Short CommunicationRare and potentially fatal ‐ Cytogenetically cryptic TNIP1::PDGFRB and PCM1::FGFR1 fusion leading to myeloid/lymphoid neoplasms with eosinophilia in children
Introduction
Myeloid/lymphoid neoplasms with eosinophilia (MLN-eo) are associated with more than 70 fusion genes [1,2]. These fusions are often cryptic and thus not detectable by classical banding analysis or even FISH. They arise from cytogenetic rearrangements, inversions or deletions leading to constitutive tyrosine kinase activity. The incidence of MLN-eo with rearrangements of PDGFRA, PDGFRB, FGFR1 and PCM1::JAK2 is unknown. These diseases are considered to be very rare entities with an estimated incidence of <1/100,000 persons [3]. MLN-eos seem to be even more rare in children, as only a few cases have been published yet [4,5].
The heterogeneous clinical picture and the extreme rarity of the disease, especially in children, may delay an early diagnosis. In addition, causative cytogenetically cryptic alterations are mostly beyond the scope of standard genetic diagnostics. Thus, genetic diagnosis must be precise and quick in order to initiate adequate therapies with either tyrosine kinase inhibitors (TKIs) or chemotherapy and hematopoietic stem cell transplantation (HSCT). The goal of therapy is to prevent eosinophil-mediated organ damage and malignant transformations and, if possible, to cure.
We report here two rare cases of MLN-eo in childhood. Patient one had a TNIP1::PDGFRB and patient two a PCM1::FGFR1 fusion. In the following, we describe the related literature available to date, concerning underlying genetic changes, typical clinical symptoms and therapies, and discuss mandatory diagnostics.
Section snippets
Fluorescence R‐banding analysis
Cytogenetic analyses were performed on cultured bone marrow aspirates and during the progression of the disease also on peripheral blood cultures in patient two. Chromosome preparation and fluorescence R-banding were carried out as previously described [6]. Twenty metaphases were analysed per patient via IKAROS software (version 5.9.1, MetaSystems, Altlußheim, Germany). Karyotypes were described according to the International System for Human Cytogenomic Nomenclature (2020) [7].
Fluorescence in‐situ hybridization (FISH) on interphases and metaphases
FISH analyses on
Results
A female patient, 13 years of age, presented with severe respiratory distress, hepatosplenomegaly and lymphadenopathy. Echocardiography showed endocarditis, left ventricular fibrosis and mitral valve insufficiency. WBC was 112 × 109l with 39% eosinophils (Fig. 1A).
Bone marrow aspirate showed features of myeloproliferative neoplasia (MPN) with eosinophilia (Fig. 1B). Cytogenetic analysis revealed a normal karyotype. However, a cryptic rearrangement involving the FGFR1 locus was detected using
Discussion
Causative gene fusions in MLN-eos can be due to various cryptic rearrangements. ArrayCGH on the second patient showed, that the gene fusion arose from an approximately 870 kb deletion affecting genetic material on chromosome 5 between PDGFRB and TNIP1 (confirmed by RNA-seq). A similar sized deletion was also found in two adult cases with TNIP1::PDGFRB fusion [9,10].
Early detection of the gene fusion enabled targeted TK inhibitor administration and thus successful treatment of the child. RNA-seq
Declaration of Competing Interest
None.
Acknowledgements
GG has been supported by the BMBF ADDRess (01GM1909A), GG, CN, AY and BSc and BS by the BMBF MyPred (01GM1911A).
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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These authors contributed equally to this work.