Autosomal dominant frontometaphyseal dysplasia: Delineation of the clinical phenotype

Emma M. Wade, Zandra A. Jenkins, Philip B. Daniel, Tim Morgan, Marie C. Addor, Lesley C. Ades, Debora Bertola, Axel Bohring, Erin Carter, Tae-Joon Cho, Christa M. de Geus, Hans-Christoph Duba, Elaine Fletcher, Kinga Hadzsiev, Raoul C. M. Hennekam, Chong A. Kim, Deborah Krakow, Eva Morava, Teresa Neuhann, David SillenceAndrea Superti-Furga, Hermine E. Veenstra-Knol, Dagmar Wieczorek, Louise C. Wilson, David M. Markie, Stephen P. Robertson*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

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    Frontometaphyseal dysplasia (FMD) is caused by gain-of-function mutations in the X-linked gene FLNA in approximately 50% of patients. Recently we characterized an autosomal dominant form of FMD (AD-FMD) caused by mutations in MAP3K7, which accounts for the condition in the majority of patients who lack a FLNA mutation. We previously also described a patient with a de novo variant in TAB2, which we hypothesized was causative of another form of AD-FMD. In this study, a cohort of 20 individuals with AD-FMD is clinically evaluated. This cohort consists of 15 individuals with the recently described, recurrent mutation (c.1454C>T) in MAP3K7, as well as three individuals with missense mutations that result in substitutions in the N-terminal kinase domain of TGF beta-activated kinase 1 (TAK1), encoded by MAP3K7. Additionally, two individuals have missense variants in the gene TAB2, which encodes a protein with a close functional relationship to TAK1, TAK1-associated binding protein 2 (TAB2). Although the X-linked and autosomal dominant forms of FMD are very similar, there are distinctions to be made between the two conditions. Individuals with AD-FMD have characteristic facial features, and are more likely to be deaf, have scoliosis and cervical fusions, and have a cleft palate. Furthermore, there are features only found in AD-FMD in our review of the literature including valgus deformity of the feet and predisposition to keloid scarring. Finally, intellectual disability is present in a small number of subjects with AD-FMD but has not been described in association with X-linked FMD.

    Original languageEnglish
    Pages (from-to)1739-1746
    Number of pages8
    JournalAmerican Journal of Medical Genetics. Part A
    Issue number7
    Publication statusPublished - Jul-2017


    • Frontometaphyseal dysplasia
    • keloid
    • locus heterogeneity
    • scoliosis
    • TAB2
    • TAK1
    • HUMANS
    • MAP3K7
    • FLNA

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