Post-COVID-19 Infant with a Hemizygous PRF1 Mutation and Overlapping Features between MIS-C and Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening disorder that requires a high index of suspicion and comprehensive evaluation for timely recognition. Its rarity, diverse clinical manifestations, and overlapping symptoms with other hyperinflammatory syndromes, such as the recently emerged Multisystem Inflammatory Syndrome in Children (MIS-C) during the COVID-19 pandemic, present unique diagnostic challenges.

Herein, we report the case of an 8-month-old infant initially suspected of MIS-C following acute liver failure after COVID-19 exposure. The diagnosis was later revised to secondary HLH with an atypical presentation. Despite initial management for MIS-C, the patient's condition deteriorated, prompting further investigation. Laboratory findings, including elevated ferritin levels, low fibrinogen, and worsening thrombocytopenia, suggested HLH, leading to targeted diagnostic evaluations. Genetic testing revealed a heterozygous PRF1 mutation, and additional laboratory investigations showed markedly elevated IL-2 receptor and CXCL9, with decreased CD107a and perforin expression in NK cells. The patient met four out of five diagnostic criteria for HLH. Treatment with intravenous immunoglobulin (IVIG) and high-dose steroids resulted in significant clinical improvement, and the patient has remained symptom-free since the episode.

This case highlights the diagnostic challenges in differentiating hyperinflammatory syndromes in pediatric patients with COVID-19 exposure. It underscores the importance of considering HLH in the differential diagnosis, even when standard HLH diagnostic criteria are not fully met at presentation and when standard treatments fail in patients suspected of having MIS-C. Given the frequent occurrence of atypical HLH presentations, early evaluation for HLH is crucial in children with hyperinflammation, such as MIS-C, especially when patients exhibit hyperferritinemia, hypofibrinogenemia, cytopenia, acute liver failure or are unresponsive to MIS-C treatment. Thorough assessment and careful consideration are essential to prevent misdiagnosis or delayed recognition of HLH, a condition that can result in severe outcomes, including death. Multidisciplinary collaboration is vital to optimize HLH diagnostic strategies and improve patient outcomes. Further research is needed to elucidate the clinical relevance of heterozygous mutations of HLH-associated genes in HLH and MIS-C.

No relevant conflicts of interest to declare.