RESEARCH LETTER Metatropic Dysplasia Is Associated with Increased Fracture Risk Michael B. Bober, 1 * Angela L. Duker, 1 Megan Carney, 1 Colleen P. Ditro, 2 Kenneth Rogers, 2 and William G. Mackenzie 2 1 Division of Medical Genetics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware 2 Department of Orthopaedics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware Manuscript Received: 13 November 2015; Manuscript Accepted: 19 January 2016 TO THE EDITOR: Metatropic dysplasia (MD) (OMIM #156530) was first described by Maroteaux et al. in 1966 [Maroteaux et al., 1966]. Its name was derived from the Greek word metatropos which means “changing pattern” because individuals with this diagnosis begin life with a short-limbed dysplasia and a long trunk with narrow chest, and over time their dysplasia becomes short-trunked due to progressive kyphoscoliosis [Boden et al., 1987]. It is now recognized that MD is caused by gain-of-function mutations in transient receptor poten- tial vanilloid 4 (TRPV4), inherited in an autosomal dominant manner and belongs to a family of dysplasias which includes: spondyloepimetaphyseal dysplasia, Maroteaux type (SEMDM), spondylometaphyseal dysplasia, Kozlowski type (SMDK), bra- chyolmia, and familial digital arthropathy with brachydactyly [Krakow et al., 2009; Bonafe et al., 2015]. Autosomal dominant loss-of-function TRPV4 mutations cause: Charcot Marie Tooth, Type 2C, congenital distal spinal muscular atrophy and scapulo- peroneal spinal muscular atrophy [Deng et al., 2010]. Yet other individuals have mixed neuromuscular and skeletal phenotypes with their TRPV4-opathy [Cho et al., 2012]. TRPV4 is a member of the transient receptor potential super family of non-selective cation channels, important in the regulation of intracellular calcium. It is widely expressed in human nervous, urinary, respiratory, and musculoskeletal systems [Everaets et al., 2010], as well as in the vasculature [Yin and Kuebler, 2009], and eyes [Mergler et al., 2011]. In our clinic, it became apparent over time that there was a higher than expected fracture frequency in MD. To explore further we designed an Institutional Review Board approved protocol for a detailed retrospective review of this patient population. Of the 20 patients evaluated at our institution in last 9 years with MD or SMDK, there were 10 males and 10 females. 8/20 (40%) of patients had at least one fracture, and 5/20 (25%) of patients had two or more fractures; see Table I. Six males and two females had history of at least one fracture. Two males and two females had a history of two or more fractures. The majority of these fractures are low energy, insufficiency type fractures which occurred in the meta- physeal regions of the long bones; see Figure 1. Taken together this would yield an estimated annual fracture rate of 72/1,000 person- years (17 fractures in 236 person-years). This is higher than the published range of 13.3–36.1/1,000 person-years described in George-Abraham et al. [2013]. This range is based upon fractures in healthy children and is derived from multiple sources. Although not uniformly obtained in each individual patient, review of available labs demonstrates increased markers of bone formation and resorption suggestive of a high-turnover state in these patients. No consistent changes were noted in the serum calcium or phos- phorus levels. Evidence of increased bone turnover, with elevated TRAP, NTX, and osteocalcin levels were noted. In addition to the clear role TRPV4 plays in the growth plate, and its dysfunction leads to short-limbed and then short-trunked dwarfism, TRPV4 gain-of-function also leads to a state of increased bone turnover and osteopenia leading to fracture. As a universal signaling molecule, changes in intracellular calcium regulate cru- cial processes in the proliferation, differentiation, and viability of all cell types. TRPV4 has been shown to be central to mechano- and osmotic responses in chondrocytes, and thus alteration in channel activity can have a profound effect on cellular phenotype [Hurd et al., 2015]. When TRPR4 is over-expressed in osteoclasts in transgenic mice, increased osteoclastic numbers, and increased resorption activity were noted. This resulted in bone loss and decreased bone mass in these mice [Masuyama et al., 2012]. Taken Conflicts of interest: The authors declare no conflict of interest. Ã Correspondence to: Michael Bober, M.D., Ph.D., Skeletal Dysplasia Program, Nemours/ Alfred I. duPont Hospital for Children, 1600 Rockland Road, Wilmington, DE 19803. E-mail: mbober@nemours.org Article first published online in Wiley Online Library (wileyonlinelibrary.com): 29 January 2016 DOI 10.1002/ajmg.a.37576 How to Cite this Article: Bober MB, Duker AL, Carney M, Ditro CP, Rogers K, Mackenzie WG. 2016. Metatropic dysplasia is associated with increased fracture risk. Am J Med Genet Part A 170A:1373–1376. Ó 2016 Wiley Periodicals, Inc. 1373