title: Mutations in RIT1 cause Noonan syndrome with possible juvenile myelomonocytic leukemia but are not involved in acute lymphoblastic leukemia.
abstract: Noonan syndrome is a heterogeneous autosomal dominant disorder caused by mutations in at least eight genes involved in the RAS/MAPK signaling pathway. Recently, RIT1 (Ras-like without CAAX 1) has been shown to be involved in the pathogenesis of some patients. We report a series of 44 patients from 30 pedigrees (including nine multiplex families) with mutations in RIT1. These patients display a typical Noonan gestalt and facial phenotype. Among the probands, 8.7% showed postnatal growth retardation, 90% had congenital heart defects, 36% had hypertrophic cardiomyopathy (a lower incidence compared with previous report), 50% displayed speech delay and 52% had learning difficulties, but only 22% required special education. None had major skin anomalies. One child died perinatally of juvenile myelomonocytic leukemia. Compared with the canonical Noonan phenotype linked to PTPN11 mutations, patients with RIT1 mutations appear to be less severely growth retarded and more frequently affected by cardiomyopathy. Based on our experience, we estimate that RIT1 could be the cause of 5% of Noonan syndrome patients. Because mutations found constitutionally in Noonan syndrome are also found in several tumors in adulthood, we evaluated the potential contribution of RIT1 to leukemogenesis in Noonan syndrome. We screened 192 pediatric cases of acute lymphoblastic leukemias (96 B-ALL and 96 T-ALL) and 110 cases of juvenile myelomonocytic leukemias (JMML), but detected no variation in these tumoral samples, suggesting that Noonan patients with germline RIT1 mutations are not at high risk to developing JMML or ALL, and that RIT1 has at most a marginal role in these sporadic malignancies.
authors.affiliation: Department of Genetics, Assistance Publique - Hôpitaux de Paris (AP-HP) - Robert Debré University Hospital, Paris, France.|INSERM UMR S1131, Institut Universitaire d'Hématologie, Denis Diderot Medical School, Sorbonne-Paris-Cité University, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Cavé
authors.affiliation: Department of Genetics, Assistance Publique - Hôpitaux de Paris (AP-HP) - Robert Debré University Hospital, Paris, France.|INSERM UMR S1131, Institut Universitaire d'Hématologie, Denis Diderot Medical School, Sorbonne-Paris-Cité University, Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Caye
authors.affiliation: Department of Genetics, Assistance Publique - Hôpitaux de Paris (AP-HP) - Robert Debré University Hospital, Paris, France.|INSERM UMR S1131, Institut Universitaire d'Hématologie, Denis Diderot Medical School, Sorbonne-Paris-Cité University, Paris, France.
authors.forename: Nehla
authors.initials: N
authors.lastname: Ghedira
authors.affiliation: Department of Genetics, Assistance Publique - Hôpitaux de Paris (AP-HP) - Robert Debré University Hospital, Paris, France.
authors.forename: Yline
authors.initials: Y
authors.lastname: Capri
authors.affiliation: Department of Genetics, Assistance Publique - Hôpitaux de Paris (AP-HP) - Robert Debré University Hospital, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pouvreau
authors.affiliation: Department of Genetics, Assistance Publique - Hôpitaux de Paris (AP-HP) - Robert Debré University Hospital, Paris, France.
authors.forename: Natacha
authors.initials: N
authors.lastname: Fillot
authors.affiliation: Department of Genetics, Assistance Publique - Hôpitaux de Paris (AP-HP) - Robert Debré University Hospital, Paris, France.|INSERM UMR S1131, Institut Universitaire d'Hématologie, Denis Diderot Medical School, Sorbonne-Paris-Cité University, Paris, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Trimouille
authors.affiliation: Department of Genetics, Assistance Publique - Hôpitaux de Paris (AP-HP) - Robert Debré University Hospital, Paris, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Vignal
authors.affiliation: Hematology Laboratory, AP-HP - Robert Debré University Hospital, Paris, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Fenneteau
authors.affiliation: Department of Genetics, University Hospital, Strasbourg, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Alembik
authors.affiliation: Department of Genetics, University Hospital, Saint Denis de la Réunion, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Alessandri
authors.affiliation: Department of Genetics, University Hospital, Montpellier, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Blanchet
authors.affiliation: Department of Genetics, Jeanne de Flandre University Hospital, Lille, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Boute
authors.affiliation: Medico-surgical Department of Child and Adult Cardiology, Louis Pradel University Hospital, Lyon University, Bron, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Bouvagnet
authors.affiliation: Department of Genetics, University Hospital, Nantes, France.
authors.forename: Albert
authors.initials: A
authors.lastname: David
authors.affiliation: Department of Genetics, Jeanne de Flandre University Hospital, Lille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Dieux Coeslier
authors.affiliation: Department of Genetics, University Hospital, Strasbourg, France.
authors.forename: Bérénice
authors.initials: B
authors.lastname: Doray
authors.affiliation: Department of Child Neurology, AP-HP-Necker-Enfants Malades Hospital, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Dulac
authors.affiliation: Department of Genetics, University Hospital, Rouen, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Drouin-Garraud
authors.affiliation: Department of Genetics, University Hospital, Caen, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Gérard
authors.affiliation: Department of Genetics, AP-HP - La Pitié-Salpétrière Hospital, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Héron
authors.affiliation: Department of Genetics, University Hospital, Nantes, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Isidor
authors.affiliation: Department of Genetics, University Hospital, Bordeaux, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.affiliation: Department of Genetics, AP-HP - Necker-Enfants Malades Hospital, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.affiliation: Department of Genetics, Assistance Publique - Hôpitaux de Paris (AP-HP) - Robert Debré University Hospital, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Perrin
authors.affiliation: Department of Genetics, AP-HP - Necker-Enfants Malades Hospital, Paris, France.
authors.forename: Marlène
authors.initials: M
authors.lastname: Rio
authors.affiliation: Department of Genetics, Intercommunal Hospital, Poissy-St Germain en Laye, France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Roume
authors.affiliation: Department of Pediatrics, AP-HP - Jean Verdier Hospital, Bondy, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Sauvion
authors.affiliation: Department of Genetics, University Hospital, Tours, France.
authors.forename: Annick
authors.initials: A
authors.lastname: Toutain
authors.affiliation: Department of Genetics, Jeanne de Flandre University Hospital, Lille, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Vincent-Delorme
authors.affiliation: Department of Genetics, AP-HP - Necker-Enfants Malades Hospital, Paris, France.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Willems
authors.affiliation: Department of Genetics, Assistance Publique - Hôpitaux de Paris (AP-HP) - Robert Debré University Hospital, Paris, France.
authors.forename: Clarisse
authors.initials: C
authors.lastname: Baumann
authors.affiliation: Department of Genetics, Assistance Publique - Hôpitaux de Paris (AP-HP) - Robert Debré University Hospital, Paris, France.|INSERM UMR 1141, Denis Diderot Medical School, Sorbonne-Paris-Cité University, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D009634:Noonan Syndrome / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D018631:ras Proteins / Q000235:genetics*
chemical_list: C486776:RIT1 protein, human; D018631:ras Proteins