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Blood, 15 September 2005, Vol. 106, No. 6, pp. 2183-2185.
Prepublished online as a Blood First Edition Paper on May 31, 2005; DOI 10.1182/blood-2005-02-0531.
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Submitted February 8, 2005
Accepted May 16, 2005
The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan Syndrome/myeloproliferative disease
Christian P Kratz, Charlotte M Niemeyer, Robert P Castleberry, Mualla Cetin, Eva Bergstrasser, Peter D Emanuel, Henrik Hasle, Gabriela Kardos, Cornelia Klein, Seiji Kojima, Jan Stary, Monika Trebo, Marco Zecca, Bruce D Gelb, Marco Tartaglia, and Mignon L Loh*
Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany
Department of Pediatric Hematology/Oncology and Division of Hematology/Oncology, Comprehensive Cancer Center, Univeristy of Alabama at Birmingham, Birmingham, AL, USA
Department of Pediatric Hematology, Ihsan Dogramaci Children's Hospital, Hacettepe University, Ankara, Turkey
Department of Pediatrics, University of Zurich, Zurich, Switzerland
Department of Pediatrics, Skejby Hospital, Aarhus University, Aarhus, Denmark
Dutch Childhood Oncology Group, The Hague, The Netherlands
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Department of Pediatrics, University Hospital Motol, Prague, Czech Republic
St Anna Children's Hospital, Vienna, Austria
Oncoematologia Pediatrica, IRCCS Policlinico San Matteo, Pavia, Italy
Departments of Pediatrics and Human Genetics, Mount Sinai School of Medicine, New York, NY, USA
Dipartimento di Biologia Cellulare e Neuroscienze, Instituto Superiore di Sanita, Rome, Italy
Department of Pediatrics and the Comprehensive Cancer Center, University of California, San Francisco, CA, USA
* Corresponding author; email: lohm{at}itsa.ucsf.edu.
Germline PTPN11 mutations cause 50% of cases of Noonan syndrome (NS). Somatic mutations in PTPN11 occur in 35% of patients with de novo, nonsyndromic juvenile myelomonocytic leukemia (JMML). Myeloproliferative disorders, either transient or more fulminant forms, can also occur in infants with NS (NS/MPD). We identified PTPN11 mutations in blood or bone marrow specimens from 77 newly reported patients with JMML (n=69) or NS/MPD (n=8). Together with previous reports, we compared the spectrum of PTPN11 mutations in three groups: (1) patients with JMML (n=107), (2) patients with NS/MPD (n=19), and (3) patients with NS (n=243). Glu76 was the most commonly affected residue in JMML (n=45), with the Glu76Lys alteration (n=29) being most frequent. Eight of 19 patients with NS/MPD carried the Thr73Ile substitution. These data suggest that there is a genotype/phenotype correlation in the spectrum of PTPN11 mutations found in patients with JMML, NS/MPD and NS. This supports the need to characterize the spectrum of hematologic abnormalities in individuals with NS and to better define the impact of the PTPN11 lesion on the disease course in patients with NS/MPD and JMML.
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