Autoimmune Lymphoproliferative Syndrome

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.¹ It can present in children or adults but usually presents in early childhood.²

Canale and Smith described a syndrome of lymphadenopathy and splenomegaly associated with haemolytic anaemia and thrombocytopenia in 1967.³ However, the genetic basis to the condition was not established until the mid-90s.³

ALPS should be considered in all children with lymphadenopathy, hepatosplenomegaly and autoimmune haematological conditions.

• Most have mutations affecting the Tumour Necrosis Factor Super Family 6 (TNFSF6) gene that codes for the Fas protein (also known as Apo-1 or CD95).¹ This means that abnormal Fas protein is produced in most people with ALPS.
• Mutations in other genes such as Fas-ligand and Caspase-10 and 8 may also cause the syndrome.³
• Autosomal dominant and autosomal recessive inheritance has been identified. Sporadic cases are also thought to occur.
• Fas is an important protein regulating apoptosis (programmed cell death), and its dysfunction leads to lymphocyte persistence and proliferation. Excess lymphocytes gather in the lymph glands, liver and spleen and B-lymphocytes secrete autoantibodies against platelets, erythrocytes or other haematological cells.

• Hepatosplenomegaly presenting in first 2–3 years of life.
• Gross lymphadenopathy, especially in the neck and axillae.
• Haemolytic anaemia
• Immune-mediated thrombocytopenia can occur and lead to nose bleeds, petechiae or other bleeding diathesis.
• Autoimmune neutropenia can occur and increases infection risk.
• Autoimmunity may less commonly affect other organs such as the skin, liver, kidney or nerves.
• Angioedema, urticaria and vasculitic rashes may occur.⁴

• Increased number of circulating alphabeta+ CD3+ CD4-CD8- T-cells (also known as double-negative T-cells).
• There are also characteristic pathological findings in the lymph nodes and spleen which may be seen on lymph node biopsy or after splenectomy.
• Autoimmune-type haemolytic anaemia, thrombocytopenia, neutropenia and hypergammaglobulinaemia may be present.

• Prednisolone may be used for the treatment of autoimmune episodes with variable success.
• Chemotherapy and granulocyte colony stimulating factor have also been used with varying results.¹
• Recently, a combination of rituximab and vincristine has been tried.⁵ Rituximab has also been used alone with good effect but relapses are common.⁶
• There have been some reports of beneficial response to the antimalarial drug sulphadoxine/pyrimethamine.¹
• Blood transfusion may be needed to treat autoimmune haemolytic anaemia.
• Splenectomy may be used with careful balancing of the benefits against the need for long-term antibiotics and immunisations to prevent capsulated organism infection.
• Bone marrow transplantation has been performed.⁷

• Long term survival does occur.² Symptoms may improve as the patient ages.
• Defective apoptosis and inappropriate survival of lymphocytes may lead to an increased risk of developing malignancies, especially lymphoma.^8,9,10,11,12
• One study looking at 200 ALPS patients over the last 15 years found the major determinants of morbidity and mortality are:
  • Severity of the autoimmune disease
  • Hypersplenism
  • Asplenia-related sepsis
  • Lymphoma risk (this requires long-term surveillance)¹¹