A novel XIAP variant in a patient with hydrops fetalis: HSCT and beyond?

BACKGROUND: X-linked lymphoproliferative syndrome-2 (XLP-2), caused by XIAP deficiency, is an inborn error of immunity classified in the context of immune dysregulation. Although initially described in patients with EBV-associated HLH, the clinical spectrum of the syndrome has broadened as additional cases have been reported. CASE PRESENTATION: The patient was born with hydrops fetalis. Additionally, he presented with cardiac defects (VSD, PDA), pancytopenia, hepatitis, and markedly elevated ferritin levels. He had an older brother with similar clinical findings, including hydrops fetalis, who died on the fourth day of life. Whole-exome sequencing revealed a novel hemizygous c.679T>C (p.Cys227Arg) variant of uncertain significance in exon 2 of the XIAP gene. Functional studies revealed defective XIAP expression and activity. The patient also fulfilled the diagnostic criteria for HLH. He underwent three HSCT procedures, with the last one being successful. Fifteen months after HSCT, he developed refractory seizures consistent with West syndrome, which progressively worsened his neurological condition. Although the precise cause of the seizures remains unclear, both drug exposure and CNS infection may have contributed. CONCLUSION: The novel XIAP variant appears to cause a severe, very early-onset phenotype, even prenatally. This case is notable as the first report of hydrops fetalis in a patient with XIAP deficiency, representing a previously undescribed loss-of-function variant.