Clinical spectrum of noonan syndrome–associated myeloproliferative disorder Free

Introduction Noonan syndrome (NS) is a genetic disorder characterized by a short stature, facial dysmorphism, and congenital heart defects owing to gain-of-function variants in genes related to the RAS/MAPK pathway. Some patients with NS with germline variants in genes, such as PTPN11, KRAS, NRAS, or RIT1, may develop NS-associated myeloproliferative disorder (NS-MPD), resembling juvenile myelomonocytic leukemia (JMML); however, it is generally self-limiting. Owing to the limited understanding of NS-MPD, we aimed to clarify the clinical spectrum of 27 patients in Japan. We also aimed to analyze this cohort in detail and review the existing literature to gain a comprehensive understanding of NS-MPD.

Methods We conducted a retrospective study of 27 cases of NS-MPD diagnosed between April 2004 and March 2022 in Japan and performed a systematic literature review of 25 articles and 79 cases to explore this condition. Clinical presentation and demographic characteristics, including age at onset, institutional diagnosis, therapeutic interventions, and survival outcomes, were collected via the questionnaire. This study was approved by the Ethics Committee of Hokkaido University and Nagoya University Graduate School of Medicine. At each institution, NS was diagnosed using the Van der Burgt criteria. MPD was defined as hepatomegaly, splenomegaly, or thrombocytopenia with a white blood cell count of ≥10 × 10⁹/L and monocyte count of ≥1 × 10⁹/L in the absence of an infection. All patients were diagnosed with JMML according to the 2016 revised criteria of the World Health Organization. Clinical response was defined using the international consensus criteria for evaluating responses and outcomes in JMML.

Results The 27 patients had a median age at diagnosis of 1.5 months (range, 0–75 months). Overall, 25 patients developed MPD within the first 6 months after birth, whereas 2 patients were older than 4 years old upon diagnosis. Congenital heart diseases were observed in 17 patients. PTPN11 and RIT1 variants were present in 26 and 1 patient, respectively. Splenomegaly, defined as ≥3 cm below the costal margin, was diagnosed in three patients, and hematological data revealed leukocytosis, monocytosis, thrombocytopenia, and presence of myeloid progenitor cells in their peripheral blood. In addition, the median percentages of blasts in peripheral blood and bone marrow were 2.5% and 2.8%, respectively. Spontaneous proliferation of myeloid progenitor cells was observed in 19 of 23 patients in colony formation assays, and GM-CSF hypersensitivity was observed in 15 of 19 patients. Meanwhile, two patients had chromosomal abnormalities, namely, monosomy 7 and t(4;9)(p16;q32). Furthermore, one patient had a concomitant somatic NRAS p.G12C variant. Of the 27 patients, 19 were followed-up without receiving treatment for MPD. Low-dose chemotherapy was administered to 7 patients (6-mercaptopurine [n = 3], cytarabine [n = 3], and azacitidine [n = 2]). Hematopoietic cell transplantation (HCT) was performed in 2 patients. The 5-year overall survival and event-free survival rates were 88.2% and 80.6%, respectively. Overall, 95 (25: this study and 70: literature cohort) patients with NS-MPD harboring PTPN11 variants had available data for analysis. In addition, we collected data of 361 patients with NS harboring the PTPN11 variant from three references. PTPN11 variants D61 and T73 were more prevalent in NS-MPD than NS: Exact logistic regression analysis in each amino acid change revealed that the D61 and T73 variants were considerably more frequent in patients with NS-MPD, whereas the N308 variants were less frequent.

Discussion This study highlighted the importance of specific PTPN11 amino acid substitutions, such as D61 and T73, in the prevalence of NS-MPD. Although most cases spontaneously resolve, some patients may develop “true JMML,” through secondary genetic events, underscoring the necessity to clearly distinguish these cases from typical infantile NS-MPD. These findings highlight the need for careful genetic evaluation and long-term hematological monitoring in the management of patients with NS.