title: Functional evaluation of circulating hematopoietic progenitors in Noonan syndrome.
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.
authors.affiliation: Pediatric Hematology-Oncology, Regina Margherita Children's Hospital, 10126 Turin, Italy. fabio.timeus@unito.it
authors.forename: Fabio
authors.initials: F
authors.lastname: Timeus
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Crescenzio
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Baldassarre
authors.forename: Alessandra
authors.initials: A
authors.lastname: Doria
authors.forename: Stefano
authors.initials: S
authors.lastname: Vallero
authors.forename: Luiselda
authors.initials: L
authors.lastname: Foglia
authors.forename: Sara
authors.initials: S
authors.lastname: Pagliano
authors.forename: Cesare
authors.initials: C
authors.lastname: Rossi
authors.forename: Margherita Cirillo
authors.initials: MC
authors.lastname: Silengo
authors.forename: Ugo
authors.initials: U
authors.lastname: Ramenghi
authors.forename: Franca
authors.initials: F
authors.lastname: Fagioli
authors.forename: Luca
authors.initials: L
authors.lastname: Cordero di Montezemolo
authors.forename: Giovanni Battista
authors.initials: GB
authors.lastname: Ferrero
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D002648:Child; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D055014:Granulocyte-Macrophage Progenitor Cells / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism; D009634:Noonan Syndrome / Q000097:blood* / Q000235:genetics / Q000473:pathology; D010976:Platelet Count / Q000379:methods; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism; D020839:Son of Sevenless Protein, Drosophila / Q000235:genetics / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D020839:Son of Sevenless Protein, Drosophila; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11