Definitive diagnosis: Both required criteria plus one primary accessory criterion. Probable diagnosis: Both required criteria plus one secondary accessory criterion.
DNT: double-negative T; FAS: Fas cell surface death receptor; TCR: T cell receptor; IL: interleukin; FASL: Fas ligand; PCR: polymerase chain reaction; FASLG: Fas ligand gene; CASP10: caspase 10; CASP8: caspase 8; FADD: Fas associated via death domain; NRAS: NRAS proto-oncogene, GTPase; KRAS: KRAS proto-oncogene, GTPase; ALPS-sFAS: ALPS due somatic variants in FAS. * Lymphoma is a late, uncommon manifestation of ALPS. It is rarely a presenting feature. ¶ DNT cells are CD3+ cells with alpha beta TCRs but neither CD4 or CD8 coreceptors. ALPS biomarkers (elevated levels of vitamin B12, IL-10, IL-18, and soluble FASL) are ascertained concurrently with DNT testing or after DNT testing if it is abnormal. Δ Testing for secondary accessory criteria is performed at the same time as testing for DNTs. Refer to UpToDate topic on diagnosis of ALPS for details. Secondary accessory criteria include:
Elevated levels of ALPS biomarkers (IL-10, IL-18, vitamin B12, and soluble FASL, although soluble FASL may be low to absent in ALPS-FASL)
Autoimmune cytopenias with elevated polyclonal IgG levels
A positive family history of confirmed ALPS or nonmalignant, noninfectious lymphoproliferation with or without autoimmunity
Typical immunohistologic findings, including lymph node pathology (usually obtained for evaluation of possible lymphoma) and T cell studies (flow cytometry, immunohistochemical analysis, and polymerase chain reaction [PCR] assessing for TCR gene rearrangement)
◊ Molecular testing is performed for germline pathogenic variants in known ALPS genes (FAS, FASLG, CASP10) using unsorted cells from blood or tissue. The ALPS panel includes the known ALPS genes and genes associated with ALPS-like conditions (CASP8, FADD, NRAS, KRAS). If the ALPS panel is not available, testing for each gene may be ordered separately. Testing for somatic FAS variants is performed on sorted DNT cells. § If a particular type of testing is not available, proceed to the next testing step. ¥ Diagnostic findings are influenced by immunosuppressive medications to varying degrees, depending on the nature, amount, and duration of medications. If the clinical condition permits discontinuation of immunosuppressive drugs, the diagnostic process can be delayed until that time. Conversely, FAS can be sequenced if continued immunosuppressive therapy is required and there is a strong suspicion of ALPS since this test will capture most patients with ALPS. Confirmation of ALPS-sFAS, the second most common type of ALPS, requires sorting DNT cells, which may not be feasible if the DNT cell compartment is reduced by immunosuppressive drugs. Thus, ALPS-sFAS cannot definitively be ruled out in patients on immunosuppressive therapy.
