The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease

Abstract

Germ line 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 (MPDs), 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 3 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.

Figure 1.

PTPN11 mutations in JMML, NS/MPD, and NS/LS. The middle sections of both panels show wild-type SHP2 amino acid residue at each position. (A) Residues located within the N-SH2 domain encoded by exon 3. (B) Residues located within the portion of the catalytic domain encoded by exon 13. Amino acid substitutions documented in JMML and NS/MPD (italics), and in NS and LS (italics) are shown above and below the wild-type SHP2 sequence, respectively. Del indicates a deletion of this amino acid. Digits in parentheses indicate the numbers of individuals with JMML, NS/MPD, or NS carrying a specific mutation. Novel mutations are identified by asterisks. Whereas virtually all mutations in JMMLand NS/MPD are located within these confined regions, mutations associated with NS alone alter other residues of SHP2 in approximately 50% of the cases. Our data, updated to January 2005, includes 107 cases with JMML, 19 with NS/MPD, 181 with NS, and 42 with LS.