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TRPV4-Associated Disorders.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.
2014 May 15.

Author information

National Institute of Neurological Disorders and Stroke, Neurogenetics Branch, National Institutes of Health, Bethesda, Maryland
Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland
Department of Pediatrics – Genetic Medicine, Johns Hopkins Hospital, Baltimore, Maryland



The TRPV4-associated disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within and between both groups is considerable. Bilateral progressive sensorineural hearing loss (SNHL) can occur in both. The three neuromuscular disorders (mildest to most severe): Charcot-Marie-Tooth disease type 2C (CMT2C). Scapuloperoneal spinal muscular atrophy (SPSMA). Congenital distal spinal muscular atrophy (CDSMA). The neuromuscular disorders are characterized by a progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six skeletal dysplasias: Mildest: Familial digital arthropathy-brachydactyly. Intermediate: Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Most severe: Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the TRPV4-associated disorders life span is normal; in the most severe it is shortened.


The diagnosis of TRPV4-associated disorders is based on clinical and neurophysiologic findings, radiographic findings in the skeletal dysplasias, and the identification of a heterozygous TRPV4 pathogenic variant on molecular genetic testing.


Treatment of manifestations: Treatment is symptomatic. Affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists. SNHL is managed by specialists to determine the best habilitation options. For neuromuscular disorders: Neuropathy and respiratory dysfunction are managed in a routine manner; laryngeal dysfunction requires speech therapy and, in some instances, surgery. For skeletal dysplasias: Physical therapy/exercise to maintain function; surgical intervention when kyphoscoliosis compromises pulmonary function and/or causes pain and/or when upper cervical spine instability and/or cervical myelopathy are present. Surveillance: For neuromuscular disorders: Routine neurologic examinations, physical therapy assessments, monitoring of laryngeal function, respiratory function, and hearing. For skeletal dysplasias: Annual evaluation for joint pain and scoliosis; assessment for odontoid hypoplasia before a child reaches school age and before surgical procedures involving general anesthesia Agents/circumstances to avoid: For neuromuscular disorders: Obesity as it makes walking more difficult; medications which are toxic or potentially toxic to persons with a peripheral neuropathy. For skeletal dysplasias: Extreme neck flexion and extension (in those with odontoid hypoplasia); activities that place undue stress on the spine and weight-bearing joints Pregnancy management: Ideally woman with TRPV4-associated disorder would seek consultation from a high-risk OB/GYN or maternal-fetal-medicine specialist to evaluate risk for pregnancy and delivery.


TRPV4-associated disorders are inherited in an autosomal dominant manner. Most individuals diagnosed with a TRPV4-associated disorder have an affected parent. However, since the most severe skeletal phenotypes can be lethal in childhood (or in utero), children with these phenotypes likely have a de novo pathogenic variant and unaffected parents. Each child of an individual with a TRPV4-associated disorder has a 50% chance of inheriting the pathogenic variant. Specific phenotype, age of onset, and disease severity cannot be predicted accurately because of incomplete penetrance and variable expressivity. However, in general, a child who inherits a TRPV4 pathogenic variant associated with neuromuscular disease or skeletal dysplasia from an affected parent is likely to have the same phenotype as the parent. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant has been identified in an affected family member.

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