Immune dysregulation, lymphoproliferation and autoinflammatory disease — formative SAQs

SAQ 1 (10)

A four-year-old presents with chronic painless splenomegaly and cervical lymphadenopathy over the past year, and a current full blood count showing a haemoglobin of 78 g/L, a platelet count of 40 and a positive direct antiglobulin test. The blood film shows no blasts. Between episodes she is well. ^[6]

1. State the most likely diagnosis and the single investigation that most strongly supports it. (3) ^[6]
2. Outline your definitive management, naming the first-line steroid-sparing agent and the operation you would avoid. (4) ^[7]
3. Explain why this disease is classified as a failure of immune control and which mechanism has failed. (3) ^[1]

Model answer

Diagnosis and supporting investigation. The most likely diagnosis is autoimmune lymphoproliferative syndrome (ALPS): chronic, non-tender splenomegaly and lymphadenopathy with autoimmune haemolysis and thrombocytopenia in an otherwise well child, with no blasts to suggest malignancy. The investigation that most strongly supports it is an immunophenotype demonstrating a population of double-negative T cells that are alpha-beta T-cell-receptor positive and both CD4-negative and CD8-negative, supported by elevated vitamin B12 and soluble Fas ligand. I would also exclude lymphoma with a film and, if needed, a node biopsy. ^[6]

Definitive management. The first-line steroid-sparing definitive therapy is sirolimus, an mTOR inhibitor that controls the chronic lymphoproliferation and the autoimmune cytopenias. The operation I would avoid is splenectomy, which historically caused overwhelming post-splenectomy infection without durably controlling the disease; it has been displaced by medical therapy. Cytopenias are managed with supportive care and immunomodulation, and the child is referred to clinical immunology with genetic testing of the FAS pathway. ^[7]

Classification and mechanism. ALPS sits in the IUIS classification of inborn errors of immunity as a disease of failed immune control rather than infection susceptibility. The mechanism that has failed is apoptosis: defects in the Fas apoptotic pathway (FAS, FASL or CASP10) prevent activated lymphocytes from dying, so they accumulate as the double-negative T cells and drive chronic organomegaly and autoimmune cytopenias. ^[1]