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Autoimmune lymphoproliferative syndrome
A rare, inherited disorder characterized by non-malignant lymphoproliferation, multilineage cytopenias, and a lifelong increased risk of Hodgkin's and non-Hodgkin's lymphoma.
ORPHA:3261Classification level: Disorder
The prevalence of ALPS is unknown. It has been characterized in more than 500 patients to date and has been reported worldwide in various ethnic groups.
ALPS is clinically heterogeneous with the following primary clinical signs: lymphoproliferation, manifesting as lymphadenopathy and hepatosplenomegaly with or without hypersplenism, often improving with age, autoimmune disease, mostly involving blood cells, and an increased risk of lymphoma lifelong. Many patients develop non-malignant lymphoproliferation during the first years of life. Clinical manifestations of autoimmunity in the form of hemolytic anemia, thrombocytopenia, neutropenia, or autoimmune hepatitis are of variable severity but these signs are often absent at the time of diagnosis. Autoimmunity has been reported to potentially affect almost any organ, leading to uveitis, pulmonary fibrosis, gastritis, colitis, nephritis, urticaria, arthritis, or rarely autoimmune neurological complications. The disease course is also variable. Several genetic subtypes based on the causative genes and types of mutations have been proposed and result in often similar clinical presentations and outcomes. These include ALPS-FAS, ALPS-FASLG (FASgene), ALPS-CASP10 (CASP10), and ALPS-U (undetermined genetic defect).
ALPS is caused by defective lymphocyte homeostasis. Germline mutations in the FAS (10q24.1), FASLG (1q23), or CASP10 (2q33-q34) genes are known to be associated with ALPS. 75% of cases are associated with heterozygous mutations in FAS. The second largest group (10%) has somatic mutations in FAS, while CASP10 (2-3%) and FASLG (<1%) mutations are extremely rarely reported. Some patients do not have mutations in any of these genes (ALPS-U). More recently one case of an ALPS-like disorder due to mutation in the PRKCD gene (3p21.31) was reported. This patient however did not have elevated DNT cells and hence does not fit the diagnostic criteria.
Diagnosis is based on clinical, laboratory and genetic findings. A definitive diagnosis is established in the presence of both of the required diagnostic criteria, i.e. chronic non-malignant, non-infectious lymphadenopathy and/or splenomegalyand elevated TCR alpha/beta-double-negative T cells (DNTs) with normal or elevated lymphocyte counts, along with one primary accessory criterion, including defective lymphocyte apoptosis, and germline or somatic mutations in FAS, FASLG or CASP10.
Depending on the specific genetic mutation, inheritance may be autosomal dominant or autosomal recessive.
Management and treatment
Some patients may require chronic immunosuppressive therapies with sirolimus and mycophenolate mofetil.
The prognosis for ALPS patients remains guarded. ALPS-FAS patients have a significantly increased risk of non-Hodgkin's and Hodgkin's lymphoma which can occur at any age and responds to conventional chemotherapy.