Neonatal-onset familial hemophagocytic lymphohistiocytosis type 2: a case report

Familial hemophagocytic lymphohistiocytosis type 2 (FHL2) is a rare autosomal recessive disorder primarily caused by mutations in the perforin-1 (PRF1) gene, leading to immune system hyperactivation and multi-organ dysfunction. FHL2 typically presents in infancy, with neonatal onset being extremely rare and particularly difficult to recognize early due to substantial clinical overlap with sepsis. Given its rapid progression, early detection is critical for effective diagnosis and management.

This case report describes a neonate with FHL2 who presented on day 8 after birth with fever (peak 38.9 °C), abdominal distension, and dyspnea, accompanied by coagulation dysfunction, liver function abnormalities, and capillary leak syndrome. Despite intensive care, the patient's condition continued to deteriorate, with progression to disseminated intravascular coagulation (DIC), polyserositis, and multi-organ failure. Despite receiving intensive care and comprehensive treatment, the patient's condition continued to deteriorate. By day 7 of hospitalization, the patient was in a moribund state, and the family requested discharge against medical advice; the patient died after discharge. Postmortem genetic testing identified a homozygous c.145G > A mutation in the PRF1 gene, resulting in a substitution of aspartic acid to asparagine at position 49 of the encoded protein (p.Asp49Asn). This mutation has been documented as pathogenic in the Human Gene Mutation Database.

FHL2 may present in the neonatal period with complex and variable clinical manifestations, frequently leading to misdiagnosis as neonatal sepsis or DIC. When neonates present with unexplained persistent fever, cytopenia, coagulation dysfunction, and multi-organ dysfunction that fails to respond to conventional anti-infective therapy, HLH should be included in the differential diagnosis, and genetic testing should be performed promptly.