Case Presentation: The World Health Organization designates a rare disease as one affecting under 6.5-10 per 10,000 people (1). We present a case of disparate findings, ultimately diagnosing Erdheim-Chester Disease (ECD), a rare non-Langerhans histiocytic multisystem disorder with fewer than 1000 reported cases (2,3).A 63-year-old man presented with months of progressively worsening anasarca, acute on chronic macrocytic anemia and acute kidney injury (AKI). Initial workup revealed severe hypoproteinemia, numerous vitamin deficiencies, hypocholesterolemia, and hepatic synthetic dysfunction with profound coagulopathy.Each successive wave of tests raised more questions than answers, resulting in a protracted hospitalization, complicated by transfusion-dependent anemia, anuric AKI requiring dialysis, profound anasarca and undifferentiated shock requiring inotropes. Our extensive workup included a bone marrow biopsy, multiple colonoscopies and esophagogastroduodenoscopies, skin and liver biopsies, a PET scan as well as whole exome sequencing. After many multidisciplinary conferences and involving multiple medical subspecialists, it was concluded that ECD was highly probable.
Discussion: This rare multisystem disorder posed a diagnostic challenge as no single test was confirmatory; the diagnosis was made instead on a combination of immunohistochemical, clinical, and radiographic criteria. Moreover, although ECD is known to involve multiple organ systems, it did not explain the transfusion-dependent anemia, acute renal failure, profound vitamin, copper and zinc deficiencies, and hypocholesterolemia, all of which remain a mystery.ECD most commonly manifests with long-bone sclerosis (2), noted on X-rays of his distal femora. Other case findings suggesting ECD include +CD68, +CD163 and negative CD1a on histiocyte immunohistochemistry, xanthogranulomas on prior conjunctival biopsy, lipidized histiocytes and touton giant cells on skin biopsy, and foamy histiocytes in bone marrow biopsy.This case highlights the inherent diagnostic difficulty of ECD, due to variable clinical presentations. 95% of cases harbor a mutation in a MAP-kinase-pathway gene (4), which was not present in this case. Osseous manifestations are often present and a majority have at least one non-bony site of involvement including cardiovascular, neurologic, endocrine, pulmonary, or thyroid, testes, gingiva, kidney, and spleen manifestations (5, 6, 7). Given the strong supporting evidence for ECD without a more likely diagnosis, treatment was initiated with cobimetinib (a MEK inhibitor) based on consensus guidelines and on surveillance follow up, most of his symptoms have slowly improved.
Conclusions: Despite improvement after initiating cobimetinib for ECD, there is continued diagnostic uncertainty. This case highlighted that uncertainty can lead to thinking about zebra diagnoses and discomfort with uncertainty. Our hunt for a unifying diagnosis resulted in a prolonged hospitalization which garnered him increasingly specific and expensive testing.As modern medicine advances and newer targeted diagnostic tests are introduced, cases such as these remind us of our limitations. Our available armamentarium of tests can cast a wide net but are not all-encompassing. This case highlights the importance of maintaining physical exam skills, exercising case-specific clinical judgment, and managing diagnostic uncertainty in a collaborative effort towards reaching that elusive final diagnosis.