Functional evaluation of circulating hematopoietic progenitors in Noonan syndrome

Timeus,Fabio; Crescenzio,Nicoletta; Baldassarre,Giuseppina; Doria,Alessandra; Vallero,Stefano; Foglia,Luiselda; Pagliano,Sara; Rossi,Cesare; Silengo,Margherita  Cirillo; Ramenghi,Ugo; Fagioli,Franca; Cordero di Montezemolo,Luca; Ferrero,Giovanni  Battista

doi:10.3892/or.2013.2535

Functional evaluation of circulating hematopoietic progenitors in Noonan syndrome

Authors:
- Fabio Timeus
- Nicoletta Crescenzio
- Giuseppina Baldassarre
- Alessandra Doria
- Stefano Vallero
- Luiselda Foglia
- Sara Pagliano
- Cesare Rossi
- Margherita Cirillo Silengo
- Ugo Ramenghi
- Franca Fagioli
- Luca Cordero di Montezemolo
- Giovanni Battista Ferrero
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Affiliations: Pediatric Hematology-Oncology, Regina Margherita Children's Hospital, 10126 Turin, Italy, Department of Pediatrics, University of Turin, 10126 Turin, Italy, Department of Genetics, University of Bologna, Policlinico S. Orsola-Malpighi, 40138 Bologna, Italy
Published online on: June 11, 2013 https://doi.org/10.3892/or.2013.2535
Pages: 553-559
Copyright: © Timeus et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Noonan syndrome (NS) is an autosomal dominant disorder, characterized by short stature, multiple dysmorphisms and congenital heart defects. A myeloproliferative disorder (NS/MPD), resembling juvenile myelomonocytic leukemia (JMML), is occasionally diagnosed in infants with NS. In the present study, we performed a functional evaluation of the circulating hematopoietic progenitors in a series of NS, NS/MPD and JMML patients. The different functional patterns were compared with the aim to identify a possible NS subgroup worthy of stringent hematological follow-up for an increased risk of MPD development. We studied 27 NS and 5 JMML patients fulfilling EWOG-MDS criteria. The more frequent molecular defects observed in NS were mutations in the PTPN11 and SOS genes. The absolute count of monocytes, circulating CD34+ hematopoietic progenitors, their apoptotic rate and the number of circulating CFU-GMs cultured in the presence of decreasing concentrations or in the absence of granulocyte-macrophage colony-stimulating factor (GM-CSF) were evaluated. All JMML patients showed monocytosis >1,000/µl. Ten out of the 27 NS patients showed monocytosis >1,000/µl, which included the 3 NS/MPD patients. In JMML patients, circulating CD34+ cells were significantly increased (median, 109.8/µl; range, 44-232) with a low rate of apoptosis (median, 2.1%; range, 0.4-12.1%), and circulating CFU-GMs were hyper-responsive to GM-CSF. NS/MPD patients showed the same flow cytometric pattern as the JMML patients (median, CD34+ cells/µl, 205.7; range, 58-1374; median apoptotic rate, 1.4%; range, 0.2-2.4%) and their circulating CFU-GMs were hyper-responsive to GM-CSF. These functional alterations appeared 10 months before the typical clinical manifestations in 1 NS/MPD patient. In NS, the CD34+ absolute cell count and circulating CFU-GMs showed a normal pattern (median CD34+ cells/µl, 4.9; range, 1.3-17.5), whereas the CD34+ cell apoptotic rate was significantly decreased in comparison with the controls (median, 8.6%; range, 0-27.7% vs. median, 17.6%; range, 2.8-49.6%), suggesting an increased CD34+ cell survival. The functional evaluation of circulating hematopoietic progenitors showed specific patterns in NS and NS/MPD. These tests are a reliable integrative tool that, together with clinical data and other hematological parameters, could help detect NS patients with a high risk for a myeloproliferative evolution.

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