TRPV4, a nonselective calcium permeable ion channel, is expressed broadly in many organs including bone and neurons. Pathogenic variants in TRPV4 are known to cause both a spectrum of skeletal dysplasias and neuropathies. Recent publications have documented a few patients who have a combined phenotype of skeletal dysplasia and neuropathy secondary to TRPV4 pathogenic variants. We present an additional patient who has an overlapping neuromuscular and skeletal phenotype secondary to a TRPV4 pathogenic variant. The patient has spondylometaphyseal dysplasia-Kozlowski type and Charcot-Marie-Tooth disease type 2C. This and prior reports illustrate that TRPV4-related skeletal dysplasias and TRPV4-related neuropathies are not fully distinct disorders secondary to unique sets of pathogenic variants as originally postulated, but rather are 2 phenotypes on the same spectrum that may or may not overlap. We suggest that evaluation for patients presenting with any TRPV4-related disorder include assessment for both skeletal and neurological findings.

Keywords:
Charcot-Marie-Tooth, CMT2C, SMD-K, Spondlyometaphyseal dysplasia Kozlowski, TRPV4
1.
Auer-Grumbach M, Olschewski A, Papic L, Kremer H, McEntagart ME, et al: Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C. Nat Genet 42:160-164 (2010).
2.
Chen DH, Sul Y, Weiss M, Hillel A, Lipe H, et al: CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene. Neurology 75:1968-1975 (2010).
3.
Cho TJ, Matsumoto K, Fano V, Dai J, Kim OH, et al: TRPV4-pathy manifesting both skeletal dysplasia and peripheral neuropathy: a report of three patients. Am J Med Genet A 158A:795-802 (2012).
4.
Dai J, Cho TJ, Unger S, Lausch E, Nishimura G, et al: TRPV4-pathy, a novel channelopathy affecting diverse systems. J Hum Genet 55:400-402 (2010).
5.
Deng HX, Klein CJ, Yan J, Shi Y, Wu Y, et al: Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4. Nat Genet 42:165-169 (2010).
6.
Dyck PJ, Litchy WJ, Minnerath S, Bird TD, Chance PF, et al: Hereditary motor and sensory neuropathy with diaphragm and vocal cord paresis. Ann Neurol 35:608-615 (1994).
7.
Evangelista T, Bansagi B, Pyle A, Griffin H, Douroudis K, et al: Phenotypic variability of TRPV4 related neuropathies. Neuromuscul Disord 25:516-521 (2015).
8.
Everaerts W, Nilius B, Owsianik G: The vanilloid transient receptor potential channel TRPV4: from structure to disease. Prog Biophys Mol Biol 103:2-17 (2010).
9.
Fecto F, Shi Y, Huda R, Martina M, Siddique T, Deng HX: Mutant TRPV4-mediated toxicity is linked to increased constitutive function in axonal neuropathies. J Biol Chem 286:17281-17291 (2011).
10.
Guilak F, Leddy HA, Liedtke W: Transient receptor potential vanilloid 4 the sixth sense of the musculoskeletal system? Ann N Y Acad Sci 1192:404-409 (2010).
11.
Jang Y, Jung J, Kim H, Oh J, Jeon JH, et al: Axonal europathy-associated TRPV4 regulates neurotrophic factor-derived axonal growth. J Biol Chem 287:6014-6024 (2012).
12.
Kozlowski K, Maroteaux P, Spranger JW: La dysostose spondylometaphisaire. Presse Med 75:2769 (1967).
13.
Kozlowski K, Beemer FA, Bens G, Dijkstra PF, Iannaccone G, et al: Spondylo-metaphyseal dysplasia. (Report of 7 cases and essay of classification). Prog Clin Biol Res 104:89-101 (1982).
14.
Krakow D, Vriens J, Camacho N, Luong P, Deixler H, et al: Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia. Am J Hum Genet 84:307-315 (2009).
15.
Landouré G, Zdebik AA, Martinez TL, Burnett BG, Stanescu HC, et al: Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. Nat Genet 42:170-174 (2010).
16.
Loukin S, Su Z, Kung C: Increased basal activity is a key determinant in the severity of human skeletal dysplasia caused by TRPV4 mutations. PLoS One 6:e19533 (2011).
17.
Masuyama R, Vriens J, Voets T, Karashima Y, Owsianik G, et al: TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts. Cell Metab 8:257-265 (2008).
18.
Muramatsu S, Wakabayashi M, Ohno T, Amano K, Ooish, R, et al: Functional gene screening system identified TRPV4 as a regulator of chondrogenic differentiation. J Biol Chem 282:32158-32167 (2007).
19.
Rock MJ, Prenen J, Funari VA, Funari TL, Merriman B, et al: Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia. Nat Genet 40:999-1003 (2008).
20.
Sullivan JM, Zimanyi CM, Aisenberg W, Bears B, Chen D, et al: Novel mutations highlight the ankyrin repeat domain in the TRPV4-mediated neuropathy. Neurol Genet 1:e29 (2015).
21.
Unger S, Lausch E, Stanzial F, Gillessen-Kaesbach G, Stefanova I, et al: Fetal akinesia in metatropic dysplasia: the combined phenotype of chondrodysplasia and neuropathy? Am J Med Genet A 155A:2860-2864 (2011).
22.
Zimoń M, Baets J, Auer-Grumbach M, Berciana, J, Garcia, A, et al: Dominant mutations in the cation channel gene transient receptor potential vanilloid 4 cause an unusual spectrum of neuropathies. Brain 133:1798-1809 (2010).
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2018
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