Autosomal Dominant Trpv4 Disorders
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.
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
| Finding | Phenotype | ||
|---|---|---|---|
| CMT2C | SPSMA | CDSMA | |
| Age at onset | Birth – adulthood | Birth – adulthood | Prenatal |
| Neuropathy | Peripheral, 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) |
| Other | See 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
| Findings | Phenotype | |||||
|---|---|---|---|---|---|---|
| Mild | Intermediate | Severe | ||||
| Familial digital arthropathy-brachydactyly | Autosomal dominant brachyolmia | Spondylo-metaphyseal dysplasia, Kozlowski type | Spondylo-epiphyseal dysplasia, Maroteaux type | Parastremmatic dysplasia 1 | Metatropic dysplasia | |
| Hands/ Feet | Normal at birth; progressive swelling & arthropathy (see details) | Clinodactyly | Brachydactyly; hypoplastic carpal bones w/severe delay in ossification | Brachydactyly | Joint contractures | Brachydactyly w/delayed carpal ossification |
| Spine | Normal | ± scoliosis, kyphosis; mild platyspondyly | Platyspondyly; overfaced pedicles 2 | Significant kyphoscoliosis; overfaced pedicles 2 | Platyspondyly; overfaced pedicles 2 | |
| Long bones | N/A | Minimal metaphyseal changes; short femoral neck w/irregular proximal femoral metaphyses | ± mild metaphyseal changes; genu varum | Mild-to-moderate metaphyseal changes; genu varum | Severe metaphyseal changes w/severe limb deformity; joint contractures; other 3 | Dumbbell-shaped long bones w/epiphyseal dysplasia & prominent joints; progressive joint contractures; other 4 |
| Pelvis | Normal | N/A | Square, short, flared iliac wings; flat, irregular acetabulae; coxa vara; ± supra-acetabular notches | Champagne-glass configuration of pelvic inlet | Halberd-shaped 5 pelvis; supra-acetabular notches | |
| Other | Average height; early-childhood onset | Mild short stature; limbs unaffected; good physical function | Short-trunk short-stature dwarfism; broad chest; early-childhood onset w/waddling gait | Short-trunk short-stature dwarfism | Significant short-trunk short-stature dwarfism | May 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 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| TRPV4 | Sequence analysis 3 | 100% 4 |
| Deletion/duplication analysis 5 | See footnote 6. |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 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].