fischer 2001].
Anticipation has not been documented in ALPS.
The prevalence of ALPS is unknown. It is a rare condition with a worldwide distribution and no predilection of race or ethnicity. It is likely as rare as other primary immunodeficiency disorders that cause disease in a heterozygous state.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
The main considerations in the differential diagnosis for autoimmune lymphoproliferative syndrome (ALPS) are other immunodeficiency disorders characterized or complicated by lymphoproliferation, autoimmune disease, and lymphoma. These include the following:
Common variable immunodeficiency disease (CVID) has an estimated incidence of one in 50,000 and occurs equally in males and females. Symptoms include recurrent infections (especially of the respiratory tract) at any age. The genetic etiology of most CVID is currently unknown. From a clinical and immunologic standpoint, CVID can be roughly classified into two groups, depending on the presence or absence of mature B cells in peripheral blood. Individuals with CVID with B cells (but absent or decreased memory B cells) are at an increased risk for autoimmune disease that often targets blood cells and for chronic lymphoproliferation including lymphadenopathy, splenomegaly, and lymphoma [Warnatz et al 2002, Piqueras et al 2003]. CVID with present B cells should be regarded in the differential diagnosis of ALPS, while the variant characterized by low or absent B cells and generally low serum concentrations of immunoglobulins should not.
The overlap between ALPS and CVID is also illustrated by the report of two individuals with CVID who were found to have heterozygous mutations in CASP8 [Chun et al 2002].
Hyper IgM (HIGM) syndrome. Several non-X-linked forms of hyper IgM syndrome have now been identified. In varying degrees, they share features with the X-linked form (see X-Linked Hyper IgM Syndrome), caused by mutations in TNFSF5 (CD40L) [Winkelstein et al 2003]. Shared features include recurrent bacterial infections such as otitis media, sinusitis, and pneumonias. Autoimmune hematologic disorders including neutropenia, thrombocytopenia, and hemolytic anemia are also found. Other complications may include lymphomas and other malignancies as well as gastrointestinal complications. Serum concentration of IgM is elevated while other immunoglobulin levels are normal; specific antibody responses are defective. In contrast to HIGM1, T-cell function in ALPS is typically within normal limits, reflected in an absence of opportunistic infections.
HIGM2 is caused by mutations in the gene 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 syndrome (XLP) is associated with an inappropriate immune response to Epstein-Barr virus (EBV) infection resulting in unusually severe and often fatal infectious mononucleosis; dysgammaglobulinemia; and/or lymphoproliferative disorders, typically of B-cell origin. Clinical manifestations of XLP vary, even among affected family members. The most common presentation is a near-fatal or fatal EBV infection associated with an unregulated and exaggerated immune response with widespread proliferation of cytotoxic T cells, EBV-infected B cells, and macrophages. Mortality is greater than 90%. In approximately one-third of males with XLP, hypogammaglobulinemia of one or more immunoglobulin subclasses is diagnosed prior to EBV infection or in rare survivors of EBV infection. The prognosis for males with this phenotype is more favorable if they are managed with regular intravenous immune globulin (IVIG). Lymphomas or other lymphoproliferative disease occur in approximately one-third of males with XLP, some of whom have hypogammaglobulinemia or have survived an initial EBV infection. The lymphomas seen in individuals with XLP are typically high-grade B-cell lymphomas, non-Hodgkin type, often extranodal, and particularly involving the intestine. Allogeneic bone marrow transplantation (BMT) is the only curative therapy for XLP. Average life expectancy without curative BMT has been estimated at less than ten years. XLP is caused by hemizygous mutations in SH2D1A.
Wiskott-Aldrich syndrome (WAS) typically manifests in infancy with thrombocytopenia, eczema, and recurrent bacterial and viral infections, particularly recurrent ear infections. At least 40% of males who survive the early complications develop one or more autoimmune conditions such as hemolytic anemia, immune thrombocytopenic purpura (ITP), immune-mediated neutropenia, arthritis, vasculitis of small and large vessels, and immune-mediated kidney and liver disease. Individuals with WAS, particularly those who have been exposed to EBV, have an increased risk of developing lymphomas, which often occur in unusual, extranodal locations such as the brain, lung, or gastrointestinal tract. Inheritance is X-linked.
Lymphoma without other manifestations of ALPS has been observed in families with ALPS Ia. 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].
To determine the presence and extent of lymphoproliferation and/or autoimmunity in an individual diagnosed with autoimmune lymphoproliferative syndrome (ALPS), the following evaluations are recommended:
Complete blood counts and flow cytometric immunophenotyping of lymphocytes, especially with regard to α/β-DNT cells, in combination with physical examination and imaging studies to assess lymphadenopathy and hepatosplenomegaly
Complete blood counts and measurement of autoantibodies (see Testing) 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
In the absence of curative treatment, current management is focused on the control and/or treatment of manifestations of lymphoproliferation and/or autoimmunity and the treatment of lymphoma [Rieux-Laucat et al 1999, Van Der Werff Ten Bosch et al 2001, van der Werff Ten Bosch et al 2002, Bleesing 2003, Rieux-Laucat et al 2003, Rao et al 2005].
Manifestations of lymphoproliferation can be suppressed with the use of immunosuppressive agents, such as corticosteroids, cyclosporine, sirolimus tacrolimus, and mycophenolate mofetil. The benefits of immunosuppression, however, are balanced by the side effects, as well as the need to monitor drug levels. Moreover, it has become clear that lymphadenopathy, as well as organomegaly, invariably return once immunosuppression is discontinued [Bleesing 2003]. Thus, one approach is to use immunosuppressive therapy only for severe complications of lymphoproliferation (e.g., airway obstruction) and/or autoimmune manifestations.
Autoimmune manifestations typically respond to short courses of immunosuppressive agents.
Mycophenolate mofetil cyclosporine, tacrolimus and sirolimus are effective in chronic recalcitrant autoimmune cytopenias and may spare steroid usage [Rao et al 2005, Teachey et al 2009].
Rituximab has been used successfully in the treatment of refractory cytopenias in ALPS, although it remains to be seen how long affected individuals remain in clinical remission [Wei & Cowie 2007].
Lymphoma is treated according to conventional protocols. The presence of defective Fas-mediated apoptosis does not appear to hinder the response to chemotherapeutic agents or radiation.
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 (ALPS 0). It is likely, however, that individuals with undiagnosed forms of ALPS, including ALPS Ia, 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].
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 et al 2006].
Splenectomy to control autoimmune cytopenias is discouraged because it typically does not lead to permanent remission of autoimmunity and may be associated with an increased risk of infections [Author, unpublished observation].
The use of over-the-counter medications such as aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) should be discussed with a physician as some of these medications can interfere with platelet function.
It is appropriate to perform molecular genetic testing on relatives at risk for ALPS Ia or ALPS II 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 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.
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.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
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).
Mode of delivery. 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 0 could pose a risk of increased bleeding in the neonate.
Gene therapy. No studies regarding gene therapy to treat ALPS Ia are ongoing; the highly regulated expression and activity of Fas pose substantial difficulties for gene therapy.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
ALPS Ia, ALPS Ib, and ALPS II are generally inherited in an autosomal dominant manner.
ALPS 0 is thought to be the consequence of homozygous (or compound heterozygous) mutations.
Parents of a proband
Most individuals diagnosed with ALPS Ia 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 symptoms of ALPS (see Penetrance).
Insufficient cases of ALPS Ib and II are available to determine risks to family members.
A proband with ALPS Ia, Ib, or II may have the disorder as the result of somatic mosaicism. The proportion of cases caused by somatic mosaicism is currently unknown.
A proband with ALPS Ia, Ib, or II may have the disorder as the result of a new gene mutation. However, the proportion of cases caused by de novo mutations is largely unknown.
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 mutational 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 Ia, Ib, or II has a 50% chance of inheriting the FAS, FASLG, or CASP10 mutation. The risk of that child developing ALPS-related complications is dependent 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 is found to have 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.
Note: Mutations in FASLG and CASP10 are also associated with ALPS (types Ib and II, respectively). Both are likely disease-causing in the heterozygous state. No additional information (i.e., penetrance, mutation rate, clinical variability) useful for genetic counseling purposes is currently available.
Parents of a proband
The parents of a child with ALPS 0 are likely to be heterozygotes, in which case each would have one FAS mutant allele.
Heterozygotes may present with ALPS-related symptoms or may be clinically asymptomatic.
Sibs of a proband
At conception, each sib of a child with ALPS 0 has an overall 75% chance of having one or two FAS mutations; a 25% chance of inheriting two FAS mutations, which would most likely result in a severe ALPS 0 phenotype; a 50% chance of inheriting a single FAS mutation, which could result in clinical manifestations of ALPS Ia or II; and a 25% chance of inheriting one normal FAS allele from each parent and having no clinical manifestations of ALPS.
Once an at-risk sib is known to be unaffected with ALPS 0, 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 0 are more likely to die at an early age and thus are not likely to reproduce.
Other family members of a proband. If a parent of the proband has a FAS mutation, his/her sibs are at 50% risk of having the mutation.
See Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.
Testing at-risk asymptomatic family members. Testing of at-risk asymptomatic family members for FAS, FASLG, or CASP10 mutations is available once the disease-causing mutation(s) is (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 of being affected.
DNA banking. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies at increased risk for a FAS, FASLG, or CASP10 mutation is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele(s) of an affected family member must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation(s) has/have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| 134637 | TUMOR NECROSIS FACTOR RECEPTOR SUPERFAMILY, MEMBER 6; TNFRSF6 |
| 134638 | TUMOR NECROSIS FACTOR LIGAND SUPERFAMILY, MEMBER 6; TNFSF6 |
| 601762 | CASPASE 10, APOPTOSIS-RELATED CYSTEINE PROTEASE; CASP10 |
| 601859 | AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; ALPS |
| 603909 | AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IIA; ALPS2A |
For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
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-in-function mutation in the gene encoding N-RAS [Oliveira et al 2007].
Finally, the genetic background may operate at the level of genes that encode regulators of other aspects of lymphocyte function and survival. The presence of clinical manifestations of ALPS at birth makes environmental influences less likely; the occurrence of murine ALPS in Fas-mutant mice kept in a germ-free environment is consistent with this assumption.
The discovery of individuals with ALPS with somatic mutations in FAS may offer new insights as the presence of mutations in some, but not all, lymphocyte subsets could allow dissection of the molecular mechanisms of ALPS in a manner that cannot be achieved in individuals with germline mutations in FAS.
Normal allelic variants. FAS consists of nine exons. Exons 1 and 2 encode a signal sequence that, upon trafficking of the Fas protein to the cell surface, is cleaved off. Exons 3, 4 and 5 encode three extracellular cysteine-rich domains (CRD). Exon 6 encodes the transmembrane domain (TM). The intracellular domains of Fas are encoded by exons 7-9, with exon 9 representing the death domain (DD) that interacts with the intracellular, apoptosis-inducing signal transduction pathway [Jackson et al 1999].
Genomic DNA of FAS spans approximately 25 kb. To date, at least eight alternatively spliced transcript variants encoding seven distinct normal allele variants have been observed. These have been documented by biochemical and functional testing in vivo and are highly unlikely to have pathologic effects on FAS expression.
Pathologic allelic variants. To date, approximately 70 pathologic variants have been identified. Mutations have been found throughout the entire coding region and exon/intron boundaries. These allele variants would lead to the absence of functional proteins or result in truncated proteins.
Most of the (reported) FAS mutations affect the intracellular domains of Fas, with approximately 60% of those located in the death domain. Mutations include missense mutations, nonsense mutations, splicing defects, small deletions/insertions, gross deletions and complex deletion/duplications.
Normal gene product. The FAS gene 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 Ia. Because Fas and FasL form homotrimers, the contribution of the mutant FAS allele versus the normal FAS allele to these trimers results in a normal Fas trimer (consisting of three normal proteins) in only one out of eight, and an abnormal Fas trimer (in which at least one of the proteins is mutated) in seven out of eight possible configurations, assuming equal amounts of mutant and wild type Fas protein [Fisher et al 1995, Jackson et al 1999]. Dominant negative interference by abnormal Fas chains has been demonstrated for mutations affecting the death domain as well as for other intracellular mutations [Jackson et al 1999, Martin et al 1999].
Extracellular heterozygous mutations affecting the FasL-binding domain (CRD2 and CRD3) are also associated with dominant negative interference because Fas proteins self-associate into trimers prior to FasL interaction. The result, as with intracellular mutations, is the assembly of faulty Fas trimers that dominantly interfere with Fas-mediated apoptosis in seven out of eight configurations [Siegel et al 2000]. For other extracellular heterozygous mutations, including mutations that affect the domain of the protein that regulates self-association into trimers, defective apoptosis can be explained by interference of truncated and/or soluble fragments of mutant Fas, or by haploinsufficiency, in which the total amount of Fas generated is below a threshold needed for physiologic induction of apoptosis [Roesler et al 2005].
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.
Normal allelic variants. FASLG (FASL) spans approximately 8 kb and comprises four exons. No normal allelic variants have been reported to date.
| DNA Nucleotide Change (Alias 1) | Protein Amino Acid Change (Alias 1) | Reference Sequences |
|---|---|---|
| c.-844T>C | None | NM_000639.1NP_000630.1 |
| c.472_555del | p.Met158_Glu185del (84-bp deletion) | |
| c.740C>A | p.Ala247Glu | |
| c. 466A>G (530A>G) | p.Arg156Gly |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).
1. Variant designation that does not conform to current naming 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. A study of peripheral blood mononuclear cells from the individual with the p.Met158_Glu185del revealed decreased FasL activity, decreased activation-induced cell death, and increased T-cell proliferation after activation [Wu et al 1996]. The individual with the homozygous missense mutation (p.Ala247Glu) showed decreased Fas-mediated cell death and Fas-dependent cytotoxicity [Del-Rey et al 2006]. Compared to controls, the c.-844T>C mutation resulted in increased expression of FasL in many types of human cancers including lung cancer [Zhang et al 2005]. The heterozygous p.Arg156Gly mutation affects the extracellular Fas-binding region of FASL. The mutation produces a dominant interfering FasL protein that binds to wild-type FasL, preventing Fas-mediated apoptosis [Bi et al 2007].
Note: The previously reported homozygous p.Val367Ile mutation [Wang et al 1999] has subsequently been deemed not be associated with ALPS II [Zhu et al 2006].
| Class of Variant Allele | DNA Nucleotide Change (Alias 1) | Protein Amino Acid Change (Alias 1) | Reference Sequences |
|---|---|---|---|
| Normal | c.1337A>G (1208A>G) | p.Tyr446Cys | NM_032977.3NP_116759.2 |
| Pathologic | c.853C>T (c.724C>T) | p.Leu285Phe (p.Leu242Phe) | |
| c.1216A>C (c.1087A>C) | p.Ile406Leu (p.Ile363Leu) | ||
| c.1228G>A (c.1099G>A) | p. Val410Ile (p. Val367Ile) |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).
1. Variant designation that does not conform to current naming conventions
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 and p.Val410Ile mutations result in decreased caspase activity and dominantly interfere with death receptor-induced apoptosis, particularly that stimulated by FasL and TRAIL. Wang et al [1999] and Shin et al [2002] expressed some CASP10 mutants in 293 cells and found that apoptosis was suppressed, possibly contributing to the pathogenesis of some human non-Hodgkin lymphomas.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
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
