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]

SAQ 2 (10)

A two-year-old has had fevers every five weeks for a year. Each attack lasts about four days, with a red throat, mouth ulcers and tender cervical adenitis, and a raised C-reactive protein; between attacks he is entirely well and grows normally. His six-month-old cousin was admitted last week with persistent fever, splenomegaly, a ferritin well above 10,000 and falling cell counts. [13]

1. Give the most likely diagnosis for the two-year-old and the expected natural history. (3) [13]
2. For the cousin, name the syndrome you must not miss and the immediate management priorities. (4) [8] [9]
3. Explain why one family can hold two very different immune-control disorders, and what this teaches about the framework. (3) [1]

Model answer

Diagnosis and natural history. The two-year-old has PFAPA syndrome: regular fevers every three to eight weeks with pharyngitis, aphthous stomatitis and cervical adenitis, complete wellbeing between attacks, and a raised acute-phase response during attacks only. The natural history is one of spontaneous resolution over years, with an excellent long-term outlook. Anticipatory corticosteroid at the very start of an attack aborts it in many children; tonsillectomy is reserved for severe, refractory cases. [13]

The cousin — must-not-miss and immediate priorities. The cousin has the cluster of persistent fever, splenomegaly, a very high ferritin and falling cell counts that defines haemophagocytic lymphohistiocytosis, or HLH, a cytokine storm that can be primary (genetic) or secondary. Immediate priorities are time-critical bloods including ferritin, triglycerides, fibrinogen, full blood count, liver function and lactate dehydrogenase, empiric broad-spectrum antibiotics because sepsis is clinically indistinguishable, and treatment for suspected primary HLH on clinical grounds per the HLH-2004 principle of early dexamethasone-based therapy with escalation to etoposide and cyclosporin as guided by the specialist team. I would escalate to a tertiary clinical immunology or rheumatology centre and paediatric intensive care without delay, and plan for haematopoietic stem cell transplant if primary disease is confirmed. [8] [9]

The framework lesson. One family can hold two different immune-control disorders because the immune system is controlled at multiple independent points — tolerance, apoptosis, and innate cytokine regulation — each governed by different genes. PFAPA is a disorder of innate immune and T-helper-1 activation, while HLH is a failure of cytotoxic and cytokine control that converges on a final cytokine storm. The teaching point is to sort every such presentation by its dominant mechanism and clear the threat gate first, rather than assuming a single unifying diagnosis. [1]