title: TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted byclinical, radiographic, and molecular studies in 21 new families.
abstract: 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.
  
  
  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.
authors.affiliation: Genetic Health Services Victoria and Murdoch Childrens Research Institute, Parkville, Victoria, Australia. elena.andreucci@unifi.it
authors.forename: Elena
authors.initials: E
authors.lastname: Andreucci
authors.forename: Salim
authors.initials: S
authors.lastname: Aftimos
authors.forename: Melanie
authors.initials: M
authors.lastname: Alcausin
authors.forename: Eric
authors.initials: E
authors.lastname: Haan
authors.forename: Warwick
authors.initials: W
authors.lastname: Hunter
authors.forename: Peter
authors.initials: P
authors.lastname: Kannu
authors.forename: Bronwyn
authors.initials: B
authors.lastname: Kerr
authors.forename: George
authors.initials: G
authors.lastname: McGillivray
authors.forename: R J
authors.initials: RJ
authors.lastname: McKinlay Gardner
authors.forename: Maria G
authors.initials: MG
authors.lastname: Patricelli
authors.forename: David
authors.initials: D
authors.lastname: Sillence
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Thompson
authors.forename: Margaret
authors.initials: M
authors.lastname: Zacharin
authors.forename: Andreas
authors.initials: A
authors.lastname: Zankl
authors.forename: Shireen R
authors.initials: SR
authors.lastname: Lamandé
authors.forename: Ravi
authors.initials: R
authors.lastname: Savarirayan
mesh_terms: D000328:Adult; D001848:Bone Diseases, Developmental / Q000145:classification / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D002675:Child, Preschool; D004392:Dwarfism / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D005190:Family; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010009:Osteochondrodysplasias / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D011859:Radiography; D050916:TRPV Cation Channels / Q000235:genetics*
chemical_list: D050916:TRPV Cation Channels; C416986:TRPV4 protein, human