Transient juvenile myelomonocytic leukemia in the setting of PTPN11 mutation and Noonan syndrome with secondary development of monosomy 7

Abstract

Juvenile myelomonocytic leukemia (JMML) is a rare childhood neoplasm with poor prognosis except in the setting of Noonan syndrome, where prognosis is generally favorable. We present the case of a child with JMML in the setting of germline PTPN11 mutation and Noonan syndrome with suspected secondary development of monosomy 7 in the bone marrow. Diagnosed shortly after birth, she has been managed with active surveillance alone. Myeloblast percentages initially fluctuated; however, bone marrow biopsy at 4 years of age showed spontaneous remission despite persistence of the monosomy 7 clone, supporting a cautious approach in similar cases.

Noonan syndrome‐associated myeloproliferative disorder with somatically acquired monosomy 7: impact on clinical decision making

“…To date, at three and a half years of age, the patient still has splenomegaly, fluctuating mild thrombocytopenia, increased PB precursor cells, and persistently high monosomy 7 (FISH > 90%). Similar to the other case with NS‐MPD and monosomy 7 reported in the literature (O'Halloran et al , ), HSCT was postponed due to severe comorbidities and a watch‐and‐wait strategy was preferred. Remarkably, as in our patient, no clinical deterioration had occurred during a follow‐up period of 4 years, despite persistence of the monosomy 7 clone (O'Halloran et al , ).…”

“…Unexpectedly, array comparative genomic hybridisation, conventional karyotype and fluorescence in situ hybridisation (FISH) detected monosomy 7 in PB and BM but not in cultured skin fibroblasts, indicative for a somatic origin. While about a quarter of JMML cases show loss of chromosome 7 in addition to a RAS pathway driver mutation (Niemeyer & Kratz ), monosomy 7 in NS‐MPD has been reported only once before in a child with a germline mutation in PTPN11 (c.1505C>T; p.Ser502Leu) (O'Halloran et al , ). Therefore, the prognostic value and utility for guiding therapy of somatically acquired monosomy 7 is still unknown in this context.…”

JMML genomics and decisions

“…24 Although polyclonality is assumed in most cases, 28 results of X-chromosome inactivation studies indicate clonal hematopoiesis in some instances, 24,28 and there are rare cases of NS/MPD with secondary monosomy 7 who achieve spontaneous remission with persistence of monosomy 7 (Barbara de Moerloose, personal communication). 29 Progression to AML has been reported in very few cases, 21 thus, questioning recent recommendations for surveillance. 30 Myeloproliferative neoplasia in early childhood mimicking JMML…”

Current Treatment of Juvenile Myelomonocytic Leukemia

“…Overall, it is likely that the presence of monosomy 7 plays a supportive role in JMML rather than being an independent pathogenetic factor [ 107 ]. This concept is also supported by the observation of secondary monosomy 7 in a watch-and-wait patient with Noonan syndrome and neonatal myeloproliferative disorder [ 102 ].…”

“…However, these patients must be monitored carefully, as there can be relevant clinical compromise from cell infiltrates, making it necessary to begin cytoreductive therapy. In individual cases, a clonal development towards a bona fide neoplastic disease is possible [ 47 , 102 , 103 ].…”