Autoimmune Lymphoproliferative Syndrome

Clinical characteristics.

Autoimmune lymphoproliferative syndrome (ALPS), caused by defective lymphocyte homeostasis, is characterized by the following:

• Non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age
• Autoimmune disease, mostly directed toward blood cells
• 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 pathogenic variants 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; in many affected individuals, however, neither splenomegaly nor the overall expansion of lymphocyte subsets in peripheral blood decreases. 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.

In ALPS-FAS caused by homozygous or compound heterozygous (biallelic) pathogenic variants in FAS, severe lymphoproliferation occurs before, at, or shortly after birth, and usually results in death at an early age.

ALPS-sFAS, resulting from somatic FAS pathogenic variants 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 pathogenic variants in FAS, although lower incidence of splenectomy and lower lymphocyte counts have been reported in ALPS-sFAS and no cases of lymphoma have yet been published.

Diagnosis/testing.

The diagnosis of ALPS is based on the following:

• Clinical findings
• Laboratory abnormalities:
  • 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 pathogenic variants in genes relevant for the Fas pathway of apoptosis. These genes include FAS (either germline or somatic pathogenic variants), CASP10, and FASGL.
  Up to 20% of those with clinical ALPS have not had a genetic etiology identified.

Management.

Treatment of manifestations: Current management is focused on monitoring for and treatment of lymphoproliferation, hypersplensim, and lymphomas and management of cytopenias and other autoimmune diseases. Corticosteroids and immunosuppressive therapy do not decrease lymphadenopathy long term and are generally reserved for severe complications of lymphoproliferation (e.g., airway obstruction, significant hypersplenism associated with splenomegaly) and/or autoimmune manifestations. Experience with sirolimus suggests that it is the preferred agent in treating lymphoproliferation in a more sustained manner, including maintenance of remission following a period of discontinued use of sirolimus; however, sirolimus is not without side effects. Lymphoma is treated with conventional protocols. Autoimmune cytopenias and other autoimmune diseases are typically treated by immune suppression with corticosteroids as well as corticosteroid-sparing agents if prolonged treatment of autoimmune cytopenias is required and/or in cases of refractory cytopenias.

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 persons 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 pathogenic variants, those with severe and/or refractory autoimmune cytopenias, those with lymphoma, and those who have 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 and imaging and laboratory studies for manifestations of lymphoproliferation and autoimmunity; specialized imaging studies to detect malignant transformation.

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

Evaluation of relatives at risk: If the pathogenic variant(s) have 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, mycophenylate mofitil, or sirolimus during pregnancy must take into consideration the potential teratogenic risks to the fetus.

Genetic counseling.

Inheritance of ALPS-CASP10, most cases of ALPS-FAS, and some cases of ALPS-FASLG is autosomal dominant. Each child of an individual with autosomal dominant ALPS has a 50% chance of inheriting the pathogenic variant. Inheritance of most cases of ALPS-FASLG and severe ALPS associated with biallelic FAS pathogenic variants is autosomal recessive. The parents of an individual with autosomal recessive ALPS are likely to be heterozygotes, in which case each has one FAS pathogenic variant; these parents may have ALPS-related findings or may be clinically asymptomatic.

Prenatal testing for a pregnancy at increased risk is possible if the pathogenic variant(s) have been identified in an affected family member.

ALPS-FAS can also be the result of somatic mosaicism. Somatic pathogenic variants have not been reported in ALPS-FASLG or ALPS-CASP10 to date.

Suggestive Findings

The diagnosis of autoimmune lymphoproliferative syndrome (ALPS) is based on a constellation of clinical findings, laboratory abnormalities, and identification of pathogenic variants in genes relevant for the tumor necrosis factor receptor superfamily member 6 (Fas) pathway of apoptosis.

ALPS should be suspected in individuals with combinations of the following [Bleesing 2003, Rieux-Laucat et al 2003]:

• Chronic non-malignant lymphoproliferation
  • Chronic and/or recurrent lymphadenopathy
  • Splenomegaly with/without hypersplenism
  • Hepatomegaly
  • Lymphocytic interstitial pneumonia (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

The diagnosis of ALPS is established in a proband who meets the clinical diagnostic criteria, which may include identification of a heterozygous pathogenic variant or biallelic pathogenic variants in one of the genes listed in Table 1.

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 (see following).
• 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 variants in CASP10, FAS, or FASLG

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
• Positive family history

Molecular Genetic Testing

Molecular genetic testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Serial single-gene testing. Sequence analysis of the gene of interest is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.

• For this disorder, it is recommended that FAS be tested first. See Figure 1 for algorithm.
• In the absence of a germline FAS pathogenic variant, FAS sequencing in sorted α/β-DNT cells to detect somatic pathogenic variants should be performed. If present, the diagnosis of ALPS-sFAS is established.
• If neither a germline nor a somatic FAS pathogenic variant is identified, CASP10 and FASLG should be tested next. The detection of germline pathogenic variants in either CASP10 or FASLG establishes the diagnosis of ALPS-CASP10 or ALPS-FASLG, respectively.
• A Fas-mediated apoptosis assay should be performed if germline pathogenic variants in CASP10 or FASLG are not identified (repeat if necessary, noting the influence of concomitant immunosuppressive therapy). If abnormal, the diagnosis of ALPS-U is established.

Figure 1.

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

Notes: (1) Absence of a positive family history is suggestive of ALPS-sFAS. (2) Loss of heterozygosity of FAS pathogenic variants has been observed in blood cells. (3) FAS somatic pathogenic variants in selected cell populations, including α/β-DNT cells, produce a phenotype similar to that caused by FAS germline pathogenic variants. (4) The presence of elevated biomarkers has not been reliably established in CASP10 or FASLG-related ALPS. (5) Thus far, somatic pathogenic variants in FAS only have been reported to cause ALPS; however, it is theoretically possible that somatic pathogenic variants in CASP10 and FASLG may also be causative.

A multigene panel that includes CASP10, FAS, FASLG, and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in ALPS

Clinical Description

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. The clinical lymphoproliferative and autoimmune phenotype of ALPS is associated with pathogenic variants which affect any domain of Fas. Lymphomas, in contrast, seem thus far to be associated mostly with pathogenic variants affecting the intracellular domains of Fas, although independent confirmation is required [Straus et al 2001, Price et al 2014].

In the majority of affected individuals, heterozygous FAS pathogenic variants are associated with ALPS-FAS by the mechanism of dominant-negative interference; however, with certain pathogenic variants 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 Pathogenesis.)

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

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] pathogenic variant has defective apoptosis) whereas the penetrance for the clinical phenotype is reduced because a significant proportion of relatives heterozygous for the pathogenic variant have no clinical findings of ALPS. In addition, other relatives have laboratory findings 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 2001].

The factors that determine the penetrance of clinical ALPS are not entirely understood. Penetrance appears to be determined by the location and type of pathogenic variant [Rieux-Laucat et al 1999, Le Deist 2004]. In initial studies, the highest penetrance (70%-90%) for the clinical phenotype occurred with missense variants affecting the intracellular domains (ICD), followed by variants 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 pathogenic variants had a penetrance of 52% (higher than previous data) and ICD pathogenic variants had a 63% penetrance (lower than previously reported). The penetrance of missense variants 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 pathogenic variants (e.g., missense variants 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].

An observation that may shed more light on the issue of penetrance, particularly as it relates to pathogenic variants affecting intracellular vs 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 pathogenic variant 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 variant 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 variant with somatic loss of heterozygosity [Hauck et al 2013].

Disease penetrance differs between males and females. In the French cohort, the likelihood of a male with a heterozygous germline FAS pathogenic variant 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].

Anticipation

Anticipation has not been documented in ALPS.

Nomenclature

Table 2.

Revised Classification of ALPS

ALPS has also been referred to as Canale-Smith syndrome.

Prevalence

Nearly 500 patients with ALPS in more than 300 families have been reported worldwide with no racial or ethnic predilection. However, the true prevalence of ALPS is still unknown as many individuals are undiagnosed or misdiagnosed [Shah et al 2014].

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
• 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
• Measurement of autoantibodies to assess for autoimmunity
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

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

• Monitoring for and treatment of lymphoproliferation, hypersplensim, and lymphomas
• Management of cytopenias and other autoimmune diseases [Madkaikar et al 2011, Rao & Oliveira 2011, Teachey 2012]

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.
• Experience with sirolimus suggests that it is the preferred agent in treating lymphoproliferation in a more sustained manner, including for maintenance of remission after initial treatment followed by a period of discontinued use [Teachey et al 2009, Bride et al 2016]. 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 cytopenias and other autoimmune diseases

• Autoimmune cytopenias are typically treated by immune suppression with corticosteroids as well as corticosteroid-sparing agents, if prolonged treatment of autoimmune cytopenias is required and/or in cases of refractory cytopenias.
  • Recent data from a multi-institutional study suggest that sirolimus should be considered as a first-line – corticosteroid-sparing – agent [Bride et al 2016]. Sirolimus requires monitoring for drug levels and toxic side effects.
  • Mycophenolate mofetil (MMF) can be used in cases when a less immunosuppressive drug (e.g., compared with sirolimus) seems sufficient, as steroids are tapered. In addition, if drug level and toxic side effects cannot be adequately monitored, MMF could be used as a first-line agent.
• 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]. Given the known risks associated with splenectomy, patients requiring this last-resort approach should be considered for curative bone marrow transplantation.
• Individuals with isolated chronic neutropenia may improve on low-dose G-CSF [Rao & Oliveira 2011]. In addition, use of a thrombopoietin (TPO) receptor agonist should be considered for isolated immune thrombocytopenia (ITP).

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 pathogenic variants in FAS, those with severe and/or refractory autoimmune cytopenias, those with lymphoma, and those who have 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 PET and CT scanning in combination with clinical and laboratory surveillance may be helpful in detection of malignant transformation, keeping in mind that PET/CT scanning is often abnormal in ALPS, such that distinguishing between "typical" ALPS findings and a new malignancy (lymphoma) can be difficult [Rao & Oliveira 2011]. Because of this, careful consideration of imaging modalities that expose the patient to radiation is warranted.

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: Antimicrobial 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 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 pathogenic variant has been identified in the proband.

Relatives who have the family-specific pathogenic variant should:

• Be advised of their increased risk for ALPS if the type and location of the ALPS-related pathogenic variant 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

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

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Inheritance of ALPS-CASP10, most cases of ALPS-FAS, and some cases of ALPS-FASLG is autosomal dominant. Inheritance of most cases of ALPS-FASLG and severe ALPS associated with biallelic FAS pathogenic variants is autosomal recessive.

ALPS-FAS can also be the result of somatic mosaicism. Somatic pathogenic variants have not been reported in ALPS-FASLG or ALPS-CASP10 to date.

Autosomal Dominant ALPS – Risk to Family Members

Parents of a proband

• Most individuals diagnosed with ALPS-FAS have a parent who has a FAS pathogenic variant. Individuals who are heterozygous for a FAS pathogenic variant 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 the likelihood that the FASLG or CASP10 pathogenic variant was inherited from a parent.
• A proband with ALPS-FAS, ALPS-FASLG, or ALPS-CASP10 may have the disorder as the result of a de novo germline pathogenic variant. The proportion of cases caused by a de novo FAS germline pathogenic variant is small (the proportion of cases caused by a de novo FASLG or CASP10 is unknown).
• Recommendations for the evaluation of parents of a proband with a possible de novo pathogenic variant (i.e., neither parent is known to be affected with ALPS) include molecular genetic testing for the pathogenic variant identified in the proband.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo somatic or germline pathogenic variant in the proband or germline mosaicism in a parent.
• Although most individuals diagnosed with ALPS have a parent with a FAS pathogenic variant, 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 the cellular phenotype in individuals with a FAS pathogenic variant), 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 pathogenic variant, each sib has a 50% chance of inheriting the variant. The risk of developing ALPS-related complications, however, depends on the nature of the variant, as well as the presence of other as-yet incompletely understood genetic or environmental factors.
• If the FAS, FASLG, or CASP10 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the empiric recurrence risk to sibs is approximately 1% because of the theoretic possibility of parental 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 pathogenic variant.
• The risk to a child who has inherited the pathogenic variant of developing ALPS-related complications depends on the nature of the pathogenic variant as well as the presence of other as-yet incompletely understood genetic or environmental factors (see Penetrance).

Other family members. 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 pathogenic variant, his or her family members may have inherited the same variant and are potentially at some increased risk of developing ALPS-related complications.

Autosomal Recessive ALPS – Risk to Family Members

Parents of a proband

• The parents of a child with ALPS-FAS or ALPS-FASLG resulting from biallelic pathogenic variants 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 pathogenic variants has:
  • An overall 75% chance of having one or two FAS/FASLG pathogenic variants;
  • A 25% chance of inheriting two FAS/FASLG pathogenic variants, which would most likely result in a severe ALPS phenotype;
  • A 50% chance of inheriting a single FAS/FASLG pathogenic variant, which could result in clinical manifestations of ALPS;
  • A 25% chance of inheriting one normal FAS/FASLG allele from each parent and having no clinical manifestations of ALPS.
• Heterozygotes may present with ALPS-related symptoms or may be clinically asymptomatic.

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

Other family members. If a parent of the proband has an ALPS-related pathogenic variant, his/her sibs are at a 50% risk of having the variant.

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.

Testing of at-risk asymptomatic family members for FAS, FASLG, or CASP10 pathogenic variants is possible once the variant(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 variant. Results of testing of at-risk asymptomatic family members can reduce morbidity and mortality through early diagnosis and treatment and 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.

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

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.
• Prior to pregnancy, affected women should be advised about the teratogenic risks associated with medications used to treat ALPS.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the FAS, FASLG, or CASP10 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for ALPS are possible.

Molecular 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]. (Note: Bleesing [2002], Figure 1 diagrams this process; login or purchase required.)

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. There are two isoforms of CASP10 transcripts. The CASP10_L isoform encodes an additional 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 variants. To date, four CASP10 pathogenic variants have been reported in individuals with ALPS [Wang et al 1999, Zhu et al 2006, Cerutti et al 2007] (see Table 3). Two missense variants, 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 pathogenic variant. 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].

Table 3.

Selected CASP10 Pathogenic Variants

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. Pathogenic variants result in decreased caspase activity and dominantly interfere with death receptor-induced apoptosis, particularly with that stimulated by FasL and TRAIL.

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.

Pathogenic variants. See Table 4. To date, fewer than ten pathogenic alleles have been reported in FASLG in association with an ALPS phenotype.

Table 4.

Selected FASLG Pathogenic Variants

Normal gene product. The FASLG cDNA encodes 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 pathogenic missense variant (p.Ala247Glu) showed decreased Fas-mediated cell death and Fas-dependent cytotoxicity [Del-Rey et al 2006]. The heterozygous p.Arg156Gly pathogenic variant affects the extracellular Fas-binding region of FASL. The variant produces a dominant interfering FasL protein that binds to wild type FasL, preventing Fas-mediated apoptosis [Bi et al 2007].

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Author History

Jack JH Bleesing, MD, PhD (2006-present)
Judith Johnson, MS, CGC; Cincinnati Children's Hospital (2006-2017)
Chinmayee Nagaraj, MS, CGC (2017-present)
Kejian Zhang, MD, MBA (2006-present)

Revision History

• 24 August 2017 (ha) Comprehensive update posted live
• 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 live
• 2 December 2005 (jj) Original submission