B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL) with the t(5;14)(q31;q32) chromosomal translocation resulting in an IGH::IL3 fusion is an exceptionally rare lymphoid malignancy presenting with hypereosinophilia. Germline PAX5 alterations, including sequence variants and deletions, are associated with a selective susceptibility to BCP‐ALL and lymphomas, based on a limited number of affected families worldwide. Here, we report a 6‐year‐old male with BCP‐ALL with the t(5;14)(q31;q32) translocation and harboring a novel constitutional PAX5 variant (NM_016734.3:c.[295dup];[=], p.[(Ile99Asnfs*3)];[(=)]). Despite the low representation of the leukemic clone in the bone marrow, the IGH::IL3 fusion was identified by both fluorescent in situ hybridization (FISH) and optical genome mapping (OGM). Although hypereosinophilia poses a risk of multiorgan damage, our patient exhibited only pneumonia and asymptomatic neuroimaging alterations in the central nervous system. The patient achieved remission by the end of induction and is currently continuing maintenance therapy. In line with existing literature, familial segregation of the PAX5 variant demonstrated high but incomplete penetrance, as two leukemia‐free mutation carriers displayed only subclinical B lymphocyte maturation abnormalities without hypogammaglobulinemia. Our report underscores the diagnostic utility of OGM, which unequivocally demonstrated the characteristic translocation. Typically, BCP‐ALL in affected family members exhibits secondary somatic aberrations involving the wild‐type PAX5 allele, including structural variants or loss of heterozygosity (LOH) of chromosome 9p, as well as PAX5 somatic mutations. To our knowledge, this is the first human report aligning with animal models, which suggests that secondary alterations activating the JAK–STAT pathway may potentially contribute to leukemogenesis in a PAX5 mutation background.

Inherited thrombocytopenias (ITs) constitute a heterogeneous group of congenital bleeding disorders caused by defects in over 50 genes that predominantly affect platelet production. GFI1B has recently emerged as a critical transcriptional regulator of megakaryocyte and erythroid differentiation. Its dysfunction underlies a rare autosomal dominant form of IT, which usually results in moderately reduced platelet counts. We report an adult male with lifelong severe thrombocytopenia (platelet count range 10–20 × 10⁹/L) and recurrent bleeding episodes since early childhood. Comprehensive molecular analysis identified a heterozygous NM_001377304.1:c.814 + 1G > A variant in the zinc finger region of GFI1B, resulting in a frameshift and premature truncation. The proband exhibited hallmark features of this IT subtype, including α‑granule deficiency and persistent CD34 expression in megakaryocytes and platelets. Based on preclinical evidence, the patient initially received eltrombopag, followed later by romiplostim, achieving a partial platelet response and improvement in bleeding symptoms. Familial analysis revealed marked variability in platelet counts and bleeding phenotypes among carriers of the same variant, including the patient’s mother, highlighting that clinical outcomes cannot be reliably predicted from genotype alone. A literature review confirmed considerable phenotypic heterogeneity in GFI1B-related thrombocytopenia, indicating that variant type and location only partially account for disease severity. This report represents the first in-human use of thrombopoietin receptor agonists in GFI1B-related thrombocytopenia. It underscores the challenges in diagnosing and managing ITs and emphasizes the importance of early genetic testing. Further studies are needed to elucidate the molecular determinants of phenotypic variability and to develop targeted therapeutic strategies for affected patients.

Background: Vascular anomalies are rare congenital disorders associated with significant morbidity. Local therapies may be insufficient for complex lesions. Sirolimus, an mTOR inhibitor, is a promising systemic treatment option. Methods: We retrospectively analyzed pediatric patients with vascular anomalies treated with sirolimus between October 2020 and June 2025. Of 29 patients who initiated treatment, 23 completed at least 12 months of therapy and had evaluable 12-month outcomes; these patients constituted the primary 12-month efficacy cohort. Treatment discontinuations were analyzed separately, and an all-treated sensitivity analysis was performed. Results: The cohort included 10 patients (43%) with lymphatic malformations (LMs), 9 (39%) with venous malformations (VMs), 2 (9%) with combined malformations, and 2 (9%) with other vascular anomalies. At 12 months, magnetic resonance imaging (MRI) demonstrated lesion size reduction in 17/23 patients (74%), stabilization in 5/23 (22%), and progression in 1/23 patients (4%). In a conservative sensitivity analysis including all 29 treated patients and classifying patients without an evaluable 12-month outcome, documented reduction or stabilization was observed in 22/29 patients (76%). Additional treatment was less frequent during treatment (30% vs. 65%, p = 0.043), although observation periods differed. Pain decreased (p = 0.021), and physical activity increased (p = 0.034). No severe adverse events led to permanent treatment discontinuation. The most common adverse events were laboratory abnormalities (47%) and aphthous stomatitis (32%). Exploratory Multiple Factor Analysis (MFA) demonstrated substantial multidimensional heterogeneity but did not identify stable radiological response phenotypes. Conclusions: Sirolimus was associated with radiological improvement or stabilization, symptom relief, and fewer additional interventions in pediatric vascular anomalies, with generally favorable tolerability.