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

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.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.Metatropic Dysplasia (MD, OMIM 156530) is a severe bone dysplasia, observable in the perinatal period, first described by Maroteaux et al in 1966. Derived from ancient Greek μετα meaning "with" and τροπη meaning "change"; the name refers to the main clinical feature of the condition, which changes from the newborn period, with long trunk and short limbs, to childhood, when, due to progressive spinal changes, it becomes a short trunk dwarfism. The main abnormalities occur in the vertebral bodies and the metaphyseal portions of the long bones, and the clinical and radiological diagnostic features are well described in the literature [1]. Some authors have suggested genetic variability in MD, with an autosomal dominant type and a more severe (lethal) autosomal recessive type,[2] but Camacho et al (2010) demonstrated TRPV4 mutations in both lethal and milder types of MD [3].Spondylometaphyseal Dysplasia Kozlowski Type (SMDK, OMIM 1842522) was first described by Kozlowski, Maroteaux and Spranger in 1967 [4]