Immune dysregulation syndrome associated with inborn errors of metabolism – hemophagocytic lymphohistiocytosis in the context of isovaleric acidemia: a case report

Hemophagocytic lymphohistiocytosis (HLH) continues to pose a diagnostic challenge in pediatric critical care, not only because of its severity but also due to the wide range of conditions that can underlie its presentation. Among these, metabolic disorders are often overlooked. We describe an 18-month-old boy who initially presented with persistent fever and respiratory symptoms, later evolving to pancytopenia, hepatosplenomegaly, and neurological deterioration, the patient fulfilled seven of the eight HLH-2004 criteria. Along the way, adenovirus and parainfluenza virus type III were identified, and anti-NMDA receptor encephalitis was confirmed, adding further complexity to the clinical picture. What proved decisive was the identification of a homozygous pathogenic variant in the IVD gene (c.1174C > T; p.Arg392Cys), establishing the diagnosis of isovaleric acidemia. This finding reframed the case. Rather than an isolated hyperinflammatory syndrome, the clinical course can be better understood as the result of a metabolic disorder capable of amplifying immune dysregulation, particularly in the setting of intercurrent infection. In this context, the features of HLH appear not as a separate entity but as part of a broader process, where metabolic decompensation, accumulation of toxic intermediates, and systemic inflammation converge. This overlap is likely underrecognized in clinical practice. Recognizing this possibility has practical implications. It shifts the diagnostic focus, but also opens the door to more tailored management strategies. In similar cases, HLH may be less an endpoint diagnosis and more a signal pointing toward an underlying metabolic or genetic condition that requires specific attention.