Autoimmune lymphoproliferative syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] David Teachey, MD [2] Sharmi Biswas, M.B.B.S

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.

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 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.

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.

The autoimmune lymphoproliferative syndrome is a disease caused by the defect in FAS-mediated apoptosis

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.

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.

There are no established risk factors for Autoimmune lymphoproliferative syndrome.

There is insufficient evidence to recommend routine screening for Autoimmune lymphoproliferative syndrome.

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

Common complication of Autoimmune lymphoproliferative syndrome include:

• Lymphoma both Hodgkins and Non Hodgkins lymphoma.

Prognosis is generally good, and the survival rate of patients with Autoimmune lymphoproliferative syndrome(ALPS) is approximately 85% by age 50

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–

• Chronic lymphadenopathy

• 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

.

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.

There is no single laboratory test to diagnose ALPS. Patients with suspected ALPS should get investigated for ALPS related mutations.

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.

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 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)

An autoimmune lymphoproliferative syndrome(ALPS) is a genetic disorder that is inherited in most cases. So, there are no primary prevention guidelines so far.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sharmi Biswas, M.B.B.S

Autoimmune lymphoproliferative syndrome(ALPS) is a rare genetic disorder which predominantly manifests in early childhood. Due to the overlapping symptoms of lymphadenopathy, cytopenia, and splenomegaly; ALPS often is misdiagnosed or undiagnosed. A genetic test to detect FAS mutation is required to confirm the diagnosis. The majority of ALPS is curable by early adulthood. Patients with ALPS are at risk of developing lymphoma, therefore routine monitoring is required. Initially, ALPS was described as Canale-Smith syndrome. In 1990, it was described as ALPS. In 2009, guidelines for diagnosis and classification of ALPS were revised in an international workshop.

• Autoimmune Lymphoproliferative Syndrome was first discovered by Canale and Smith, in 1967.Five patients were reported with lymphadenopathy, cytopenia and splenomegaly.^{[1] [2]}
• The syndrome was initially named as Canale-Smith Syndrome.
• In 1990, ALPS was first characterized
• In 1992, a mutation of lpr (lymphoproliferation phenotype) and gld (generalized lymphoproliferative disease phenotype), a human equivalent of murine disease is reported.
• In 1995, association between inborn mutation of Fas gene and the development of Autoimmune lymphoproliferative syndrome was discovered.
• In 2003, new mutation in Fas Ligand (FasL) gene mutation and caspase 8 or 10 gene mutations.

• In 1995, FAS gene mutation in ALPS was discovered.^[3]
• In 2009, an international workshop held at NIH in Uthe United States, announced revised diagnostic criteria and classification of ALPS.^[4]
• In 2017, mTOR inhibitor found to be an effective treatment for treatment refractory cytopenias related to ALPS.^[5]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: David Teachey, MD [2] Sharmi Biswas, M.B.B.S

Classification of ALPS is based on the recommendations made by first international ALPS workshop held at National Institutes of Health in 2009.

The revised classification of ALPS is as following ^[1]

Previous nomenclature	Revised nomenclature	Gene	Definition
ALPStype IIb	CEDS	CASP8	Splenomegaly, marginal raised DNT, recurrent infections, germline mutations in caspase 8
ALPS type IV	RALD	NRAS	Autoimmunity, lymphadenopathy and/or splenomegaly, elevated or normal DNTs, somatic mutations in NRAS
DALD	DALD	Unknown	Lymphadenopathy and /or splenomegaly, autoimmunity, normal DNTs, defective in vitro FAS-mediated apoptosis
XLP1	XLP1	SH2D1A	Hypogammaglobulinemia, fulminant Epstein- Barr virus infection, or lymphoma

Editor-In-Chief: David Teachey, MD [1] Sharmi Biswas, M.B.B.S

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.

• Autoimmune cytopenias: Most common. Can be mild to very severe. Can be intermittent or chronic.^[1]
  • Autoimmune Hemolytic Anemia
  • Autoimmune Neutropenia
  • Autoimmune Thrombocytopenia
• Other: Can affect any organ system similar to systemic lupus erythematosis (most rare affecting <5% of patients)
  • Nervous: Autoimmune cerebellar ataxia; Guillain-Barre; Transverse myelitis
  • GI: Autoimmune esophagitis, gastritis, colitis, hepatitis, pancreatitis
  • Derm: Urticaria
  • Pulmonary: Bronchiolitis obliterans
  • Renal: Autoimmune glomerulonephritis, nephrotic syndrome
• Cancer: Secondary neoplasms affect approximately 10% of patients. True prevalence unknown as <20 reported cases of cancer. Most common EBER+ Non-Hodgkin’s and Hodgkin’s lymphoma

Histopathological study findings can be helpful to diagnose Autoimmune lymphoproliferative syndrome. The findings are

• Paracortical expansion with infiltration of polyclonal TCR α/β+ DNT cells.^[2]
• DNT cells express TIA-1 and CD57, CD45RO negative
• Follicular hyperplasia
• Polyclonal plasmacytosis
• Spleen has expanded T cell areas dominated by DNT cells.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Sharmi Biswas, M.B.B.S

The autoimmune lymphoproliferative syndrome is a disease caused by the defect in FAS-mediated apoptosis.

• Most of the cases autosomal dominant, heterozygous germline mutation in FAS. ^[1]
• Somatic FAS mutation is the second most common cause.
• Minority of cases mutations in the genes encoding FAS ligand, caspase 10, caspase 8, and neuroblastoma RAS.
• One-third of patients have unidentified genetic defects.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sharmi Biswas, M.B.B.S

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.

Differentiating diagnosis of Lymphoma	Symptoms					Signs			Diagnosis	Additional Findings
	Fever	Rash	Diarrhea	Abdominal pain	Weight loss	Painful lymphadenopathy	Hepatosplenomegaly	Arthritis	Lab Findings
Autoimmune lymphoproliferative syndrome	-/+	+	–	–	–	–	+	–	Increased CD4– and CD8– cells. Increased vitamin B 12.	Weakness, fatigue, pallor, bruise, mouth ulcers , slow wound healing, painless lymphadenopathy.[1]
Lymphoma		–	–	+	+	–	+	–	Increase ESR, increased LDH	Night sweats, constant fatigue
Brucellosis	+	+	–	+	+	+	+	+	Relative lymphocytosis	Night sweats, often with a characteristic smell, likened to wet hay
Typhoid fever	+	+	–	+	–	–	+	+	Decreased hemoglobin	Incremental increase in temperature initially and than sustained fever as high as 40°C (104°F)
Malaria	+	–	+	+	–	–	+	+	Microcytosis, elevated LDH	“Tertian” fever: paroxysms occur every second day
Tuberculosis	+	+	–	+	+	+	–	+	Mild normocytic anemia, hyponatremia, and hypercalcemia	Night sweats, constant fatigue
Mumps	+	–	–	–	–	+	–	–	Relative lymphocytosis, serum amylaseelevated	Parotidswelling/tenderness
Rheumatoid arthritis	–	+	–	–	–	–	–	+	ESR and CRP elevated, positive rheumatoid factor	Morning stiffness
SLE	–	+	–	+	+	–	–	+	ESR and CRP elevated, positive ANA	Fatigue
HIV	–	–	–	+	+	+	–	+	Leukopenia	Constant fatigue

Disease	Differentiating signs and symptoms	Differentiating tests
Autoimmune lymphoproliferative syndrome	Most of the patients are in early childhood Generalized lymphadenopathy, splenomegaly	Elevated levels of CD4- and CD8-negative T lymphocytes, Genetic study showing mutation in apoptosis pathway of lymphocytes[2]
CNS lymphoma	Patient is immunocompetent Focal symptoms indicative of a mass lesion Seizure	Single solitary ring enhancing lesion on CT or MRI
Disseminated tuberculosis	Prior history of residence in an endemic area Chronic cough, weight loss, hemoptysis	PCR of CSF for tuberculosis Mycobacterial culture of CSF Brain biopsy for acid-fast bacilli staining Culture and acid stain positive for acid-fast bacilli CXR shows cavitations
Aspergillosis	Pulmonary lesions in addition to CNS lesions Symptoms may include cough, chest pain, and hemoptysis	CSF fungal culture, galactomannan
Cryptococcosis	Symptoms include cough, chest pain, and hemoptysis	Cryptococcal antigen from CSF and serum CSF fungal culture
Chagas disease	History of residence in Central or South America Acute infection is rarely symptomatic Encephalitis or focal brain lesions Myocarditis Chronic infections in immunocompromised patients develop into encephalitis with necrotic brain lesions causing a mass effect	Trypanosoma cruzi in blood, tissue, or CSF, PCR of tissue or body fluids, and serologic tests
CMV infection	Most common CNS opportunistic infection in AIDS patients Presents with encephalitis, retinitis, progressive myelitis, or polyradiculitis In disseminated disease, it involves both the liver and kidneys	Brain CT/MRI/biopsy: location of lesions is usually near the brain stem or periventricular areas PCR of CSF with detectable virus is diagnostic Brain biopsy with + staining for CMV or evidence of owl’s eyes is also diagnostic, but it is rarely performed because of the location of brain lesions
HSV infection	Seizures, headache, confusion and/or urinary retention can be seen in disseminated disease, which usually affects only the immunocompromised or acute infections In pregnant women, it may be associated with concurrent genital/oral lesions; can be spread to the neonate during acute infection in the mother, or via viral shedding in the birth canal Neonatal HSV can range from localized skin infections to encephalitis, pneumonitis, and disseminated disease	Brain CT/MRI/biopsy: location of lesions is usually the medial temporal lobe or the orbital surface of the frontal lobe. PCR of CSF with detectable virus is diagnostic
Varicella Zoster infection	Multifocal involvement has subacute course, usually only in immunosuppressed, with headache, fever, focal deficits, and seizures. Unifocal involvement is more typically seen in immunocompetent hosts, occurring after contralateral cranial nerve herpes zoster, with mental status changes, TIAs, and stroke Disseminated varicella zoster virus can occur in adults during primary infection, presenting with pneumonitis and/or hepatitis Disease is a vasculopathy with hemorrhage and stroke	PCR of CSF with detectable virus is diagnostic
Brain abscess	Associated with sinusitis (abutting the sinuses) or with bacteremia Signs and symptoms includes fever and necrotizing brain lesions with mass effect	CSF culture or culture of brain abscess
Progressive multifocal leukoencephalopathy	Symptoms are often more insidious in onset and progress over months. Symptoms include progressive weakness, poor coordination, with gradual slowing of mental function. Only seen in the immunosuppressed. Rarely associated with fever or other systemic symptoms	PCR of CSF for JC virus Biopsy reveals white matter lesions and not well-circumscribed lesions.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sharmi Biswas, M.B.B.S

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.

• The incidence of Autoimmune lymphoproliferative syndrome(ALPS) is unknown as many cases remain undiagnosed or misdiagnosed.^[1]

• The prevalence is not known as many cases are left unidentified. A total of 500 patients with ALPS have been identified, from more than 300 families.^[2]

• The mortality rate is 15% in patients with ALPS-FAS by age 50.^[2]

• Patients of all age groups may develop Autoimmune lymphoproliferative syndrome.^[3]
• Typically ALPS appears in early childhood. The median age at diagnosis is 3 years.^[4]

• There is no racial predilection to Autoimmune Lymphoproliferative Syndrome.

• Males are more commonly affected by Autoimmune lymphoproliferative syndrome than females. The male to female ratio is 14:4.^[3]

• There is no information about any specific region where Autoimmune lymphoproliferative syndrome is prevalent.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sharmi Biswas, M.B.B.S

There are no established risk factors for Autoimmune lymphoproliferative syndrome.

There are no established risk factors for Autoimmune lymphoproliferative syndrome.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sharmi Biswas, M.B.B.S

There is insufficient evidence to recommend routine screening for Autoimmune lymphoproliferative syndrome.

No recommendation for routine screening of Autoimmune lymphoproliferative syndrome.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sharmi Biswas, M.B.B.S

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 patients present with fatigue, pallor and jaundice which are due to autoimmune hemolytic anemia,symptoms of thrombocytopenia as spontaneous bruises,and mucocutaneous hemorrhages or neutropenia associated infections Common complication of Autoimmune lymphoproliferative syndrome include, lymphoma both Hodgkins and Non Hodgkins lymphoma. Prognosis is generally good, and the survival rate of patients with Autoimmune lymphoproliferative syndrome(ALPS) is approximately 85% by age 50.

• 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 patients present with fatigue, pallor and jaundice which are due to autoimmune hemolytic anemia,symptoms of thrombocytopenia as spontaneous bruises,and mucocutaneous hemorrhages or neutropenia associated infections.^[1][2]

• Common complication of Autoimmune lymphoproliferative syndrome include:
  • Lymphoma both Hodgkins and Non Hodgkins lymphoma.^[2]
  • Sepsis follwed by splenectomy

• Prognosis is generally good, and the survival rate of patients with Autoimmune lymphoproliferative syndrome(ALPS) is approximately 85% by age 50.^[3]
• Cytopenia related to ALPS improve with age and respond to immunosuppressive treatment.
• Chronic lymphoproliferation regress with age and does not need any treatment.
• Patients with mutation in the extracellular domain of FAS usually cause milder disease.
• Mutations in the intracellular domain of FAS cause a worse prognosis.^[4]