Marion Strullu1, Aurélie Caye1, Julie Lachenaud1, Bruno Cassinat2, Steven Gazal3, Odile Fenneteau4, Nathalie Pouvreau5, Sabrina Pereira5, Clarisse Baumann5, Audrey Contet6, Nicolas Sirvent7, Françoise Méchinaud8, Isabelle Guellec9, Dalila Adjaoud10, Catherine Paillard11, Corinne Alberti12, Martin Zenker13, Christine Chomienne2, Yves Bertrand14, André Baruchel15, Alain Verloes16, Hélène Cavé1. 1. 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. 2. 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. 3. INSERM UMR_1137, IAME, Plateforme de Génétique constitutionnelle-Nord (PfGC-Nord), Université Paris Diderot, Paris, France. 4. Service d'Hématologie Biologique, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Paris, France. 5. Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, Paris, France. 6. Service d'Onco-Hématologie pédiatrique, Hôpital d'Enfants de Brabois, Vandoeuvre lès Nancy, France. 7. Service d'Onco-Hématologie pédiatrique, CHU de Nice, Nice, France. 8. Service d'Onco-Hématologie pédiatrique, CHU de Nantes, Nantes, France. 9. Réanimation néonatale pédiatrique, Paris Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Trousseau, Paris, France. 10. Service d'Onco-Hématologie pédiatrique, CHU de Grenoble, Grenoble, France. 11. Service de Pédiatrie, Hôpital de Hautepierre, Strasbourg, France. 12. 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. 13. Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany. 14. Département d'Immunologie et Hématologie Pédiatrique, Institut d'Hémato-Oncologie Pédiatrique (IHOP), Lyon, France. 15. Service d'Hématologie pédiatrique, Assistance Publique des Hôpitaux de Paris AP-HP, Hôpital Robert Debré, Paris, France. 16. 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.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: Yline Capri; Elisabetta Flex; Oliver H F Krumbach; Giovanna Carpentieri; Serena Cecchetti; Christina Lißewski; Soheila Rezaei Adariani; Denny Schanze; Julia Brinkmann; Juliette Piard; Francesca Pantaleoni; Francesca R Lepri; Elaine Suk-Ying Goh; Karen Chong; Elliot Stieglitz; Julia Meyer; Alma Kuechler; Nuria C Bramswig; Stephanie Sacharow; Marion Strullu; Yoann Vial; Cédric Vignal; George Kensah; Goran Cuturilo; Neda S Kazemein Jasemi; Radovan Dvorsky; Kristin G Monaghan; Lisa M Vincent; Hélène Cavé; Alain Verloes; Mohammad R Ahmadian; Marco Tartaglia; Martin Zenker Journal: Am J Hum Genet Date: 2019-05-23 Impact factor: 11.025
Authors: Heather Mason-Suares; Diana Toledo; Jean Gekas; Katherine A Lafferty; Naomi Meeks; M Cristina Pacheco; David Sharpe; Thomas E Mullen; Matthew S Lebo Journal: Eur J Hum Genet Date: 2017-01-18 Impact factor: 4.246
Authors: Franziska Altmüller; Christina Lissewski; Debora Bertola; Elisabetta Flex; Zornitza Stark; Stephanie Spranger; Gareth Baynam; Michelle Buscarilli; Sarah Dyack; Jane Gillis; Helger G Yntema; Francesca Pantaleoni; Rosa LE van Loon; Sara MacKay; Kym Mina; Ina Schanze; Tiong Yang Tan; Maie Walsh; Susan M White; Marena R Niewisch; Sixto García-Miñaúr; Diego Plaza; Mohammad Reza Ahmadian; Hélène Cavé; Marco Tartaglia; Martin Zenker Journal: Eur J Hum Genet Date: 2017-05-03 Impact factor: 4.246