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Autosomal Dominant TRPV4 Disorders

, MD, PhD, , MS, CGC, , MD, PhD, and , MD.

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Initial Posting: ; Last Update: September 17, 2020.

Estimated reading time: 31 minutes

Summary

Clinical characteristics.

The autosomal dominant TRPV4 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 each group is considerable. Affected individuals typically have either neuromuscular or skeletal manifestations alone, and in only rare instances an overlap syndrome has been reported.

The three autosomal dominant neuromuscular disorders (mildest to most severe) are:

  • Charcot-Marie-Tooth disease type 2C
  • Scapuloperoneal spinal muscular atrophy
  • Congenital distal spinal muscular atrophy

The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures.

The six autosomal dominant skeletal dysplasias (mildest to most severe) are:

  • Familial digital arthropathy-brachydactyly
  • Autosomal dominant brachyolmia
  • Spondylometaphyseal dysplasia, Kozlowski type
  • Spondyloepiphyseal dysplasia, Maroteaux type
  • 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 autosomal dominant TRPV4 disorders life span is normal; in the most severe it is shortened.

Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias.

Diagnosis/testing.

The diagnosis of an autosomal dominant TRPV4 disorder is established in a proband with characteristic clinical and neurophysiologic findings, radiographic findings in the skeletal dysplasias, and a heterozygous TRPV4 pathogenic variant identified on molecular genetic testing.

Management.

Treatment of manifestations: Treatment is focused on symptom management. Affected individuals are often evaluated and managed by a multidisciplinary team that may include neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists. SNHL is managed by specialists to determine the best management options.

  • For neuromuscular disorders, neuropathy and respiratory dysfunction are managed in a routine manner; individuals with laryngeal dysfunction require ENT evaluation that should include speech therapy, laryngoscopy, and, in some instances, surgery.
  • For skeletal dysplasias, physical therapy/exercise and heel-cord stretching 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, annual neurologic examinations, physical therapy assessments, ENT monitoring of laryngeal function, dynamic breathing chest x-ray, and hearing assessment. 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; annual hearing assessment.

Agents/circumstances to avoid: For neuromuscular disorders, obesity, as it makes walking more difficult; diabetes; medications that 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 a woman with TRPV4 disorder would seek consultation from a high-risk OB-GYN or maternal-fetal medicine specialist to evaluate risk associated with pregnancy and delivery.

Genetic counseling.

TRPV4 disorders are inherited in an autosomal dominant manner. Most individuals diagnosed with an autosomal dominant TRPV4 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 an autosomal dominant TRPV4 disorder has a 50% chance of inheriting the pathogenic variant. Specific phenotype, age of onset, and disease severity cannot be predicted accurately because of reduced 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 and preimplantation genetic testing are possible if the pathogenic variant has been identified in an affected family member.

GeneReview Scope

Autosomal Dominant TRPV4 Disorders: Included Phenotypes 1
Neuromuscular disorders
  • Charcot-Marie-Tooth neuropathy type 2C (CMT2C)
  • Scapuloperoneal spinal muscular atrophy (SPSMA)
  • Congenital distal spinal muscular atrophy (CDSMA)
Skeletal dysplasias
  • Familial digital arthropathy-brachydactyly
  • Autosomal dominant brachyolmia
  • Spondylometaphyseal dysplasia, Kozlowski type
  • Spondyloepiphyseal dysplasia, Maroteaux type
  • Parastremmatic dysplasia
  • Metatropic dysplasia

For synonyms and outdated names see Nomenclature.

1.

The phenotypes comprising the two groups of autosomal dominant TRPV4 disorders are listed from mildest to most severe. For other genetic causes of these phenotypes see Differential Diagnosis.

Diagnosis

Suggestive Findings

Neuromuscular Disorders

An autosomal dominant TRPV4 neuromuscular disorder should be suspected in individuals with the following range of clinical findings (see Table 1).

Charcot-Marie-Tooth disease type 2C (CMT2C)

  • A progressive peripheral neuronopathy/neuropathy (primarily motor, rather than sensory) associated with pes cavus, distal amyotrophy, and foot drop
    • Nerve conduction studies [Dyck et al 1994, Zimoń et al 2010] show: (1) reduced compound motor action potential (CMAP) amplitudes with normal velocities (>40-60 m/s), although occasionally they may be mildly abnormal (36-40 m/s); and (2) normal, decreased, or absent distal sensory nerve action potential (SNAP) amplitudes.
    • Electromyography shows predominantly chronic neurogenic changes.
    • Nerve biopsy is infrequently employed, as the findings (loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments) do not differentiate between various causes of axonal neuropathy.
  • Laryngeal dysfunction (i.e., vocal fold paresis) that may be bilateral and severe (resulting in inspiratory stridor and/or a raspy [hoarse] voice) or asymmetric (often more severe on the left than the right). Mild paresis may be inferred by presence of flaccid dysphonia [Dyck et al 1994]. Laryngoscopy often shows paresis of one or both vocal folds.
  • Sensorineural hearing loss (SNHL), which is bilateral and progressive and ranges from mild to moderate. Onset is from childhood to adulthood [Kannu et al 2007, Landouré et al 2010].
  • Respiratory dysfunction in some cases including intercostal and diaphragm muscle weakness, which may lead to respiratory insufficiency and/or sleep apnea [Chen et al 2010]. Chest radiograph and pulmonary function tests may demonstrate diaphragm weakness with decreased inspiratory and expiratory pressures [Dyck et al 1994, Donaghy & Kennett 1999].
  • Joint contractures (appearing similar to arthrogryposis multiplex congenita [AMC]) and short stature in some cases
  • A family history consistent with autosomal dominant inheritance

Scapuloperoneal spinal muscular atrophy (SPSMA)

  • Slowly progressive lower motor neuron loss associated with muscle weakness and atrophy proximally in the shoulder girdle region (with characteristic scapular winging) and distally in the peroneal (lower leg) muscles. In severe cases, absence of muscle and weakness are evident at birth [DeLong & Siddique 1992, Auer-Grumbach et al 2010, Deng et al 2010].
  • Muscle biopsy (infrequently performed) shows evidence of denervation and renervation [Deng et al 2010, Berciano et al 2011].
  • Laryngeal dysfunction (laryngomalacia and vocal fold anomalies as in CMT2C), vocal cord paresis, and transient dysphonia [Berciano et al 2011]
  • SNHL (as in CMT2C)
  • Sensory deficits (rare)
  • Kyphoscoliosis

Congenital distal spinal muscular atrophy (CDSMA)

  • Congenital-onset, non-progressive or slowly progressive lower motor neuron loss associated with muscle weakness and atrophy, predominantly affecting the lower extremities (distal greater than proximal)
  • Flexion contractures of the knees and hips often present at birth (i.e., AMC). Severe bilateral clubfoot is also seen.
  • MRI of calf and thigh muscles shows a distinct pattern of fatty atrophy with preservation of the biceps femoris in the lateral thighs and of the medial gastrocnemius in the posteromedial calves [Astrea et al 2012].

Table 1.

Neurologic Findings by TRPV4 Neuromuscular Phenotype

FindingPhenotype
CMT2CSPSMACDSMA
Age at onsetBirth – adulthoodBirth – adulthoodPrenatal
NeuropathyPeripheral, progressive (distal)Peripheral, progressive (distal > proximal)Paresis of legs at birth 1
Vocal cord
paralysis
++ (transient dysphonia)±
SNHL++
Respiratory
dysfunction 2
++±
Joint
contractures
AMC (mainly involving feet, knees, & hips)
OtherSee footnote 3.See footnote 4.See footnote 5.

AMC = arthrogryposis multiplex congenita; CMT2C = Charcot-Marie-Tooth disease type 2C; CDSMA = congenital distal spinal muscular atrophy; SNHL= sensorineural hearing loss; SPSMA = scapuloperoneal spinal muscular atrophy

1.

More mild manifestation: congenital weakness of the distal part of the lower limbs only. More severe manifestation: weakness of the pelvic girdle and trunk muscles, resulting in scoliosis.

2.

Secondary to diaphragmatic and intercostal muscle involvement

3.

Cold sensitivity (i.e., worsening of hand weakness in the cold)

4.

Rounded shoulders, laterally displaced scapulae

5.

Proximal muscle weakness (shoulder girdle, pelvic girdle) later in the disease course

Skeletal Dysplasias

An autosomal dominant TRPV4 skeletal dysplasia should be suspected in individuals with the following skeletal findings:

  • Familial digital arthropathy-brachydactyly characterized by the following:
    • Normal hands and feet at birth, then relative shortening of the middle and distal phalanges with swelling and decreased range of motion of the interphalangeal joints in early childhood
    • Progressive arthropathy of the other joints of the hands and feet with pain and deformity
    • No clinical overlap with other TRPV4 skeletal dysplasias
  • The other autosomal dominant TRPV4 skeletal dysplasias (autosomal dominant brachyolmia; spondylometaphyseal dysplasia, Kozlowski type; spondyloepiphyseal dysplasia, Maroteaux type; parastremmatic dysplasia; and metatropic dysplasia) form a phenotypic continuum of overlapping disorders from mild to severe, each with:
    • Short stature
    • Progressive spinal deformity with scoliosis with or without kyphosis, and radiographic features of platyspondyly and overfaced pedicles
    • At least one additional distinctive feature (See Table 2.)

Table 2.

Radiographic and Clinical Features of Autosomal Dominant TRPV4 Skeletal Dysplasias

FindingsPhenotype
MildIntermediateSevere
Familial digital arthropathy-brachydactylyAutosomal dominant brachyolmiaSpondylo-metaphyseal dysplasia, Kozlowski typeSpondylo-epiphyseal dysplasia, Maroteaux typeParastremmatic dysplasia 1Metatropic dysplasia
Hands/
Feet
Normal at birth; progressive swelling & arthropathy (see details)ClinodactylyBrachydactyly; hypoplastic carpal bones w/severe delay in ossificationBrachydactylyJoint contracturesBrachydactyly w/delayed carpal ossification
SpineNormal± scoliosis, kyphosis; mild platyspondylyPlatyspondyly; overfaced pedicles 2Significant kyphoscoliosis; overfaced pedicles 2Platyspondyly; overfaced pedicles 2
Long bonesN/AMinimal metaphyseal changes; short femoral neck w/irregular proximal femoral metaphyses± mild metaphyseal changes; genu varumMild-to-moderate metaphyseal changes; genu varumSevere metaphyseal changes w/severe limb deformity; joint contractures; other 3Dumbbell-shaped long bones w/epiphyseal dysplasia & prominent joints; progressive joint contractures; other 4
PelvisNormalN/ASquare, short, flared iliac wings; flat, irregular acetabulae; coxa vara; ± supra-acetabular notchesChampagne-glass configuration of pelvic inletHalberd-shaped 5 pelvis; supra-acetabular notches
OtherAverage height; early-childhood onsetMild short stature; limbs unaffected; good physical functionShort-trunk short-stature dwarfism; broad chest; early-childhood onset w/waddling gaitShort-trunk short-stature dwarfismSignificant short-trunk short-stature dwarfismMay be lethal prenatally or perinatally; at birth, short-limb short-stature dwarfism 6
1.

Rarest TRPV4-related skeletal dysplasia

2.

Overfaced pedicles = lateral border of the vertebrae appears outside the lateral edge of the pedicles, a characteristic feature of TRPV4 skeletal dysplasias best viewed on AP x-ray of the spine; images in Nemec et al [2012].

3.

Additional findings: hyperplastic femoral trochanters, severe genu valgum, bowing of long bones, legs twisted along the long axis

4.

Histologic findings: thin seal of bone at the chondroosseous junction, absent primary metaphyseal spongiosa, abnormal metaphyseal vascular invasion, arrest of endochondral ring structures with persistence of circumferential growth

5.

The term "Halberd-shaped pelvis" is derived from the shape of a Swedish battle ax.

6.

Progressive kyphoscoliosis and platyspondyly subsequently alter proportions from short-limb to short-trunk dwarfism.

Establishing the Diagnosis

The diagnosis of an autosomal dominant TRPV4 disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in TRPV4 identified by molecular genetic testing (see Table 3).

Note: Identification of a heterozygous TRPV4 variant of uncertain significance does not establish or rule out a diagnosis of this disorder.

Single-gene testing. Sequence analysis of TRPV4 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: (1) Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. (2) To date, a large TRPV4 deletion or duplication has not been reported in an individual with an autosomal dominant TRPV4 disorder.

A multigene panel that includes TRPV4 and other genes of interest (see Differential Diagnosis) can be considered to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 3.

Molecular Genetic Testing Used in Autosomal Dominant TRPV4 Disorders

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
TRPV4Sequence analysis 3100% 4
Deletion/duplication analysis 5See footnote 6.
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis can detect variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

The authors are unaware of a whole-gene or contiguous gene deletion of TRPV4 causing one of the recognized phenotypes.

Clinical Characteristics

Clinical Description

The two groups of disorders and the phenotypes comprising autosomal dominant TRPV4 disorders (listed from mildest to most severe) are:

  • Neuromuscular disorders (see Table 1):
    • Charcot-Marie-Tooth disease type 2C
    • Scapuloperoneal spinal muscular atrophy
    • Congenital distal spinal muscular atrophy
  • Skeletal dysplasias (see Table 2):
    • Familial digital arthropathy-brachydactyly
    • Autosomal dominant brachyolmia
    • Spondylometaphyseal dysplasia, Kozlowski type
    • Spondyloepiphyseal dysplasia, Maroteaux type
    • Parastremmatic dysplasia
    • Metatropic dysplasia

The phenotypic spectra within both neuromuscular and skeletal groups are broad and overlapping, and the phenotypes of both groups can in rare cases overlap as well [Chen et al 2010, Unger et al 2011, Cho et al 2012].

Of note, sensorineural hearing loss (SNHL), which is bilateral and progressive and ranges from mild to moderate, can occur in both phenotypes. Onset is from childhood to adulthood [Kannu et al 2007, Landouré et al 2010].

Neuromuscular Disorders

The autosomal dominant TRPV4 neuromuscular disorders are peripheral neuropathies/neuronopathies in which motor nerves are more prominently affected than sensory nerves [Landouré et al 2010].

Clinical findings and age of onset can be extremely variable in TRPV4 neuromuscular disorders both between and within families [Dyck et al 1994, Donaghy & Kennett 1999, Zimoń et al 2010, Echaniz-Laguna et al 2014]. Affected individuals usually become symptomatic between early childhood and age 25 years; however, disease onset can range from birth, with breathing difficulties and delayed walking, to after the eighth decade [Zimoń et al 2010, Echaniz-Laguna et al 2014]. In some, the manifestations can be so mild as to go unrecognized by the affected individual and his/her physicians.

Affected individuals typically demonstrate progressive weakness and atrophy of distal muscles in the feet and/or hands, usually associated with depressed tendon reflexes and mild or no sensory loss. However, the congenital phenotypes, scapuloperoneal spinal muscular atrophy (SPSMA) and congenital distal spinal muscular atrophy (CDSMA), are characterized by long plateau periods without obvious deterioration [Vlam et al 2012]. Atrophy of the intrinsic hand muscles is common, but tendon reflexes may be intact in the arms. Proximal limb muscles may be involved, particularly in SPSMA. The pattern of muscle involvement in SPSMA includes progressive shoulder girdle atrophy and weakness leading to scapular winging (scapula alata) and involvement of the two muscle groups below the knee (peroneal distribution) [DeLong & Siddique 1992]. Mild sensory deficits of position, vibration, and pain/temperature may occur in the feet or sensation may be intact.

Laryngeal dysfunction is a hallmark of Charcot-Marie-Tooth disease type 2C (CMT2C) and is often observed in individuals with SPSMA and CDSMA [Auer-Grumbach et al 2010, Deng et al 2010, Landouré et al 2010, Zimoń et al 2010, Echaniz-Laguna et al 2014]. The typical presenting symptoms are difficulty with phonation and breathing (inspiratory stridor and hoarseness) and distal leg weakness and atrophy.

Individuals with severe features may have a decreased life span secondary to respiratory complications [Santoro et al 2002, McEntagart et al 2005].

Skeletal Dysplasias

Familial digital arthropathy-brachydactyly is not evident at birth because the hands and feet and skeletal examination (including radiographs) are normal. In early childhood relative shortening of the middle and distal phalanges and swelling and decreased range of motion of the interphalangeal joints become apparent. Later, in the first decade and beyond, the other joints of the hands and feet become painful and deformed. No overlap is currently recognized with the manifestations of the other autosomal dominant TRPV4 skeletal dysplasias.

The remaining autosomal dominant TRPV4 skeletal disorders are characterized by varying degrees of disproportionate short stature and progressive spinal deformity with scoliosis with or without kyphosis.

Autosomal dominant brachyolmia is the mildest of the short stature TRPV4 skeletal conditions. Its name derives from the Greek roots brachy-, meaning "short," and -olmos, meaning "trunk" or "shoulder." Affected individuals have only mild short stature and the limbs are typically unaffected; thus, physical function is unaffected.

Spondylometaphyseal dysplasia, Kozlowski type is characterized by short-trunk short stature, although the chest is broader than in some of the more severe autosomal dominant TRPV4 skeletal dysplasias. Birth length is average. Affected children usually come to medical attention in early childhood when poor growth with disproportionate stature and a waddling gait with genu varum become evident. Premature osteoarthritis of the joints is common.

Spondyloepiphyseal dysplasia, Maroteaux type is characterized by short-trunk dwarfism and brachydactyly. Birth length is usually average. Poor growth with a short trunk and overall short stature become evident in childhood. Over time, genu valgum and kyphoscoliosis develop. Osteoporosis has been described.

Parastremmatic dysplasia, probably the rarest of the autosomal dominant TRPV4 skeletal dysplasias, is characterized by severe limb deformities and joint malalignment, short stature, and kyphoscoliosis, which are present at birth and progressively worsen throughout life.

Metatropic dysplasia (from the Greek metatropos, meaning "with change/changing pattern") was named after the striking reversal of body proportions between birth and childhood. At birth, the limbs are disproportionately short (due to the long bone metaphyseal abnormalities) compared to the trunk. In childhood, when the platyspondyly and scoliosis and/or kyphosis become more severe, the trunk becomes relatively short compared to the limbs.

Metatropic dysplasia may be lethal in the prenatal or perinatal period, largely due to an extremely narrow chest and hypoplastic lung parenchyma. Infants who survive the perinatal period typically develop severe kyphoscoliosis that eventually compromises pulmonary function. Other skeletal findings in some individuals with severe metatropic dysplasia are poor joint range of motion, joint contractures, and torticollis; these arthrogryposis multiplex congenita-like contractures represent an overlap between the neuromuscular and skeletal phenotypes of autosomal dominant TRPV4 disorders [Unger et al 2011].

Genotype-Phenotype Correlations

In general, specific sets of TRPV4 pathogenic variants have been associated with either neuromuscular disorders or skeletal dysplasia; overlap may occur, however, making genotype-phenotype correlations difficult (see Molecular Genetics) [Unger et al 2011, Sullivan & Earley 2013].

Functional studies suggest that TRPV4 pathogenic variants associated with neuromuscular disorders and skeletal dysplasias may cause a gain-of-channel function [Rock et al 2008, Krakow et al 2009, Nilius & Voets 2013, Sullivan et al 2015], whereas the pathogenic variants associated with familial digital arthropathy-brachydactyly (FDAB) may cause a loss-of-channel function.

TRPV4 neuromuscular disorders. Several studies suggest that most TRPV4 pathogenic variants associated with a neuromuscular phenotype cluster on the highly positively charged convex surface of the ankyrin repeats domain and target arginine residues that are strictly conserved throughout 27 available TRPV4 orthologs [Auer-Grumbach et al 2010, Deng et al 2010, Landouré et al 2010, Sullivan et al 2015]. These surface pathogenic variants are located in three consecutive finger loops of the protein, a distinct region of the TRPV4 ankyrin repeats. The most commonly reported and best validated pathogenic TRPV4 variants are the following: p.Arg186Gln, p.Arg232Cys, p.Arg269Cys, p.Arg269His, p.Arg315Trp, p.Arg316Cys, and p.Arg316His [Auer-Grumbach et al 2010, Deng et al 2010, Landouré et al 2010, Klein et al 2011, Landouré et al 2012]. Variable phenotypes have been reported, even among members of the same family [Landouré et al 2010].

TRPV4 skeletal dysplasias. In total, more than 50 pathogenic variants in TRPV4 have been reported to cause brachyolmias. While the pathogenic variants are spread throughout the gene, two hot spots have been observed at residues Pro799 in exon 15 and Arg594 in exon 11 [Nishimura et al 2012], which localize to the channel pore region.

The familial digital arthropathy-brachydactyly-causing pathogenic variants are restricted to finger 3 of the ankyrin repeats domain (pathogenic variants p.Gly270Val, p.Arg271Pro, p.Phe273Leu) [Nilius & Voets 2013].

Overlap of TRPV4 neuromuscular disorders and skeletal dysplasias. Of note, the pathogenic variants p.Ala217Ser, p.Glu278Lys, p.Arg269Cys, p.Arg315Trp, p.Tyr591Cys, p.Arg594His, p.Val620Ile, p.Glu797Lys, and p.Pro799Arg have been associated with both neuromuscular disease and skeletal dysplasia [Zimoń et al 2010, Cho et al 2012, Faye et al 2019]. In addition, the pathogenic variant p.Ser542Tyr caused both CMT2C and short stature in one family [Chen et al 2010].

Penetrance

Autosomal dominant TRPV4 neuromuscular disorders. Penetrance is reduced with the neuromuscular disease-associated pathogenic variants.

Autosomal dominant TRPV4 skeletal dysplasias. In contrast, penetrance of the skeletal dysplasia phenotype appears to be high; however, intra- and interfamilial variability is significant [Dai et al 2010].

Nomenclature

Charcot-Marie-Tooth neuropathy type 2C is also referred to as hereditary motor and sensory neuropathy type 2C.

Spondyloepiphyseal dysplasia, Maroteaux type is also referred to as pseudo-Morquio syndrome type 2.

Prevalence

The prevalence of the autosomal dominant TRPV4 neuromuscular and skeletal dysplasias has not been well studied.

Fawcett et al [2012] determined that 13 (<1%) of 422 individuals with a CMT2 (axonal CMT) phenotype were heterozygous for a TRPV4 pathogenic variant. Of note, the detection of a TRPV4 pathogenic variant increased to between 9% and 16% in those with a CMT2 phenotype with additional unusual features (e.g., vocal fold weakness, diaphragmatic paresis, skeletal dysplasia) [Fawcett et al 2012, Echaniz-Laguna et al 2014].

Differential Diagnosis

Autosomal Dominant TRPV4 Neuromuscular Disorders

Autosomal dominant TRPV4 neuromuscular disorders (Charcot-Marie-Tooth disease type 2C, scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy) resemble several other disorders (see Table 4):

Note: See Charcot-Marie-Tooth Hereditary Neuropathy Overview for a general overview of CMT2.

Table 4.

Genes of Interest in the Differential Diagnosis of Autosomal Dominant TRPV4 Neuromuscular Disorders

GeneMOIDisorder
ATP7AXLdSMA (see ATP7A-Related Copper Transport Disorders)
BICD2ADLower extremity-predominant SMA (SMA2A; SMA2B) (OMIM 615290)
BSCL2ADdHMN5A (see BSCL2 Neurologic Disorders/Seipinopathy)
DCTN1ADdHMN7B (OMIM 607641): motor neuropathy w/vocal cord paralysis
DYNC1H1ADCMT2O (see CMT Overview); lower extremity-predominant SMA
GARS1ADGARS1-associated axonal neuropathy (CMT2D; dSMA-V)
HSPB1ADdHMN2B; CMT2F (see CMT Overview)
HSPB3ADdHMN2C (OMIM 613376)
HSPB8ADdHMN2A (OMIM 158590)
IGHMBP2ARCMT2S (see CMT Overview); dSMA1
JAG1ADCMT2C 1: mild neuropathy w/severe vocal cord paralysis
MYH14ADPeripheral neuropathy, myopathy, hoarseness, and hearing loss (OMIM 614369): hoarseness w/o vocal cord paralysis; reported in 1 family
PLEKHG5ARIntermediate CMTC (see CMT Overview); dSMA4: variably assoc w/scapular winging & diaphragmatic weakness
SETXADJuvenile ALS (dHMN)
SLC5A7ADdHMN7A (OMIM 158580): motor neuropathy w/vocal cord paralysis

Genes are listed in alphabetic order.

AD = autosomal dominant; ALS = amyotrophic lateral sclerosis; AR = autosomal recessive; CMT = Charcot-Marie-Tooth neuropathy; dHMN = distal hereditary motor neuropathy; dSMA = distal spinal muscular atrophy; MOI = mode of inheritance; SMA = spinal muscular atrophy; XL = X-linked

1.

Autosomal Dominant TRPV4 Skeletal Dysplasias

Autosomal dominant TRPV4 skeletal dysplasias have a broad phenotypic spectrum and, thus, many skeletal dysplasias to consider in the differential diagnosis.

Mild (familial digital arthropathy-brachydactyly). The differential diagnosis includes reactive arthropathy, diabetic arthropathy, and other forms of brachydactyly [Amor et al 2002].

Intermediate (autosomal dominant brachyolmia; spondylometaphyseal dysplasia, Kozlowski type; and spondyloepiphyseal dysplasia, Maroteaux type) and severe (parastremmatic dysplasia and metatropic dysplasia). See Table 5.

Table 5.

Genes of Interest in the Differential Diagnosis of Intermediate and Severe Autosomal Dominant TRPV4 Skeletal Dysplasias

PhenotypeGeneMOIDisorder
IntermediateCOL2A1AD
(AR)
Spondyloepiphyseal dysplasia congenita (see Type II Collagen Disorders Overview)
GALNSARMorquio syndrome type A (MPS IVA)
GLB1ARMorquio syndrome type B (MPS IVB)
TRAPPC2XLX-linked spondyloepiphyseal dysplasia tarda
SevereCOL2A1ADKniest dysplasia (see Type II Collagen Disorders Overview): platyspondyly & coronal cleft, shortened tubular bones & metaphyseal flaring, broad & short thorax
COL11A1
COL11A2
AR
AD
Fibrochondrogenesis 1 & 2 (OMIM PS228520): rhizomelic limb shortening, broad dumbbell-shaped metaphyses, pear-shaped vertebral bodies, short & distally cupped ribs
COL11A2AR
AD
Otospondylomegaepiphyseal dysplasia 1 (OMIM 184840, 215150)
HSPG2ARDyssegmental dysplasia, Silverman-Handmaker type (OMIM 224410)

AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; MPS = mucopolysaccharidosis; XL = X-linked

1.

Autosomal recessive otospondylomegaepiphyseal dysplasia may also be referred to as Weissenbacher Zweymuller syndrome.

Brachyolmia types 1 and 2 (OMIM 271530 and 613678) can also be considered in the differential diagnosis of intermediate autosomal dominant TRPV4 skeletal dysplasias. The molecular basis of these disorders is unknown.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an autosomal dominant TRPV4 neuromuscular disorder, the evaluations summarized in Table 6a (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 6a.

Recommended Evaluations Following Initial Diagnosis in Individuals with an Autosomal Dominant TRPV4 Neuromuscular Disorder

System/ConcernEvaluationComment
NeurologicPhysical/neurologic examTo determine extent of weakness & atrophy, pes cavus, gait stability, & sensory loss
EMG w/NCVAs needed to document status of neuropathy
ENT consult w/laryngoscopyAs needed to document status of vocal folds
RespiratoryPulmonary function testing & dynamic breathing chest x-rayAs needed to assess pulmonary & respiratory function
AudiologicHearing assessmentSee Hereditary Hearing Loss and Deafness Overview for different types of hearing assessment.
SkeletalSkeletal x-raysTo identify any assoc skeletal dysplasia
Genetic
counseling
By genetics professionals 1To inform individuals & families re nature, MOI, & implications of TRPV4 disorders to facilitate medical & personal decision making
Family support/
resources
Assess:
  • Use of community or online resources such as Parent to Parent;
  • Need for social work involvement for parental support;
  • Need for home nursing referral;
  • Need for referral to physiatry, PT, OT, & speech therapy.

EMG = electromyography; NCV = nerve conduction velocity; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy

1.

Medical geneticist, certified genetic counselor, or certified advanced genetic nurse

To establish the extent of disease and needs in an individual diagnosed with an autosomal dominant TRPV4 skeletal dysplasia, the evaluations summarized in Table 6b (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 6b.

Recommended Evaluations Following Initial Diagnosis in Individuals with an Autosomal Dominant TRPV4 Skeletal Dysplasia

System/ConcernEvaluationComment
SkeletalSkeletal x-raysTo document involvement of long bones & spine, which can help determine individual needs & provide baseline for comparison w/future studies
Flexion/extension cervical spine filmsTo determine if there is atlanto-axial instability secondary to odontoid hypoplasia
RespiratoryPulmonary function testing &/or sleep studyIf thorax is particularly narrow &/or kyphoscoliosis is progressive
AudiologyHearing assessmentSee Hereditary Hearing Loss and Deafness Overview for different types of hearing assessment.
Genetic
counseling
By genetics professionals 1To inform individuals & families re nature, MOI, & implications of TRPV4 disorders to facilitate medical & personal decision making
Family support/
resources
Assess:

MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy

1.

Medical geneticist, certified genetic counselor, or certified advanced genetic nurse

Treatment of Manifestations

Treatment is focused on symptom management. Affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, ENT specialists, and physical and occupational therapists.

Table 7a.

Treatment of Manifestations in Individuals with an Autosomal Dominant TRPV4 Neuromuscular Disorder

Manifestation/ConcernTreatmentConsiderations/Other
Neuropathy
  • Special shoes, incl those w/good ankle support
  • AFO to correct foot drop & aid walking
  • Orthopedic surgery to correct severe pes cavus deformity as needed
  • Forearm crutches, canes/walkers for gait stability, & wheelchairs
  • Exercise w/in person's capability (Many remain physically active.)
Pain & depressionSymptomatic treatment
Vocal cord involvement
  • Laryngeal surgery for vocal fold paresis (arytenoidectomy & tracheostomy)
  • Speech therapy
Respiratory dysfunctionRespiratory therapy/support (e.g., BiPAP)
SNHLTreatment per hearing loss specialists to determine best habilitation optionsSee Hereditary Hearing Loss and Deafness Overview for discussion of management issues.

AFO = ankle-foot orthosis; BiPAP = bilevel positive airway pressure; SNHL = sensorineural hearing loss

Table 7b.

Treatment of Manifestations in Individuals with an Autosomal Dominant TRPV4 Skeletal Dysplasia

Manifestation/ConcernTreatmentConsiderations/Other
ContracturesPT/exerciseTo maintain as much function as possible
Daily heel cord-stretching exercisesTo prevent Achilles tendon shortening
KyphoscoliosisOrthopedic eval w/consideration of surgical intervention (e.g., spinal fusion)If kyphoscoliosis results in pain &/or compromised pulmonary function
Odontoid hypoplasia /
Cervical myelopathy
Occipito-cervical or upper cervical decompression & fusion are required to stabilize upper cervical spine & relieve cervical cord compression when upper cervical spine instability is documented or when clinical findings of cervical myelopathy are present.It is preferred that intervention in children occur when signs of cervical compression are present by MRI, even in absence of symptoms to minimize neurologic injury & maximize function. Those undergoing surgical fusion typically do well; minor secondary complications can incl pin site infections, pressure sores, & long-term difficulty w/endotracheal intubation.
If myelopathy is suspected:
  • Obtain cervical spine radiographs & MRI;
  • Refer for eval by pediatric orthopedic surgeon or neurosurgeon at tertiary care facility.
Upper cervical instability may result in deteriorating endurance & worsening gait.
SNHLTreatment per hearing loss specialists to determine best habilitation optionsSee Hereditary Hearing Loss and Deafness Overview for discussion of management issues.
Pain & depressionSymptomatic treatmentChronic pain management preceding or following orthopedic surgery is standard & often required.

PT = physical therapy; SNHL = sensorineural hearing loss

Surveillance

Table 8a.

Recommended Surveillance for Individuals with an Autosomal Dominant TRPV4 Neuromuscular Disorder

System/ConcernEvaluationFrequency
NeuropathyNeurologic exam to determine extent of weakness & atrophy, & sensory lossAnnually
PT exam to monitor feet to determine need for bracing, special shoes, &/or surgery
Vocal cord involvementENT consult w/laryngoscopy
Respiratory dysfunctionDynamic breathing chest x-ray
SNHLHearing assessment

PT = physical therapy; SNHL = sensorineural hearing loss

Table 8b.

Recommended Surveillance for Individuals with an Autosomal Dominant TRPV4 Skeletal Dysplasia

System/ConcernEvaluationFrequency
MusculoskeletalAssessment for development of joint pain & scoliosisAnnually
Cervical spinal films to assess for clinically significant odontoid hypoplasiaBefore:
  • A child reaches school age;
  • Surgical procedures involving general anesthesia.
SNHLHearing assessmentAnnually

SNHL = sensorineural hearing loss

Agents/Circumstances to Avoid

In general, obesity is to be avoided because it makes walking more difficult for individuals with neuropathy, skeletal dysplasia, or both

For neuromuscular disorders. Preventive health care to avoid diabetes-related complications is recommended. Neurotoxic medications should be avoided. Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association website (pdf) for an up-to-date list. See also the Inherited Neuropathy Consortium website for additional information.

For skeletal dysplasias

  • In individuals with odontoid hypoplasia, avoid extreme neck flexion and extension.
  • Avoid activities and occupations that place undue stress on the spine and weight-bearing joints.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

There is no registry or data regarding the frequency or outcome of pregnancies in women with a TRPV4-related disorder; however, the following general information may be reasonable to consider. Ideally a woman with an autosomal dominant TRPV4 disorder would seek consultation from a high-risk OB-GYN or maternal-fetal medicine specialist to evaluate her risks for pregnancy and delivery. Increased risk of ectopic pregnancy has been reported [Li et al 2019].

Autosomal dominant TRPV4 neuromuscular disorders. Argov & de Visser [2009] reviewed pregnancy issues in hereditary neuromuscular disorders including CMTs. About 50% of women with CMT described increased weakness during pregnancy that usually resolved post partum [Rudnik-Schöneborn et al 1993]. Operative deliveries were reported more commonly in women with CMT in Norway [Hoff et al 2005]. Greenwood & Scott [2007] described the obstetric approach to women with mild and severe forms of CMT. Brock et al [2009] describe use of anesthesia during delivery in a single case study, indicating that regional management is the preferred and safer method, compared to general anesthesia. A German study reviewed 63 pregnancies in 33 women with CMT [Awater et al 2012] and found no increase in the frequency of cesarean section, forceps delivery, premature birth, or neonatal problems. About one third of mothers felt a worsening of CMT symptoms during pregnancy; in one fifth of mothers the changes were felt to be persistent.

Autosomal dominant TRPV4 skeletal dysplasias. In autosomal dominant TRPV4 skeletal dysplasias, the degree of pulmonary compromise (from the short trunk and decreased lung capacity) may affect the ability to carry a pregnancy to term. Thus, it is unlikely that a woman with metatropic dysplasia could carry a pregnancy. Pregnant women with a TRPV4 skeletal dysplasia generally undergo cesarean section delivery because of the small size of the pelvis.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Mathis et al [2015] have reviewed the future of therapeutic options in CMT.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Career and employment choices may be influenced by persistent weakness of hands and/or feet and orthopedic involvement.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

TRPV4 neuromuscular and skeletal disorders caused by a heterozygous TRPV4 pathogenic variant are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Because the most severe TRPV4 skeletal phenotypes can be lethal in childhood (or in utero), children with these phenotypes typically have a de novo pathogenic variant and unaffected parents.
  • Individuals with less severe skeletal phenotypes or neuromuscular phenotypes often have the disorder as the result of a TRPV4 pathogenic variant inherited from a heterozygous parent. (Note: A heterozygous parent may appear asymptomatic or have more or less severe clinical manifestations than the proband; see Penetrance and Genotype-Phenotype Correlations.) De novo variants have also been described in individuals with these phenotypes.
  • Molecular genetic testing is recommended for the parents of a proband to confirm their genetic status and to allow reliable recurrence risk counseling.
  • If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
    • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
    • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
  • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotype or reduced penetrance in the parent with the pathogenic variant. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing indicates that neither parent has the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband’s parents:

Offspring of a proband

  • Each child of an individual with a TRPV4 disorder has a 50% chance of inheriting the TRPV4 pathogenic variant. Specific phenotype, age of onset, and disease severity cannot be predicted accurately because of reduced penetrance and variable expressivity.
  • Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with a TRPV4 skeletal disorder may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals may be distinct from those of the parents.
    If the proband and the proband's reproductive partner are affected with different dominantly inherited skeletal dysplasias, each child has a 25% likelihood of having average stature, a 25% likelihood of having the same skeletal dysplasia as the father, a 25% likelihood of having the same skeletal dysplasia as the mother, and a 25% likelihood of inheriting a pathogenic variant from both parents and being at risk for a potentially poor outcome.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the TRPV4 pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
  • Genetic counseling is recommended when both parents have a skeletal dysplasia.

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

  • Predictive testing for at-risk relatives is possible once the TRPV4 pathogenic variant has been identified in an affected family member. If identified to have inherited a TRPV4 pathogenic variant, further clinical evaluation, electromyography/nerve conduction velocity testing, and/or skeletal survey may be appropriate. No treatment is available to individuals early in the course of the disease. Thus, such testing is for personal decision making only.
  • Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years)

  • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
  • For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of a TRPV4 disorder, it is appropriate to consider testing of symptomatic individuals regardless of age.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the TRPV4 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for an autosomal dominant TRPV4 disorder are possible. However, specific phenotype, age of onset, and/or disease severity cannot be reliably predicted based on the results of prenatal testing.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Alexander Graham Bell Association for the Deaf and Hard of Hearing
    3417 Volta Place Northwest
    Washington DC 20007
    Phone: 866-337-5220 (toll-free); 202-337-5220; 202-337-5221 (TTY)
    Fax: 202-337-8314
    Email: info@agbell.org
  • Charcot-Marie-Tooth Association (CMTA)
    PO Box 105
    Glenolden PA 19036
    Phone: 800-606-2682 (toll-free); 610-499-9264
    Fax: 610-499-9267
    Email: info@cmtausa.org
  • Child Growth Foundation
    21 Malvern Drive
    West Midlands B76 1PZ
    United Kingdom
    Phone: 020 8995 0257
    Email: nfo@childgrowthfoundation.org
  • Hereditary Neuropathy Foundation
    Phone: 855-435-7268 (toll-free); 212-722-8396
    Fax: 917-591-2758
    Email: info@hnf-cure.org
  • Inherited Neuropathy Consortium (INC)
    Phone: 319-353-8400
    Fax: 319-384-7199
    Email: Shawna-Feely@uiowa.edu
  • International Skeletal Dysplasia Registry
    UCLA
    615 Charles E. Young Drive
    South Room 410
    Los Angeles CA 90095-7358
    Phone: 310-825-8998
    Fax: 310-206-5266
    Email: Salon@mednet.ucla.edu

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Autosomal Dominant TRPV4 Disorders: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Autosomal Dominant TRPV4 Disorders (View All in OMIM)

113500BRACHYOLMIA TYPE 3; BCYM3
156530METATROPIC DYSPLASIA
168400PARASTREMMATIC DWARFISM
181405SCAPULOPERONEAL SPINAL MUSCULAR ATROPHY; SPSMA
184095SPONDYLOEPIPHYSEAL DYSPLASIA, MAROTEAUX TYPE
184252SPONDYLOMETAPHYSEAL DYSPLASIA, KOZLOWSKI TYPE; SMDK
600175NEURONOPATHY, DISTAL HEREDITARY MOTOR, TYPE VIII; HMN8
605427TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY V, MEMBER 4; TRPV4
606071HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC; HMSN2C
606835DIGITAL ARTHROPATHY-BRACHYDACTYLY, FAMILIAL; FDAB
606845GOLGI-ASSOCIATED PDZ AND COILED-COIL DOMAINS-CONTAINING PROTEIN; GOPC
617383AVASCULAR NECROSIS OF FEMORAL HEAD, PRIMARY, 2; ANFH2

Molecular Pathogenesis

TRPV4 encodes a nonselective Ca2+-permeable cation channel that is predominantly expressed at the plasma membrane [Garcia-Elias et al 2014]. TRPV4 can be activated by a wide range of stimuli including hypo-osmolarity, heat, and mechanical stretch, as well as numerous endogenous (e.g., endocannabinoid anandamide, arachidonic acid) and synthetic compounds (4α-phorbol-12,13-didecanoate [4αPDD]) [Garcia-Elias et al 2014]. TRPV4 is broadly expressed and has diverse physiologic roles in different tissues types:

While the precise mechanisms of pathogenesis in TRPV4 disorders are not completely understood, the preponderance of evidence suggests that pathogenic variants cause toxicity through gain of ion channel function [Nilius & Voets 2013]. Given the incredibly diverse signaling pathways regulated by intracellular calcium influx, many possible downstream pathologic events are conceivable, including activation of calcium-sensitive proteases (such as calpains) or kinases (such as CaMKII), alterations in calcium-sensitive transcriptional programs, disruption of axonal transport, dysregulation of cytoskeletal remodeling, and altered neuronal excitability, among others. In addition, the downstream consequences of TRPV4 gain-of-channel function are likely to be dependent on cell type- and tissue-specific factors.

Mechanism of disease causation. TRPV4 disorders are diverse, but are likely linked through gain of TRPV4 ion channel function with tissue-specific downstream consequences. Notably, the vast majority of pathogenic variants reported are missense variants.

  • Neuromuscular disorders. Gain of ion channel function, potentially via altered gating properties or altered responsiveness to activating stimuli has been proposed. The majority of disease variants causing neuromuscular disorders result in increased calcium influx in vitro [Deng et al 2010, Landouré et al 2010, Klein et al 2011, Sullivan et al 2015], and a Drosophila model of TRPV4 neuropathy demonstrated several neurologic phenotypes that could be ameliorated by genetic or pharmacologic inhibition of TRPV4 ion channel activity [Woolums et al 2020].
    The p.Arg186Gln, p.Arg237Leu, p.Arg269His, p.Arg269Cys, p.Arg316Cys, p.Arg316His, and p.Arg232Cys pathogenic variants showed increased ion channel activity resulting in intracellular calcium levels in vitro, and p.Arg269Cys led to increased intracellular calcium in vivo [Deng et al 2010, Landouré et al 2010, Klein et al 2011, Sullivan et al 2015, Woolums et al 2020].
  • Skeletal dysplasias. The vast majority of skeletal dysplasia pathogenic variants are missense variants that are believed to cause gain of abnormal function, although frameshift and deletion variants have been reported [Dai et al 2010, Nishimura et al 2010]. Like pathogenic variants associated with neuromuscular disorders, skeletal dysplasia-associated variants also generally cause increased basal calcium influx [Loukin et al 2011]. The precise downstream pathogenic events remain unknown, although excessive inhibition of bone morphogenic protein with resultant impairment in endochondral ossification has been proposed based on in vitro studies and a knock-in mouse model [Leddy et al 2014a, Leddy et al 2014b].

Table 9.

Notable TRPV4 Pathogenic Variants

Reference SequencesPredominant PhenotypeDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_021625​.4
NP_067638​.3
Neuromuscularc.557G>Ap.Arg186GlnSee Genotype-Phenotype Correlations
[Auer-Grumbach et al 2010, Deng et al 2010, Landouré et al 2010, Klein et al 2011, Landouré et al 2012].
c.694C>Tp.Arg232Cys 1
c.710G>Tp.Arg237Leu
c.805C>Tp.Arg269Cys
c.806G>Ap.Arg269His
c.943C>Tp.Arg315Trp
c.946C>Tp.Arg316Cys
c.947G>Ap.Arg316His
SkeletalN/AN/ATwo mutation hot spots identified. See Genotype-Phenotype Correlations [Nishimura et al 2012].
Familial digital arthropathy-brachydactylyc.809G>Tp.Gly270ValSee Genotype-Phenotype Correlations [Nilius & Voets 2013].
c.812G>Cp.Arg271Pro
c.819C>Gp.Phe273Leu

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Denotes a combined neuromuscular and skeletal phenotype

References

Published Guidelines / Consensus Statements

  • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 8-24-20. [PubMed: 23428972]
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2018. Accessed 8-24-20.

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Chapter Notes

Revision History

  • 17 September 2020 (sw) Comprehensive update posted live
  • 15 May 2014 (me) Review posted live
  • 30 July 2013 (as) Original submission
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