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Juvenile myelomonocytic leukaemia and Noonan syndrome
Marion Strullu1, Aurélie Caye1, Julie Lachenaud1
1INSERM UMR_S1131, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris-Sorbonne-Cité, Paris, France Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Paris, France.
Insights
Juvenile myelomonocytic leukaemia (JMML) is a serious risk for infants with Noonan syndrome (NS) and PTPN11 mutations, often leading to early death. This condition can be overlooked, making early diagnosis crucial for PTPN11-associated NS patients.
Area of Science:
- Hematology
- Oncology
- Genetics
Background:
- Infants with Noonan syndrome (NS) have an increased risk of developing juvenile myelomonocytic leukaemia (JMML) or JMML-like myeloproliferative disorders (MPD).
- While sporadic JMML is aggressive, NS-associated JMML is often considered benign, but data are limited.
- Understanding JMML in NS is critical due to its potential severity.
Purpose of the Study:
- To investigate the occurrence and characteristics of JMML in patients with germline PTPN11 mutations.
- To determine the clinical course and outcomes of JMML in the context of Noonan syndrome.
- To identify specific PTPN11 mutations associated with an increased risk of MPD/JMML.
Main Methods:
- Prospective cohort study of 641 patients with germline PTPN11 mutations.
- Identification and diagnosis of MPD/JMML based on consensus criteria.
- Genomic analysis including SNP array and whole exome sequencing.
Main Results:
- MPD features were identified in 5.6% of patients, with 3% meeting JMML criteria.
- Severe neonatal JMML occurred in 60% of diagnosed JMML patients, with a high mortality rate (10/20 died within the first month).
- Specific PTPN11 mutations (Asp61, Thr73Ile) were associated with increased MPD/JMML risk, but no second acquired mutations were found.
Conclusions:
- JMML is a primary cause of mortality in PTPN11-associated Noonan syndrome.
- JMML in NS may be underdiagnosed due to early mortality or comorbidities.
- Early detection and confirmatory testing are essential for managing JMML in PTPN11-associated NS.
Background:
Infants with Noonan syndrome (NS) are predisposed to developing juvenile myelomonocytic leukaemia (JMML) or JMML-like myeloproliferative disorders (MPD). Whereas sporadic JMML is known to be aggressive, JMML occurring in patients with NS is often considered as benign and transitory. However, little information is available regarding the occurrence and characteristics of JMML in NS.
Methods And Results:
Within a large prospective cohort of 641 patients with a germline PTPN11 mutation, we identified MPD features in 36 (5.6%) patients, including 20 patients (3%) who fully met the consensus diagnostic criteria for JMML. Sixty percent of the latter (12/20) had severe neonatal manifestations, and 10/20 died in the first month of life. Almost all (11/12) patients with severe neonatal JMML were males. Two females who survived MPD/JMML subsequently developed another malignancy during childhood. Although the risk of developing MPD/JMML could not be fully predicted by the underlying PTPN11 mutation, some germline PTPN11 mutations were preferentially associated with myeloproliferation: 10/48 patients with NS (20.8%) with a mutation in codon Asp61 developed MPD/JMML in infancy. Patients with a p.Thr73Ile mutation also had more chances of developing MPD/JMML but with a milder clinical course. SNP array and whole exome sequencing in paired tumoral and constitutional samples identified no second acquired somatic mutation to explain the occurrence of myeloproliferation.
Conclusions:
JMML represents the first cause of death in PTPN11-associated NS. Few patients have been reported so far, suggesting that JMML may sometimes be overlooked due to early death, comorbidities or lack of confirmatory tests.
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