title: Frontometaphyseal dysplasia: mutations in FLNA and phenotypic diversity.
abstract: Frontometaphyseal dysplasia is an X-linked trait primarily characterized by a skeletal dysplasia comprising hyperostosis of the skull and modeling anomalies of the tubular bones. Extraskeletal features include tracheobronchial, cardiac, and urological malformations. A proportion of individuals have missense mutations or small deletions in the X-linked gene, FLNA. We report here our experience with comprehensive screening of the FLNA gene in a group of 23 unrelated probands (11 familial instances, 12 simplex cases; total affected individuals 32) with FMD. We found missense mutations leading to substitutions in the actin-binding domain and within filamin repeats 9, 10, 14, 16, 22, and 23 of filamin A in 13/23 (57%) of individuals in this cohort. Some mutations present with a male phenotype that is characterized by a severe skeletal dysplasia, cardiac, and genitourinary malformations that leads to perinatal death. Although no phenotypic feature consistently discriminates between females with FMD who are heterozygous for FLNA mutations and those in whom no FLNA mutation can be identified, there is a difference in the degree of skewing of X-inactivation between these two groups. This observation suggests that locus heterogeneity may exist for this disorder.
authors.affiliation: Department of Paediatrics and Child Health, Dunedin School of Medicine, Dunedin, New Zealand. stephen.robertson@stonebow.otago.ac.nz
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Robertson
authors.forename: Zandra A
authors.initials: ZA
authors.lastname: Jenkins
authors.forename: Timothy
authors.initials: T
authors.lastname: Morgan
authors.forename: Lesley
authors.initials: L
authors.lastname: Adès
authors.forename: Salim
authors.initials: S
authors.lastname: Aftimos
authors.forename: Odile
authors.initials: O
authors.lastname: Boute
authors.forename: Torunn
authors.initials: T
authors.lastname: Fiskerstrand
authors.forename: Sixto
authors.initials: S
authors.lastname: Garcia-Miñaur
authors.forename: Arthur
authors.initials: A
authors.lastname: Grix
authors.forename: Andrew
authors.initials: A
authors.lastname: Green
authors.forename: Vazken
authors.initials: V
authors.lastname: Der Kaloustian
authors.forename: Ray
authors.initials: R
authors.lastname: Lewkonia
authors.forename: Brenda
authors.initials: B
authors.lastname: McInnes
authors.forename: Mieke M
authors.initials: MM
authors.lastname: van Haelst
authors.forename: Grazia
authors.initials: G
authors.lastname: Mancini
authors.forename: Grazia
authors.initials: G
authors.lastname: Macini
authors.forename: Tamás
authors.initials: T
authors.lastname: Illés
authors.forename: Geert
authors.initials: G
authors.lastname: Mortier
authors.forename: Ruth
authors.initials: R
authors.lastname: Newbury-Ecob
authors.forename: Linda
authors.initials: L
authors.lastname: Nicholson
authors.forename: Charles I
authors.initials: CI
authors.lastname: Scott
authors.forename: Karolina
authors.initials: K
authors.lastname: Ochman
authors.forename: Izabela
authors.initials: I
authors.lastname: Brozek
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Shears
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Mohnish
authors.initials: M
authors.lastname: Suri
authors.forename: Margo
authors.initials: M
authors.lastname: Whiteford
authors.forename: Andrew O M
authors.initials: AO
authors.lastname: Wilkie
authors.forename: Deborah
authors.initials: D
authors.lastname: Krakow
mesh_terms: D000328:Adult; D002675:Child, Preschool; D015331:Cohort Studies; D003285:Contractile Proteins / Q000235:genetics*; D005260:Female; D064448:Filamins; D050172:Genes, X-Linked; D014644:Genetic Variation; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010009:Osteochondrodysplasias / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D011859:Radiography; D049951:X Chromosome Inactivation / Q000235:genetics
chemical_list: D003285:Contractile Proteins; D064448:Filamins; D008840:Microfilament Proteins