Other manifestations can affect the skin (hives), lungs (bronchiolitis obliterans), or kidneys (autoimmune glomerulonephritis and nephrotic syndrome). Another sign are cancers such as Hodgkin and non-Hodgkin lymphomas, which appear to be increased, possibly due to Epstein–Barr virus-encoded RNA-positivity. Some carcinomas may occur. Unaffected family members with genetic mutations are also at an increased risk of developing cancer. Genetics
This condition is usually caused by mutations in the FAS gene. Rarely cases due to mutations in other genes including the
FAS ligand gene have been reported. The disease is inherited in an autosomal dominant manner, but it shows incomplete penetrance with up to 40% of people with a FAS mutation not showing symptoms. Diagnosis
Diagnostic algorithm
The old diagnostic criteria for the illness included: Chronic non-malignant lymphoproliferation, elevated peripheral blood DNTs and defective in vitro Fas mediated apoptosis. The new criteria require chronic non-malignant lymphoproliferation (over six months lymphadenopathy and/or splenomegaly), elevated peripheral blood DNTs. A primary accessory in diagnosis is defective in vitro Fas mediated apoptosis and somatic or germline mutation in ALPS causative gene (FAS, FASL, CASP10). The secondary accessory in diagnosis are elevated biomarkers (plasma sFASL over 200 pg/ml, plasma IL-10 >20 pg/ml, plasma or serum vitamin B12 >1500 ng/L, Plasma IL-18 >500pg/ml) and immunohistochemical findings on biopsy consistent with ALPS as determined by an experienced hematopathologist. Another sign is autoimmune cytopenias and polyclonal hypergammaglobulinemia and a family history of ALPS or non-malignant lymphoproliferation.A definitive diagnosis is chronic non-malignant lymphoproliferation and/or elevated peripheral blood DNTs plus one primary accessory criterion.
A probable diagnosis is the same but with one secondary accessory criterion. Classification
2003 nomenclature
IA - Fas
IB - Fas ligand
IIA - Caspase 10
IIB  - Caspase 8
III - unknown
IV - Neuroblastoma RAS viral oncogene homologRevised nomenclature (2010)
ALPS-FAS: Fas. Germline FAS mutations. 70% of patients. Autosomal dominant. Dominant negative and haploinsufficient mutations described. ALPS-sFAS: Fas. Somatic FAS mutations in DNT compartment. 10% of patients
ALPS-FASL: Fas ligand. Germline FASL mutations. 3 reported cases
ALPS-CASP10: Caspase 10. Germline CASP10 mutation. 2% of patients
ALPS-U: Undefined. 20% of patients
CEDS: Caspase 8 deficiency state. No longer considered a subtype of ALPS but distinct disorder
RALD: NRAS, KRAS. Somatic mutations in NRAS and KRAS in lymphocyte compartment. No longer considered a subtype of ALPS but distinct disease

Treatment
Treatment is most commonly directed at autoimmune disease and may be needed to treat bulky lymphoproliferation. First line therapies include corticosteroids (very active but toxic with chronic use), and IVIgG, which are not as effective as in other immune cytopenia syndromes.Second line therapies include: mycophenolate mofetil (cellcept) which inactivates inosine monophosphate, most studied in clinical trials with responses varying (relapse, resolution, partial response). It does not affect lymphoproliferation or reduce DNTs, with no drug-drug interactions. This treatment is commonly used agent in patients who require chronic treatment based on tolerance and efficacy.