P2.L228: Incidental hepatosplenomegaly leads to a rare diagnosis of autoimmune lymphoproliferative syndrome

Introduction: Hepatosplenomegaly is an important clinical finding suggesting an underlying hematologic, metabolic, infectious, or inflammatory problem. Rarely, this finding can be secondary to inborn errors of immunity. Autoimmune Lymphoproliferative Syndrome (ALPS) is an immune defect that affects the FAS apoptosis pathway, which is crucial for lymphoid homeostasis (Figure 1). Loss of function in the FAS pathway leads to T cell dysregulation, hyperproliferation, and resulting autoimmunity. In this report, we present a case of incidental hepatosplenomegaly leading to a diagnosis of ALPS.

Case Description: A 1-year-old with a history of idiopathic urate nephrolithiasis presented to the Nephrology clinic for a surveillance renal ultrasound. Imaging revealed incidental hepatosplenomegaly and abdominal lymphadenopathy. He was referred for urgent Hematology evaluation, but he presented to the Emergency Department (ED) three days later for a high fever. He was found to have adenovirus but work-up also revealed new-onset neutropenia (1.8 x109/L ) and normocytic anemia (7.2 g/dL). Flow cytometry, metabolic genetic panel, immunoglobulins, and lymphocyte enumeration panel were obtained and all were unremarkable. LDH was elevated, but haptoglobin and direct antiglobulin testing were negative. Reticulocyte count was appropriately elevated. He had near full resolution of his neutropenia the following week with only supportive care. Anemia and hepatosplenomegaly were persistent, yet improving, at the time of discharge. Further diagnostics by Hematology including glucose-6-phosphate dehydrogenase mutation, osmotic fragility, and electrophoresis testing were all unremarkable.

Eight months later, he again presented to the ED with a high fever as well as a large cervical lymphadenopathy. He was again found to have significant neutropenia with worsening anemia. He underwent lymph node and bone marrow biopsies which revealed clonal expansion of double-negative T cells. He was found to have a heterozygous c.334+2dup in the Fas gene consistent with ALPS. He was started on Sirolimus with a full resolution of his symptoms within the following weeks.

Discussion: Approximately 1,000 cases of ALPS have been identified worldwide, though this is likely an underestimation. Defects in the Fas gene are most commonly implicated, but defects in downstream proteins have been described. Enlarged lymphatic organs and concomitant autoimmunity have traditionally characterized ALPS. Affected patients should be closely monitored given their high risk for secondary lymphoma.

Notably, there is no correlation between urate nephropathy and ALPS in the literature. We hypothesize that increased immune-mediated cellular breakdown leads to increased purine degradation, and thus uric acid excretion. Further investigation is needed to determine potential links between these syndromes.

Conclusion: Hepatosplenomegaly is a critical clinical sign with a broad differential diagnosis. Inborn errors of immunity are important in this differential, but overall are rare which may lead to delayed diagnosis as seen in this patient.