Immune Dysregulation Syndrome Associated with Inborn Errors of Metabolism – Hemophagocytic Lymphohistiocytosis in the Context of Isovaleric Acidemia: A Case Report

Hemophagocytic lymphohistiocytosis (HLH) remains one of the greatest diagnostic challenges in pediatric critical care because of its high mortality and the complexity of its clinical presentations. We report the case of an 18-month-old boy who presented with persistent fever, a respiratory tract infection, pancytopenia, hepatosplenomegaly, and progressive neurological deterioration, fulfilling the diagnostic criteria of the HLH-2004 protocol [2]. His clinical course was complicated by concurrent viral infections (adenovirus and parainfluenza virus type III) and antibody-mediated neurological autoimmunity (anti-NMDA receptor encephalitis), an association rarely reported in the current literature [4,5]. A broad differential diagnosis was evaluated with immunologic, genetic, and neuroimaging studies. The combination of autoimmunity, recurrent infections, and positive family history suggested secondary HLH on the background of an underlying primary immunodeficiency [9]. The patient's outcome and the death of a sibling with a similar clinical picture indicate that this episode was not merely secondary HLH, but the first manifestation of a severe primary immune dysregulation, possibly related to mutations in genes such as CTLA4, LRBA, or STAT3—genes recognized within the spectrum of autoimmune lymphoproliferative immunodeficiency disorders (ALPID) [9,10]. This case illustrates the most aggressive facet of pediatric HLH and underscores the need to suspect hidden primary immunodeficiencies in patients with recurrent infections and early autoimmunity. Early recognition of this phenotype can make the difference between a fatal outcome and the possibility of offering targeted immunomodulatory or potentially curative therapies [12,13]. In critical pediatrics, HLH should no longer be considered a final diagnosis but rather a warning sign of an underlying genetic immune dysregulation.