Rare Conditions: EHA 2026 Highlights Diagnostic Challenges

Rare haematological conditions, by definition, affect a small proportion of the population, leading to limited clinical experience among general practitioners and even many specialists. This scarcity of direct exposure contributes to diagnostic challenges, often resulting in delayed or missed diagnoses. The consequences of such delays can be severe, ranging from disease progression and irreversible organ damage to increased morbidity and mortality. For instance, conditions like atypical haemolytic uremic syndrome (aHUS) or paroxysmal nocturnal haemoglobinuria (PNH) require prompt and specific interventions to prevent life-threatening complications. The EHA 2026 session aimed to address these challenges by presenting real-world cases that illustrate the diagnostic complexities and the systematic approaches required for accurate identification. The session also underscored the importance of early recognition, as many rare haematological disorders, despite their low prevalence, carry significant morbidity and mortality if left untreated. Understanding the underlying pathophysiology, such as complement dysregulation in aHUS or GPI-anchored protein deficiency in PNH, is crucial for guiding diagnostic investigations and therapeutic strategies.¹

The Sherlock Holmes Approach: Case Studies

The session, 'The Sherlock Holmes Approach: Real Cases, Rare Conditions,' focused on a series of anonymized patient cases involving rare haematological disorders. These cases were selected for their atypical presentations, initial misdiagnoses, and the eventual diagnostic pathways that led to correct identification. The methodology involved a step-by-step analysis of each case, starting from the initial patient presentation and progressing through the differential diagnoses considered, the diagnostic tests performed, and the expert consultations sought. The emphasis was on demonstrating how a structured, hypothesis-driven approach, akin to deductive reasoning, can navigate complex clinical scenarios. For example, one case detailed a patient presenting with unexplained anaemia, thrombocytopenia, and renal dysfunction. Initial investigations focused on common causes of kidney injury and cytopenias. However, the persistence of symptoms despite standard treatments, coupled with specific laboratory markers (e.g., elevated lactate dehydrogenase, negative Coombs test, schistocytes on peripheral smear), eventually pointed towards a thrombotic microangiopathy. Further specialized testing, including complement pathway analysis, confirmed a diagnosis of aHUS. This case exemplified the need for clinicians to maintain a high index of suspicion for rare diseases, particularly when common etiologies are ruled out or when patients do not respond to conventional therapies.²

Another presented case involved a patient with chronic fatigue, abdominal pain, and dark urine, initially misdiagnosed as irritable bowel syndrome and iron deficiency anaemia. The diagnostic breakthrough occurred when a flow cytometry analysis for CD55 and CD59 on red blood cells was performed, revealing a deficiency consistent with PNH. This case highlighted the importance of considering rare conditions when common explanations are exhausted and symptoms persist or recur. The session also emphasized the role of interdisciplinary collaboration, particularly with nephrologists, gastroenterologists, and geneticists, in piecing together disparate clinical clues. The presenters underscored that a comprehensive review of the patient's entire clinical history, rather than focusing solely on the most prominent symptom, was critical. The integration of genetic testing and specialized biomarker analysis was also highlighted as essential tools in confirming diagnoses for many rare haematological conditions. These tools are increasingly accessible and provide definitive diagnostic evidence, moving beyond phenotypic observations.³

Limitations and Clinical Implications

While the case-based approach effectively illustrated diagnostic strategies, a limitation of such sessions is the inherent selection bias; cases presented are typically those where a diagnosis was eventually reached, potentially overlooking the challenges of truly undiagnosed rare conditions. Furthermore, the availability of advanced diagnostic tools and specialist expertise, as demonstrated in the presented cases, may not be uniformly accessible across all healthcare settings. The session did not provide quantitative data on the overall reduction in diagnostic delay across a large cohort, but the qualitative evidence from the cases strongly suggested that a systematic approach can significantly shorten the diagnostic odyssey. Future research could involve prospective studies evaluating the impact of structured diagnostic algorithms on time to diagnosis in suspected rare haematological conditions. The immediate takeaway for clinicians is the reinforcement of meticulous clinical data collection, persistent investigation of unexplained symptoms, and proactive engagement with specialist networks. This approach is particularly relevant for patient populations with non-specific symptoms that could mask underlying rare conditions, such as unexplained cytopenias, thrombotic events without clear risk factors, or unexplained organ dysfunction.⁴

For deeper insights into diagnosing and managing complex haematological conditions, we recommend consulting the Oxford Handbook of Clinical Haematology.