Clinical Diagnosis

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.

Recently, a revised set of diagnostic criteria were proposed [Oliveira et al 2010]:

• A definitive diagnosis of ALPS is based on the presence of both required criteria and one primary accessory criterion below.
• A probable diagnosis is based on the presence of both required criteria plus one secondary accessory criterion.

Required 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 plasma soluble FASL levels or elevated plasma interleukin-10 levels or elevated serum vitamin B₁₂ levels or elevated plasma interleukin-18 levels
• Typical immunohistologic findings as determined by an experienced hematopathologist,
• Autoimmune cytopenias with elevated (polyclonal) immunoglobulin G levels
• Positive family history

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

Testing

Although no specific laboratory abnormality alone is diagnostic of ALPS, the detection of the following facilitates the diagnosis [Bleesing 2003, Oliveira et al 2010]:

• Defective Fas-mediated apoptosis in 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.

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]:

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 (sIL-2Ralpha), CD27, CD30, and Fas ligand(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

Normal findings in ALPS

• Neutrophil function
• Complement 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-FASL).
• Antibody responses to protein antigens (e.g., diphtheria, tetanus)

Note: (1) The abnormal and normal laboratory findings listed have been most reliably established for individuals with ALPS caused by either germline or somatic mutations in FAS. (2) Cell surface expression of Fas (CD95) can be normal, increased, or decreased and is in general not helpful in the diagnosis of ALPS. (3) When interpreting laboratory data of individuals with (suspected) ALPS, the influence of concurrent immunosuppressive agents at the time of testing needs to be considered.

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 FAS detects approximately 90% of all reported FAS mutations [NHGRI ALPS Database].
• FASLG. The mutation detection rate for sequence analysis of the entire coding region is not known. Only a few mutations in FASLG have been reported.
• CASP10. The mutation detection rate for sequence analysis of the entire coding region is not known. CASP10 mutations have been reported in only two families, one of which was later found to have another mutation in TNFRSF1A, consistent with a diagnosis of TNF receptor-associated periodic syndrome.
• In two recently described patients, ALPS was presumed to result from co-inherited mutations in FAS and CASP10 that were hypothesized to cooperate in causing ALPS [Cerutti et al 2007].
• Detection of FAS somatic mutations requires specialized genetic testing of α/β-DNT cells sorted by either flow cytometric immunophenotyping or by magnetic bead immunophenotyping.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband. A recently proposed algorithm for diagnostic workup for patients with suspected ALPS based on the presence of required and accessory criteria is outlined in the revised diagnostic criteria for ALPS [Oliveira et al 2010]. The key components of this algorithm (keeping in mind that the presence of chronic non-malignant lymphoproliferation and α/β-DNT cells has already been established) are:

• Identification of a germline FAS mutation in unsorted cells;
• Measurement of plasma or serum biomarkers (interleukin-10, soluble FasL, vitamin B₁₂);
• Identification of a somatic FAS mutation in sorted α/β-DNT cells;
• Identification of a germline mutation in FASLG or CASP10 and defective Fas-mediated apoptosis in vitro.

The proposed algorithm recommends the following:

1.

Sequence analysis to determine presence of germline FAS mutation(s) in unsorted cells. If present, the diagnosis of ALPS is established and classified as ALPS-FAS.

2.

In the absence of a germline FAS mutation(s): determine if biomarkers (as listed above) are elevated. If so, obtain sorted α/β-DNT cells to assess somatic mutation in FAS. If present, the diagnosis of ALPS is established and classified as ALPS-sFAS.

Note: absence of a positive family history is suggestive of ALPS-sFAS as well.

3.

If neither a germline nor a somatic FAS mutation is identified, consider sequence analysis of CASP10 and FASLG.

Note: The presence of elevated biomarkers has not reliably been established in these ALPS genotypes.

4.

If germline mutations in either CASP10 or FASLG have been identified, the diagnosis of ALPS is established and classified as ALPS-CASP10 or ALPS-FASLG, respectively.

5.

If germline mutations in CASP10 or FASLG are not identified, perform Fas-mediated apoptosis assay (repeat if necessary, noting the influence of concomitant immunosuppressive therapy). If abnormal, the diagnosis of ALPS is established and classified as ALPS-U.

6.

If Fas-mediated apoptosis assay is normal, consider somatic mutations in CASP10 or FASLG (using previously sorted DNTCs), or consider an alternative diagnosis.

Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

FAS. No phenotype other than ALPS is known to be associated with germline or somatic mutations in FAS.

FASLG, CASP10. Because only a few individuals with mutations in FASLG and CASP10 have been reported, it is currently unknown whether clinical phenotypes other than ALPS may be associated with mutations in these two genes; however, this possibility is considered unlikely.

Natural 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.

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 only with mutations affecting the intracellular domains of Fas, though independent confirmation is required [Straus et al 2001].

Despite this similar clinical phenotype, in vitro Fas-mediated apoptosis is less defective in individuals with mutations affecting extracellular domains than in those with mutations affecting intracellular domains [Bleesing et al 2001b].

In the majority of affected individuals, heterozygous FAS mutations are associated with ALPS-FAS by the mechanism of dominant-negative interference; however, with certain mutations affecting extracellular domain, the mechanism is haploinsufficiency. In the latter case, the ALPS clinical phenotype may be less severe, linked to less defective in vitro apoptosis [Kuehn et al 2011]. (For further discussion see Molecular Genetic Pathogenesis.)

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

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 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 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; however, further study and independent confirmation are needed [Rieux-Laucat et al 1999, Le Deist 2004]. 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 has been estimated at 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 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.

Anticipation

Anticipation has not been documented in ALPS.

Nomenclature

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 predilection of race or ethnicity.

Evaluations Following Initial Diagnosis

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 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

Treatment of Manifestations

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 typically can be suppressed with the use of immunosuppressive agents including corticosteroids, cyclosporine, sirolimus tacrolimus, and mycophenolate mofetil. The benefits of immunosuppression, however, are balanced by the side effects, as well as the need to monitor drug levels. Moreover, it has become clear that lymphadenopathy, as well as organomegaly, invariably return once immunosuppression is discontinued [Bleesing 2003]. Thus, one approach is to use immunosuppressive therapy only for severe complications of lymphoproliferation (e.g., airway obstruction) and/or autoimmune manifestations.

Early experience with sirolimus suggests that this agent may affect lymphoproliferation in a more sustained manner [Teachey et al 2009].

In severe cases, more potent – lymphodepleting – agents may be required to sufficiently control lymphoproliferative manifestations. Agents include cyclophosphamide, antithymocyte globulin (ATG) and select monoclonal antibodies such as alemtuzumab (Campath^®).

Autoimmune manifestations typically respond to short courses of immunosuppressive agents.

• Mycophenolate mofetil cyclosporine, tacrolimus, and sirolimus are effective in chronic recalcitrant autoimmune cytopenias and may spare steroid usage [Rao et al 2005, Teachey et al 2009].
• Rituximab has been used successfully in the treatment of refractory cytopenias in ALPS, although it remains to be seen how long affected individuals remain in clinical remission [Wei & Cowie 2007, Rao et al 2009].

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

Prevention of Primary 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. 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 et al 2006].

Agents/Circumstances to Avoid

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 for infections [Author, unpublished observation, Price et al 2010].

The use of over-the-counter medications such as aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) should be discussed with a physician as some of these medications can interfere with platelet function.

Evaluation of Relatives at 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.

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.

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).

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.

Mode of Inheritance

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

ALPS-FAS caused by biallelic mutations is inherited in an autosomal recessive manner.

Risk to Family Members —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. The proportion of cases caused by somatic mosaicism is currently unknown.
• A proband with ALPS-FAS, ALPS-FASLG, or ALPS-CASP10 may have the disorder as the result of a new 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 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 Resulting from Biallelic Mutations

Parents of a proband

• The parents of a child with ALPS -FAS resulting from biallelic mutations are likely to be heterozygotes, in which case each would have one FAS mutant allele.
• 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 resulting from biallelic mutations 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 phenotype; a 50% chance of inheriting a single FAS mutation, which could result in clinical manifestations of ALPS-FAS; 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-FAS 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-FAS resulting from biallelic mutations 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 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation(s) have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

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 an option for some families in which the disease-causing mutation(s) have been identified.

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-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.

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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. 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]
4. Niemela JE, Lu L, Fleisher TA, Davis J, Caminha I, Natter M, Beer LA, Dowdell KC, Pittaluga S, Raffeld M, Rao VK, Oliveira JB. Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis. Blood. 2011;117:2883–6. [PMC free article: PMC3062298] [PubMed: 21079152]
5. Rensing-Ehl A, Warnatz K, Fuchs S, Schlesier M, Salzer U, Draeger R, Bondzio I, Joos Y, Janda A, Gomes M, Abinun M, Hambleton S, Cant A, Shackley F, Flood T, Waruiru C, Beutel K, Siepermann K, Dueckers G, Niehues T, Wiesel T, Schuster V, Seidel MG, Minkov M, Sirkiä K, Kopp MV, Korhonen M, Schwarz K, Ehl S, Speckmann C. Clinical and immunological overlap between autoimmune lymphoproliferative syndrome and common variable immunodeficiency. Clin Immunol. 2010;137:357–65. [PubMed: 20832369]
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Revision History

• 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