Acute Liver Failure in a 17‐Year‐Old Boy Caused by a Blastic Plasmacytoid Dendritic Cell Neoplasm With a Novel MYB Rearrangement

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with an aggressive clinical presentation and poor prognosis. The incidence of BPDCN in pediatric patients is extremely low, with fewer than 100 cases reported. Approximately 75%–90% of these patients presented with cutaneous involvement [1, 2]. However, acute liver failure (ALF) has not previously been reported as a manifestation of BPDCN. Diagnosis is based on clinical manifestations, histopathological features, and immunophenotypic marker expression patterns. However, due to the rarity of BPDCN, particularly in patients with atypical or nonspecific skin lesions, diagnosis can be challenging, and misdiagnosis with other hematological malignancies is common. Recently, MYB rearrangements have been identified as causative mutations in BPDCN [3, 4]. Here, we describe a pediatric case of BPDCN with a novel MYB rearrangement that manifested primarily as ALF without cutaneous involvement. A previously healthy 17-year-old boy was admitted to our hospital with asymptomatic submandibular lymphadenopathy lasting 1 month, as well as high-grade fever (39.2°C) and abdominal pain for 3 days. On admission, he was alert and exhibited submandibular, cervical, axillary, and inguinal lymphadenopathy, scleral jaundice, and no skin lesions. Hepatosplenomegaly was observed, with the spleen palpable 2 cm below the left costal margin and the liver palpable 6 cm below the right costal margin. Laboratory findings included the following: white blood cell count, 17.5 × 10⁹/L with 82% lymphoblast-like cells; hemoglobin, 12.8 g/dL; and platelet count, 51 × 10⁹/L. The bone marrow (BM) aspirate was replaced by 95% blasts with large appearances, slightly irregular nuclei, fine chromatin, and inconspicuous nucleoli, resembling lymphoblasts (Figure 1A). In-house flow cytometric immunophenotyping of BM specimens revealed a significant blast population in the dim CD45-positive blast gate, which was positive for CD7, CD56, and HLA-DR, and negative for CD3, CD4, CD19, CD20, CD22, cyCD79a, CD13, CD14, CD34, CD41, CD117, and myeloperoxidase. Low-dose prednisolone and cytarabine were administered intravenously for suspected natural killer cell leukemia, despite coagulopathy (fibrinogen, 3.7 g/L; prothrombin time [PT], 15.8 s; international normalized ratio [INR], 1.42) and liver dysfunction (aspartate aminotransferase, 1787 IU/L; alanine aminotransferase, 1810 IU/L; total bilirubin, 4.8 mg/dL). On the second day after admission, peripheral blood blast counts decreased, but the patient experienced impaired consciousness (Grade II–III hepatic encephalopathy). Blood tests showed elevated ammonia levels, prolonged PT-INR, and worsening liver function, consistent with ALF. Liver biopsy was not performed due to coagulopathy. Despite supportive measures, including mechanical ventilation, therapeutic plasma exchange, and online hemodiafiltration, the patient died 12 days after admission. Flow cytometric immunophenotyping of BM specimens in the central laboratory confirmed positivity for CD123 and TCL1. Immunohistochemical staining of the BM revealed positive CD4, CD56, and CD123 cells (Figure 1B–D), which were negative for CD3, CD20, CD79a, and MPO. RNA sequencing-based transcriptome analysis of blast cells revealed an MYB rearrangement resulting in the fusion gene MYB::RBM20 (Figure 1E,F). These results were obtained after the patient's condition deteriorated, and a diagnosis of BPDCN was made. Autopsy findings included a shrunken liver weighing 510 g with massive necrosis, no leukemic infiltration, no hemophagocytosis, and the absence of most normal hepatocytes (Figure 2A–C). No malignant cells or hemophagocytosis were identified in the BM (Figure 2D). Tests for Epstein–Barr virus, cytomegalovirus, hepatitis B and C viruses, and autoimmune markers were negative. In this case, a novel rearrangement between MYB (6q23.3) and RBM20 (10q25.2) was identified and confirmed by breakpoint analysis using reverse transcription PCR and Sanger sequencing (Figure 1E). This rearrangement, involving exon 8 of MYB and exon 11 of RBM20, resulted in a 658-amino acid in-frame MYB::RBM20 fusion protein. This protein retained the MYB DNA-binding domain but lacked part of the transcription activation domain (TAD) and all negative regulatory domains (Figure 1F). Unlike most previously reported MYB rearrangements in BPDCN, which include the MYB TAD [3, 4], this novel fusion excludes a portion of the TAD. Functional studies are needed to assess whether the truncated MYB lacking the full TAD is sufficient to trigger leukemogenesis. ALF in pediatric patients is most commonly caused by infections, drug toxicity, metabolic diseases, or autoimmune processes. ALF is extremely rare as a primary manifestation of leukemia and is associated with poor prognosis [5]. Several mechanisms have been proposed to explain the pathogenesis of ALF in leukemia, including comorbidities with viral infections, sepsis, autoimmune hepatitis, or ischemia caused by infiltration of leukemic cells leading to an obstruction of hepatic blood flow [6, 7]. Although liver biopsy cannot be performed for definitive diagnosis due to coagulopathy and poor condition, it should have been considered earlier in our case, using minimally invasive liver biopsy techniques. The autopsy revealed massive hepatic necrosis and no evidence of leukemia cells in the liver or BM, suggesting that prednisolone and cytarabine effectively eradicated the leukemia cells in these tissues. This case highlights a rare presentation of BPDCN as ALF in a pediatric patient. Given the aggressive nature and poor prognosis of BPDCN, early diagnosis and treatment are critical. Awareness of the potential association between BPDCN and ALF may aid in optimizing management strategies for such patients. Informed consent was obtained from the legal representative and Institutional board authorization was granted. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.