Synonym: Canale-Smith syndrome

Autoimmune lymphoproliferative syndrome (ALPS) is a rare disorder in which there is chronic non-malignant lymphoproliferation and autoimmunity, most often involving cells of the haematopoietic system. It can present in children or adults but usually presents in early childhood.¹

Canale and Smith described a syndrome of lymphadenopathy and splenomegaly associated with haemolytic anaemia and thrombocytopenia in 1967. However, the genetic basis to the condition was not established until the mid-90s.²

ALPS should be considered in all children with unexplained lymphadenopathy, organomegaly, or autoimmune cytopenias.¹

Aetiology^1,2

Autoimmune lymphoproliferative syndrome (ALPS) is caused by genetic defects in the genes controlling apoptosis (programmed cell death):

• The defective pathway is Fas-mediated apoptosis, which is part of the normal downregulation of the immune system involving T and B lymphocytes.
• This leads to chronic lymphoproliferation, autoimmunity and an increased risk of malignancies.
• Approximately 70% of patients have an identifiable genetic mutation.

Presentation¹

Onset and time course

• Most patients present with lymphoproliferation (see below) in early childhood (median age approximately 1 year).
• The autoimmune manifestations usually present in early childhood; this can occur months to years after the lymphoproliferation onset.
• More rarely, can present in adulthood.³
• Both lymphoproliferation and autoimmunity may improve with age.

Clinical features

Lymphoproliferation:

• The most common feature of autoimmune lymphoproliferative syndrome (ALPS).
• Comprises lymphadenopathy, hepatomegaly or splenomegaly.

Autoimmunity:

• Autoimmune destruction of blood cells is the most common feature, varying from mild and asymptomatic to severe. It affects 70% of patients and may cause:
  • Autoimmune haemolytic anaemia.
  • Immune thrombocytopenia.
  • Autoimmune neutropenia - but usually without increased risk of invasive infection, as ALPS patients can mount a neutrophil response to infection.

Other autoimmune manifestations (less common):

• Nephritis
• Hepatitis
• Uveitis
• Autoimmune cerebellar syndrome
• Colitis
• Urticarial rashes⁴
• Pulmonary fibrosis
• Almost any organ can be involved

The autoimmunity may fluctuate and can flare up with systemic illness.

Investigations¹

General investigations

Blood tests may show:

• Autoimmune-type haemolytic anaemia, thrombocytopenia, neutropenia and hypergammaglobulinaemia.
• T- and B-cell lymphocytosis.
• Positive direct Coombs' test - direct antiglobulin test (DAT).
• Positive autoantibodies (antiplatelet and antineutrophil and antinuclear).
• Raised IgG levels, possibly also raised IgA or IgM; but some patients have hypogammaglobulinaemia.
• Raised serum B12.
• Raised interleukin-10 (IL-10).

Biopsy:

• Most patients merit tissue biopsy (bone marrow or lymph nodes) initially to rule out malignancy, infections and other lymphoproliferative disorders.
• Histology of lymph nodes shows marked paracortical expansion of T cells, and other characteristic features.

Radiology:

• Imaging of the liver, spleen or lymph nodes cannot accurately distinguish benign from malignant lymphoproliferation in the context of autoimmune lymphoproliferative syndrome (ALPS).

Diagnostic tests

The following are tests used in diagnosing ALPS and require a specialised laboratory:

• Circulating 'double-negative T cells' (cell phenotype CD4^-/CD8^-, CD3⁺, TCRαβ⁺):
  • These are markedly increased in ALPS patients (>5% increase).
  • However, false negatives can occur if there is lymphopenia.
• Defective in vitro Fas-mediated apoptosis:
  • An expensive and lengthy test only available in a few research laboratories.
  • Does not identify all subtypes of ALPS.

Diagnostic criteria¹

The accepted diagnostic criteria for autoimmune lymphoproliferative syndrome (ALPS) are:

1. Chronic nonmalignant lymphoproliferation (>6 months and if limited to lymph nodes, must affect ≥2 distinct nodal groups)
2. Elevated blood double-negative T cells.
3. Defective in vitro Fas-mediated apoptosis.

However, these criteria require the in vitro test for Fas-mediated apoptosis, which has drawbacks (above). Therefore, new diagnostic criteria have been developed which allow ALPS to be diagnosed without this test, based on other clinical and laboratory findings.

Differential diagnosis¹

• The differential diagnosis is wide, involving other autoimmune, infectious, malignant and lymphoproliferative disorders.
• Includes Evans' syndrome (autoimmune destruction of at least 2 cell types) - a recent study suggests that some children diagnosed with Evans' syndrome have autoimmune lymphoproliferative syndrome (ALPS).⁵

Management¹

Patient care involves haematology, immunology and genetic specialists.

Some patients do not need any treatment.

In many cases, treatment for autoimmunity is required. This is usually given as short bursts of immunosuppressive medication. A suggested new treatment algorithm uses the following:

• First-line - prednisolone (1 mg/kg bd).
• Second-line - mycophenolate mofetil (moderate disease) or sirolimus (severe disease).
• Third-line - vincristine or methotrexate or mercaptopurine or pyrimethamine/sulfadoxine.
• Fourth-line - consider rituximab, splenectomy or combined immunosuppressants.

Also:

• Splenectomy should be avoided except in cases of uncontrollable hypersplenism.
• A small subset of patients responds to intravenous immunoglobulin (but most do not).
• Stem cell transplantation may have a role - currently it is reserved for those with severe disease not responding to other treatment.

Long-term follow-up is required, including surveillance for lymphoma.⁶

Complications¹

Increased risk of malignancy:

• Lymphoma (Hodgkin's or non-Hodgkin's) is the most common.
• The magnitude of increased risk is unknown. In one study, the risk of Hodgkin's lymphoma in individuals with inherited Fas mutations was 51 times greater than that of the general population aged below 65; for non-Hodgkin's lymphoma it was 14 times greater. In this study, the average age of lymphoma diagnosis was 28 years.⁷
• Relatives who inherit the same genetic mutation may have an increased malignancy risk.⁷
• Fas gene mutations have been reported in tumour cells from T-cell leukaemia, multiple myeloma, melanoma, non-small cell lung cancer and transitional cell carcinoma of the bladder. However, the relevance of these findings to ALPS patients is not clear.⁸

Infections:

• Increased risk of postsplenectomy pneumococcal sepsis, even with vaccination and antibiotic prophylaxis.
• The autoimmune neutropenia itself does not usually confer an increased risk of infection, as there is usually a neutrophil response to infection. However, immunosuppressive medication (if used) may increase infection risk.
• Some patients develop common variable immunodeficiency (5-10%).

Prognosis

• Long-term prognostic data are lacking, because this is a rare and recently identified disease.² Autoimmune lymphoproliferative syndrome (ALPS) patients can live into adulthood.^2,3
• Symptoms may improve as the patient ages.
• One study looking at 200 ALPS patients over the previous 15 years found the major determinants of morbidity and mortality are:⁶
  • Severity of the autoimmune disease.
  • Hypersplenism.
  • Asplenia-related sepsis.
  • Lymphoma risk (see Complications above) - this requires long-term surveillance.

Document references

1. Teachey DT, Seif AE, Grupp SA; Advances in the management and understanding of autoimmune lymphoproliferative Br J Haematol. 2010 Jan;148(2):205-16. Epub 2009 Nov 23. [abstract]
2. Straus SE, Sneller M, Lenardo MJ, et al; An inherited disorder of lymphocyte apoptosis: the autoimmune lymphoproliferative syndrome. Ann Intern Med. 1999 Apr 6;130(7):591-601. [abstract]
3. Deutsch M, Tsopanou E, Dourakis SP; The autoimmune lymphoproliferative syndrome (Canale-Smith) in adulthood. Clin Rheumatol. 2004 Feb;23(1):43-4. Epub 2003 Dec 20. [abstract]
4. Auricchio L, Vitiello L, Adriani M, et al; Cutaneous manifestations as presenting sign of autoimmune lymphoproliferative syndrome in childhood. Dermatology. 2005;210(4):336-40. [abstract]
5. Teachey DT, Manno CS, Axsom KM, et al; Unmasking Evans syndrome: T-cell phenotype and apoptotic response reveal Blood. 2005 Mar 15;105(6):2443-8. Epub 2004 Nov 12. [abstract]
6. Rao VK, Straus SE; Causes and consequences of the autoimmune lymphoproliferative syndrome. Hematology. 2006 Feb;11(1):15-23. [abstract]
7. Straus SE, Jaffe ES, Puck JM, et al; The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. Blood. 2001 Jul 1;98(1):194-200. [abstract]
8. Jackson CE, Puck JM; Autoimmune lymphoproliferative syndrome, a disorder of apoptosis. Curr Opin Pediatr. 1999 Dec;11(6):521-7. [abstract]

Internet and further reading

• Bleesing JJ, Straus SE, Fleisher TA; Autoimmune lymphoproliferative syndrome. A human disorder of abnormal lymphocyte survival. Pediatr Clin North Am. 2000 Dec;47(6):1291-310. [abstract]

Acknowledgements