Diagnostic Overshadowing and the Unseen Spectrum: A Narrative Review of Rare Complications in Sickle Cell Disease.

Sickle cell disease (SCD) is a hereditary hemoglobin disorder characterized by chronic hemolysis and recurrent vaso-occlusive crises, leading to a wide spectrum of complications. While common SCD manifestations have well-established management protocols, rare and atypical complications pose significant diagnostic and therapeutic challenges. A critical barrier is diagnostic overshadowing, where common SCD symptoms (pain, fever, respiratory distress) mask infrequent but life-threatening conditions, resulting in delayed recognition and suboptimal outcomes. This narrative review synthesizes the literature from 2000-2025 on rare SCD complications, including atypical neurological events (e.g., spontaneous epidural or subdural hematoma, central retinal artery occlusion, cerebral arteriovenous malformations, posterior reversible encephalopathy syndrome), uncommon hematologic syndromes (acute leukemia, extramedullary hematopoiesis in unusual sites, hemophagocytic lymphohistiocytosis), severe cardiopulmonary emergencies (acute multiorgan failure and fat embolism syndromes), unusual hepatic crises (acute hepatic sequestration, intrahepatic cholestasis), and others (e.g., compartment syndrome). Key insights underscore the need for high clinical suspicion and prompt use of advanced diagnostics (e.g., MRI, specialized laboratory tests) when patients present with atypical or disproportionate symptoms. Clinical implications: Heightening clinician awareness of these rare complications and implementing structured diagnostic strategies can facilitate earlier intervention, improving outcomes and reducing the high morbidity and mortality associated with these infrequent but severe events.