Germline PTPN11 mutation affecting exon 8 in a case of syndromic juvenile myelomonocytic leukemia

Juvenile myelomonocitic leukemia (JMML) is an aggressive clonal myeloproliferative disorder (MPD) that occurs mostly in infancy or early childhood, being the median age at diagnosis 24 months. Somatic mutations affecting genes involved in the Ras-mitogen-activated protein kinase (MAPK) pathway are responsible for about 80% of JMML (PTPN11 35%, KRAS/NRAS 25%, CBL 10%, NF1 11%) [1] and [2]. Instead, germ-line mutations in the PTPN11 gene are responsible for about 50% of Noonan syndrome (NS), a developmental disorder that occasionally displays MPD sharing similarities with JMML. While the clonal proliferative advantage in non-syndromic JMML cells results from acquired PTPN11 lesions driving to enhanced signal flow through the RAS–MAPK pathway, MPD occurring in NS is associated to a relatively narrow spectrum of germ-line mutations that have less potency in dysregulating this signalling cascade [2]. Consistently, MPD in NS usually regresses spontaneously, while non-syndromic JMML has a poor prognosis, requiring aggressive therapeutic strategies [1]. Therefore distinguish germ-line from somatic mutations is pivotal for patient management and therapy. So far, data from the literature indicate that PTPN11 mutations associated with syndromic and non-syndromic JMML/MPD cluster in exon 3 (90%) and 13 (10%) and these represent the only coding portions of the gene screened in the majority of patients, in both Europe and United States [2] and [3]. Here, we describe a case of a syndromic JMML associated with a mutation in the exon 8 of PTPN11 gene.