Molecular Characterization of the Idiopathic Hypereosinophilic Syndrome (HES) in 35 French Patients with Normal Conventional Cytogenetics.

HES, characterized by unexplained and persistent hypereosinophilia, is heterogeneous and comprises several entities including a myeloproliferative form where myeloid lineages are involved with interstitial chromosome 4q12 deletion leading to fusion between FIP1L1 and PDGFRA (F/P) genes, the latter acquiring increased tyrosine kinase activity, and a lymphocytic variant where hypereosinophilia is secondary to a primitive T lymphoid disorder demonstrated by the presence of a circulating T cell clone.

Patients and methods: 35 HES patients diagnosed in 6 French centers and with normal karyotype by conventional cytogenetic analysis were included in this study. 9 patients had clinical or hematological features of myeloproliferative syndrome; 4 patients had recurrent diarrhea with intestinal eosinophilic infiltration. No patient had clinical or pathological features for systemic mastocytosis. At the time they were tested, any patient received imatinib. Patients were studied for clonality of T-cell-receptor gamma gene rearrangements, detection of F/P by FISH and/or RT-PCR, and screening for activating mutations in the juxtamembrane and TK regions of PDGFRA and PDGFRB genes. Relashionships between molecular features and IL5 and serum tryptase levels were analyzed.

Results: We found a high occurrence of T-cell related HES (11 patients, 31%) and none of them had F/P deletion. 6 patients (17%) presented the F/P fusion by RT-PCR. In agreement with previous reports, we found a significantly elevated tryptase serum level in all of these F/P deleted patients (p= 0.006, Mann-Whitney test). Sequence of fusion transcripts in 6 F/P patients revealed breakpoints scattered between FIP1L1-exons 10 to 13, whereas breakpoints were restricted to exon 12 of PDGFRA. Clinical improvement and complete hematological remission under imatinib was observed in all 6 F/P patients at the end of the study. In the 29 patients without F/P, no activating mutation of PDGFRA/PDGFRB was detected, however one patient respond to imatinib. FISH analysis of the F/P was concordant with RT-PCR data, and previous May-Gründwald-Giemsa staining of slides suggested an heterogeneous eosinophilic population.

Conclusion : We described here a high occurrence of T-cell related HES, fully representative since none of the patients has been recruited from dermatology clinics, and none of them had F/P deletion, suggesting that F/P deletion in HES may involved the myeloid lineage. No significant higher IL5 serum level was observed between T-cell associated HES patients and other case of HES in our study, but F/P and elevated serum tryptase level define a strongly overlapping group of HES patients. In our study, F/P deleted cells have been observed by FISH analyses in a part of the eosinophilic population. Extensive analysis of aberrant-T cells and of the nature of F/P affected cells could then improve the HES classification.