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J Med Genet. 2014 Oct;51(10):689-97. doi: 10.1136/jmedgenet-2014-102611. Epub 2014 Aug 5.

Juvenile myelomonocytic leukaemia and Noonan syndrome.

Author information

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.

KEYWORDS:

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

PMID:
25097206
DOI:
10.1136/jmedgenet-2014-102611
[Indexed for MEDLINE]

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