TRPV4-Related Disorders (Skeletal Dysplasias and Motor Neuropathies)

An autosomal dominant allelic family of the TRPV4 cation channel (12q24.11), with two groups of phenotypes that are usually separate but overlap: five skeletal dysplasias ordered by severity, from familial digital arthropathy with brachydactyly to lethal metatropic dysplasia, and three predominantly motor neuromuscular diseases (Charcot-Marie-Tooth type 2C, scapuloperoneal spinal muscular atrophy and congenital distal spinal muscular atrophy), almost all due to gain-of-function missense variants.

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition of the class

TRPV4-related disorders form an allelic family of autosomal dominant diseases caused by heterozygous variants in the gene encoding the TRPV4 cation channel, a non-selective calcium-permeable channel activated by osmotic, thermal and mechanical stimuli. GeneReviews divides them into two main groups: the skeletal dysplasias, ranging from familial digital arthropathy with brachydactyly to metatropic dysplasia, and the neuromuscular diseases, which include Charcot-Marie-Tooth disease type 2C (CMT2C), scapuloperoneal spinal muscular atrophy (SPSMA) and congenital distal spinal muscular atrophy (CDSMA). Most patients have manifestations of only one group, but overlap phenotypes exist, and severity ranges from a form lethal in the perinatal period to forms so mild that they go unnoticed, with normal life expectancy at the mild end and reduced life expectancy at the severe end [1]. The designation “TRPV4-pathies” was proposed to emphasise that entities described for decades as independent diseases turned out to be expressions of the same gene [4].

1.2. Founding descriptions of the dysplasias

The first case of lethal metatropic dysplasia was probably described by Kaufmann in 1892, under the name chondrodystrophia hyperplastica [8]. The entity was defined in 1966 by Maroteaux, Spranger and Wiedemann, with five of their own cases and twelve reinterpreted from the literature, under the name “metatropic dwarfism” [29, 30]. The term comes from the Greek metatropos, “changing pattern”, and refers to the reversal of body proportions: the newborn has short limbs and a relatively long trunk, and the child, as kyphoscoliosis progresses, comes to have a short trunk [1, 30]. Maroteaux noted that the child was taken for achondroplastic at birth and for having Morquio disease later, because of the short spine and severe scoliosis [9]. In 1987, Boden and colleagues described, in an infant who died at 7 months, the histology that explains the dumbbell metaphyses [31]. Spondylometaphyseal dysplasia, Kozlowski type, was delineated in 1967 by Kozlowski, Maroteaux and Spranger and is the best-known and most frequent type of spondylometaphyseal dysplasia [13, 32]. Parastremmatic dysplasia was described by Langer, Petersen and Spranger in 1970, and spondyloepiphyseal dysplasia, Maroteaux type, by Doman, Maroteaux and Lyne in 1990, as a form limited to the skeleton and distinct from Morquio disease [8, 12]. The term “brachyolmia” was coined by Maroteaux in 1969 for dysplasias with a short trunk and vertebral involvement without significant changes in the long bones [33], and familial digital arthropathy with brachydactyly was described by Amor and colleagues in 2002, in a five-generation Australian family [34].

1.3. Founding descriptions of the neuromuscular diseases

In 1985, Fleury and Hageman described a four-generation Dutch family with 21 individuals affected by a congenital, non-progressive lower motor neurone disease limited to the lower half of the body, with arthrogryposis in 15 [19, 35]. In 1992, DeLong and Siddique described a New England family of French-Canadian origin with 20 individuals affected over five generations by a scapuloperoneal neurogenic amyotrophy with laryngeal palsy, congenital absence of muscles and bone anomalies [18, 36]. In 1994, Dyck and colleagues defined hereditary motor and sensory neuropathy type IIC, with paresis of the vocal cords, diaphragm and intercostal muscles and life expectancy reduced by respiratory failure [16, 37].

1.4. Milestones of the molecular discovery

The gene was cloned in 2000 in three laboratories, as a channel activated by hypotonicity [5]. In 2008, Rock and colleagues mapped autosomal dominant brachyolmia to 12q24.1–q24.2, selected TRPV4 because of its expression about 10 times higher in cartilage and demonstrated gain-of-function variants in two families [14, 38]. In 2009, Krakow and colleagues identified variants of the same gene in SMD Kozlowski and metatropic dysplasia and proposed the “TRPV4 dysplasia family” [39]. In 2010, Nishimura and colleagues added Maroteaux-type dysplasia and parastremmatic dysplasia [40], and Dai and colleagues described 42 probands and the preferential codons Pro799 and Arg594 [41]. In the same year, three simultaneous articles linked the gene to the three neuromuscular forms, showing that they were allelic diseases [42–44]. In 2011, Lamandé and colleagues identified TRPV4 in familial digital arthropathy with brachydactyly [45], and Unger and colleagues described fetal akinesia in metatropic dysplasia as a combined skeletal and neuropathic phenotype [46]. In 2016, avascular necrosis of the femoral head in a Greek family was added [5].

1.5. Nomenclature and reclassifications

Until the end of the twentieth century, metatropic dysplasia was divided into three types (non-lethal recessive, non-lethal dominant and lethal, presumably recessive), as proposed by Beck and colleagues (1983). The observation that the mild, classical and lethal forms overlap, the similarity between father–daughter and brother–sister pairs, and the ratio of affected to unaffected individuals in families, close to 1:20, led Kannu and colleagues to conclude that it is a single dominant disease, with recurrence in siblings explained by gonadal mosaicism [9, 47]. Hereditary motor and sensory neuropathy type IIC and CMT2C are synonyms; spondyloepimetaphyseal dysplasia, Maroteaux type, was called pseudo-Morquio type 2, and parastremmatic dysplasia is now considered part of its phenotype [1]. The bone dysplasia atlas by Spranger and colleagues (2018) still groups parastremmatic dysplasia with metatropic dysplasia and orders the spectrum by decreasing severity: lethal metatropic dysplasia, parastremmatic dysplasia, classical metatropic dysplasia, mild metatropic variant, SMD Kozlowski, SED Maroteaux, dominant brachyolmia and digital arthropathy with brachydactyly [8]. The 2023 Nosology, which adopted dyadic nomenclature (phenotype associated with the gene), lists five entities in the “TRPV4 disorders” group: TRPV4-related metatropic dysplasia (08-0010; includes the “hyperplastic”, lethal and non-lethal forms and somatic mosaicism), TRPV4-related spondyloepimetaphyseal dysplasia, Maroteaux type (08-0020; includes parastremmatic dwarfism, MIM 168400, as a phenotypic variation), Kozlowski-type dysplasia (08-0030), TRPV4-related brachyolmia (08-0040) and TRPV4-related familial digital arthropathy with brachydactyly (08-0050), with the note that the skeletal phenotypes may be associated with neuropathy [2]. Andreucci and colleagues proposed that dominant brachyolmia is not a distinct entity but the mildest expression of SMD Kozlowski, because all patients with this diagnosis and a TRPV4 variant have metaphyseal changes [33]. GeneReviews orders the dysplasias differently (digital arthropathy, brachyolmia, SMD Kozlowski, SEMD Maroteaux and metatropic dysplasia, from mildest to most severe), placing SEMD Maroteaux above SMD Kozlowski [1]; the atlas uses the reverse order [8]. The difference reflects the variability within each entity and does not change management.

1.6. Entities within scope

The class covers the five skeletal dysplasias (with parastremmatic dysplasia), the three neuromuscular diseases, the mixed forms, the rare biallelic forms and avascular necrosis of the femoral head. Outside the scope are the population association between the p.(Pro19Ser) polymorphism and serum sodium, which does not constitute a Mendelian disease [5], and somatic giant cell lesions of the jaws with TRPV4 variants, which enter the differential diagnosis of cherubism.

2. Molecular Genetics and Pathophysiology

2.1. Gene and protein

The TRPV4 gene is located at 12q24.11 (GRCh38 12:109,783,087–109,833,398), has 15 exons and encodes a protein of 872 amino acids with six transmembrane segments, a pore loop and intracellular N- and C-termini; the N-terminal domain contains ankyrin repeats (ARD, ankyrin repeat domain) and an intrinsically disordered region [1, 5]. The channel functions as a homotetramer in the plasma membrane [24]. It is activated by hypo-osmolarity, moderate heat, mechanical stretch, low pH, arachidonic acid metabolites (epoxyeicosatrienoic acids), the endocannabinoid anandamide and synthetic compounds such as 4α-phorbol 12,13-didecanoate [1, 5]. The MANE reference transcript is NM_021625.5, with the protein NP_067638.3 [7].

2.2. Expression and physiological functions

TRPV4 is widely expressed: kidney, lung, spleen, testis, adipose tissue, sensory ganglia, inner ear hair cells, Merkel cells, urothelium and vascular endothelium [5]. In the growth plate, expression is highest in the proliferative zone, decreases in the prehypertrophic zone and disappears in hypertrophic chondrocytes; in articular chondrocytes it is comparable to that of proliferative chondrocytes [5]. In the human spinal cord, expression is about 95% lower than in tracheal cartilage [5]. The functions described include osmosensation and flow sensing in the kidney, endothelial barrier function and cerebral and pulmonary vascular tone, mechanosensation and nociception, bladder function, skin homeostasis, chondrogenesis and bone homeostasis, and immunity [1]. Trpv4 knockout mice have subtle phenotypes — reduced sensitivity to pressure and to acid nociception, reduced sensitivity to sour taste, increased bladder capacity and increased bone mass — without motor deficit [5, 24].

2.3. Disease mechanism: gain of function

Most pathogenic variants are missense and increase channel activity, with greater basal calcium influx and a greater response to agonists [1]. In brachyolmia, the p.(Arg616Gln) and p.(Val620Ile) variants increased the fraction of constitutively open channels [38]. In the neuropathies, the first studies diverged: Auer-Grumbach and colleagues observed cytoplasmic aggregates and reduced surface expression and proposed haploinsufficiency, whereas Deng, Landouré and Klein showed normal trafficking, increased activity and cell death suppressed by the blocker ruthenium red; the divergence was attributed to differences in protocol, and gain of function is now the accepted mechanism [5, 48]. Excess intracellular calcium can activate proteases such as calpains, kinases such as CaMKII, calcium-sensitive transcriptional programmes and cytoskeletal remodelling, with consequences specific to each tissue [1]. In Drosophila and mouse neurones, the toxicity of mutant TRPV4 depends on CaMKII and disrupts axonal transport of mitochondria [1, 49].

2.4. Neuromuscular mechanism: the blood–spinal cord barrier

Mice with the human variants R269C and R232C introduced into the endogenous gene develop weakness, early lethality and regional loss of motor neurones. Removal of the mutant allele only from endothelial cells, and not from neurones, glia or muscle, prevents the phenotype. Symptomatic animals have focal disruptions of the blood–spinal cord barrier, with channel gain of function in neural vascular endothelial cells and altered tight junctions; systemic administration of a selective TRPV4 antagonist reverses the barrier dysfunction and rescues the phenotype [24]. Neurodegeneration would thus be non-cell-autonomous, mediated by the endothelium; this mechanism has not been demonstrated in patients [1]. The ARD interactome includes 78 proteins, among them the ubiquitin ligase NEDD4L and the exchange factor ARHGEF10; 21 interactions are altered by the neuromuscular variants, and inhibition of the channel by ARHGEF10 is lost with them — ARHGEF10 is itself a neuromuscular disease gene [50].

2.5. Skeletal mechanism and histology

In metatropic dysplasia, histology shows absence of normal primary spongiosa, a thin bony seal at the chondro-osseous junction, abnormal metaphyseal vascular invasion and arrest of the structures of the endochondral ring with persistence of circumferential growth; this uncoupling between endochondral and perichondral growth explains the dumbbell metaphyses [1, 9]. In the lethal forms there is thick cartilage with nodular proliferation, short diaphyses and loss of chondrocyte columns [51], and in the trachea and bronchi exuberant cartilage is seen, which led to the designation “hyperchondrogenesis” [9]. In vitro and mouse studies suggest reduced bone morphogenetic protein signalling and suppression of chondrocyte hypertrophic differentiation [1]. The mouse expressing the p.R594H variant only in chondrocytes reproduces the human dysplasia of the long bones, spine and skull, with disorganised chondrocyte columns and reduced hypertrophic differentiation [25].

2.6. Variant spectrum

More than 50 variants have been described in the dysplasias, scattered across almost all domains, with two preferential codons: Pro799 in exon 15, mainly in metatropic dysplasia, and Arg594 in exon 11, mainly in SMD Kozlowski, both in the pore region of the channel [1, 52]. In the series by Dai and colleagues, with 22 probands with metatropic dysplasia and 20 with SMD Kozlowski, a variant was found in all but one case of metatropic dysplasia; p.(Pro799Leu) was present in 9 patients with metatropic dysplasia and three other substitutions of the same codon in a further 4, and p.(Arg594His) was present in 12 of the 20 patients with SMD Kozlowski [41]. In a review of 52 patients from 44 families, p.(Pro799Leu) accounted for 9 of the 44 families (20.5%) and p.(Arg594His) for 4 (9.1%), and exon 14 contained 6 of 31 different variants (19.4%) [49]. In the neuromuscular diseases, variants cluster on the convex, positively charged face of the ARD, at arginines conserved in 27 orthologues and located in three consecutive loops (“fingers”) of the domain; the best validated are p.(Arg186Gln), p.(Arg232Cys), p.(Arg269Cys), p.(Arg269His), p.(Arg315Trp), p.(Arg316Cys) and p.(Arg316His), joined by variants of the disordered N-terminal region, such as p.(Ser93Phe) and p.(Pro97Arg) [1]. The gain-of-function ARD residues lie at the interface with the GTPase RhoA; residues outside that interface have normal or reduced activity, and the variants of the transmembrane domain and of other parts of the disordered region that were assessed do not cause gain of function and are probably benign [53]. In digital arthropathy with brachydactyly, the variants are confined to the third “finger” of the ARD (p.(Gly270Val), p.(Arg271Pro), p.(Phe273Leu)) [1]. Small in-frame deletions and duplications (p.(Phe471del), p.(Leu523dup), p.(Asn796del)), a 17-nucleotide deletion in SEMD Maroteaux and a terminal frameshift variant (p.(Val829Trpfs*3)) in avascular necrosis of the femoral head have also been described [5, 49, 54].

2.7. Table of normalised variants

The variants were normalised in VariantValidator on the MANE transcript and checked against ClinVar [7, 55]. Two historical OMIM descriptions do not match the current numbering: the brachyolmia variant p.(Val620Ile) is c.1858G>A (OMIM writes “c.858G-A”) and the metatropic dysplasia variant p.(Ile331Phe) is c.991A>T (OMIM writes “c.1080A-T”) [5, 7]. The Spranger atlas writes “c.819G>C” for p.(Phe273Leu), whose correct description is c.819C>G [7, 22].

2.8. Genotype–phenotype correlations

In general terms, distinct sets of variants are associated with the neuromuscular group or the skeletal group, but the overlap makes correlations difficult, and neuromuscular variants can give rise to any of the subtypes, with different presentations in the same family [1]. At least 19 variants have been associated with both neuromuscular disease and skeletal dysplasia, mainly p.(Arg269His), p.(Ser542Tyr) and p.(Trp785Cys) [1, 64]. Variants causing severe mixed phenotypes have earlier onset, raise intracellular calcium more, are more cytotoxic and are less sensitive to antagonists; two of them appear to open the channel constitutively by disrupting the S5 segment [64]. The same residue can give different phenotypes: the p.(Arg616Gln) substitution causes isolated brachyolmia, and p.(Arg616Gly) was described in a 2-year-old child with severe neuropathy and bilateral vocal cord palsy [64]. In the same family, p.(Arg594His) gave the radiology of metatropic dysplasia in one son and of SMD Kozlowski in the other [9]. At least five variants (p.(Arg315Trp), p.(Ser542Tyr), p.(Arg594His), p.(Leu618Pro) and p.(Pro799Leu)) have been described in both isolated and combined phenotypes [49]. In metatropic dysplasia, severity shows no consistent relationship with variant type or domain, but the degree of constitutive channel activation appears to track severity [51]. In neuromuscular disease, variants with gain of function and cytotoxicity are associated with congenital onset, vocal cord weakness and motor predominance, whereas probably benign variants occur more often in patients with late onset and sensory predominance [53]. Nishimura and colleagues noted that the phenotypic expression of most skeletal variants is relatively constant, so clinical and radiographic assessment guides molecular interpretation [52].

2.9. Loss-of-function variants

Not all pathogenic variants increase channel activity. The variants of digital arthropathy with brachydactyly reduced channel activity in Lamandé's studies, although later studies also attribute gain-of-function properties to them [1, 15]. In SMD Kozlowski, two loss-of-function variants were described in 2025–2026: p.(Trp785Ser), which reduces calcium influx and agonist-induced currents, in a patient with a relatively mild phenotype [62], and de novo p.(Pro827Ala), which reduces the transcript, the protein and intracellular calcium, with delayed skeletal development in homozygous mice [63]. The lethal variant p.(Leu618Pro) behaves in neuronal cell lines as non-activatable by agonists, with changes in organelle temperature, mitochondrial calcium and ATP production [65]. These data, still from isolated studies, show that pharmacological inhibition of the channel will not be appropriate for all patients and reinforce the need for functional characterisation of the variant before therapeutic trials.

2.10. Penetrance and expressivity

Penetrance is reduced for neuromuscular variants and high for the skeletal dysplasias, with great intra- and interfamilial variability in both groups [1]. In a family with p.(Arg269Cys), of the five carriers, the 44-year-old mother had SPSMA, the 7-year-old daughter had congenital distal SMA with arthrogryposis, and the other three were clinically and electrophysiologically asymptomatic at 9, 40 and 70 years [58]. In a French series, 2 of 12 carriers of a pathogenic variant were asymptomatic [66]. In the Swedish family with brachyolmia and p.(Arg616Gln), 11 affected individuals over four generations had pain and paraesthesias that were absent in the American family with the same variant [14].

2.11. Mosaicism

Gonadal mosaicism explains affected siblings of unaffected parents in metatropic dysplasia [8, 30]; it was documented in Chinese half-siblings with different fathers and in half-sisters with SMD Kozlowski who were daughters of the same father [9, 13]. Somatic mosaicism attenuates the phenotype: a child with non-lethal metatropic dysplasia had the p.(Leu618Pro) variant, lethal in the heterozygous state, in 16 of 71 exome sequencing reads (about 15% of alleles in blood, that is, about 30% of heterozygous cells), with negative Sanger sequencing and negative parents [9, 57].

2.12. Allelic diseases and atypical inheritance

Patients homozygous for p.(Ser94Leu) with neuromuscular disease have been described; a 2-year-old boy had arthrogryposis multiplex congenita, severe skeletal anomalies, torticollis, vocal cord palsy and reduced lower limb movement, and the variant showed partial gain of function [1, 10]. Two siblings with two partial loss-of-function variants had microcephaly, dystonia, hearing loss, retinopathy, skeletal anomalies and neuropathy, but the pathogenicity of these variants has not been established [1]. In a Greek family, four siblings with avascular necrosis of the femoral head had the p.(Val829Trpfs*3) variant, which prevents channel closure [5]. The p.(Pro19Ser) polymorphism (rs3742030) was associated with lower serum sodium and hyponatraemia in older men [5].

3. Clinical Spectrum and Manifestations by System

3.1. Organisation of the spectrum

The phenotypes are distributed along two axes. On the skeletal axis, digital arthropathy with brachydactyly affects only the hands and feet and does not overlap with the other dysplasias; brachyolmia, SMD Kozlowski, SEMD Maroteaux and metatropic dysplasia form a continuum of increasing severity with three common features — short stature, progressive vertebral deformity with platyspondyly and “overfaced” pedicles on the anteroposterior radiograph (the lateral border of the vertebral body extends beyond that of the pedicles) and at least one distinctive feature [1]. On the neuromuscular axis, CMT2C, SPSMA and CDSMA share a predominantly motor, non-length-dependent peripheral neuronopathy or neuropathy, with onset from the prenatal period to late adulthood, and probably constitute an overlapping spectrum, often impossible to separate clinically [1]. The two axes intersect in the mixed phenotypes [64].

3.2. Comparative table of the skeletal dysplasias

3.3. Metatropic dysplasia

3.3.1. Prenatal and neonatal period

Metatropic dysplasia can be lethal in the prenatal or perinatal period, mainly because of a very narrow thorax and pulmonary hypoplasia [1]. It has been diagnosed at 20 weeks of gestation from the short limbs [8]. The newborn has normal length or length above the 97th centile, a disproportionately long trunk, short limbs, a narrow thorax with short ribs, prominent joints with reduced mobility and, frequently, a tail-like appendage over the sacrum [8, 30]. The face shows a prominent forehead, midface hypoplasia and a square mandible [30]. In a series of 22 patients with non-lethal metatropic dysplasia, only the prominent joints were constant; the narrow thorax and coccygeal tail, considered characteristic, were absent in some cases, and some adolescents retained short limbs without reversal of proportions [9]. In the most severe forms there is fetal akinesia, with arthrogryposis-like contractures; in a series of four patients, three pregnancies were terminated after ultrasound showing absence of movements, severe contractures and signs of metatropic dysplasia, and the fourth newborn, without lower limb movements, had absent voluntary activity and signs of chronic axonal denervation on electromyography at 3 months and died at 4 months of respiratory complications [9, 46]. This picture represents the overlap between the skeletal and neuromuscular groups [1].

3.3.2. Airway and respiratory system

The respiratory difficulties have several causes: a small, poorly mobile thorax, abnormal vocal cords with arytenoid fusion and laryngotracheomalacia [30]. In the series by Kannu and colleagues (11 patients, from 20 weeks of gestation to 70 years, data spanning 37 years), upper airway obstruction due to laryngotracheal dysfunction in infancy was identified as a preventable cause of mortality [9, 47]. Infant mortality is increased by respiratory failure, and the main cause of death is cardiorespiratory failure secondary to kyphoscoliosis and the narrow thorax [8, 30].

3.3.3. Spine and craniocervical junction

Thoracic kyphoscoliosis progresses rapidly in childhood and shortens the initially long trunk, and has often been relentless and resistant to surgery [8, 47]. Hypoplasia of the odontoid process and of the anterior arch of C1 causes cervical hypermobility, C1–C2 subluxation and spinal stenosis, with a risk of spinal cord compression, tetraplegia and death [8, 30]. In Andreucci's series, a female infant with p.(Pro799Ser) died at 4.5 months, probably from spinal cord compression and respiratory decompensation linked to severe cervical instability [5]. Canal stenosis may occur at several levels from a young age [68]. Occasionally there is macrocephaly, ventriculomegaly, a small foramen magnum and supernumerary vertebrae [30].

3.3.4. Appendicular skeleton, bone and joints

The knee and hip joints are prominent and have restricted mobility, in contrast with the hyperextensibility of the fingers [8, 30]. Increased bone turnover reduces stability and increases the risk of fractures, especially metaphyseal [8, 30]. In a Turkish study of 13 patients followed for a median of 6.5 years, bone pain on running, walking and climbing stairs appeared from 5 years of age in metatropic dysplasia and SMD Kozlowski and worsened with age; in metatropic dysplasia, irregularity and marked widening of the femoral neck were observed [69]. Degenerative joint deformity is a cause of disability in adults [47].

3.3.5. Hearing, intellect and other systems

Sensorineural hearing loss is frequent [30, 47]. Intellectual development is normal in survivors [8, 47], but patients with seizures and global developmental delay have been described, sometimes with spinal dysraphism or narrowing of the craniocervical junction, which may reflect the neurological overlap or spinal complications [49]. In a Chinese series of 10 patients, two of the four with metatropic dysplasia had neurological deficits [70]. Rare manifestations include thyroid agenesis and colonic obstruction due to constriction of the pelvic outlet [30].

3.3.6. Course and final height

Adult height ranges from 107 to 135 cm in Kannu's series and from 110 to 145.5 cm in other sources [8, 30, 47]. The course is not always one of worsening: one of Maroteaux's original patients, followed from 15 days to 30 years of age, had marked improvement of the long bones and almost normal vertebrae at 15 years [9]. In the mild form (“metatropic variant”), there is marked platyspondyly without kyphoscoliosis, straight legs and relatively preserved proportions [8].

3.4. Parastremmatic dysplasia

Parastremmatic dysplasia is distinguished by severe distortion of the lower limbs (“parastremma” means twisted limb), kyphoscoliosis, thoracic deformity and a normal head; radiologically, the flocculent, “popcorn-like” ossification of the vertebral bodies, iliac crest and proximal femora, with wide, lucent metaphyses and distal femoral bowing producing marked genu valgum, is the distinctive sign [8]. A 7-year-old girl with this phenotype had the p.(Arg594His) variant, the same as in SMD Kozlowski [5].

3.5. Spondyloepimetaphyseal dysplasia, Maroteaux type

Length at birth is normal, and short-trunk short stature and brachydactyly become evident during childhood; diagnosis is therefore often late [1, 54]. There is a barrel chest with pectus carinatum, kyphoscoliosis, early degenerative disease of the large joints and short, stubby hands and feet [54]. There are no corneal opacities or mucopolysacchariduria, and intelligence is normal [12]. Adult stature is very short, and kyphoscoliosis and C1–C2 instability can cause myelopathy; a 65-year-old man required neurosurgery for myeloradiculopathy [12, 54]. An 11-year-old girl had generalised osteoporosis, cervical instability and laxity of the distal joints [12]. Nishimura and colleagues wrote in 2010 that kyphosis and scoliosis are not observed in this entity, unlike metatropic dysplasia [12]; the Spranger atlas and GeneReviews describe kyphoscoliosis [1, 54], and this divergence reflects differences between small series.

3.6. Spondylometaphyseal dysplasia, Kozlowski type

Children are normal at birth; a waddling gait with joint limitation appears at 15–20 months and is often the first sign, and growth retardation, especially of the trunk, appears between 1 and 4 years [32]. Kyphosis appears at around 2 years and, in some cases, scoliosis is recognised at birth and progresses rapidly [21]. The neck and trunk are short, there is pectus carinatum, the hands are short and stubby, and the elbows are more affected than the knees [32]. Occasionally there is genu valgum, and degenerative joint changes appear early [21, 32]. Narrowing of the pelvic outlet may necessitate caesarean section in affected women; intellectual development and life expectancy are normal, and adult stature is usually below 140 cm [21]. In the Turkish series, patients with SMD Kozlowski had bone pain from 5 years of age, kyphosis increasing with age, severe platyspondyly persisting into adulthood and irregularity of the proximal femur with destruction of the femoral head at the end of puberty [69]. Progressive digital arthropathy, without brachydactyly, may also occur in this phenotype [22], and peripheral neuropathy or motor neurone disease is rarely associated [21, 32].

3.7. Autosomal dominant brachyolmia

Short stature is mild, the limbs are normal and physical function is preserved [1]. The disease manifests in childhood; growth retardation affects the trunk more than the limbs, and kyphoscoliosis, back pain, limb pain and paraesthesias appear [67]. In the Swedish family with p.(Arg616Gln), 11 affected individuals over four generations, the 2-year-old proband had a normal growth curve but typical radiology; with age, the vertebrae became flatter, with irregular endplates, narrow discs, short pedicles and a narrow canal, suggestive of spinal stenosis; adults reported spinal stiffness, pain in the extremities and hips from mid- or late childhood and burning or prickling paraesthesias; the oldest affected individual was in a wheelchair at 83 years because of pain, kyphoscoliosis and hip osteoarthritis, and two adults changed occupation because of musculoskeletal pain; adult height was 138 to 159 cm, with a median Z-score of −1.95 [14, 56, 67]. In the Turkish series, severe scoliosis was more frequent in brachyolmia than in the other dysplasias [69].

3.8. Familial digital arthropathy with brachydactyly

The hands and feet are normal at birth, including on radiographs [1]. In the first decade, irregularities of the proximal articular surfaces of the distal interphalangeal joints, swelling and limitation of the interphalangeal joints and relative shortening of the middle and distal phalanges appear; in adults, all the interphalangeal, metacarpophalangeal and metatarsophalangeal joints are affected by a painful, deforming osteoarthritis, more in the hands than in the feet, radiologically identical to Heberden and Bouchard nodes [15, 22]. The carpometacarpal joint of the thumb is spared, unlike in common osteoarthritis [22]. The rest of the skeleton is normal [15]. Amor and colleagues postulated a primary subchondral pathology of the heads of the phalanges, metacarpals and metatarsals, with secondary arthropathy and brachydactyly [34]. In the family described in the atlas, with p.(Phe273Leu), a 14.5-year-old boy already had proximal and distal interphalangeal osteoarthritis, and a 61-year-old man also had metacarpophalangeal and metatarsophalangeal involvement [22].

3.9. Neuromuscular diseases

3.9.1. Common picture and registry data

Patients have progressive weakness and atrophy of the muscles of the feet and hands, reduced reflexes and mild or absent sensory loss; shoulder girdle weakness with scapular winging is frequent, knee extension and hip flexion may be affected, and asymmetry is common [1]. Symptoms usually begin between early childhood and 25 years, but onset ranges from birth, with respiratory difficulty and late walking, to after the eighth decade, and some forms are so mild that neither the patient nor the physician recognises them [1]. In the North American registry of 68 patients with a pathogenic variant (40 with a questionnaire), age at onset was bimodal, with the larger peak in the first 2 years of life; compared with CMT1A, patients had more walking difficulties and more proximal involvement of the arms and legs; they reported fewer sensory symptoms, but examination frequently detected sensory dysfunction; 55% had vocal cord weakness, 55% shortness of breath, 11% needed ventilatory support, 64% had scoliosis and 33% arthrogryposis, and patients with infantile onset had less sensory involvement and less progression [23]. In a French series of 169 patients with hereditary axonal neuropathy, the 12 with a pathogenic variant all had childhood-onset motor neuropathy, foot deformities (100%), kyphoscoliosis (100%), raised serum creatine kinase (100%), vocal cord palsy (94%), scapular winging (53%), respiratory failure (29%), hearing loss (24%), skeletal dysplasia (18%) and arthrogryposis (12%) [5, 66].

3.9.2. Larynx and airway

Laryngeal dysfunction is the hallmark of neuromuscular disease and can occur in any subtype; vocal cord paresis may be bilateral and severe, with inspiratory stridor and a hoarse voice, or asymmetric, often more on the left [1]. Motor severity in the limbs and laryngeal dysfunction do not correlate [1]. In Dyck's family followed by Chen and colleagues, the proband had acute stridor at 6 months and permanent tracheostomy at 3 years, and her daughter had severe stridor at 8 months [16, 61]. Upper respiratory infections can cause swelling of the vocal cords and worsen obstruction [1].

3.9.3. Breathing and sleep

Diaphragmatic weakness can cause respiratory failure, orthopnoea and sleep apnoea, with reduced maximal inspiratory and expiratory pressures; central apnoea has also been described [1]. A 55-year-old patient from a British family needed respiratory assistance for hypercapnic respiratory failure and obstructive apnoea [16]. Severely affected patients may have reduced life expectancy due to respiratory complications [1, 37].

3.9.4. Hearing, bladder, skin and other

Sensorineural hearing loss, when present, is bilateral, progressive and mild to moderate, with onset between childhood and adulthood [1]. Bladder dysfunction, mainly incontinence and urinary frequency, and skin changes (scaling, dryness, pruritus and fissures) have been described in the registry [1]. Hand weakness can worsen with cold [16]. Some families have cranial nerve palsies (abducens, third nerve) [16, 18].

3.9.5. Orthopaedics and tethered cord

Contractures mainly affect the ankles, knees and hips; hip dysplasia and scoliosis are common, and tethered cord was found in 7.5% of a cohort of 40 patients, not only in the congenital forms [1]. Some patients with CMT2C have short stature [1]; in a family with p.(Ser542Tyr), all 6 affected individuals had proportionate short stature, and one had vertebrae of reduced height [16, 61].

3.9.6. CMT2C

CMT2C is a progressive, predominantly motor neuronopathy/neuropathy, with bilateral pes cavus, distal amyotrophy and foot drop; when there is sensory loss, vibration is more affected than pain [1]. In the original families, intrafamilial variability was marked: one woman had mild late-onset weakness and her daughter tetraparesis and respiratory failure [16]. Biopsy of a severely affected patient showed marked neurogenic atrophy of the gastrocnemius and modest loss of sensory axons [16]. In an Ashkenazi and Sephardic Jewish family with p.(Arg315Trp), the proband was born with stridor, clubfeet, congenital hip dislocation and knee contractures and needed a tracheostomy; her mother had only a hoarse voice since childhood and fatigue from the age of 30, and a 14-year-old carrier was asymptomatic [5, 59].

3.9.7. Scapuloperoneal spinal muscular atrophy

SPSMA is a slowly progressive loss of lower motor neurones with weakness and atrophy of the shoulder girdle, with scapular winging, and of the peroneal muscles, without sensory involvement; severe forms have congenital absence of muscles and weakness at birth, similar to CDSMA [1]. In the New England family there was torticollis and hip dysplasia at birth, motor delay, proximal weakness, facial and abducens palsy, neck flexor weakness, laterally displaced scapulae, limb dysmetria, a wide-based gait and Gowers' sign, with little or no progression; skeletal anomalies such as hip dysplasia, scoliosis, small hands with clinodactyly and limb asymmetry accompany the picture [18].

3.9.8. Congenital distal spinal muscular atrophy

CDSMA begins before birth and is non-progressive or slowly progressive, with weakness and atrophy mainly of the lower limbs, flexion contractures of the knees and hips at birth (arthrogryposis multiplex congenita) and severe bilateral clubfoot [1]. In mild forms, congenital weakness is limited to the distal lower limbs; in severe forms, it affects the pelvic girdle and trunk, with scoliosis [1, 19]. The congenital forms can have long periods of stability, but progression may appear in adulthood [1]. The Oxford Desk Reference describes it as non-progressive congenital spinal muscular atrophy with contractures, allelic to HMSN2C [71]. A woman with CDSMA had bowel and bladder dysfunction from an early age and had no progression at 24 years [19].

3.10. Mixed phenotypes

A minority of patients have both skeletal dysplasia and neuropathy [52, 64]. The fetal akinesia of severe metatropic dysplasia and the short stature of some families with CMT2C are the most frequent expressions of this overlap [46, 61]. A child initially diagnosed with SMD Kozlowski developed muscle weakness and gait changes, and the diagnosis was revised to CMT2C [49]. In a Turkish series of 11 patients from 6 families, the overlap between and within groups was considerable [4].

3.11. Natural history and treated disease

Natural history data come from small series and an ongoing neuromuscular registry; there are no cohorts of patients treated with disease-modifying interventions, because none exist [1, 23]. Spinal surgery in the dysplasias and non-invasive ventilation in the neuromuscular forms modify the course, but the series do not rigorously separate natural from treated evolution; in metatropic dysplasia, kyphoscoliosis has been described as resistant to surgery [47].

4. Clinical Recognition and Warning Signs

4.1. Prenatal period

Ultrasound may show short limbs with widened metaphyses, a narrow thorax, flat vertebral bodies and, in the most severe forms, absence of fetal movements and contractures [8, 46]. Metatropic dysplasia can be mistaken for thanatophoric dysplasia: in one case, ultrasound at 37 weeks described a cloverleaf skull, a narrow thorax and growth restriction [49]. Fetal akinesia with signs of skeletal dysplasia should suggest the combined TRPV4 phenotype [46]. The congenital neuromuscular forms manifest prenatally with contractures and clubfeet [1].

4.2. Newborn and infant

Metatropic dysplasia is suspected in the presence of short limbs with a long trunk, a narrow thorax, large stiff joints and a tail-like sacrococcygeal appendage [8, 30]. Inspiratory stridor, a weak or hoarse voice and respiratory difficulty in a newborn with arthrogryposis, clubfeet or hip dislocation suggest CDSMA or congenital-onset CMT2C [1, 59]. The neuromuscular registry shows that the peak onset of neuromuscular disease is in the first 2 years [23].

4.3. Child

A waddling gait with joint limitation between 15 and 20 months, followed by growth retardation of the trunk and kyphosis, is the pattern of SMD Kozlowski [21, 32]. A child with mild short stature, a still normal growth curve and platyspondyly on a radiological examination may have brachyolmia [14]. Painful swelling of the interphalangeal joints with progressive shortening of the phalanges in the first decade suggests familial digital arthropathy [1, 22]. Bone pain on running and climbing stairs from 5 years of age is frequent in SMD Kozlowski and metatropic dysplasia [69].

4.4. Adolescent and adult

A predominantly motor, non-length-dependent axonal neuropathy with proximal weakness or scapular winging, hoarseness, exertional stridor, orthopnoea, hearing loss or scoliosis should lead to testing of TRPV4 [1, 72]. The probability of finding a TRPV4 variant is low in pure CMT2 and rises when there are unusual signs: in a French series, it was 7% in the whole cohort, 16% in patients with vocal cord paresis or skeletal dysplasia and 0% in 95 patients with pure CMT2 [5, 66]. In a cohort of adults with non-5q spinal muscular atrophy, TRPV4 was the second most frequent gene, and severe involvement of the sternocleidomastoid on magnetic resonance imaging occurred in 2 of 4 patients, being spared in all others [73]. Early interphalangeal osteoarthritis that spares the base of the thumb is a sign of familial digital arthropathy [22].

4.5. Warning and emergency signs

4.6. Newborn screening

There is no newborn screening for these diseases.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

The diagnosis is established in a proband with characteristic clinical and neurophysiological findings, with the radiographic findings in the dysplasias, and a heterozygous pathogenic or likely pathogenic variant in TRPV4 presumed to cause gain of function; the exception is the p.(Ser94Leu) variant, associated with recessive disease [1]. A variant of uncertain significance neither confirms nor excludes the diagnosis [1]. Absence of a family history does not exclude the diagnosis, because the severe forms are usually de novo and the neuromuscular forms have reduced penetrance [1].

5.2. Radiology of the dysplasias

Skeletal radiological examination is the first diagnostic step in the dysplasias and guides molecular interpretation [52]. The most useful common sign is platyspondyly with overfaced pedicles on the anteroposterior view of the spine [1]. In metatropic dysplasia, the newborn has wafer-thin vertebrae, with deficient ossification of the posterior part of the bodies, hyperplastic pedicles and neural arches, thin ribs with flared ends, crescent-shaped iliac crests with hypoplastic basilar portions, short tubular bones with greatly widened, convex (“dumbbell”) metaphyses, distal femora with double contour of the condyles, irregular talus and calcaneus, and early calcification of the hyoid and cricoid cartilage [8, 9]. Later, the vertebrae become flat, with anterior wedging and accumulation of bone in the central and posterior parts of the endplates, and the proximal femur is hyperplastic with small epiphyses [8]. The presence or absence of dumbbell femora separates metatropic dysplasia from SMD Kozlowski [9, 41]. In SMD Kozlowski, the metaphyseal changes predominate in the proximal femur, with coxa vara and short necks; in the other metaphyses they may be so subtle that they go unnoticed, and delayed carpal bone age, considered a diagnostic criterion, was absent in half the patients of a large series [13, 69]. In brachyolmia, platyspondyly with irregular endplates, narrow discs and vertical striations of the femoral necks dominates, and the long bones are almost normal [67]. In SEMD Maroteaux, the vertebral bodies are rectangular and elongated, the ilia wide with short sciatic notches, and there is brachydactyly type E [54]. In digital arthropathy, radiographs show shortening of the middle and distal phalanges, osteophytes, joint-space narrowing and deformity of the interphalangeal, metacarpophalangeal and metatarsophalangeal joints, with the first carpometacarpal joint spared [22]. Conventional radiographs at standardised ages remain essential for delineating the spectrum [1, 9].

5.3. Neurophysiology and muscle imaging

In the neuromuscular forms, nerve conduction studies show reduced compound muscle action potential amplitudes with normal velocities (above 40–60 m/s) and normal, reduced or absent sensory potentials; electromyography shows chronic neurogenic changes [1]. Serum creatine kinase may be raised [19, 66]. Muscle magnetic resonance imaging in CDSMA showed extensive fatty atrophy with sparing of the biceps femoris and medial gastrocnemius, a pattern different from non-TRPV4 SMA [74]; in adults with non-5q SMA, the patterns were heterogeneous, with possible involvement of the sternocleidomastoid [73]. Muscle biopsy, rarely needed, shows denervation and reinnervation [1].

5.4. Initial evaluation after diagnosis

5.5. Genetic testing

Sequencing of TRPV4 detects missense, nonsense and splicing variants and small insertions or deletions, and has identified all known pathogenic variants; no deletion or duplication of exons or of the whole gene has been described with these phenotypes, and the known variants are presumed to be gain of function [1]. Single-gene testing may be used when the phenotype is typical, or a multigene skeletal dysplasia or neuropathy panel, which limits findings in genes unrelated to the phenotype [1]. Exome or genome sequencing is indicated when the phenotype is non-specific; genome sequencing increased the diagnostic yield in a large British CMT series [75]. In a family with CMT2C, the p.(Arg186Gln) variant was missed by the initial study because of the primers and was found only by exome sequencing [60].

5.6. Limitations of testing

A negative result does not exclude the disease: Sanger sequencing restricted to one exon, such as exon 14 in a Mexican series, misses variants in other exons [49]; Sanger sequencing may not detect low-level somatic mosaicism, which next-generation sequencing identified with 16 of 71 reads [57]; the level of mosaicism in the target tissue (cartilage) cannot be assessed in blood [9]. In Andreucci's series, patients without a variant had features atypical for the clinical diagnosis, and in brachyolmia without metaphyseal changes the absence of a TRPV4 variant points to other causes [33]. Two families with dominant brachyolmia had no TRPV4 variant, which indicates genetic heterogeneity [14]. The proportion of variants detectable by sequencing is not the same as clinical sensitivity: the GeneReviews figure of 100% refers to published pathogenic variants, and not to the proportion of patients with the phenotype who will have a variant identified [1].

5.7. Variant interpretation

The report should state the gene, the reference transcript and version (NM_021625.5), the variant in HGVS nomenclature, the zygosity and the class according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology [1, 7]. Many variants found by exome or genome sequencing remain variants of uncertain significance [53]. Location helps: in neuromuscular disease, variants on the face of the ARD that contacts RhoA and those in a cluster of the intrinsically disordered region tend to have gain of function, whereas those of the transmembrane domain and of other parts of the disordered region studied do not; congenital onset, vocal cord weakness and motor predominance support pathogenicity, and late onset with sensory predominance points the other way [53]. Family segregation is informative in the dysplasias, which have high penetrance, but should be read with caution in the neuromuscular forms, in which there are asymptomatic carriers [1, 58]. Confirmation of de novo status requires testing both parents with confirmation of parentage [1]. The GeneReviews authors offer to review variants of uncertain significance in patients with a neuromuscular phenotype [1].

5.8. Algorithm

Sources: [1, 8, 41, 53, 66].

5.9. Prenatal and preimplantation diagnosis

Prenatal diagnosis and preimplantation genetic testing are possible when the familial variant is known, but they do not allow prediction of the phenotype, age at onset or severity [1]. In pregnancies without a family history, suspicion arises from ultrasound, and molecular diagnosis on a fetal sample allows metatropic dysplasia to be distinguished from other severe dysplasias [8, 49].

6. Differential Diagnosis

6.1. Skeletal dysplasias

Within the spectrum, metatropic dysplasia is separated from SMD Kozlowski by the dumbbell femora, the more severe epiphyseal dysplasia and the crescent-shaped iliac wings [21, 41]; SEMD Maroteaux has normal or slightly widened metaphyses, unlike metatropic dysplasia, and brachydactyly, unlike brachyolmia [54]; dominant brachyolmia is distinguished from the recessive forms by inheritance and by the mild metaphyseal changes of the proximal femur [67, 77]. The nosology classifies SMD Kozlowski among several spondylometaphyseal dysplasias, some with a different molecular basis, such as the axial forms due to CFAP410 or NEK1 and the severe Sedaghatian form due to GPX4 [2].

6.2. Neuromuscular diseases

Vocal cord paresis brings TRPV4 disease close to the neuropathies due to SLC5A7, DCTN1 and JAG1, and diaphragmatic weakness and scapular winging bring it close to the PLEKHG5 forms [1]. HMN VII is distinguished from CMT2C by the absence of sensory involvement [16]. The combination of motor neuropathy with hearing loss, scoliosis, skeletal dysplasia or short stature is the most specific clue to TRPV4 [66, 72].

7. Treatments and Risk Management Strategies

7.1. Principles and sources of the recommendations

There are no clinical practice guidelines specific to TRPV4-related disorders; the GeneReviews recommendations are based on the authors' experience [1]. For the dysplasias, the best practice guidelines of the Skeletal Dysplasia Management Consortium apply, obtained by Delphi consensus with agreement above 80%, on the spine (2020), the perioperative period (2017) and pregnancy and delivery (2018) [68, 79, 80]. Treatment is supportive and directed at the manifestations, by a multidisciplinary team that includes neurology, physical medicine and rehabilitation, orthopaedics, otology and audiology, laryngology, respiratory medicine, genetics, physiotherapy and occupational therapy, with attention to the prevention of obesity and the treatment of pain and depression [1]. There is no approved drug indicated for these diseases, so there are no doses of targeted therapy to present.

7.2. Neuromuscular diseases

Foot surgery in the hereditary neuropathies follows the general principles of pes cavus correction, but the case of a 10-year-old girl with p.(Arg269His), who underwent Achilles tendon lengthening, releases, tendon transfers and calcaneocuboid arthrodesis and developed dehiscence of several incisions without infection, requiring debridement, negative pressure therapy and dermal matrix, raised the hypothesis of a genotype-related vulnerability of wound healing; the patient's skin fibroblasts grew more slowly and adhered less in culture, but causality was not demonstrated [81].

7.3. Skeletal dysplasias

7.4. Spine in the dysplasias: consensus recommendations

Metatropic dysplasia is among the dysplasias with significant spinal manifestations — cervical instability, cervical stenosis, kyphosis and scoliosis — and may have multilevel stenosis from a young age [68]. The 2020 consensus recommends considering flexion and extension radiographs of the cervical spine in all patients with a known risk of C1–C2 instability; using flexion and extension computed tomography or magnetic resonance imaging as an adjunct; suspecting spinal cord compression in the presence of imbalance, a wide-based gait, limb weakness, upper motor neurone signs or urinary incontinence; urgently assessing any clinical sign of myelopathy; considering surgery when there is cervical instability or significant spinal cord compression with myelopathic signs; obtaining advanced imaging before upper cervical surgery, because the vertebral and vertebral artery anatomy is variable; considering neuromonitoring in all surgical procedures in patients with an “at-risk spine”; repeatedly assessing cervical and thoracolumbar kyphosis; stabilising thoracolumbar kyphosis that is progressive, with neurological compromise or with refractory pain, aiming for sagittal balance; monitoring respiratory function in thoracic deformities; using braces or casts in flexible, progressive scoliosis in young children and growth-preserving techniques in early-onset scoliosis; and obtaining advanced imaging before any instrumentation, knowing that surgical complications are more frequent than in the general population [68]. The same consensus does not recommend prophylactic C1–C2 fusion without spinal cord compression or myelopathic signs, and did not reach agreement on routine whole-spine MRI [68]. Smith's Recognizable Patterns recommends considering C1–C2 fusion in all cases of metatropic dysplasia with subluxation and measuring the foramen magnum [30]; the more recent consensus guidance reserves surgery for compression or myelopathy, and GeneReviews accepts intervention with compression on MRI even without symptoms [1, 68].

7.5. Anaesthesia and the perioperative period

The 2017 perioperative consensus (13 experts, 19 of 22 recommendations approved) recommends preoperative pulmonary, polysomnographic, cardiac and neurological assessment, imaging of the cervical spine and planning for a difficult airway at intubation and extubation [79]. In a series of 23 patients with metatropic dysplasia who underwent 188 anaesthetics, 61% for orthopaedic procedures, 14 (60.8%) became progressively difficult to intubate, 12 of them after cervical fusion; spinal canal stenosis was frequent and no patient received neuraxial anaesthesia [82]. The Spranger atlas recommends the utmost care in anaesthesia because of cervical instability [8]. Before general anaesthesia, GeneReviews recommends cervical radiographs to exclude significant odontoid hypoplasia [1]. In the neuromuscular forms, vocal cord paresis, diaphragmatic weakness and scoliosis require respiratory and laryngeal assessment before surgery [1].

7.6. Agents and circumstances to avoid

Obesity should be avoided because it hinders walking [1]. In the neuromuscular forms, prevention of diabetes and its complications and avoidance of neurotoxic drugs, according to the updated list of the Charcot-Marie-Tooth Association, are recommended [1, 83]. In the dysplasias with odontoid hypoplasia, extreme flexion and extension of the neck should be avoided, as should activities and occupations that overload the spine and weight-bearing joints [1].

7.7. Pregnancy, delivery and lactation

There are no records on pregnancy in TRPV4-related disorders; follow-up by high-risk obstetrics or maternal–fetal medicine is recommended, and an increased risk of ectopic pregnancy has been described [1]. Data for the neuropathies come from CMT in general: in the Italian registry, there was more placenta praevia, abnormal presentations and preterm births, with neonatal outcomes similar to those of the population; in a European review, polyhydramnios, preterm delivery, miscarriages and caesarean sections were frequent; about half of women with CMT reported worsening weakness in pregnancy, usually reversible after delivery; in a German study of 63 pregnancies in 33 women, the frequency of caesarean section, forceps, prematurity and neonatal problems was not increased; and about one third experienced worsening, persistent in one fifth [1]. Regional anaesthesia was preferred to general anaesthesia in a published case [1]. In the dysplasias, pulmonary compromise may prevent a term pregnancy; a woman with metatropic dysplasia is unlikely to be able to carry a pregnancy to term, and pregnant women with TRPV4-related dysplasia usually deliver by caesarean section because of the small pelvis [1, 21]. The 2018 best practice guidelines on prenatal assessment and delivery in skeletal dysplasias (40 consensus statements) apply to these women and to affected fetuses [80]. In metatropic dysplasia, canal stenosis and difficult intubation should be considered in the anaesthetic plan for delivery [82]. There are no specific data on lactation.

7.8. Transition to adulthood and working life

Persistent weakness of the hands and feet and orthopaedic involvement may constrain career choice [1]. In the Swedish family with brachyolmia, two adults changed occupation because of musculoskeletal pain [14]. Transition requires maintaining the respiratory, laryngeal, cervical and auditory surveillance begun in childhood and access to adult orthopaedics and neurology.

7.9. Targeted therapy: TRPV4 antagonists

The gain of function of the channel suggests that its inhibition might treat the disease. In mice with the neuromuscular variants R269C and R232C, systemic administration of the selective antagonist GSK219 reversed the blood–spinal cord barrier dysfunction and rescued the motor phenotype of symptomatic animals [24]. In the mouse expressing the skeletal variant p.R594H in chondrocytes, the oral inhibitor GSK2798745 improved the radiographic phenotype and normalised growth plate histology; the same compound inhibited in vitro a broad set of channel-activating variants [25]. Variants causing severe mixed phenotypes are less sensitive to antagonists [64], and the loss-of-function variants described in SMD Kozlowski and digital arthropathy would not be candidates for inhibition [15, 62, 63]. GSK2798745 was well tolerated in phase 1 and 2 trials in other indications (pulmonary oedema, heart failure, chronic cough), and Trpv4 knockout mice have mild phenotypes, which supports the theoretical tolerability of inhibition [24, 84]. None of these trials included patients with TRPV4-related disorders [84].

7.10. Regulatory status

Sources: [1, 26, 84].

7.11. Trials and clinical studies

There are no efficacy trials in patients with TRPV4-related disorders. Efficacy data come from animal models, which do not automatically translate into clinical benefit, and the choice of outcomes for future trials is itself a problem: the North American registry concluded that trials should use measures that capture non-length-dependent motor weakness, vocal cord weakness and respiratory disease, given the clinical profile observed and the slower progression of infantile-onset forms [23]. Patient selection will require functional demonstration of the gain of function of the variant [53, 64]. A ClinicalTrials.gov search by sponsor did not find the registration of the ABS-0871 trial, and the available information comes from sponsor press releases, a lower level of evidence than a registration or publication [26].

7.12. Developments in the last 12 months

7.13. Recommendations of the sources and divergences

The sources agree on the essentials: annual multidisciplinary surveillance, assessment of the cervical spine before school age and before anaesthesia, cervical surgical intervention when there is instability or compression, thoracolumbar spinal surgery when the deformity compromises respiratory function or causes pain, and laryngeal and ventilatory support in the neuromuscular forms [1, 68, 79]. The main divergence concerns cervical fusion in patients with odontoid hypoplasia: Smith's Recognizable Patterns suggests considering C1–C2 fusion in all cases of subluxation in metatropic dysplasia [30]; the 2020 consensus does not recommend prophylactic fusion without compression or myelopathy [68]; and GeneReviews prefers to intervene in children when MRI shows compression, even without symptoms [1]. In practice, the decision is based on dynamic imaging and MRI, and not on odontoid hypoplasia alone. Another divergence is the frequency of imaging: GeneReviews defines time points (before school age and before general anaesthesia), whereas the spine consensus did not reach agreement on routine whole-spine MRI [1, 68].

8. Reproductive Options and Family Counselling

8.1. Mode of inheritance and recurrence risk

TRPV4-related disorders are transmitted in an autosomal dominant manner [1]. The most severe skeletal forms, lethal in infancy or in utero, almost always result from a de novo variant in children of unaffected parents; the less severe skeletal forms and the neuromuscular forms are frequently inherited from a heterozygous parent, although they also occur de novo [1]. Each child of a patient has a 50% probability of inheriting the variant [1].

8.2. Parental mosaicism

Gonadal mosaicism explains affected siblings of unaffected parents in metatropic dysplasia and has been documented in half-brothers and half-sisters with metatropic dysplasia and SMD Kozlowski [8, 9, 13]. A parent with somatic and gonadal mosaicism may have minimal manifestations, and analysis of leucocyte DNA may not detect all somatic mosaicism or exclusively gonadal mosaicism [1]. Therefore, a de novo variant is confirmed only when both parents are negative, and even then a residual risk of recurrence remains [1].

8.3. Cascade testing and predictive testing

Testing of at-risk relatives is possible once the familial variant has been identified; in carriers, clinical assessment, electromyography with nerve conduction studies or skeletal radiological examination may be indicated [1]. As there is no disease-modifying treatment, predictive testing mainly serves personal decision-making and should be preceded by formal counselling on its consequences, including socioeconomic ones, and on the need for follow-up [1]. The reduced penetrance of the neuromuscular forms limits the predictive value of a positive result: in one family, three of five carriers were asymptomatic at 9, 40 and 70 years [58].

8.4. Minors

Predictive testing in asymptomatic minors for a disease that may begin in adulthood and whose early treatment does not change the course should be discussed in formal counselling, giving priority to the minor's future autonomy and considering deferring testing until the minor can decide [1]. Symptomatic children from a family with an established diagnosis can be tested at any age [1]. In the dysplasias, which have high penetrance and manifest in childhood, early diagnosis guides surveillance of the cervical spine and hearing [1].

8.5. Reproductive planning

The ideal time to determine genetic risk and discuss prenatal diagnosis and preimplantation genetic testing is before pregnancy, and counselling should be offered to affected or at-risk young adults and to couples in which both partners have a skeletal dysplasia [1]. Prenatal diagnosis and preimplantation testing are possible with a known familial variant, but they do not allow prediction of the phenotype, age at onset or severity, and views on their use may differ between professionals and families [1]. In a pregnancy with ultrasound suspicion of a severe dysplasia without a family history, specialised ultrasound and fetal molecular testing follow the best practice guidelines for skeletal dysplasias [80].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

There are no population prevalence studies of TRPV4-related disorders [1]. Orphanet classifies the point prevalence of each entity (metatropic dysplasia, SEMD Maroteaux, dominant brachyolmia, SMD Kozlowski in Europe, CMT2C and SPSMA) as below 1/1,000,000, based on the number of published cases (about 81 cases or families of metatropic dysplasia, 10 of SEMD Maroteaux, 30 of dominant brachyolmia, 17 of CMT2C and 31 of SPSMA), and gives no value for familial digital arthropathy [20]. The only population-based estimate is the birth prevalence of metatropic dysplasia in Europe, 1–9/1,000,000, derived from the EUROCAT registries from 2005 to 2012 [20]. These figures measure diagnosed and published cases and probably underestimate the mild forms, which may go unnoticed [1].

9.2. Proportion among referred patients

In the neuropathies, the available data are diagnostic proportions in referred cohorts, not prevalences. In a British series, 13 of 422 patients with a CMT2 phenotype (less than 1%) had a pathogenic TRPV4 variant, and in a British series studied by genome sequencing the proportion was 1.1% in 443 patients with CMT2 or hereditary motor neuropathy [1, 75, 86]. In an American cohort of 62 patients with CMT2 without variants in the most frequent genes, two had a TRPV4 variant [72]. In a French series of 169 patients, the proportion was 7%, rising to 16% in patients with vocal cord paresis or skeletal dysplasia and falling to 0% in the 95 with pure CMT2 [66]. GeneReviews summarises these data as 1% to 3.5% of CMT2 and hereditary motor neuropathies [1]. In French adults with non-5q spinal muscular atrophy, TRPV4 was the second most frequent gene (4 of 23 with a diagnosis) [73]. The sponsor of ABS-0871 estimates about 2,500 patients with CMT2C in the USA, a commercial figure without epidemiological validation [26].

9.3. Populations studied

The published families and series come from the USA (original CMT2C families and the French-Canadian SPSMA family from New England; Inherited Neuropathy Consortium registry), the Netherlands (congenital distal SMA family), the United Kingdom, France, Italy, Spain, Sweden (brachyolmia), Australia (digital arthropathy), Israel (Ashkenazi and Sephardic Jewish family), Greece (femoral head necrosis), South Africa (Xhosa family with brachyolmia), Japan (SEMD Maroteaux), Turkey, China and Mexico [4, 5, 12, 14, 16, 18, 19, 23, 49, 58, 69, 70, 87]. No founder variants have been described; the recurrent variants p.(Pro799Leu) and p.(Arg594His) arise de novo in several populations and correspond to preferential codons, not to founder effects [41, 49]. The sources consulted do not include data from Portugal or Brazil, which does not demonstrate the absence of patients in those countries.

9.4. Special populations

Children with metatropic dysplasia and a narrow thorax or laryngeal dysfunction are the group at greatest risk of death in the first year [8, 47]. Women with dysplasia have high-risk pregnancies because of pulmonary restriction and a small pelvis [1]. Patients with odontoid hypoplasia and those who have undergone cervical fusion are at anaesthetic risk [79, 82].

9.5. European networks and patient associations

The skeletal dysplasias are covered by the European Reference Network for rare bone diseases, ERN BOND, and the neuromuscular forms by ERN EURO-NMD [27, 28]. In Portugal, ANDO Portugal (Associação Nacional de Displasias Ósseas) supports people with skeletal dysplasias [88]. The Hereditary Neuropathy Foundation runs a programme dedicated to TRPV4 hereditary neuropathy and the global GRIN registry, and the Charcot-Marie-Tooth Association provides centres of excellence and the list of potentially neurotoxic drugs [1, 83, 89]. The Inherited Neuropathy Consortium includes a TRPV4 neuromuscular disease registry, and the NCT05600764 study is recruiting patients for the natural history of TRPV4 neuropathy [1, 85]. The International Skeletal Dysplasia Registry of the University of California, Los Angeles, and Little People of America are additional resources for the dysplasias [1].

10. Illustrative Clinical Case

10.1. Metatropic dysplasia with recurrent fractures and neurological involvement (p.(Pro799Leu))

Robles-Espinoza and colleagues described in 2025 three Mexican patients with metatropic dysplasia and de novo TRPV4 variants, of differing severity [49]. The third patient was a boy, the only child of non-consanguineous parents aged 42 (mother) and 49 years (father), in whose pregnancy ultrasound in the eighth month had shown fetal growth restriction and oligohydramnios. He was born at 39 weeks with appropriate weight and length, and a coccygeal skin appendage was removed at 2 weeks. He had global developmental delay and seizures from 4 months, treated with levetiracetam. On examination he had a broad forehead, upslanting palpebral fissures, micrognathia and retrognathia, low-set ears, a short neck with limited mobility, a bell-shaped chest, rhizomelic and mesomelic shortening of the limbs and restricted hip mobility. Computed tomography showed spinal dysraphism at L5–S1, and radiographs showed cervical, thoracic and lumbar platyspondyly, metaphyseal widening, short long bones and an irregular carpus, talus and calcaneus [49].

The course was marked by fractures. At 2 years and 11 months he fractured his left femur in a fall from standing height; at 4 years he had a fissure fracture of the right femur with no known cause and at 5 years a diaphyseal refracture of the left femur. Densitometry showed a bone mineral density of −3.6 standard deviations, and he started zoledronic acid. At 6 years he had a further fracture of the right femur, with a density of −2.5 standard deviations; a second cycle at 7 years normalised the density and there were no new fractures up to publication. Sanger sequencing of exon 14 identified the heterozygous variant NM_021625.5:c.2396C>T p.(Pro799Leu) [7, 49]. The same variant, de novo, was found in the second patient of the series, who had a mild phenotype, with improved cervical mobility and a favourable prognosis; the first patient, with p.(Asn796del), was initially diagnosed with thanatophoric dysplasia and had severe reflux with gastrostomy, cardiac arrest during surgery, seizures, neurogenic bladder and narrowing of the craniocervical junction [49].

Figure 1 of the article shows the thoracic, spinal and limb radiographs of the three patients, with a bell-shaped chest, marked platyspondyly, variable scoliosis and short long bones with widened, irregular metaphyses (https://pmc.ncbi.nlm.nih.gov/articles/PMC12524330/figure/ijms-26-09783-f001/); Figure 2 shows the electropherograms of the variants and their location in the C-terminal domain of the protein (https://pmc.ncbi.nlm.nih.gov/articles/PMC12524330/figure/ijms-26-09783-f002/) [49].

10.2. Lessons from the case

The case illustrates three points. First, the same variant, p.(Pro799Leu), gave very different phenotypes in two patients, which confirms that the variant does not predict severity [49, 51]. Second, bone fragility with metaphyseal and diaphyseal fractures is part of metatropic dysplasia [8, 30]. Third, the neurological manifestations (seizures, developmental delay) require neurological assessment and assessment of the craniocervical junction, since intellectual development is usually normal [8, 49]. The use of zoledronic acid in this patient was an individual decision, with no dose stated in the report and no studies in TRPV4-related dysplasias; it is not recommended by any guideline and should not be taken as routine. Analysis limited to exon 14 detected the variant in this patient, but would not have detected variants in other exons [49].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Prognosis ranges from normal life expectancy in the mild forms to prenatal or perinatal lethality in the most severe forms [1]. In metatropic dysplasia, half the patients in a series of 10 had the lethal form, with death in the neonatal period or in infancy [51]; laryngotracheal obstruction in infancy is a preventable cause of death, and in survivors the main cause of death is cardiorespiratory failure due to kyphoscoliosis and a narrow thorax [30, 47]. Intellectual development in survivors is normal in most, and adult stature lies between 107 and 145.5 cm [8, 30, 47]. In SMD Kozlowski, intellect and life expectancy are normal, with adult stature usually below 140 cm and pain and osteoarthritis from childhood [21, 32, 69]. In brachyolmia, physical function is good, but pain, paraesthesias and spinal stenosis may limit working life and, in old age, mobility [1, 14]. Digital arthropathy causes painful deformity of the hands and feet from early adulthood, without involvement of the rest of the skeleton [22]. In the neuromuscular forms, severely affected patients may die of respiratory complications; in the registry, 11% needed ventilatory support and infantile-onset forms progressed less than late-onset forms [1, 23].

11.2. Surveillance table

The annual frequency of laryngoscopy, respiratory assessment and audiology matches that of section 7. GeneReviews does not define a fixed interval for cervical MRI in the dysplasias, and the spine consensus did not reach agreement on routine whole-spine MRI [1, 68].

11.3. Long-term follow-up

Kyphosis and scoliosis progress with age in SMD Kozlowski and metatropic dysplasia, and severe scoliosis is frequent in brachyolmia, so spinal surveillance should continue into adolescence and adulthood [69]. Destruction of the femoral head at the end of puberty in SMD Kozlowski and early osteoarthritis justify orthopaedic follow-up of the hips [21, 69]. After cervical fusion, intubation difficulty tends to increase, which should be recorded in the clinical record for future anaesthetics [1, 82]. In the neuromuscular forms, patients may have long plateaus and late progression, which precludes discharge from respiratory and laryngeal surveillance [1].

12. Summary and Final Considerations

TRPV4-related disorders bring together, in a single gene, skeletal dysplasias ranging from familial digital arthropathy with brachydactyly to lethal metatropic dysplasia and predominantly motor neuromuscular diseases that include CMT2C, scapuloperoneal spinal muscular atrophy and congenital distal spinal muscular atrophy [1]. Almost all result from heterozygous missense variants that increase channel activity and calcium influx, with tissue-specific consequences: disruption of endochondral ossification in the growth plate and, in mouse models, endothelium-mediated breakdown of the blood–spinal cord barrier in neuromuscular disease [1, 24, 25]. Skeletal variants cluster at codons Pro799 and Arg594, and neuromuscular variants on the face of the ankyrin repeat domain that contacts RhoA; the overlap, the mixed phenotypes and the recently described loss-of-function variants make the genotype–phenotype correlation imperfect [41, 53, 62, 64].

Clinical recognition rests on two patterns: in the dysplasias, short-trunk short stature with platyspondyly, overfaced pedicles and progressive kyphoscoliosis, with dumbbell femora distinguishing metatropic dysplasia; in the neuromuscular forms, non-length-dependent motor weakness with vocal cord paresis, diaphragmatic weakness, scapular winging, hearing loss, scoliosis and contractures [1, 23]. Sequencing of TRPV4, alone or in a panel, confirms the diagnosis; interpretation of variants of uncertain significance benefits from their location in the protein, functional study and phenotype, and mosaicism may escape Sanger sequencing [1, 53, 57].

Treatment is supportive and multidisciplinary. The points of greatest risk are the airway (laryngeal paresis, laryngotracheomalacia, difficult intubation after cervical fusion), the craniocervical junction (odontoid hypoplasia and stenosis), respiratory function (narrow thorax, kyphoscoliosis, diaphragmatic weakness) and the bone fragility of metatropic dysplasia [1, 47, 82]. Annual neurological, laryngeal, respiratory, auditory and musculoskeletal surveillance and assessment of the cervical spine before school age and before general anaesthesia form the core of follow-up [1, 68]. Genetic counselling should take into account dominant inheritance, the reduced penetrance of the neuromuscular forms, gonadal mosaicism with a residual risk of about 1% for siblings and the impossibility of predicting severity from the variant [1].

Pharmacological inhibition of TRPV4 has rescued the neuromuscular and skeletal phenotypes in mice, and an oral inhibitor is in a phase 1 trial with CMT2C as its target; to date there are no efficacy data in patients, and the ongoing natural history study and the neuromuscular registry should provide the outcomes for future trials [23–26, 85].

13. References

1. McCray BA, Schindler A, Hoover-Fong JE, Sumner CJ. Autosomal Dominant TRPV4-Related Disorders. 2014 May 15 [updated 2025 Dec 4]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK201366/
2. Unger S, Ferreira CR, Mortier GR, Ali H, Bertola DR, Calder A, et al. Nosology of genetic skeletal disorders: 2023 revision. Am J Med Genet A. 2023;191(5):1164-1209. doi:10.1002/ajmg.a.63132. PMID: 36779427.
3. Orphanet. TRPV4-related bone disorder (ORPHA:364820) and related entities: metatropic dysplasia (ORPHA:2635), parastremmatic dysplasia (ORPHA:2646), spondylometaphyseal dysplasia, Kozlowski type (ORPHA:93314), spondyloepimetaphyseal dysplasia, Maroteaux type (ORPHA:263482), autosomal dominant brachyolmia (ORPHA:93304), familial digital arthropathy with brachydactyly (ORPHA:85169), scapuloperoneal spinal muscular atrophy (ORPHA:431255), autosomal dominant benign congenital spinal muscular atrophy (ORPHA:1216). Paris: INSERM; accessed 1 Nov 2026. Available from: https://www.orpha.net/en/disease/detail/364820
4. Ürel-Demir G, Şimşek-Kiper PÖ, Öncel İ, Utine GE, Haliloğlu G, Boduroğlu K. Natural history of TRPV4-Related disorders: From skeletal dysplasia to neuromuscular phenotype. Eur J Paediatr Neurol. 2021;32:46-55. doi:10.1016/j.ejpn.2021.03.011. PMID: 33774370.
5. Online Mendelian Inheritance in Man, OMIM®. *605427 Transient receptor potential cation channel, subfamily V, member 4; TRPV4. Baltimore (MD): Johns Hopkins University. Available from: https://www.omim.org/entry/605427
6. GeneGuidance. TRPV4 gene record (version of 2026-09-26). Clinical gene curation database.
7. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-68. doi:10.1002/humu.23348. NM_021625.5 (GRCh38), accessed 1 Nov 2026. Available from: https://variantvalidator.org/
8. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. Chapter 6.1, Metatropic dysplasia. p. 135–142.
9. Online Mendelian Inheritance in Man, OMIM®. #156530 Metatropic dysplasia; MTD. Baltimore (MD): Johns Hopkins University. Available from: https://www.omim.org/entry/156530
10. Velilla J, Marchetti MM, Toth-Petroczy A, Grosgogeat C, Bennett AH, Carmichael N, et al. Homozygous TRPV4 mutation causes congenital distal spinal muscular atrophy and arthrogryposis. Neurol Genet. 2019;5(2):e312. doi:10.1212/NXG.0000000000000312. PMID: 31041394.
11. Orphanet. Metatropic dysplasia (ORPHA:2635). Paris: INSERM; 2026. Available from: https://www.orpha.net/en/disease/detail/2635
12. Online Mendelian Inheritance in Man, OMIM®. #184095 Spondyloepiphyseal dysplasia, Maroteaux type; SEDM. Baltimore (MD): Johns Hopkins University. Available from: https://www.omim.org/entry/184095
13. Online Mendelian Inheritance in Man, OMIM®. #184252 Spondylometaphyseal dysplasia, Kozlowski type; SMDK. Baltimore (MD): Johns Hopkins University. Available from: https://www.omim.org/entry/184252
14. Online Mendelian Inheritance in Man, OMIM®. #113500 Brachyolmia type 3; BCYM3. Baltimore (MD): Johns Hopkins University. Available from: https://www.omim.org/entry/113500
15. Online Mendelian Inheritance in Man, OMIM®. #606835 Digital arthropathy-brachydactyly, familial; FDAB. Baltimore (MD): Johns Hopkins University. Available from: https://www.omim.org/entry/606835
16. Online Mendelian Inheritance in Man, OMIM®. #606071 Hereditary motor and sensory neuropathy, type IIC; HMSN2C. Baltimore (MD): Johns Hopkins University. Available from: https://www.omim.org/entry/606071
17. Orphanet. Autosomal dominant Charcot-Marie-Tooth disease type 2C (ORPHA:99937). Paris: INSERM; 2026. Available from: https://www.orpha.net/en/disease/detail/99937
18. Online Mendelian Inheritance in Man, OMIM®. #181405 Scapuloperoneal spinal muscular atrophy; SPSMA. Baltimore (MD): Johns Hopkins University. Available from: https://www.omim.org/entry/181405
19. Online Mendelian Inheritance in Man, OMIM®. #600175 Neuronopathy, distal hereditary motor, autosomal dominant 8; HMND8. Baltimore (MD): Johns Hopkins University. Available from: https://www.omim.org/entry/600175
20. Orphanet. Orphadata: Epidemiological data — prevalence and natural history of rare diseases (en_product9_prev.xml; en_product9_ages.xml). Paris: INSERM; 2026. Available from: https://www.orphadata.com/epidemiology/
21. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. Chapter 6.3, Spondylometaphyseal dysplasia, Kozlowski type. p. 146–150.
22. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. Chapter 6.5, Familial digital arthropathy with brachydactyly. p. 154–156.
23. Kosmanopoulos GP, Donohue JK, Hoke M, Thomas S, Peyton MA, Vo L, et al. TRPV4 neuromuscular disease registry highlights bulbar, skeletal and proximal limb manifestations. Brain. 2025;148(1):238-251. doi:10.1093/brain/awae201. PMID: 38917025.
24. Sullivan JM, Bagnell AM, Alevy J, Avila EM, Mihaljević L, Saavedra-Rivera PC, et al. Gain-of-function mutations of TRPV4 acting in endothelial cells drive blood-CNS barrier breakdown and motor neuron degeneration in mice. Sci Transl Med. 2024;16(748):eadk1358. doi:10.1126/scitranslmed.adk1358. PMID: 38776392.
25. Nevarez L, Ismaili TK, Zieba J, Martin J, Wachtell D, Diaz D, et al. Small molecule inhibition rescues the skeletal dysplasia phenotype of Trpv4 mutant mice. JCI Insight. 2026;11(2). doi:10.1172/jci.insight.182439. PMID: 41574606.
26. Actio Biosciences. Actio Biosciences secures $66 million Series B financing to advance genetics-driven pipeline of small molecule therapeutics for rare and common diseases [press release]. San Diego (CA): Actio Biosciences; 18 Jun 2025. Available from: https://actiobiosciences.com/actio-biosciences-secures-66-million-series-b-financing-to-advance-genetics-driven-pipeline-of-small-molecule-therapeutics-for-rare-and-common-diseases/
27. ERN BOND — European Reference Network on Rare Bone Diseases. Available from: https://ernbond.eu/
28. ERN EURO-NMD — European Reference Network for Rare Neuromuscular Diseases. Available from: https://ern-euro-nmd.eu/
29. Maroteaux P, Spranger J, Wiedemann HR. [Metatrophic dwarfism]. Arch Kinderheilkd. 1966;173(3):211-26. doi:. PMID: 4963592.
30. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. Metatropic dysplasia. p. 512–515.
31. Boden SD, Kaplan FS, Fallon MD, Ruddy R, Belik J, Anday E, et al. Metatropic dwarfism. Uncoupling of endochondral and perichondral growth. J Bone Joint Surg Am. 1987;69(2):174-84. doi:. PMID: 3805078.
32. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. Spondylometaphyseal dysplasia, Kozlowski type. p. 510–511.
33. Andreucci E, Aftimos S, Alcausin M, Haan E, Hunter W, Kannu P, et al. TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted byclinical, radiographic, and molecular studies in 21 new families. Orphanet J Rare Dis. 2011;6:37. doi:10.1186/1750-1172-6-37. PMID: 21658220.
34. Amor DJ, Tudball C, Gardner RJ, Lamandé SR, Bateman JF, Savarirayan R. Familial digital arthropathy-brachydactyly. Am J Med Genet. 2002;108(3):235-40. doi:10.1002/ajmg.10269. PMID: 11891693.
35. Fleury P, Hageman G. A dominantly inherited lower motor neuron disorder presenting at birth with associated arthrogryposis. J Neurol Neurosurg Psychiatry. 1985;48(10):1037-48. doi:10.1136/jnnp.48.10.1037. PMID: 4056805.
36. DeLong R, Siddique T. A large New England kindred with autosomal dominant neurogenic scapuloperoneal amyotrophy with unique features. Arch Neurol. 1992;49(9):905-8. doi:10.1001/archneur.1992.00530330027010. PMID: 1520078.
37. Dyck PJ, Litchy WJ, Minnerath S, Bird TD, Chance PF, Schaid DJ, et al. Hereditary motor and sensory neuropathy with diaphragm and vocal cord paresis. Ann Neurol. 1994;35(5):608-15. doi:10.1002/ana.410350515. PMID: 8179305.
38. Rock MJ, Prenen J, Funari VA, Funari TL, Merriman B, Nelson SF, et al. Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia. Nat Genet. 2008;40(8):999-1003. doi:10.1038/ng.166. PMID: 18587396.
39. Krakow D, Vriens J, Camacho N, Luong P, Deixler H, Funari TL, 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. 2009;84(3):307-15. doi:10.1016/j.ajhg.2009.01.021. PMID: 19232556.
40. Nishimura G, Dai J, Lausch E, Unger S, Megarbané A, Kitoh H, et al. Spondylo-epiphyseal dysplasia, Maroteaux type (pseudo-Morquio syndrome type 2), and parastremmatic dysplasia are caused by TRPV4 mutations. Am J Med Genet A. 2010;152A(6):1443-9. doi:10.1002/ajmg.a.33414. PMID: 20503319.
41. Dai J, Kim OH, Cho TJ, Schmidt-Rimpler M, Tonoki H, Takikawa K, et al. Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family. J Med Genet. 2010;47(10):704-9. doi:10.1136/jmg.2009.075358. PMID: 20577006.
42. Auer-Grumbach M, Olschewski A, Papić L, Kremer H, McEntagart ME, Uhrig S, et al. Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C. Nat Genet. 2010;42(2):160-4. doi:10.1038/ng.508. PMID: 20037588.
43. Deng HX, Klein CJ, Yan J, Shi Y, Wu Y, Fecto F, et al. Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4. Nat Genet. 2010;42(2):165-9. doi:10.1038/ng.509. PMID: 20037587.
44. Landouré G, Zdebik AA, Martinez TL, Burnett BG, Stanescu HC, Inada H, et al. Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. Nat Genet. 2010;42(2):170-4. doi:10.1038/ng.512. PMID: 20037586.
45. Lamandé SR, Yuan Y, Gresshoff IL, Rowley L, Belluoccio D, Kaluarachchi K, et al. Mutations in TRPV4 cause an inherited arthropathy of hands and feet. Nat Genet. 2011;43(11):1142-6. doi:10.1038/ng.945. PMID: 21964574.
46. Unger S, Lausch E, Stanzial F, Gillessen-Kaesbach G, Stefanova I, Di Stefano CM, et al. Fetal akinesia in metatropic dysplasia: The combined phenotype of chondrodysplasia and neuropathy?. Am J Med Genet A. 2011;155A(11):2860-4. doi:10.1002/ajmg.a.34268. PMID: 21964829.
47. Kannu P, Aftimos S, Mayne V, Donnan L, Savarirayan R. Metatropic dysplasia: clinical and radiographic findings in 11 patients demonstrating long-term natural history. Am J Med Genet A. 2007;143A(21):2512-22. doi:10.1002/ajmg.a.31941. PMID: 17879966.
48. Klein CJ, Shi Y, Fecto F, Donaghy M, Nicholson G, McEntagart ME, et al. TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies. Neurology. 2011;76(10):887-94. doi:10.1212/WNL.0b013e31820f2de3. PMID: 21288981.
49. Robles-Espinoza K, Esparza-García E, González García JR, Magaña-Torres MT. The Broad Clinical Spectrum of Metatropic Dysplasia: A Case Series and Literature Review. Int J Mol Sci. 2025;26(19). doi:10.3390/ijms26199783. PMID: 41097048.
50. Loder AK, Kosmanopoulos GP, Aisenberg WH, Cox E, Meeker AR, Blackshaw S, et al. Profiling the TRPV4 ankyrin repeat domain interactome and its disruption by neuromuscular disease-causing mutations. J Biol Chem. 2026;302(1):110991. doi:10.1016/j.jbc.2025.110991. PMID: 41338459.
51. Camacho N, Krakow D, Johnykutty S, Katzman PJ, Pepkowitz S, Vriens J, et al. Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia. Am J Med Genet A. 2010;152A(5):1169-77. doi:10.1002/ajmg.a.33392. PMID: 20425821.
52. Nishimura G, Lausch E, Savarirayan R, Shiba M, Spranger J, Zabel B, et al. TRPV4-associated skeletal dysplasias. Am J Med Genet C Semin Med Genet. 2012;160C(3):190-204. doi:10.1002/ajmg.c.31335. PMID: 22791502.
53. Berth SH, Vo L, Kwon DH, Grider T, Damayanti YS, Kosmanopoulos G, et al. Combined clinical, structural and cellular studies discriminate pathogenic and benign TRPV4 variants. Brain. 2025;148(2):564-579. doi:10.1093/brain/awae243. PMID: 39021275.
54. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. Chapter 6.2, Spondyloepiphyseal dysplasia, Maroteaux type. p. 143–145.
55. National Center for Biotechnology Information. ClinVar [database]. Bethesda (MD): NCBI; accessed 1 Nov 2026. Records VCV000004994, VCV000004998, VCV000004992, VCV000005000, VCV000005002, VCV000004999, VCV000005001, VCV000030472, VCV000126483, VCV000030469, VCV000216734, VCV000126473, VCV000039419 (TRPV4). Available from: https://www.ncbi.nlm.nih.gov/clinvar/?term=TRPV4%5Bgene%5D
56. Grigelioniene G, Geiberger S, Horemuzova E, Moström E, Jäntti N, Neumeyer L, et al. Autosomal dominant brachyolmia in a large Swedish family: phenotypic spectrum and natural course. Am J Med Genet A. 2014;164A(7):1635-41. doi:10.1002/ajmg.a.36502. PMID: 24677493.
57. Weinstein MM, Kang T, Lachman RS, Bamshad M, Nickerson DA, Krakow D, et al. Somatic mosaicism for a lethal TRPV4 mutation results in non-lethal metatropic dysplasia. Am J Med Genet A. 2016;170(12):3298-3302. doi:10.1002/ajmg.a.37942. PMID: 27530454.
58. Berciano J, Baets J, Gallardo E, Zimoń M, García A, López-Laso E, et al. Reduced penetrance in hereditary motor neuropathy caused by TRPV4 Arg269Cys mutation. J Neurol. 2011;258(8):1413-21. doi:10.1007/s00415-011-5947-7. PMID: 21336783.
59. Aharoni S, Harlalka G, Offiah A, Shuper A, Crosby AH, McEntagart M. Striking phenotypic variability in familial TRPV4-axonal neuropathy spectrum disorder. Am J Med Genet A. 2011;155A(12):3153-6. doi:10.1002/ajmg.a.34327. PMID: 22065612.
60. Landouré G, Sullivan JM, Johnson JO, Munns CH, Shi Y, Diallo O, et al. Exome sequencing identifies a novel TRPV4 mutation in a CMT2C family. Neurology. 2012;79(2):192-4. doi:10.1212/WNL.0b013e31825f04b2. PMID: 22675077.
61. Chen DH, Sul Y, Weiss M, Hillel A, Lipe H, Wolff J, et al. CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene. Neurology. 2010;75(22):1968-75. doi:10.1212/WNL.0b013e3181ffe4bb. PMID: 21115951.
62. Wang H, Li S, Xu Y, Feng B, Zhao X, Weng X. A novel TRPV4 variant in spondylometaphyseal dysplasia, kozlowski type reveals a previously unreported loss-of-function mechanism. Orphanet J Rare Dis. 2025;20(1):575. doi:10.1186/s13023-025-04070-y. PMID: 41225599.
63. Teng C, He M, Zhang C, Yang J, Jiang T, Yang Y, et al. A de novo TRPV4 variant c.2479C>G (p.Pro827Ala) in Spondylometaphyseal dysplasia Kozlowski type: identification and functional analysis. Hum Mol Genet. 2026;35(15). doi:10.1093/hmg/ddag064. PMID: 42456048.
64. Taga A, Peyton MA, Goretzki B, Gallagher TQ, Ritter A, Harper A, et al. TRPV4 mutations causing mixed neuropathy and skeletal phenotypes result in severe gain of function. Ann Clin Transl Neurol. 2022;9(3):375-391. doi:10.1002/acn3.51523. PMID: 35170874.
65. Mishra S, Dubey NK, Das NK, Das B, Rajalaxmi S, Kumar S, et al. From loss of Ca(2+)-influx to altered organelle temperature and energy failure: A neonatal-lethal TRPV4 mutant (L618P). Life Sci. 2025;383:124039. doi:10.1016/j.lfs.2025.124039. PMID: 41125143.
66. Echaniz-Laguna A, Dubourg O, Carlier P, Carlier RY, Sabouraud P, Péréon Y, et al. Phenotypic spectrum and incidence of TRPV4 mutations in patients with inherited axonal neuropathy. Neurology. 2014;82(21):1919-26. doi:10.1212/WNL.0000000000000450. PMID: 24789864.
67. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. Chapter 6.4, Brachyolmia, autosomal dominant. p. 151–153.
68. White KK, Bober MB, Cho TJ, Goldberg MJ, Hoover-Fong J, Irving M, et al. Best practice guidelines for management of spinal disorders in skeletal dysplasia. Orphanet J Rare Dis. 2020;15(1):161. doi:10.1186/s13023-020-01415-7. PMID: 32580780.
69. Güneş N, Alkaya DU, Kurugoğlu S, Özyalvaç N, Bursalı A, Elçioğlu NH, et al. Comparison of the natural course of clinical and radiologic features in 13 patients with TRPV4-related skeletal dysplasias. Pediatr Radiol. 2025;55(3):505-519. doi:10.1007/s00247-024-06145-7. PMID: 39825918.
70. Dong L, Ho KC, Tan Z, He Y, Zhou Y, Yin S, et al. Expanding the Genotype and Phenotype Diversity in a Chinese Cohort With TRPV4-Related Dysplasia. Clin Genet. 2026;109(4):796-802. doi:10.1111/cge.70103. PMID: 41263626.
71. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Spinal muscular atrophy (SMA). p. 526–529.
72. Deng S, Feely SME, Shi Y, Zhai H, Zhan L, Siddique T, et al. Incidence and Clinical Features of TRPV4-Linked Axonal Neuropathies in a USA Cohort of Charcot-Marie-Tooth Disease Type 2. Neuromolecular Med. 2020;22(1):68-72. doi:10.1007/s12017-019-08564-4. PMID: 31468327.
73. Berling E, Reyngoudt H, Le Guillou A, Noury JB, Cintas P, Cadot B, et al. Whole-Body Muscle MRI in Non-5q Spinal Muscular Atrophy: Patterns, Genotype Prediction, and Diagnostic Implications. Neurol Genet. 2026;12(5):e200433. doi:10.1212/NXG.0000000000200433. PMID: 42662709.
74. Astrea G, Brisca G, Fiorillo C, Valle M, Tosetti M, Bruno C, et al. Muscle MRI in TRPV4-related congenital distal SMA. Neurology. 2012;78(5):364-5. doi:10.1212/WNL.0b013e318245295a. PMID: 22291064.
75. Record CJ, Pipis M, Skorupinska M, Blake J, Poh R, Polke JM, et al. Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease. Brain. 2024;147(9):3144-3156. doi:10.1093/brain/awae064. PMID: 38481354.
76. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Skeletal dysplasia charts. p. 853–855.
77. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. Chapter 7.7, Spondyloepimetaphyseal dysplasia, PAPSS2 type, and brachyolmia, autosomal recessive type. p. 175–177.
78. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. Chapter 7.13, Spondyloepiphyseal dysplasia tarda, X-linked. p. 205–208.
79. White KK, Bompadre V, Goldberg MJ, Bober MB, Cho TJ, Hoover-Fong JE, et al. Best practices in peri-operative management of patients with skeletal dysplasias. Am J Med Genet A. 2017;173(10):2584-2595. doi:10.1002/ajmg.a.38357. PMID: 28763154.
80. Savarirayan R, Rossiter JP, Hoover-Fong JE, Irving M, Bompadre V, Goldberg MJ, et al. Best practice guidelines regarding prenatal evaluation and delivery of patients with skeletal dysplasia. Am J Obstet Gynecol. 2018;219(6):545-562. doi:10.1016/j.ajog.2018.07.017. PMID: 30048634.
81. Elhaddad M, Stibelman J, Carrillo-Kashani A, Pfeffer G. Severe Multifocal Noninfectious Wound Dehiscence After Cavovarus Reconstruction in TRPV4-Associated Charcot-Marie-Tooth Disease Type 2C: A Case Report. Foot Ankle Spec. 2026:19386400261465090. doi:10.1177/19386400261465090. PMID: 42446062.
82. Theroux MC, Lopez M, Olszewsky PJ, DiCindio S, Arai L, Ditro C, et al. Metatropic dysplasia-a skeletal dysplasia with challenging airway and other anesthetic concerns. Paediatr Anaesth. 2017;27(6):596-603. doi:10.1111/pan.13101. PMID: 28321993.
83. Charcot-Marie-Tooth Association (CMTA). Available from: https://www.cmtausa.org/
84. ClinicalTrials.gov. Trials of the TRPV4 antagonist GSK2798745 (GlaxoSmithKline): NCT02119260, NCT02497937, NCT03372603, NCT03511105, NCT02135861. Bethesda (MD): National Library of Medicine. Available from: https://clinicaltrials.gov/search?term=GSK2798745
85. Johns Hopkins University. The Natural History of TRPV4 Neuropathy. ClinicalTrials.gov identifier: NCT05600764. Bethesda (MD): National Library of Medicine; updated 4 Nov 2025. Available from: https://clinicaltrials.gov/study/NCT05600764
86. Fawcett KA, Murphy SM, Polke JM, Wray S, Burchell VS, Manji H, et al. Comprehensive analysis of the TRPV4 gene in a large series of inherited neuropathies and controls. J Neurol Neurosurg Psychiatry. 2012;83(12):1204-9. doi:10.1136/jnnp-2012-303055. PMID: 22851605.
87. Biasini F, Portaro S, Mazzeo A, Vita G, Fabrizi GM, Taioli F, et al. TRPV4 related scapuloperoneal spinal muscular atrophy: Report of an Italian family and review of the literature. Neuromuscul Disord. 2016;26(4-5):312-5. doi:10.1016/j.nmd.2016.02.010. PMID: 26948711.
88. ANDO Portugal — Associação Nacional de Displasias Ósseas. Available from: https://www.andoportugal.org/
89. Hereditary Neuropathy Foundation / CureCMT. Available from: https://www.hnf-cure.org/