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Original article
Juvenile myelomonocytic leukaemia and Noonan syndrome
  1. Marion Strullu1,2,
  2. Aurélie Caye1,2,
  3. Julie Lachenaud1,2,
  4. Bruno Cassinat1,3,
  5. Steven Gazal4,
  6. Odile Fenneteau5,
  7. Nathalie Pouvreau2,
  8. Sabrina Pereira2,
  9. Clarisse Baumann2,
  10. Audrey Contet6,
  11. Nicolas Sirvent7,
  12. Françoise Méchinaud8,
  13. Isabelle Guellec9,
  14. Dalila Adjaoud10,
  15. Catherine Paillard11,
  16. Corinne Alberti12,13,
  17. Martin Zenker14,
  18. Christine Chomienne1,3,
  19. Yves Bertrand15,
  20. André Baruchel16,
  21. Alain Verloes2,17,
  22. Hélène Cavé1,2
  1. 1INSERM UMR_S1131, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris-Sorbonne-Cité, Paris, France
  2. 2Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Paris, France
  3. 3Service de Biologie Cellulaire, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Saint Louis, Paris, France
  4. 4INSERM UMR_1137, IAME, Plateforme de Génétique constitutionnelle-Nord (PfGC-Nord), Université Paris Diderot, Paris, France
  5. 5Service d'Hématologie Biologique, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Paris, France
  6. 6Service d'Onco-Hématologie pédiatrique, Hôpital d'Enfants de Brabois, Vandoeuvre lès Nancy, France
  7. 7Service d'Onco-Hématologie pédiatrique, CHU de Nice, Nice, France
  8. 8Service d'Onco-Hématologie pédiatrique, CHU de Nantes, Nantes, France
  9. 9Réanimation néonatale pédiatrique, Paris Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Trousseau, Paris, France
  10. 10Service d'Onco-Hématologie pédiatrique, CHU de Grenoble, Grenoble, France
  11. 11Service de Pédiatrie, Hôpital de Hautepierre, Strasbourg, France
  12. 12Unité d'Epidémiolgie Clinique, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Paris, France
  13. 13INSERM, U1123 et CIC-EC 1426, ECEVE, Université Paris Diderot, Paris-Sorbonne-Cité, Paris, France
  14. 14Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany
  15. 15Département d'Immunologie et Hématologie Pédiatrique, Institut d'Hémato-Oncologie Pédiatrique (IHOP), Lyon, France
  16. 16Service d'Hématologie pédiatrique, Assistance Publique des Hôpitaux de Paris AP-HP, Hôpital Robert Debré, Paris, France
  17. 17INSERM UMR_S1141, Hôpital Robert Debré, Université Paris Diderot, Paris-Sorbonne-Cité, Paris, France
  1. Correspondence to Dr Hélène Cavé, UF de Génétique Moléculaire, Hôpital Robert Debré, 48, Boulevard Sérurier, Paris 75019, France; helene.cave{at}rdb.aphp.fr

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.

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.

  • Haematology (Incl Blood Transfusion)
  • Molecular Genetics
  • Paediatric Oncology

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