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Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome of overwhelming immune activation causing multiorgan dysfunction that may be genetic and/or acquired. Patients with familial HLH often present by one year of age, though most are asymptomatic in the first month of life. We present the case of a neonate with diarrhea and malnutrition who developed signs and symptoms consistent with a clinical diagnosis of HLH.
Case: A neonate born at 35 5/7 weeks was transferred to a Level IV neonatal intensive care unit at 39 4/7 weeks for failure to thrive. Though feeding adequately and non-dysmorphic, he had persistent diarrhea on multiple formulas and only gained small amounts of weight via total parental nutrition. He was the first child of consanguineous parents of South Asian descent. Evaluation was inconsistent with milk soy protein intolerance and malabsorption syndromes. Very-early-onset inflammatory bowel disease and congenital diarrheas/enteropathies were considered. Intestinal biopsy was concerning for an underlying primary immunodeficiency. Additional studies showed a mild increase in T cells and low IgM. Lymphocyte proliferation to mitogens and expression of FOXP3, XIAP, and SAP by flow cytometry were unremarkable. At age 44 weeks, he acutely became lethargic, with fevers to 40°C and metabolic acidosis, further developing anemia, thrombocytopenia, lymphocytosis, transaminitis, and hepatosplenomegaly. Hypofibrinogenemia, hyperferritinemia (>10,000), and elevated Soluble IL-2R level led to HLH diagnosis. Per HLH-94 protocol, he began dexamethasone and etoposide; he also received emapalumab. Despite treatment, fulminant liver failure with uncontrollable DIC ensued. Life-sustaining treatments were withdrawn and he died at 46 3/7 weeks.
Discussion: Though colitis is not classically a feature of most primary HLH syndromes, it has been described in one subset of familial HLH. However, sequencing of the associated gene (STXBP2) was normal in our patient. Similarly, among EBV-driven HLH, X-linked lymphoproliferative disease and XIAP deficiency are associated with hypogammaglobulinemia and colitis respectively, but expression of these was normal without evidence of EBV. Perforin/granzyme B expression was increased. Whole-exome sequencing (WES) revealed several variants of unknown significance but was ultimately nondiagnostic. While neonates are more likely to have genetic causes for HLH, around 40% of neonates do not have established genetic diagnoses after WES.
Conclusion: Timely recognition of HLH maximizes the potential for effective treatment like hematopoietic stem cell transplantation. Recognition of colitis as a presenting symptom may facilitate this challenging diagnosis. Rapid and inclusive genetic evaluation, including WES, may help identify the underlying etiology and guide treatment for neonatal HLH.
Tarantino, Laura, "Severe Colitis and Malnutrition in Association with Neonatal Hemophagocytic Lymphohistiocytosis" (2021). Child Health Research Institute Pediatric Research Forum. 14.