Dasatinib induces a dramatic response in a child with refractory juvenile xanthogranuloma with a novel MRC1-PDGFRB fusion

Eissa, Shaimaa S; Clay, Michael R.; Santiago, Teresa; Wu, Gang; Wang, Lu; Shulkin, Barry L.; Picarsic, Jennifer; Nichols, Kim E.; Campbell, Patrick

doi:10.1182/bloodadvances.2020001890

Cited by 11 publications

(13 citation statements)

References 32 publications

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“…We are aware of only one previous case report describing cyclin D1 staining in XG, where it was suggested to be a surrogate marker for RTK mutation in a case of aggressive, disseminated XG. 24 Because cyclin D1 protein is transcriptionally regulated by numerous signaling pathways, its expression may suggest that at least one of these pathways is aberrantly activated. Approximately 75% of XG lesions, including localized cutaneous lesions, showed activating RTK/MAPK mutations or gene fusions in a recent study by Durham et al 13 Eighty percent of the lesions in our limited study showed strong and diffuse staining for cyclin D1.…”

Section: Discussionmentioning

confidence: 99%

Utility of Cyclin D1 Immunostaining in Cutaneous Xanthogranuloma

Sharma

McAfee

Wang³

et al. 2021

The American Journal of Dermatopathology

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Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase pathway activation has recently been found to be associated with almost all Langerhans cell histiocytosis cases. In BRAF V600E mutation-positive cases, this activation is seen as a downstream activation. In addition, cyclin D1 is a downstream target of the MAPK pathway. Recent studies have argued in favor of using cyclin D1 as a potential neoplastic marker to differentiate Langerhans cell histiocytosis from other reactive Langerhans cell proliferations in the skin and lymph nodes. Therefore, we chose to study the immunohistochemical expression of cyclin D1 in cutaneous xanthogranuloma (XG) cases. Fifteen XG cases were retrieved and stained for cyclin D1, BRAF (v-raf murine sarcoma viral oncogene homolog B1), CD1a, and langerin (CD207). Twelve cases showed strong and diffuse nuclear positivity for cyclin D1, both in the XG cells and in the multinucleated osteoclast-like giant cells. Three cases showed focal weak nuclear staining for cyclin D1. All 15 cases showed negative immunoreactivity for BRAF, CD1a, and CD207. Although limited by small sample size, we conclude that most cases of cutaneous XG should show at least weak nuclear staining with cyclin D1. The histogenesis of XG is still largely unknown, and the finding of cyclin D1 positivity in a majority of cases may indicate a role for the MAPK/extracellular signalregulated kinase pathway in cutaneous XG.

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Section: Discussionmentioning

confidence: 99%

Utility of Cyclin D1 Immunostaining in Cutaneous Xanthogranuloma

Sharma

McAfee

Wang³

et al. 2021

The American Journal of Dermatopathology

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“…Histiocytic disorders usually involve a single somatic alteration; however, genomic studies on histiocytoses have showed an increasing number of gene fusions involving NTRK1, BRAF, RET, and ALK. 3,5,16 Although there is a shared understanding of the histopathology of NLCH, the molecular characterization is not fully elucidated. Evaluation of this patient will include ongoing management with hematology and oncology as a result of ANKRD26-mutation-associated risk for myeloid malignancies.…”

Section: Lab Resultsmentioning

confidence: 99%

“…4 In general, malignant systemic NLCH has a poor prognosis, on the other hand cutaneous NLCH usually is benign with a good prognosis and likelihood of spontaneous regression. 5 However, some reported cases of cutaneous NLCH may progress rapidly and require systemic therapy. 6 Approximately 10% of adults with non-LCH will have concomitant myeloid neoplasms, which may also exhibit BRAF mutations and in turn, require targeted therapy.…”

Section: Discussionmentioning

confidence: 99%

Novel ANKRD26 and PDGFRB gene mutations in pediatric case of non‐Langerhans cell histiocytosis: Case report and literature review

et al. 2023

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Cutaneous non‐Langerhans cell histiocytosis (NLCH) is a rare and biologically benign entity that can be broadly classified into two categories: xanthogranuloma and non‐xanthogranuloma. The xanthogranuloma family is characterized by a proliferation of histiocytes with both macrophage and dendritic cell differentiation, negative BRAF mutation, and rare Touton‐type giant cells. Molecular studies have reported that mutations involved in the MAPK signaling pathways are implicated in the pathophysiology of histiocytoses. While LCH is associated with the somatic mutation of BRAF v600e, however, mutations and gene fusions in NLCH cases are undefined. We hereby present a 19‐month‐old female with recalcitrant nodular rashes diagnosed as NLCH with associated novel genetic mutation involving ANKRD26 and PDGFRB genes, as well as PDGFRB::CD74 fusion mRNA. Immunohistochemical staining showed strong and diffuse CD68 and CD163 positivity, and negative CD1a, CD207, ALK D5F3, S100 protein, and BRAF V600E (VE1). Albeit unknown significance, this case of an ANKRD26 and PDGFRB gene mutation in cutaneous NLCH has not been reported prior in the literature. Our case highlights the advantage of pathology and genetic studies in cutaneous NLCH to increase the understanding of this heterogeneous enigmatic disorder and identify further options in management.

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“…17,18 Recently, disseminated JXG with specific genetic mutations have been targeted with tyrosine kinase inhibitors. 19 The overall prognosis of JXG is good but a high degree of morbidity and mortality is associated with disseminated JXG in infants with extensive visceral involvement. 10 Our patient showed gradual spontaneous regression of lesions and their growth was negligible compared with the relative growth of the patient, by 6 months of age (►Fig.…”

Section: Discussionmentioning

confidence: 99%

Disseminated Juvenile Xanthogranuloma with a Novel MYH9-FLT3 Fusion Presenting as a Blueberry Muffin Rash in a Neonate

Clark

Walton

Chow

et al. 2023

AJP Rep

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INTRODUCTION: Juvenile Xanthogranuloma (JXG) is a benign proliferative histiocytic disorder of the dendritic cell phenotype. It mostly presents in the pediatric age group as a solitary skin lesion. We describe a rare case of an infant born with disseminated JXG who presented with a blueberry muffin rash at birth. CASE DESCRIPTION: A term infant was noted to have multiple petechiae, purple nodules, and macules (1 mm-2 cm in diameter) and hepatosplenomegaly, at the time of birth. Further investigations revealed thrombocytopenia and direct hyperbilirubinemia and an MRI showed scattered tiny foci of restricted diffusion in multiple areas of the brain. Patient received multiple platelet transfusions in the first few weeks with gradual improvement in thrombocytopenia. Ultimately, a biopsy of one of the lesions revealed the diagnosis of disseminated JXG with notable atypical features. Somatic mutation analysis showed a novel MYH9-FLT3 fusion, but a bone marrow biopsy was negative. The lesions faded over time, relative to patient’s growth and normal neurodevelopment was noted at 18 months of age. CONCULSION: JXG should be considered in the differentials of blueberry muffin rash in an infant. Although, JXG is mostly a self-limited condition, congenital disseminated JXG may be associated with significant morbidity and mortality.

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Dasatinib induces a dramatic response in a child with refractory juvenile xanthogranuloma with a novel MRC1-PDGFRB fusion

Abstract: Key Points Juvenile xanthogranuloma (JXG) usually presents with lesions isolated to the skin; however, aggressive, disseminated forms also occur. Identification of a novel MRC1-PDGFRB fusion in a child with JXG guided targeted therapy with dasatinib, leading to a dramatic response.

Cited by 11 publications

References 32 publications

Utility of Cyclin D1 Immunostaining in Cutaneous Xanthogranuloma

Utility of Cyclin D1 Immunostaining in Cutaneous Xanthogranuloma

Novel ANKRD26 and PDGFRB gene mutations in pediatric case of non‐Langerhans cell histiocytosis: Case report and literature review

Disseminated Juvenile Xanthogranuloma with a Novel MYH9-FLT3 Fusion Presenting as a Blueberry Muffin Rash in a Neonate

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