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Hypereosinophilic syndrome (HES) is a rare clinical entity defined by a persistent absolute eosinophil count (AEC) of 15 000/μL for longer than 6 months, organ damage, and exclusion of reactive eosinophilia or other hematologic cancers described by the World Health Organization.1,2 (To convert eosinophils to ×109/L, multiply by 0.001.) Skin manifestations are common, affecting up to 50% of patients with HES. Skin findings include vesicles, petechiae, angioedema, livedo reticularis, necrosis, gangrene, Raynaud phenomenon, eosinophilic cellulitis and vasculitis, urticaria, symmetrical hyperkeratosis, mucosal ulcerations, and pruritus.3 We now know that hypereosinophilia is often associated with predictable genetic alterations and rearrangements, understanding of which is crucial to guiding therapy. We describe a patient with a novel inversion of chromosome 5 (inv(5)) involving PDGFRB gene rearrangement and hypereosinophilic syndrome successfully treated with imatinib.
A man in his 40s presented with intermittent chest pain, fatigue, and subjective fevers lasting 3 weeks. He had noticed progressive infiltration of his upper lids, night sweats, and an unintentional 80-pound weight loss over 2 months. He had no medical history or medication use. Laboratory findings revealed leukocytosis (white blood cell count, 28 800/μL with 45% eosinophils; AEC, 12 990/μL) and mild normocytic anemia (hemoglobin, 9.6 g/L). (To convert white blood cells to ×109/L, multiply by 0.001; hemoglobin to grams per liter, multiply by 10.) Findings of cardiac ischemic workup were negative. Chest computed tomography demonstrated bilateral fibrotic changes in the upper lobes with bilateral pleural effusions.
The primary diagnosis on admission was pneumonia, and appropriate therapy was begun. Findings of the workup for secondary causes of HES were negative. Transthoracic echocardiography demonstrated pathognomonic inferior septal and posterior apical wall motion abnormalities with ejection fraction (EF) of 40%. Cardiac magnetic resonance imaging revealed a 2.2 × 1.4-cm apical left ventricular thrombus with subendocardial fibrosis. Bone-marrow biopsy revealed hypercellularity (>95%); 13% of the total cells were eosinophils. Cytogenetic studies revealed an inversion of chromosome 5, 46,XY,inv(5)(q13q33). Findings of fluorescence in situ hybridization testing for PDGFRB rearrangement were positive, BCR-ABL1, PDGFRA, FLPILI, and JAK2 findings were negative. The patient was diagnosed with Loeffler endocarditis and started on treatment with systemic anticoagulation for the left ventricular thrombus and prednisone, 1 mg/kg, for immunosuppressive therapy.
After 1 month, the patient had a decreased AEC (1720/μL) and EF recovery, but he had developed new dermal plaques on the forehead, eyelids (Figure 1A), and arms. A biopsy of lesional skin showed extensive infiltration of histiocytoid and xanthomatous cells with sparse eosinophils throughout the dermis. These xanthomatous cells tested positive for CD68, Factor XIIIa, and S100 and negative for CD1a (Figure 2). Given his PDGFRB rearrangement, his treatment was transitioned to imatinib mesylate, 400 mg/d. After 2 months of this therapy, hematologic remission was achieved, and his dermal plaques resolved (Figure 1B). By repeat fluorescence in situ hybridization, PDGFRB in the peripheral blood was undetectable. At last follow-up 3 years later, there had been no recurrence.
A, This image shows firm, infiltrated dermal plaques on the upper lids, temple, and malar cheek. B, Interval improvement of the plaques was seen after 2 months of imatinib therapy.
A, Extensive inflammatory infiltrates. B, Foamy cytoplasm characteristic of xanthomatous cells (F) interspersed with rare mast cells (M) and eosinophils (E).
Several fusion proteins have been identified resulting in constitutively activated tyrosine kinases such as mutations in platelet-derived growth factor receptor alpha (PDGFRA), platelet-derived growth factor receptor beta (PDGFRB), and fibroblast growth factor receptor-1 (FGFR1). Since the discovery of the PDGFRB fusion gene in 1994 by Golub et al,4 more than 20 fusion partners involving chromosome 5 have been reported. Review of the literature shows 1 prior case report of a patient with eosinophilic fasciitis associated with inv(5).5 Interestingly, this case was not associated with a PDGFRB fusion protein. Durable remission was seen in a retrospective cohort of 26 patients with myeloproliferative neoplasm and PDGFRB rearrangements treated with imatinib.6
To our knowledge, this is the only described case of HES associated with a PDGFRB rearrangement and inv(5). It is important that dermatologists are aware of novel fusion partners with PDGFRB, such as inv(5), essential for both understanding and guiding treatment decisions in this heterogeneous disorder.
Corresponding Author: Jennifer N. Saultz, DO, Divisions of Medical Oncology and Hematology, Department of Internal Medicine, The Ohio State University, Starling-Loving Hall, Room M365, 320 W 10th Ave, Columbus, OH 43210 (firstname.lastname@example.org).
Published Online: September 28, 2016. doi:10.1001/jamadermatol.2016.3175
Conflict of Interest Disclosures: None reported.
Additional Contributions: We thank the patient for granting permission to publish this information. We are also indebted to The Ohio State Department of Pathology for biopsy images; they received no compensation for their contributions beyond that provided in the normal course of employment.
Saultz JN, Kaffenberger BH, Taylor M, Heerema NA, Klisovic R. Novel Chromosome 5 Inversion Associated With PDGFRB Rearrangement in Hypereosinophilic Syndrome. JAMA Dermatol. 2016;152(12):1391–1393. doi:https://doi.org/10.1001/jamadermatol.2016.3175
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