title: Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia.
abstract: BACKGROUND
  CBL missense mutations have recently been associated with juvenile myelomonocytic leukaemia (JMML), an aggressive myeloproliferative and myelodysplastic neoplasm of early childhood characterised by excessive macrophage/monocyte proliferation. CBL, an E3 ubiquitin ligase and a multi-adaptor protein, controls proliferative signalling networks by downregulating the growth factor receptor signalling cascades in various cell types.
  
  
  RESULTS
  CBL mutations were screened in 65 patients with JMML. A homozygous mutation of CBL was found in leukaemic cells of 4/65 (6%) patients. In all cases, copy neutral loss of heterozygosity of the 11q23 chromosomal region, encompassing the CBL locus, was demonstrated. Three of these four patients displayed additional features suggestive of an underlying developmental condition. A heterozygous germline CBL p.Y371H substitution was found in each of them and was inherited from the father in one patient. The germline mutation represents the first hit, with somatic loss of heterozygosity being the second hit positively selected in JMML cells. The three patients display a variable combination of dysmorphic features, hyperpigmented skin lesions and microcephaly that enable a 'CBL syndrome' to be tentatively delineated. Learning difficulties and postnatal growth retardation may be part of the phenotype.
  
  
  CONCLUSIONS
  A report of germline mutations of CBL in three patients with JMML is presented here, confirming the existence of an unreported inheritable condition associated with a predisposition to JMML.
authors.affiliation: APHP, Hôpital Robert Debré, Département de Génétique; Université Paris 7-Denis Diderot, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Pérez
authors.forename: F
authors.initials: F
authors.lastname: Mechinaud
authors.forename: C
authors.initials: C
authors.lastname: Galambrun
authors.forename: N
authors.initials: N
authors.lastname: Ben Romdhane
authors.forename: B
authors.initials: B
authors.lastname: Isidor
authors.forename: N
authors.initials: N
authors.lastname: Philip
authors.forename: J
authors.initials: J
authors.lastname: Derain-Court
authors.forename: B
authors.initials: B
authors.lastname: Cassinat
authors.forename: J
authors.initials: J
authors.lastname: Lachenaud
authors.forename: S
authors.initials: S
authors.lastname: Kaltenbach
authors.forename: A
authors.initials: A
authors.lastname: Salmon
authors.forename: C
authors.initials: C
authors.lastname: Désirée
authors.forename: S
authors.initials: S
authors.lastname: Pereira
authors.forename: M L
authors.initials: ML
authors.lastname: Menot
authors.forename: N
authors.initials: N
authors.lastname: Royer
authors.forename: O
authors.initials: O
authors.lastname: Fenneteau
authors.forename: A
authors.initials: A
authors.lastname: Baruchel
authors.forename: C
authors.initials: C
authors.lastname: Chomienne
authors.forename: A
authors.initials: A
authors.lastname: Verloes
authors.forename: H
authors.initials: H
authors.lastname: Cavé
mesh_terms: D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000150:complications / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006130:Growth Disorders / Q000150:complications / Q000235:genetics; D006801:Humans; D054429:Leukemia, Myelomonocytic, Juvenile / Q000150:complications / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000150:complications / Q000235:genetics; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics*; D013577:Syndrome
chemical_list: D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human