Dermatology MCQ - Infiltrative and Neoplastic Disorders - Haemophagocytic lymphohistiocytosis

A 6-month-old infant is admitted with a 1-week history of high-grade fever, diffuse macular rash, and hepatosplenomegaly. Laboratory investigations reveal pancytopenia, hypertriglyceridemia, hypofibrinogenemia, and a markedly elevated serum ferritin level. A bone marrow biopsy is performed and shows histiocytes engulfing erythrocytes and other hematopoietic elements. What is the most likely diagnosis and the underlying pathophysiological defect?

A. Severe Sepsis with Disseminated Intravascular Coagulation (DIC); caused by uncontrolled infection.
B. Langerhans Cell Histiocytosis; caused by a clonal proliferation of CD1a+ dendritic cells.
C. Haemophagocytic Lymphohistiocytosis (HLH); caused by defective cytotoxic T-cell and NK-cell function leading to uncontrolled immune activation.
D. Leukemia; caused by malignant proliferation of hematopoietic precursors.
E. Macrophage Activation Syndrome (MAS); this term is used specifically in the context of underlying systemic Juvenile Idiopathic Arthritis.

Correct Answer: C. Haemophagocytic Lymphohistiocytosis (HLH); caused by defective cytotoxic T-cell and NK-cell function leading to uncontrolled immune activation.

Answer and Explanation

The correct answer is C. This question presents the classic clinical and laboratory picture of Haemophagocytic Lymphohistiocytosis (HLH). The key features are the persistent fever, hepatosplenomegaly, cytopenias, and the characteristic biochemical triad of hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia. The bone marrow finding of haemophagocytosis (histiocytes engulfing blood cells) is a hallmark, though it is not always present. The core pathophysiology is a severe, dysregulated immune response due to defective cytotoxic function of T-cells and Natural Killer (NK) cells, leading to uncontrolled proliferation and activation of histiocytes/macrophages and a massive cytokine storm.

Why the Other Options are Incorrect:

• A. Severe Sepsis with DIC: While sepsis and DIC can cause fever, cytopenias, and organ dysfunction, they do not typically cause the massive hyperferritinemia or hypertriglyceridemia seen in HLH. HLH is essentially a syndrome of extreme immune activation, which can be triggered by infection (most commonly EBV), but the pathophysiology is distinct from straightforward sepsis.

• B. Langerhans Cell Histiocytosis: LCH is a proliferative disorder of specific dendritic cells (Langerhans cells). It does not typically present with the acute, fulminant systemic inflammatory picture, cytopenias, or the specific lipid/ferritin abnormalities of HLH.

• D. Leukemia: Leukemia can cause cytopenias and fever, but it would not explain the hypertriglyceridemia, hypofibrinogenemia, or extreme hyperferritinemia. The bone marrow in leukemia would be replaced by blasts, not show haemophagocytosis as the primary finding.

• E. Macrophage Activation Syndrome (MAS): This is a trick option because MAS is a form of secondary HLH. It is not incorrect per se, but the term is most accurately applied when HLH occurs in the context of a rheumatic disease, most commonly Systemic Juvenile Idiopathic Arthritis (sJIA). In an infant without a known rheumatic disease, the more general term HLH is the best answer.

Additional High-Yield Information for Exams:

• Diagnostic Criteria (HLH-2004): A diagnosis of HLH is made by fulfilling either 1) a molecular diagnosis consistent with HLH (e.g., PRF1, UNC13D mutations) OR 2) fulfilling 5 out of 8 the following criteria:

  1. Fever

  2. Splenomegaly

  3. Cytopenias (affecting ≥2 of 3 lineages in the peripheral blood)

  4. Hypertriglyceridemia (≥265 mg/dL) and/or hypofibrinogenemia (≤150 mg/dL)

  5. Haemophagocytosis in bone marrow, spleen, or lymph nodes

  6. Low or absent NK-cell activity

  7. Ferritin ≥500 ng/mL (Note: in HLH, it is often >10,000 ng/mL)

  8. Elevated soluble CD25 (sIL-2 receptor) ≥ 2400 U/mL

• Types of HLH:

  • Primary (Familial) HLH: Autosomal recessive genetic defects in perforin-mediated cytotoxic killing (e.g., in PRF1, UNC13D genes). Typically presents in infancy, as in this question.

  • Secondary HLH: Triggered by infections (EBV is most common), malignancies, or rheumatic diseases (where it is called MAS).

• Prognosis: HLH is life-threatening with a high mortality rate if not treated aggressively and promptly.

• Management & Rationale:

  • Rationale: The goal is to suppress the life-threatening hyperinflammation and, for primary HLH, to bridge the patient to a definitive cure.

  • First-line Therapy: The initial standard is the HLH-94/2004 protocol, which includes dexamethasone, etoposide, and cyclosporine A. This regimen is designed to kill activated T-cells and macrophages and suppress the cytokine storm.

  • Targeted Therapy: Emapalumab, an anti-interferon-gamma monoclonal antibody, is now approved for refractory or intolerant primary HLH.

  • Definitive Cure: For primary HLH, the only curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT).