Frontometaphyseal dysplasia: mutations in FLNA and phenotypic diversity

Stephen P Robertson, Zandra A Jenkins, Timothy Morgan, Lesley Adès, Salim Aftimos, Odile Boute, Torunn Fiskerstrand, Sixto Garcia-Miñaur, Arthur Grix, Andrew Green, Vazken Der Kaloustian, Ray Lewkonia, Brenda McInnes, Mieke M van Haelst, Grazia Mancini, Grazia Macini, Tamás Illés, Geert Mortier, Ruth Newbury-Ecob, Linda NicholsonCharles I Scott, Karolina Ochman, Izabela Brozek, Deborah J Shears, Andrea Superti-Furga, Mohnish Suri, Margo Whiteford, Andrew O M Wilkie, Deborah Krakow

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64 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1726-36
Number of pages11
JournalAmerican Journal of Medical Genetics Part A
Issue number16
Publication statusPublished - 15 Aug 2006


  • Adult
  • Child, Preschool
  • Cohort Studies
  • Contractile Proteins/genetics
  • Female
  • Filamins
  • Genes, X-Linked
  • Genetic Variation
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Microfilament Proteins/genetics
  • Middle Aged
  • Mutation
  • Osteochondrodysplasias/diagnosis
  • Phenotype
  • Radiography
  • X Chromosome Inactivation/genetics

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