Abstract
BackgroundThe 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 ResultsWe 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.ConclusionsOur 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.
Highlights
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
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 autosomal dominant (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 spondylometaphyseal dysplasia Kozlowski type (SMDK)
Summary
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. Spondylometaphyseal Dysplasia Kozlowski Type (SMDK, OMIM 1842522) was first described by Kozlowski, Maroteaux and Spranger in 1967 [4] and it is the best-characterized SMD It is an autosomal dominant (AD) condition, with postnatal short stature, and progressive spine deformities. Brachyolmia was a term coined in 1969 by Maroteaux for a group of bone dysplasias which displayed short trunk short stature, with radiological involvement of the spine and no significant abnormalities of the long bones [7]. Twenty years later this group was classified into 4 different types: Hobaek, Toledo and Maroteaux, with autosomal recessive inheritance, and an autosomal dominant type of brachyolmia (OMIM 113500). In 2008 Rock et al demonstrated that AD brachyolmia is caused by gain of function mutations in the TRPV4 gene [9]
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