Rapid whole‐genome sequencing leading to specific treatment for two infants with haemophagocytic lymphohistiocytosis due to Wolman disease

To the Editor: Haemophagocytic lymphohistiocytosis (HLH) is a severe disorder of systemic hyperinflammation, manifesting with fevers, cytopenias, hepatosplenomegaly and derangements in specific biomarkers (ferritin, soluble CD25, triglycerides and/or fibrinogen).1 Mortality can be as high as 30%.2 There are many triggers for HLH, including malignancy, infection, primary genetic causes and genetic conditions where HLH is a rare secondarymanifestation.1 We report two infants presenting with HLH diagnosed with Wolman disease (WD) via ultra-rapid whole-genome sequencing (urWGS), through the Acute Care Genomics study.3 In both cases, a molecular diagnosis was confirmed within three days of sample receipt in the laboratory, allowing rapid commencement of enzyme replacement therapy (ERT) and specific dietary treatment. Patient 1 presented at twomonths of agewith hepatosplenomegaly, following a one-month history of intermittent vomiting. He soon developed fevers, abdominal distension and secondary tachypnoea requiring admission. Blood results (Table 1) were also consistent with a diagnosis ofHLH, and treatmentwas commencedwith dexamethasone and etoposide. Concomitant Cytomegalovirus infection was managed with ganciclovir. Worsening abdominal distension and ascites resulted in respiratory decompensation, requiring transfer to the intensive care unit for non-invasive ventilation. Chest radiographs demonstrated bilateral adrenal calcifications, suspicious for a diagnosis of WD. Breastfeeding and parenteral lipids