Differential Diagnosis

The patient's presentation of extremely low C4 and normal C3, combined with a history of hereditary angioedema and possible lymphoma, suggests several potential diagnoses. These can be categorized as follows:

• Single Most Likely Diagnosis

  • Hereditary Angioedema (HAE) with C1 esterase inhibitor deficiency: This condition is characterized by recurrent episodes of angioedema, often without urticaria, and is associated with low levels of C4 due to unregulated activation of the classical complement pathway. The normal C3 level helps to differentiate it from other complement pathway abnormalities.

• Other Likely Diagnoses

  • Lymphoma: Certain types of lymphoma can consume complement components, leading to low levels. The involvement of C4 without affecting C3 could be seen in specific lymphoma types, although this is less common.
  • Autoimmune disorders: Conditions like systemic lupus erythematosus (SLE) can lead to low C4 levels due to complement activation. However, C3 is often also decreased in these conditions, making this less likely given the normal C3 level in this patient.

• Do Not Miss Diagnoses

  • SLE with a specific pattern of complement consumption: Although less common, SLE can present with isolated low C4 levels if the disease process preferentially consumes C4. Missing this diagnosis could lead to delayed treatment and significant morbidity.
  • Post-streptococcal glomerulonephritis (PSGN): This condition can also present with low C4 levels due to complement activation. It's crucial to consider PSGN, especially if there's a history of recent streptococcal infection, as it requires prompt treatment to prevent long-term renal damage.

• Rare Diagnoses

  • C4-binding protein deficiency: A rare condition that could lead to low C4 levels due to increased consumption or degradation of C4.
  • Specific types of complement component deficiencies: Other than C1 esterase inhibitor deficiency, deficiencies in other components of the classical pathway (like C1q, C1r, C1s, C2, or C4 itself) could potentially lead to low C4 levels. These are rare and often present with increased susceptibility to infections.
  • Paroxysmal Nocturnal Hemoglobinuria (PNH): Although primarily known for its hemolytic manifestations, PNH can also involve complement pathway abnormalities. However, low C4 with normal C3 would be an unusual presentation for PNH.