Clinical Guidance

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 . 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 . (For further discussion see .) ALPS-FASLG and ALPS-CASP10.

Source: GeneReviews — "Autoimmune Lymphoproliferative Syndrome"

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 .

Source: GeneReviews — "Autoimmune Lymphoproliferative Syndrome"

Diagnostic Criteria

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 :

• 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.

Source: GeneReviews — "Autoimmune Lymphoproliferative Syndrome"

Differential Diagnosis

ALPS-like disorders. Pathogenic variants in genes inside (other than FAS, FASLG, and CASP10) and outside Fas/FasL pathway have been reported in association with clinical findings similar to ALPS. However, they either do not fulfill the current diagnostic criteria of ALPS or have other distinct phenotypes, and therefore are listed as ALPS-like disorders. These include:

Source: GeneReviews — "Autoimmune Lymphoproliferative Syndrome"

Management Guidelines

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 /-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

Monitoring for and treatment of lymphoproliferation and hypersplenism

Source: GeneReviews — "Autoimmune Lymphoproliferative Syndrome"

Clinical Guidance

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 adherence was a risk factor in the French cohort . 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.

Source: GeneReviews — "Autoimmune Lymphoproliferative Syndrome"

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.

Source: GeneReviews — "Autoimmune Lymphoproliferative Syndrome"

Surveillance Guidelines

Clinical assessment, imaging, and laboratory studies outlined in 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 . Because of this, careful consideration of imaging modalities that expose the affected individual to radiation is warranted.

Source: GeneReviews — "Autoimmune Lymphoproliferative Syndrome"