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TRPV4-pathy manifesting both skeletal dysplasia and peripheral neuropathy: A report of three patients


  • Tae-Joon Cho, Kazu Matsumoto, and Virginia Fano contributed equally to the work.

  • How to Cite this Article: Cho T-J, Matsumoto K, Fano V, Dai J, Kim O-H, Chae JH, Yoo WJ, Tanaka Y, Matsui Y, Takigami I, Monges S, Zabel B, Shimizu K, Nishimura G, Lausch E, Ikegawa S. 2012. TRPV4-pathy manifesting both skeletal dysplasia and peripheral neuropathy: A report of three patients. Am J Med Genet Part A 158A:795–802.


Heterozygous missense mutations of transient receptor potential vanilloid 4 channel (TRPV4) cause a spectrum of skeletal disorders, including brachyolmia, spondylometaphyseal dysplasia Kozlowski type, metatropic dysplasia, parastremmatic dysplasia, and spondyloepimetaphyseal dysplasia Maroteaux type. Similarly, heterozygous missense mutations of TRPV4 cause a spectrum of peripheral neuropathy, including hereditary motor and sensory neuropathy type IIC, congenital spinal muscular atrophy, and scapuloperoneal spinal muscular atrophy. There are no apparent differences in the amino acid positions affected or type of change predicted by the TRPV4 mutations responsible for the two disease spectrums; nevertheless, no fundamental phenotypic overlap has been shown between the two spectrums. Here, we report on three patients who had both skeletal dysplasia and peripheral neuropathy caused by heterozygous TRPV4 missense mutations. The skeletal and neurologic phenotypes of these patients covered the wide spectrum of reported TRPV4-pathies (disease caused by TRPV4 mutations). The molecular data are complementary, proving that “neuropathic” mutations can cause skeletal dysplasia but also the “skeletopathic” mutations can lead to neuropathies. Our findings suggest that pathogenic mechanisms of TRPV4-pathies in skeletal and nervous systems are not always mutually exclusive and provide further evidence that there is no clear genotype–phenotype correlation for either spectrum. Co-occurrence of skeletal dysplasia and degenerative neuropathy should be kept in mind in clinical practice including diagnostic testing, surgical evaluation, and genetic counseling. © 2012 Wiley Periodicals, Inc.