title: Germline gain-of-function mutations of ALK disrupt central nervous system development.
abstract: Neuroblastoma (NB) is a frequent embryonal tumor of sympathetic ganglia and adrenals with extremely variable outcome. Recently, somatic amplification and gain-of-function mutations of the anaplastic lymphoma receptor tyrosine kinase (ALK) gene, either somatic or germline, were identified in a significant proportion of NB cases. Here we report a novel syndromic presentation associating congenital NB with severe encephalopathy and abnormal shape of the brainstem on brain MRI in two unrelated sporadic cases harboring de novo, germline, heterozygous ALK gene mutations. Both mutations are gain-of-function mutations that have been reported in NB and NB cell lines. These observations further illustrate the role of oncogenes in both tumour predisposition and normal development, and shed light on the pleiotropic and activity-dependent role of ALK in humans. More generally, missing germline mutations relative to the spectrum of somatic mutations reported for a given oncogene may be a reflection of severe effects during embryonic development, and may prompt mutation screening in patients with extreme phenotypes.
authors.affiliation: Université Paris Descartes, INSERM U-781, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: de Pontual
authors.forename: Dania
authors.initials: D
authors.lastname: Kettaneh
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Gordon
authors.forename: Myriam
authors.initials: M
authors.lastname: Oufadem
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.forename: Melissa
authors.initials: M
authors.lastname: Lees
authors.forename: Laurent
authors.initials: L
authors.lastname: Balu
authors.forename: Eric
authors.initials: E
authors.lastname: Lachassinne
authors.forename: Andy
authors.initials: A
authors.lastname: Petros
authors.forename: Julie
authors.initials: J
authors.lastname: Mollet
authors.forename: Louise C
authors.initials: LC
authors.lastname: Wilson
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Laurence
authors.initials: L
authors.lastname: Brugière
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.forename: Michel
authors.initials: M
authors.lastname: Vekemans
authors.forename: Heather
authors.initials: H
authors.lastname: Etchevers
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Isabelle
authors.initials: I
authors.lastname: Janoueix-Lerosey
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
mesh_terms: D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D001933:Brain Stem / Q000002:abnormalities*; D002490:Central Nervous System / Q000196:embryology; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D020125:Mutation, Missense; D009447:Neuroblastoma / Q000151:congenital / Q000235:genetics* / Q000473:pathology*; D009857:Oncogenes; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D013577:Syndrome
chemical_list: C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases