TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted byclinical, radiographic, and molecular studies in 21 new families

Elena Andreucci, Salim Aftimos, Melanie Alcuasin, Eric Haan, Warwick Hunter, Peter Kannu, Bronwyn Kerr, George McGillivray, RJ McKinlay Gardner, Maria Patricelli, David Sillence, Elizabeth Thompson, Margaret Zacharin, Andreas Zankl, Shireen Lamande, Ravi Savarirayan

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    39 Citations (Scopus)


    Background: The TRPV4 gene encodes a calcium-permeable ion-channel that is widely expressed, responds to many different stimuli and participates in an extraordinarily wide range of physiologic processes. Autosomal dominant brachyolmia, spondylometaphyseal dysplasia Kozlowski type (SMDK) and metatropic dysplasia (MD) are currently considered three distinct skeletal dysplasias with some shared clinical features, including short stature, platyspondyly, and progressive scoliosis. Recently, TRPV4 mutations have been found in patients diagnosed with these skeletal phenotypes. Methods and Results. We critically analysed the clinical and radiographic data on 26 subjects from 21 families, all of whom had a clinical diagnosis of one of the conditions described above: 15 with MD; 9 with SMDK; and 2 with brachyolmia. We sequenced TRPV4 and identified 9 different mutations in 22 patients, 4 previously described, and 5 novel. There were 4 mutation-negative cases: one with MD and one with SMDK, both displaying atypical clinical and radiographic features for these diagnoses; and two with brachyolmia, who had isolated spine changes and no metaphyseal involvement. Conclusions: Our data suggest the TRPV4 skeletal dysplasias represent a continuum of severity with areas of phenotypic overlap, even within the same family. We propose that AD brachyolmia lies at the mildest end of this spectrum and, since all cases described with this diagnosis and TRPV4 mutations display metaphyseal changes, we suggest that it is not a distinct entity but represents the mildest phenotypic expression of SMDK.

    Original languageEnglish
    Article number37
    Number of pages8
    JournalOrphanet Journal of Rare Diseases
    Issue numberArticle 37
    Publication statusPublished - 2011


    • Autosomal Dominant Brachyolmia (ADBO)
    • Metatropic Dysplasia (MD)
    • Spondilometaphyseal Dysplasia Kozlowski Type (SMDK)
    • TRPV4


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