Autoimmune lymphoproliferative syndrome overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] David Teachey, MD [2] Sharmi Biswas, M.B.B.S
Overview
Autoimmune lymphoproliferative syndrome is a form of lymphoproliferative disorder. It affects lymphocyte apoptosis. Autoimmune lymphoproliferative syndrome (ALPS) is a rare disorder of abnormal lymphocyte survival caused defective Fas mediated apoptosis. ALPS was first reported in 1967 by Canale and Smith; thus it was named initially as Canale and Smith syndrome. According to the 2010 revised guidelines, now ALPS is defined by the presence of chronic, non-malignant, and non-infectious lymphadenopathy along with autoimmune cytopenias. ALPS was first explained in 1990 in a cohort of patients with chronic lymphoproliferation and increased numbers of double-negative T cells (DNTs). Also ALPS is associated with increased level of IL-10,IL-12,vitamin B 12, soluble FAS ligand and IgG in serum. In vitro evidence of defective FAS mediated apoptosis is also found in ALPS. For proper development of immune system and regulation of apoptosis FAS receptor pathway is very important. Heterozygous mutation in genes in the FAS pathway cause ALPS. Other different kinds of mutations also identified and gene based nomenclature is recommended nowadays to describe new cases. The true incidence and prevalence of ALPS are still not known due to the high rate of misdiagnosis or remain undiagnosed. FAS plays an important role in controlling the malignant transformation of lymphocytes. Hence, ALPS patients are at high risk of developing lymphoma. Germline FAS mutation is the most common while somatic mutation is the second most common cause. Many of the patients with ALPS have unidentified genetic defects. ALPS mostly occur in early childhood with a median age of 18 months. Common clinical features are chronic lymphadenopathy(95% of patients), splenomegaly(90% of patients), or hepatomegaly(40-50% of patients). Lymphoproliferation is the earliest symptom with a median age of onset is 11.5 months. Lymphoproliferation can get worsen in adolescence and eventually get resolved in early 20s.Most of the ALPS patients have non tender, enlarged lymph nodes for a prolonged duration. In ALPS, second most common clinical manifestations are related to autoimmunity as hemolytic anemia, thrombocytopenia and neutropenia. Cytopenias are accompanied with elevated or reduced serum IgG. Autoimmune cytopenias might be absent in the intital periods of ALPS but Coombs positive autoimmune hemolytic anemia and thrombocytopenia with or without autoantibodies might get detected even before any clinical manifestations. Autoimmune cytopenias can be asymptomatic to life threatening illiness. Treatment of cytopenias in ALPS may range from periodic treatment to chronic. Similar to lymphoproliferation, autoimmune cytopenias may improve with age but less chance of complete resolution by adulthood.10-20% of patients with ALPS can have autoimmune manifestations involving other organ systems such as skin rashes, pulmonary fibrosis, hepatitis, uveitis,colitis,pancreatitis,Systemic lupus erythematosus,Guillain-Barre syndrome, transverse myelitis, cerebellar ataxia and arthritis. Anticardiolipin antibodies are also commonly found but thromboembolic events are rare. The symptoms of lymphadenopathy, splenomegaly and autoimmune cytopenias in ALPS create a challenge to reach proper diagnosis as these symptoms overlap with other childhood hematologic disorders as histiocytosis,lymphoma,heredietary spherocytosis, Evans syndrome and Rosai-Dorfman syndrome. Immune disorders with autoimmune componenet as common variable immunodeficiency and Wiskott-Aldrich syndrome also should be excluded. According to the revised guideline in 2010, to diagnose ALPS there should be 2 required and 6 additional criterias.Required criterias are chronic Lymphadenopathy with or without splenomegaly and increased TCRαβ+ DNT cells in circulation. Primary additional criterias are abnormal lymphocyte apoptosis assay and the presence of pathogenic mutations in FAS gene.Definitive diagnosis of ALPS requires 2 required criteria and one of the two primary additional criteria. There is no single laboratory test to diagnose ALPS. Patients with suspected ALPS should get investigated for ALPS related mutations.Treatment of ALPS is focused mainly on immunosuppression to treat autoimmune symptoms as cytopenias and to avoid splenectomy. In severe cases of ALPS which are refractory to immunosuppressors, hematopoietic stem cell transplant is the final treatment of choice.
Historical Perspective
ALPS was first reported in 1967 by Canale and Smith; thus it was named initially as Canale and Smith syndrome. According to the 2010 revised guidelines, now ALPS is defined by the presence of chronic, non-malignant, and non-infectious lymphadenopathy along with autoimmune cytopenias. ALPS was first explained in 1990 in a cohort of patients with chronic lymphoproliferation and increased numbers of double-negative T cells (DNTs). Also ALPS is associated with increased level of IL-10,IL-12,vitamin B 12, soluble FAS ligand and IgG in serum. In vitro evidence of defective FAS mediated apoptosis is also found in ALPS.
Classification
Classification of Autoimmune lymphoproliferative syndrome is done by following the revised diagnostic criteria and classification guidelines came from an international workshop held in NIH in September 2009.
Pathophysiology
Autoimmune lymphoproliferative syndrome(ALPS) is the first disease in human beings which are caused by apoptosis defect. Defect in FAS signaling cause benign chronic lymphoproliferation followed by accumulation of TCRαβ(+) CD4(-) CD8(-) double-negative T (DNT) cells. FAS also prevent the mailgnant proliferation of lymphocytes , so ALPS patients are at higher risk of developing lymphoma.There is an identified genetic defect in 2/3 rd of the total cases of ALPS. Germline mutation is the most common type. Somatic mutation, mutations in the proteins of FAS ligand(FASL) and caspase are also responsible in some cases.The pathogenesis of ALPS is still not very clear and research is ongoing.
Causes
The autoimmune lymphoproliferative syndrome is a disease caused by the defect in FAS-mediated apoptosis
Differentiating Autoimmune lymphoproliferative syndrome from Other Diseases
Due to having overlapping presenting symptoms with other hematologic disorders, Autoimmune lymphoproliferative syndrome in children should be excluded from infection, autoimmune disease, inherited immune disorders, and lymphoma.
Epidemiology and Demographics
Autoimmune lymphoproliferative syndrome (ALPS) is a rare disease that mostly affects children of early age. The incidence and prevalence of ALPS are unknown. Male predominance has been found.
Risk Factors
There are no established risk factors for Autoimmune lymphoproliferative syndrome.
Screening
There is insufficient evidence to recommend routine screening for Autoimmune lymphoproliferative syndrome.
Natural History, Complications, and Prognosis
Natural History
The symptoms of Autoimmune lymphoproliferative syndrome usually develop in the first decade of life and start with chronic lymphadenopathy with or without splenomegaly and hepatomegaly or both.The median age of initiation of lymphadenopathy is 11.5 months.Some of the pateints present with fatigue, pallor and jauncice which are due to autoimmune hemolytic anemia,symptoms of thrombocytopenia as spontaneous bruises,and mucocutaneous hemorrhages or neutropenia associated infections
Complications
Common complication of Autoimmune lymphoproliferative syndrome include:
- Lymphoma both Hodgkins and Non Hodgkins lymphoma.
Prognosis
Prognosis is generally good, and the survival rate of patients with Autoimmune lymphoproliferative syndrome(ALPS) is approximately 85% by age 50
Diagnosis
Diagnostic Criteria
Following the international conference in 2009, a revised set of diagnostic criteria was published in 2010. According to this set of criteria, to reach a definitive diagnosis it is mandatory to have the presence of two required criteria and one primary accessory criteria. The presence of two required criteria and one secondary criterion together indicates the probable diagnosis. Required criteria-
- Splenomegaly (+/-)
- Increased circulating TCRαβ+ DNT cells
Additional criteria-
- Primary
- Abnormal lymphocyte apoptosis assay
- Presence of pathogenic mutations in FAS pathway genes
- Secondary-
- Elevated circulating biomarkers
- characteristic histopathology of ALPS
- Family history of ALPS
Definitive diagnosis of ALPS- 2 required criteria and either of the 2 primary additional criteria
Probable diagnosis- 2 required criteria and one of the primary additional criteria
.
History and Symptoms
Autoimmune lymphoproliferative syndrome (ALPS) hard to diagnose due to expressions of different phenotypes and overlapping symptoms with other hematological disorders. The most common symptoms of ALPS are related to lymphadenopathy predominantly in cervical region, splenomegaly with or without features of hypersplenism or hepatomegaly, and autoimmune cytopenias as thrombocytopenia, hemolytic anemia or occasional neutropenia. Autoimmune cytopenia and lymphoproliferation occur simultaneously in most cases but can also happen separately or in an interval.
Laboratory Findings
There is no single laboratory test to diagnose ALPS. Patients with suspected ALPS should get investigated for ALPS related mutations.
Imaging Findings
There are no CT scan or MRI findings associated with Autoimmune lymphoproliferative syndrome(ALPS). However, a CT scan and MRI may be helpful in the diagnosis of complications of ALPS, as lymphoma.
Other Diagnostic Studies
The histopathologic study may be helpful in the diagnosis of Autoimmune lymphoproliferative syndrome(ALPS). Findings suggestive of ALPS include paracortical expansion due to infiltration of polyclonal TCR α/β+ DNT cells, follicular hyperplasia, and polyclonal plasmacytosis.
Treatment
Medical Therapy
Treatment of ALPS is focused mainly on immunosuppression to treat autoimmune symptoms as cytopenias and to avoid splenectomy. In severe cases of ALPS which are refractory to immunosuppressors, hematopoietic stem cell transplant is the final treatment of choice. ===Surgery===No definitive surgery is required to treat Autoimmune lymphoproliferative syndrome(ALPS)
Prevention
An autoimmune lymphoproliferative syndrome(ALPS) is a genetic disorder that is inherited in most cases. So, there are no primary prevention guidelines so far.