Pediatrics

Autoimmune Lymphoproliferative Syndrome (ALPS)

OVERVIEW: What every practitioner needs to know

Are you sure your patient has autoimmune lymphoproliferative syndrome? What are the typical findings for this disease?

Autoimmune lymphoproliferative syndrome symptoms:

The most common symptoms are: Lymphadenopathy, splenomegaly (with or without hypersplenism).

The next most common symptoms are hepatomegaly, blood cytopenias (particularly autoimmune thrombocytopenia [ITP], autoimmune hemolytic anemia [AIHA], and - less frequently - autoimmune neutropenia [AN]).

Note: there often is a delay between lymphoproliferative disease manifestations and the occurrence of autoimmunity, varying from months to many years.

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

What other disease/condition shares some of these symptoms?

The main manifestations of ALPS are lymphoproliferative disease (lymphadenopathy, splenomegaly, hepatomegaly), autoimmune disease, mainly confined to blood cells, and the development of lymphoma (manifestation of lymphoproliferative disease). Consequently, other immunological/hematological conditions that exhibit these manifestations should be considered in the differential diagnosis. In that context, many well-classified primary immunodeficiency disorders can present with lymphoproliferation, including lymphoma, and autoimmune cytopenias.

With the above in mind, some of the more common conditions that may present with both lymphoproliferation (lymphoma) and autoimmunity are listed below.

Common Variable Immunodeficiency Disease (CVID)

CVID has an estimated incidence of one in 50,000 and occurs equally in males and females. Findings 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. 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.

Wiskot-Aldrich Syndrome (WAS)

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 Epstein-Barr virus (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. X-linked Lymphoproliferative Syndrome (XLP) is associated with an inappropriate immune response to 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.

Demonstration of defective T-cell receptor restimulation apoptosis in persons with XLP suggests that altered lymphocyte homeostasis impacts disease pathogenesis as well. 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.

Other lymphoproliferative disorders

Several, equally rare, lymphoproliferative disorders that can mimick ALPS include: Dianzani Autoimmune Lymphoproliferative Disease (DALD), Kikuchi-Fujimoto disease, Caspase-8 Deficiency Syndrome (CEDS), Rosai-Dorfman Disease and Ras-associated Leukoproliferative Disorder (RALD).

Note: Evans syndrome is sometimes considered a specific diagnosis or disorder (entity). However, it is better used as a descriptive term, meaning the presence of ITP and AIHA, either concomitantly and/or sequentially. As such, it should be regarded a manifestation of an underlying immunologic/hematologic disorder (such as ALPS), even if a specific diagnosis cannot be made.

What caused this disease to develop at this time?

ALPS is a genetically determined disorder, in which the genetic defect and defective Fas-mediated apoptosis are (intrinsically) present at birth.

The reason (or reasons) why ALPS is often not present at birth is/are not understood, but could be related to extrinsic factors that are acquired in an unpredictable manner, but are necessary to interact with defective apoptosis. Infections, for example viral infections, are one possible explanation. However, studies in mice with a similar disorder, have shown that raising these mice in a sterile environment does not prevent the ultimate development of their ALPS-like disease, suggesting that development of ALPS is a function of time.

It should be realized that "delayed" expression of a clinical phenotype, in the presence of a congenitally present genotype is not unusual (e.g., CVID).

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Although no specific laboratory abnormality alone is diagnostic of ALPS, laboratory studies are instrumental in the diagnostic workup. Most of the laboratory findings are not specific for ALPS (i.e. are observed in other disorders, characterized by lymphoproliferation/autoimmunity as well), with several important exceptions.

Specific findings for ALPS:

-defective Fas-mediated apoptosis in vitro

-an expansion of T cells that express the alpha/beta T-cell receptor but lack both CD4 and CD8 (so-called alpha/beta-positive CD4/CD8 double-negative T cells [a/b-DNT cells] in peripheral blood or tissue specimens). These cells are rare in healthy individuals, making up less than 2% of the total peripheral blood lymphocyte pool, and not found in other disorders.

-elevated level of vitamin B12 in serum

-elevated levels of interleukin-10 (IL-10), IL-18 and soluble Fas Ligand (FasL) in plasma or serum

In addition to these “ALPS-specific” findings, other laboratory findings that can be found in other disorders as well, include:

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

Decreased numbers of CD4+/CD25+ T cells

Decreased numbers of CD27+ B cells

Elevated concentrations of IgG, IgA, and IgE; normal or decreased concentrations of IgM

Autoantibodies (most often positive direct or indirect anti-globulin test, antiplatelet antibody, anti-neutrophil antibody, anti-phospholipid antibody, antinuclear antibody, rheumatoid factor)

Lymph node pathology (paracortical expansion with immunoblasts/plasma cells in interfollicular areas, florid follicular hyperplasia, progressive transformation of germinal centers [PTGC])

Chemistry:

Liver function abnormalities (in case of autoimmune hepatitis)

Proteinuria (in case of glomerulonephritis)

Would imaging studies be helpful? If so, which ones?

Imaging studies are important in delineating extend and localization of lymphoproliferative manifestations, as it relates to lymphadenopathy and splenomegaly (hepatomegaly), as well as determining whether treatment is warranted (e.g. lymphadenopathy compromising airway patency). By the same token, imaging can be helpful to determine ALPS disease activity and response to therapy (and as a tool to evaluate specific treatment modalities).

Imaging modalities include: CT, MRI and ultrasound. CT scanning is among the most cost-effective imaging modality, while MRI and ultrasound do not involve radiation. Conventional X-ray does not add much to the diagnostic process.

One of the problems in ALPS is difficulty in predicting and/or detecting lymphoma. The reason for this has to do with the fact that one often already finds a multitude of enlarged (suspicious-looking) lymph nodes, as well as splenomegaly, as a “routine” feature of ALPS. Thus, standard imaging (i.e. CT scanning) might not be able to reliably distinguish a “good” node from a “bad” (malignant) node.

PET (Positronic Emission Tomography) scanning has shown promise, considering the likelihood that a malignant node would show higher proliferative (metabolic) activity on a cellular level (i.e. is “hot” in PET scannng). Routine PET scanning, particularly when combined with CT scanning shows anatomical location and biological behavior simultaneously. In the absence of lymphoma, the nodes generally show little or only modest isotope uptake which changes over time. In contrast, a malignant node or nodes have significant and persistent isotope uptake. PET or PET/CT is thus useful in evaluating lymph nodes or planning a possible surgical procedure to rule-out lymphoma, as it provides an assessment of biological activity in addition to the anatomy.

It remains to be seen what the appropriate frequency of surveillance PET scanning would be (e.g. one a year, every other year), how interpretation is influenced by treatment, and whether in the long run, PET scanning is cost-effective, or more cost-effective than regular clinical follow-up. Education of patients, such that they have good insight into (their) ALPS, and how lymphoma may be accompanied with new/unusual symptomes (e.g. weight loss, nightsweats), coupled with regular follow-up, might be as effective (and much less expensive and bothersome).

Confirming the diagnosis

There are two components to the approach to diagnostic testing in patients, suspected of having ALPS.

First, a new set of diagnostic criteria has recently been established. This followed after a International Consensus Meeting was convened to review the strength and weaknesses of available evidence, as established and tested during the “first decade” of ALPS awareness”. Based on a revised determination of strength, criteria have been re-classified as “required”, “primary accessory” and “secondary accessory”. In addition, the diagnostic criteria were reviewed from the perspective that one should at least be able to suspect an ALPS diagnosis, without needing specialized (complicated) diagnostic testing that is only performed in a limited number of specialized centers.

A definitive diagnosis of ALPS is based on the presence of both required criteria and one primary accessory criterion. 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 or splenomegaly, or both

- Elevated a/b-DNT cells

- 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 IL-10 levels or elevated plasma vitamin B12 levels or elevated plasma IL-18 levels

- Typical immunohistological findings as determined by an experienced hematopathologist

- Autoimmune cytopenias with elevated (polyclonal) IgG levels

- A positive family history

The second component in the diagnostic workup proposes a diagnostic algorithm. The key components of this algorithm - keeping in mind that the presence of chronic non-malignant lymphoproliferation and a/b-DNT cells has already been established - are:

- Identification of a FAS mutation in unsorted cells

- Measurement of biomarkers (interleukin-10, soluble FasL, vitamin B12)

- Identification of a somatic FAS mutation in sorted a/b-DNTcells

- Identification of mutations in FASLG or CASP10 and defective Fas-mediated apoptosis in vitro

The proposed algorithm recommends the following (see also Table I, showing the ALPS genotypes, and associated classification):

Table I.

ALPS Classification
Gene Symbol ALPS Type Proportion of ALPS Patients
FAS ALPS-FAS 65-70%1
ALPS-sFAS ~15-20%2
FASLG ALPS- FASLG <5%3
CASP10 ALPS- CASP10 <5%4

1. Determine presence of germline FAS mutation 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; determine if biomarkers (as listed above) are elevated. If that is the case, obtain sorted a/b-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 not, consider genetic defect in caspase-10 or Fas ligand (given the fact that 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 not, perform Fas-mediated apoptosis assay (repeat if necessary, and keep in mind influence of concomitant immunosuppressive therapy). If abnormal, the diagnosis of ALPS is established and classified as ALPS-U.

6. If not, consider somatic mutations in CASP10 or FASLG (using previously sorted a/b-DNT cells if possible), or consider an alternative diagnosis. Note: no cases of somatic mutations, affecting CAPS10 or FASLG, in sorted a/b-DNT cells have been reported.

Genetic testing as part of the diagnostic workup

As is clear from these criteria, genotyping of the genes associated with ALPS is an important part of the diagnostic workup. In addition to providing a molecular genetic diagnosis that allows for family studies and genetic counseling (an important part of ALPS management), it is helpful in patients with confusing clinical and/or laboratory findings, patients that have been treated with (significant amounts of) immunosuppressive agents, resulting in unreliable laboratory studies.

Genetic/Family studies are an important aspect of genetic testing. One should consider mode of inheritance, genotype-phenotype relationships and penetrance (i.e. the proportion of individuals – for example in a family – with a mutation in an ALPS-causing gene who will exhibit ALPS). Identification of a mutation in any of the genes, associated with ALPS, should invite sequencing of the same gene in parents (siblings).

Fas Structure

For a discussion on ALPS genetics, it should be noted that the FAS gene consists of 9 exons; the first 5 exons encode an extracellulardomain (ECD) of the Fas protein. The ECD consists of 3 cysteine-rich domains (CRDs) that serve as the pre-ligand assembly domain (PLAD) and the ligand-binding domain (Fas Ligand). The 6th exon encodes a transmembranedomain, while exons 7 through 9 encode an intracellular domain (ICD) that includes the "Death Domain", the part of Fas that engages the intracellular apoptosis pathway through connecting with FADD.

Mode of Inheritance:

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

ALPS-FAS due to bi-allelic mutations is inherited in an autosomal recessive manner. Only a handful of patients with bi-allelic mutations (encompassing both homozygous mutations and compound heterozygous mutations) have been reported to date. These patients typically have a severe form of ALPS, presented at, or shortly, after birth.

Genotype - Phenotype relationships (applies only to FAS mutations):

No clear relationship has been found between specific FAS mutations and disease manifestations and laboratory manifestations. The only reported association is a higher incidence of lymphomas in patients with ICD mutations (or looking at the data in another way; no reported lymphomas in patients with ECD mutations).

Penetrance (applies only to FAS mutations):

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

Family studies to date show that penetrance of the defective Fas-mediated apoptosis cellular phenotype approximates 100% - i.e., every individual heterozygous for an inherited (germline) mutation has defective apoptosis - whereas the penetrance for the clinical phenotype is reduced because a significant proportion of relatives heterozygous for the 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.

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. The highest penetrance (70%-90%) for the clinical phenotype occurs with missense mutations affecting the intracellular domains (ICD), followed by mutations leading to truncation of the intracellular domains. The penetrance for the clinical phenotype with extracellular domain (ECD) 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.

Recently, an interesting 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 patients, 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. Analysis of a/b-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.

Thus, individuals in those families with both the germline mutation affecting the ECD part of Fas, and the (secondary) somatic mutation in a/b-DNT cells, acquired the clinical ALPS phenotype, while individuals, carrying only the germline mutation did not. It should be noted that it remains unclear if the second somatic mutation occurred during embryogenesis or was acquired after birth. From a disease pathogenesis standpoint, the possibility that somatic genetic events can be acquired during life, has far-fetching ramifications.

Genetic testing as part of the diagnostic workup - technical aspects

Patients with somatic mutations in FAS (approximately 15-20% of cases) were initially missed, because of two cardinal features in their diagnostic workup. Since the mutation affects only a minority of blood lymphocytes, predominantly the a/b-DNT, in vitro apoptosis studies were typically normal, because the a/b-DNT cells do not survive the 2-week culture conditions, thereby not contributing to in vitro apoptosis. Secondly, conventional genotyping of peripheral blood cells, the usual approach to sequencing of suspected genes, could not find the mutated allele, as the vast majority of blood cells only showed the wild-type allele, using standard Sanger sequencing.

If you are able to confirm that the patient has autoimmune lymphoproliferative syndrome, what treatment should be initiated?

It should be noted that allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for ALPS and is invariably required.

Lymphoproliferative and/or autoimmune manifestations of ALPS can be treated with immunosuppressive agents and/or B-cell depleting agents. Several key issues need to be kept in mind.

These treatment modalities do not permanently control ALPS features. Typically, lymphadenopathy, splenomegaly (hepatomegaly) rebound after immunosuppressive drugs are discontinued.

Treatment of lymphadenopathy, splenomegaly and hepatomegaly should be based on the degree of lymphoproliferation, whether splenomegaly is associated with hypersplenism (causing cytopenias), whether these manifestations are associated with significant morbidity, and recognizing that lymphoproliferation in ALPS appears to have a waxing/waning natural history by itself.

As discussed, autoimmunity is not always present early/initially in the course of ALPS. From a treatment perspective, development of autoimmunity (on a clinical level, causing symptoms; not by presence of autoantibodies alone) appears to be a demarcation point in the natural history of ALPS and, consequently, treatment requirements, especially with respect to the need to start and/or escalate therapy. In addition, patients often are not able to go back to a “pre-autoimmunity” treatment status.

The benefits of immunosuppression should be balanced by the risks associated with using these agents. This balance is not a static balance and should also be regarded in the context of age, co-morbidities, etc. Thus, it would seem naïve to consider that a young child with ALPS can be treated with immunosuppressive agents with impunity for prolonged periods of time. Spontaneous resolution of ALPS manifestations after having been on immunosuppressive drugs for (many) years should prompt an investigation into the integrity of overall the immune system of the patient on a regular basis, including the ability to respond to infections and vaccinations.

Therapy of ALPS manifestations should be evaluated on a regular basis. This includes weaning/discontinuing immunosuppressive drugs to determine disease activity (and the need for medications). This is an important aspect of long-term management of ALPS patients and may provide additional insight into their clinical phenotype that cannot be ascertained by knowledge regarding the genotype alone.

The experience seems to be that low-impact immunosuppressive therapy (e.g., mycophenolate mofetil [Cellcept]) can provide significant clinical relief (i.e. the patient is not, or minimally, affected by ALPS), but that the laboratory or imaging abnormalities do not significantly change, and certainly not resolve. It is not clear if long-term immunosuppressive therapy is able to postpone or prevent autoimmunity, although this could be possible. The use of sirolimus is of interest in this regard in that it might have effects on the natural history of ALPS that other agents lack. It should be noted that sirolimus is a potent immunosuppressive agent, requiring considerable "labor", in terms of monitoring of drug levels, side effects, and effects on the immune system and host defense.

The treatment of ALPS patients requires a dynamic patient-specific approach: in the absence of clinical autoimmunity and significant hypersplenism (i.e. having normal blood counts), a watchful-waiting approach is appropriate. Clinically relevant lymphoproliferation, especially splenomegaly, accompanied by hypersplenism, warrants a trial of immunosuppressive therapy: in a step-wise approach, from least immunosuppressive (and least “labor-intensive”; for example mycophenolate mofetil [Cellcept]) to most immunosuppressive (requiring more intense monitoring of drug levels, side effects and risks of opportunistic infections; for example, sirolimus, cyclosporine).

A short course (several weeks) of corticosteroids can be used to (rapidly) induce clinical remission, while the patient settles on a more specific T-cell agent. Prolonged mono-therapy with corticosteroids is not recommended.

Significant autoimmunity, especially if it requires transfusion support (red cells and/or platelets), may require combination therapy, for example using (high-dose) corticosteroids to stabilize the process, a B-cell depleting agent (e.g., rituximab) and a T-cell agent for ongoing immunosuppression and prevention of relapse. High-dose IVIG therapy and WinRho have been used as well.

B-cell depletion agents, such as rituximab, are likely not able to induce “permanent” remission of autoimmunity in ALPS. In addition, hypogammaglobulinemia has been reported post rituximab. This is a typical complication when rituximab is used in other conditions. B-cell reconstitution analysis can help in assessing duration of remission (as autoantibodies may not disappear).

Depending on the degree of therapy-related immunosuppression, patients may require anti-microbial prophylaxis to prevent opportunistic infections. In addition, one should consider supporting a patient with IVIG substitution, particularly in young patients, and/or patients receiving rituximab and/or other forms of immunosuppression. In addition, in these patients, one should consider the timing of routine childhood vaccinations (when on immunosuppressive therapy) and avoid using live vaccines (including avoidance of live virus vaccines in family members).

Patients, showing a severe ALPS phenotype, as demonstrated by the need of treatment within the first couple of years of life and/or treatment in an escalating and/or combinational fashion, and/or the need for continuous or near-continuous treatment for more than a few years, should be evaluated by a Center, experienced in complex immunodeficiency disorders and allogenic stem cell transplantation for these disorders.

Although overall experience is limited, it appears that defective Fas-mediated apoptosis does not constitute a barrier to successfull treatment of lymphoma.

Therapies that should be instituted immediately:

Although splenectomy should be avoided if possible, acute splenectomy may be required in the context of trauma or infarction. If feasible, vaccinations to deal with encapsulated organisms should be administered and antibiotic prophylaxis should be initiated before or soon after the surgical procedure. Moreover, it is the experience that ALPS patients may not have intact immune responses to encapsulated organisms (despite vaccinations). IVIG substitution may be necessary and strict patient/family education (including providing a medical alert bracelet) is essential.

Long term treatment:

Ideally, treatment of ALPS patients should be coordinated and managed by, or in close consultation with, an expert in complex immunological/hematological conditions, experienced in the (chronic) use of immunosuppressive therapy, its complications, and the multidisciplinary approach that these patients often require. This most likely involves (Pediatric) Hematology/Oncology and - less frequently - (Pediatric) Immunology.

Given the fact that the majority of ALPS patients are not “local”, the Author uses a model in which a network is created consisting of a local Pediatrician and a Hematologist/Oncologist (occasionally an Immunologist) in a local facility (often, but not always, a Children’s Hospital regional to the patient/family). The local team manages the day-to-day issues, with the Expert available for consultation, and regular follow-up and/or intervention at the “Center of Expertise”.

There is insufficient drug-trial proven data to support any particular drug and dose. Current approaches to therapy are almost exclusively “individualized’, referring to both the Practitioner and the Patient.

What are the adverse effects associated with each treatment option?

No drug therapy of ALPS is free of adverse effects and side effects. That is why drug treatment of ALPS patients should be individualized and managed by Physicians experienced in ALPS and the (long-term) use of immunosuppressive agents. A general discussion of the adverse effects of immunosuppressive agents is beyond the scope of this article. As in other primary immunodeficiency disorders – special attention should also be directed towards prevention of infections, including opportunistic, viral and fungal infections.

What are the possible outcomes of autoimmune lymphoproliferative syndrome?

Much remains to be learned about the prognosis of ALPS. While non-malignant lymphoproliferative manifestations often regress or improve over time, autoimmunity appears to show no permanent remission with advancing age. Moreover, the risk for development of lymphoma likely appears to be life-long. Thus, in the absence of curative treatment, the overall prognosis for ALPS remains guarded, necessitating long-term clinical studies to better understand its natural history.

As discussed, in some patients, 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. Analysis of a/b-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. There is reason to believe that this may be particularly relevant in patients with ECD mutations affecting FAS.

In considering risk/benefit options with a patient and family, it should be kept in mind that this discussion may need to be conducted more than once, depending on the development, as well as possible resolution.

What causes this disease and how frequent is it?

Autoimmune lymphoproliferative syndrome (ALPS) can be considered a prototypic disorder of defective lymphocyte homeostasis.

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. As a consequence, defects in this pathway lead to expansion of antigen-specific lymphocyte populations. Fas also appear to play a role in suppression of malignant transformation of lymphocytes, although it is not firmly established whether this involves the Fas/FasL pathway in a similar way. The pathogenesis of ALPS remains an ongoing topic of research.

In most patients, heterozygous mutations cause defective apoptosis and clinical ALPS through the mechanism of dominant negative interference. In vitro studies have demonstrated that mutation-bearing Fas proteins were able to interfere with Fas-mediated apoptosis when mixed with normal (wild type) proteins. The reason for this is the fact that Fas (and FasL) form homotrimers on the cell surface. In this setting, only one out of eight possible Fas trimer configurations is normal, and in seven out of eight configurations, abnormal Fas trimers are forms, leading to dominant negative interference.

In patients with mutations affecting the ECD of Fas, the mechanism of disease appears to be haploinsufficiency. From a laboratory standpoint, in vitro Fas-mediated apoptosis may not be as severely affected as in the case of ICD mutations and dominant negative interferences, keeping in mind that this is not a "rule".

The reduced penetrance for ALPS in some families suggests that one or more additional pathogenic factors interact with defective Fas-mediated apoptosis to cause the clinical phenotype of ALPS. On the other hand, the high penetrance for the clinical phenotype in families associated with missense mutations affecting the death domain of FAS, cast doubt on that assumption, indicating that an appropriate FAS genotype sufficient to cause ALPS. This variability in penetrance may be explained in part by a subsequent somatic mutation of the second FAS allele, as described above.

Somatic FAS mutations are of particular interest in better understanding the pathogenesis of ALPS, because they may help identify the impact of the FAS mutation relative to other potential pathogenic factors or the sequence of events in the pathogenesis of ALPS. As an example, the somatic mutation is mostly confined to a/b-DNT cells and typically is not found (in substantial amounts) in other lymphocyte subsets, such as B cells. Although not (yet) proven, it is possible that the somatic mutation is acquired after birth.

The incidence and prevalence of ALPS are unknown. Estimated cases of ALPS worldwide exceed 500, but that number has not reliably been confirmed. Many cases of ALPS probably remain undiagnosed due to variable phenotypic expression and a constellation of symptoms that overlap with many other conditions, particularly Evans’ syndrome and other lymphoproliferative disorders.

ALPS usually manifests itselfs in the first years of life and has been diagnosed in all ethnic backgrounds. Although the frequency seems to be equal for males and females, studies of large cohorts of patients suggest that males might show more severe disease manifestations. See above for a discussion on genetics (including Table I).

How do these pathogens/genes/exposures cause the disease?

N/A

Other clinical manifestations that might help with diagnosis and management

N/A

Are additional laboratory studies available; even some that are not widely available?

N/A

How can autoimmune lymphoproliferative syndrome be prevented?

ALPS is not an acquired disease, but is present at birth, either as an inherited disorder or because of the occurrence of a somatic mutation in FAS, presumed to occur during embryogenesis. As such, ALPS cannot be prevented after the birth of an affected individual. In case of an inherited form of ALPS, genetic testing and counseling are important, as family planning is an option.

What is the evidence?

These two articles provide a general review and outline approaches to disease management:

Bleesing, JJ. "Autoimmune lymphoproliferative syndrome (ALPS)". Curr Pharm Des. vol. 9. 2003. pp. 265.

Van Der Werff Ten Bosch, J, Otten, J, Thielemans, K. "Autoimmune lymphoproliferative syndrome type III: an indefinite disorder". Leuk Lymphoma. vol. 41. 2001. pp. 55.

van der Werff Ten Bosch, J, Schotte, P, Ferster, A. "Reversion of autoimmune lymphoproliferative syndrome with an antimalarial drug: preliminary results of a clinical cohort study and molecular observation". Br J Haematol. vol. 117. 2002. pp. 176.

Rao, VK, Dugan, F, Dale, JK. "Use of mycophenolate mofetil for chronic, refractory immune cytopenias in children with autoimmune lymphoproliferative syndrome". Br J Haematol. vol. 129. 2005. pp. 534.

Ongoing controversies regarding etiology, diagnosis, treatment

ALPS is a complex disease that transcends artificial bounderies such as created by defined medical subspecialties, as well as defined by age of the patient. Thus, patients with (suspected) ALPS may enter the medical arena through a variety of "doors" that influence the diagnostic and therapeutic approach to the disease.

The NIH-sponsored ALPS workshop in 2009 created a more uniform (and agreed upon) approach to diagnosis and classification. What is needed next is a similar process for treatment, particularly multi-institutional designed treatment protocols, and the role of HSCT in ALPS, as this remains somewhat of a controversy, or an area of ongoing discussion.

Loading links....

Sign Up for Free e-newsletters

Regimen and Drug Listings

GET FULL LISTINGS OF TREATMENT Regimens and Drug INFORMATION

Bone Cancer Regimens Drugs
Brain Cancer Regimens Drugs
Breast Cancer Regimens Drugs
Endocrine Cancer Regimens Drugs
Gastrointestinal Cancer Regimens Drugs
Genitourinary Cancer Regimens Drugs
Gynecologic Cancer Regimens Drugs
Head and Neck Cancer Regimens Drugs
Hematologic Cancer Regimens Drugs
Lung Cancer Regimens Drugs
Other Cancers Regimens
Rare Cancers Regimens
Skin Cancer Regimens Drugs