title: Juvenile myelomonocytic leukaemia and Noonan syndrome.
abstract: 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.
  
  
  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.
authors.affiliation: INSERM 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.
authors.forename: Marion
authors.initials: M
authors.lastname: Strullu
authors.affiliation: INSERM 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.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Caye
authors.affiliation: INSERM 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.
authors.forename: Julie
authors.initials: J
authors.lastname: Lachenaud
authors.affiliation: INSERM UMR_S1131, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris-Sorbonne-Cité, Paris, France Service de Biologie Cellulaire, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Saint Louis, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Cassinat
authors.affiliation: INSERM UMR_1137, IAME, Plateforme de Génétique constitutionnelle-Nord (PfGC-Nord), Université Paris Diderot, Paris, France.
authors.forename: Steven
authors.initials: S
authors.lastname: Gazal
authors.affiliation: Service d'Hématologie Biologique, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Paris, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Fenneteau
authors.affiliation: Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pouvreau
authors.affiliation: Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Paris, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pereira
authors.affiliation: Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Paris, France.
authors.forename: Clarisse
authors.initials: C
authors.lastname: Baumann
authors.affiliation: Service d'Onco-Hématologie pédiatrique, Hôpital d'Enfants de Brabois, Vandoeuvre lès Nancy, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Contet
authors.affiliation: Service d'Onco-Hématologie pédiatrique, CHU de Nice, Nice, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sirvent
authors.affiliation: Service d'Onco-Hématologie pédiatrique, CHU de Nantes, Nantes, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Méchinaud
authors.affiliation: Réanimation néonatale pédiatrique, Paris Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Trousseau, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Guellec
authors.affiliation: Service d'Onco-Hématologie pédiatrique, CHU de Grenoble, Grenoble, France.
authors.forename: Dalila
authors.initials: D
authors.lastname: Adjaoud
authors.affiliation: Service de Pédiatrie, Hôpital de Hautepierre, Strasbourg, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Paillard
authors.affiliation: Unité d'Epidémiolgie Clinique, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Paris, France INSERM, U1123 et CIC-EC 1426, ECEVE, Université Paris Diderot, Paris-Sorbonne-Cité, Paris, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Alberti
authors.affiliation: Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.affiliation: INSERM UMR_S1131, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris-Sorbonne-Cité, Paris, France Service de Biologie Cellulaire, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Saint Louis, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Chomienne
authors.affiliation: Département d'Immunologie et Hématologie Pédiatrique, Institut d'Hémato-Oncologie Pédiatrique (IHOP), Lyon, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Bertrand
authors.affiliation: Service d'Hématologie pédiatrique, Assistance Publique des Hôpitaux de Paris AP-HP, Hôpital Robert Debré, Paris, France.
authors.forename: André
authors.initials: A
authors.lastname: Baruchel
authors.affiliation: Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Paris, France INSERM UMR_S1141, Hôpital Robert Debré, Université Paris Diderot, Paris-Sorbonne-Cité, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
authors.affiliation: INSERM 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.
authors.forename: Hélène
authors.initials: H
authors.lastname: Cavé
mesh_terms: D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D054429:Leukemia, Myelomonocytic, Juvenile / Q000150:complications* / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D008297:Male; D009154:Mutation; D009634:Noonan Syndrome / Q000150:complications* / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D011446:Prospective Studies; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics
chemical_list: C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
keywords: Haematology (Incl Blood Transfusion); Molecular Genetics; Paediatric Oncology