Table 1.
Summary of TRPV4 phenotypes and disease
| TRPV4 phenotypes | Skeletal | Neuro | Muscular | Respiratory | Onset | Progression | Other | Ref |
|---|---|---|---|---|---|---|---|---|
| Avascular necrosis of femoral head, primary, 2 |
Pelvis: degenerative arthritis in hip joints Limbs: AVN of femoral head bilateral, patchy sclerosis, and cystic changes in femoral head, collapse of femoral head |
3rd‐4th decade | Based on 1 family | 1 | ||||
| Brachyolmia, type 3 |
Height: normal birth length, short stature, short trunk in childhood Spine: Gibbus, kyphosis, scoliosis, platyspondyly, short neck, barrel chest Pelvis: short femoral neck Hands: clinodactyly |
Spinal cord compression | Eyes: hyperopia | 2 | ||||
| Digital arthropathy‐brachydactyly, familial | Hands/feet: progressive brachydactyly of middle/distal phalanges, progressive arthropathy of interphalangeal and metatarsophalangeal/metacarpophalangeal joints, radially deviated phalanges | 1st decade | Hands with more severity than feet | 3 | ||||
| Hereditary motor and sensory neuropathy, type IIC |
Short stature Spine: scoliosis Feet: hammertoes, pes cavus |
Peripheral neuropathy, upper and lower limbs, abducens nerve and oculomotor nerve palsy, sensory impairment, areflexia | Shoulder girdle muscle atrophy, distal limb muscle weakness/atrophy, wasting hand muscles, intercostal muscle involvement | Vocal cord paresis, respiratory failure (muscle and diaphragm), obstructive sleep apnea, stridor | Variable | Increased hand weakness with cold, earlier onset correlates with increased severity | 4 | |
| Metatropic dysplasia |
Dwarfism, short limbs Narrow chest, short ribs Spine: short spine, scoliosis, kyphosis, long coccyx, coccygeal tail, anisospondyly, platyspondyly Pelvis: Halberd‐shaped pelvis, hypertrophic trochanters Limbs: flared femurs/humerus, dumbbell‐shaped metaphyses Hands: brachydactyly, joint contractures |
Fetal akinesia, peripheral axonal neuropathy | Respiratory failure, Exuberant cartilage in trachea/bronchi | 5 | ||||
| Parastremmatic dwarfism |
Dwarfism, short neck Spine: kyphosis, scoliosis Limbs: bowing of long bones, legs twisted along the long axis, severe genu valgum Joint contractures |
Dwarfism noted in late infancy | 6 | |||||
| Scapuloperoneal spinal muscular atrophy |
Spine: hyperlordosis, scoliosis, kyphosis Pelvis: hip dysplasia Limbs: asymmetric limb length Hands: small, clinodactyly Feet: clubbed, metatarsus varus |
Delayed motor development, wide‐based gait, peripheral motor neuropathy, areflexia, decreased sensation | Scapular muscle weakness/atrophy with rounded shoulders, scapular winging, weak neck flexion, torticollis, muscle atrophy/weakness | Voice hoarseness (laryngeal palsy), stridor, respiratory insufficiency in infancy | Birth or infancy | Nonprogressive or slowly progressive | 7 | |
| SED, Maroteaux type |
Spondyloepiphyseal dysplasia, platyspondyly Limbs: short/stubby hands and feet, genu valgum Pelvis: champagne‐glass pelvic inlet |
8 | ||||||
| Spinal muscular atrophy, distal, congenital, nonprogressive |
Arthrogryposis Spine: lordosis, scoliosis, kyphosis Pelvis: hip contractures Limbs: elbow/knee contractures Feet: clubbed, pes equinovarus, pes planus |
Areflexia, hyporeflexia | Muscle weakness, distal, lower limbs, muscle atrophy distal, weakness proximal/pelvic girdle, trunk, fatty atrophy, decreased fetal movement | Prenatal or at birth | Nonprogressive | 9 | ||
| Spondylometaphyseal dysplasia, Kozlowski type |
Short‐trunk dwarfism, short neck, delayed skeletal maturation, sphenoid hypoplasia, pectus carinatum Spine: odontoid hypoplasia, platyspondyly, scoliosis, kyphoscoliosis, open staircase vertebral bodies Pelvis: square, short iliac wings, flaring of iliac wings, flat irregular acetabula, coxa vara Limbs: mildly curved, metaphyseal flaring or irregularity, prominent joints Hands: hypoplastic carpal bones Short, stubby hands & feet |
Normal at birth, waddling gait noted at 15–20 months | 10 |
1. AVN, 2: Mah, W., Sonkusare, S. K., Wang, T., Azeddine, B., Pupavac, M., Carrot‐Zhang, J., Hong, K., Majewski, J., Harvey, E. J., Russell, L., Chalk, C., Rosenblatt, D. S., Nelson, M. T., Seguin, C. Gain‐of‐function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head. J. Med. Genet. 53: 705–709, 2016. [PubMed: 27330106].
2. Brachyolima: Rock, M. J., Prenen, J., Funari, V. A., Funari, T. L., Merriman, B., Nelson, S. F., Lachman, R. S., Wilcox, W. R., Reyno, S., Quadrelli, R., Vaglio, A., Owsianik, G., Janssens, A., Voets, T., Ikegawa, S., Nagai, T., Rimoin, D. L., Nilius, B., Cohn, D. H. Gain‐of‐function mutations in TRPV4 cause autosomal dominant brachyolmia. Nature Genet. 40: 999–1003, 2008.
3. Digital arthropathy‐brachydactyly, familial: Amor, D. J., Tudball, C., Gardner, R. J. M., Lamande, S. R., Bateman, J. F., Savarirayan, R. Familial digital arthropathy‐brachydactyly. Am. J. Med. Genet. 108: 235–240, 2002.
4. Hereditary motor and sensory neuropathy, type IIC: Aharoni, S., Harlalka, G., Offiah, A., Shuper, A., Crosby, A. H., McEntagart, M. Striking phenotypic variability in familial TRPV4‐axonal neuropathy spectrum disorder. Am. J. Med. Genet. 155A: 3153–3156, 2011. [PubMed: 22065612, related citations]; Chen, D.‐H., Sul, Y., Weiss, M., Hillel, A., Lipe, H., Wolff, J., Matsushita, M., Raskind, W., Bird, T. CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene. Neurology 75: 1968–1975, 2010. [PubMed: 21115951, images, related citations]; Donaghy, M., Kennett, R. Varying occurrence of vocal cord paralysis in a family with autosomal dominant hereditary motor and sensory neuropathy. J. Neurol. 246: 552–555, 1999. [PubMed: 10463355, related citations]; Dyck, P. J., Litchy, W. J., Minnerath, S., Bird, T. D., Chance, P. F., Schaid, D. J., Aronson, A. E. Hereditary motor and sensory neuropathy with diaphragm and vocal cord paresis. Ann. Neurol. 35: 608–615, 1994. [PubMed: 8179305, related citations]; Klein, C. J., Cunningham, J. M., Atkinson, E. J., Schaid, D. J., Hebbring, S. J., Anderson, S. A., Klein, D. M., Dyck, P. J. B., Litchy, W. J., Thibodeau, S. N., Dyck, P. J. The gene for HMSN2C maps to 12q23‐24: a region of neuromuscular disorders. Neurology 60: 1151–1156, 2003. [PubMed: 12682323, related citations]; Landoure, G., Sullivan, J. M., Johnson, J. O., Munns, C. H., Shi, Y., Diallo, O., Gibbs, J. R., Gaudet, R., Ludlow, C. L., Fischbeck, K. H., Traynor, B. J., Burnett, B. G., Sumner, C. J. Exome sequencing identifies a novel TRPV4 mutation in a CMT2C family. Neurology 79: 192–194, 2012. [PubMed: 22675077, related citations]; Landoure, G., Zdebik, A. A., Martinez, T. L., Burnett, B. G., Stanescu, H. C., Inada, H., Shi, Y., Taye, A. A., Kong, L., Munns, C. H., Choo, S. S., Phelps, C. B., and 8 others. Mutations in TRPV4 cause Charcot‐Marie‐Tooth disease type 2C. Nature Genet. 42: 170–174, 2010. [PubMed: 20037586, images, related citations]; McEntagart, M., Norton, N., Williams, H., Teare, M. D., Dunstan, M., Baker, P., Houlden, H., Reilly, M., Wood, N., Harper, P. S., Futreal, P. A., Williams, N., Rahman, N. Localization of the gene for distal hereditary motor neuronopathy VII (dHMN‐VII) to chromosome 2q14. Am. J. Hum. Genet. 68: 1270–1276, 2001. [PubMed: 11294660, images, related citations]; McEntagart, M. E., Reid, S. L., Irrthum, A., Douglas, J. B., Eyre, K. E. D., Donaghy, M. J., Anderson, N. E., Rahman, N. Confirmation of a hereditary motor and sensory neuropathy IIC locus at chromosome 12q23‐q24. Ann. Neurol. 57: 293–297, 2005. Note: Erratum: Ann. Neurol. 57: 609 only, 2005.
5. Metatropic dysplasia: Boden, S. D., Kaplan, F. S., Fallon, M. D., Ruddy, R., Belik, J., Anday, E., Zackai, E., Ellis, J. Metatropic dwarfism: uncoupling of endochondral and perichondral growth. J. Bone Joint Surg. Am. 69: 174–184, 1987. [PubMed: 3805078,]; Camacho, N., Krakow, D., Johnykutty, S., Katzman, P. J., Pepkowitz, S., Vriens, J., Nilius, B., Boyce, B. F., Cohn, D. H. Dominant TRPV4 mutations in nonlethal and lethal metatropic dysplasia. Am. J. Med. Genet. 152A: 1169–1177, 2010. [PubMed: 20425821]; Dai, J., Kim, O.‐H., Cho, T.‐J., Schmidt‐Rimpler, M., Tonoki, H., Takikawa, K., Haga, N., Miyoshi, K., Kitoh, H., Yoo, W.‐J., Choi, I.‐H., Song, H.‐R., and 23 others. Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family. J. Med. Genet. 47: 704–709, 2010. [PubMed: 20577006,]; Genevieve, D., Le Merrer, M., Feingold, J., Munnich, A., Maroteaux, P., Cormier‐Daire, V. Revisiting metatropic dysplasia: presentation of a series of 19 novel patients and review of the literature. Am. J. Med. Genet. 146A: 992–996, 2008. [PubMed: 18348257,]; Houston, C. S., Awen, C. F., Kent, H. P. Fatal neonatal dwarfism. J. Canad. Assoc. Radiol. 23: 45–61, 1972.; Kannu, P., Aftimos, S., Mayne, V., Donnan, L., Savarirayan, R. Metatropic dysplasia: clinical Genet. 143A: 2512–2522, 2007. [PubMed: 17879966,]; Kaufmann, E. Untersuchungen ueber die sogenannte foetale Rachitis. (Chondrodystrophia foetalis). Berlin: Georg Reimer (pub.) 1892.; Krakow, D., Vriens, J., Camacho, N., Luong, P., Deixler, H., Funari, T. L., Bacino, C. A., Irons, M. B., Holm, I. A., Sadler, L., Okenfuss, E. B., Janssens, A., Voets, T., Rimoin, D. L., Lachman, R. S., Nilius, B., Cohn, D. H. Mutations in the gene encoding the calcium‐permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia. Am. J. Hum. Genet. 84: 307–315, 2009. [PubMed: 19232556]; MacCallum, W. G. Chondrodystrophia foetalis: notes on the pathological changes in four cases. Johns Hopkins Hosp. Bull. 26: 182–185, 1915.; Maroteaux, P., Spranger, J. W., Wiedemann, H.‐R. Der metatropische Zwergwuchs. Arch. Kinderheilk. 173: 211–226, 1966. [PubMed: 4963592,]; Michail, J., Matsoukas, J., Theodorou, S. D., Houliaras, K. Maladie de Morquio (osteochondrodystrophie polyepiphysaire deformante) chez deux freres. Helv. Paediat. Acta 11: 403–413, 1956. [PubMed: 13405333,]; Unger, S., Lausch, E., Stanzial, F., Gillessen‐Kaesbach, G., Stefanova, I., Di Stefano, C. M., Bertini, E., Dionisi‐Vici, C., Nilius, B., Zabel, B., Superti‐Furga, A. Fetal akinesia in metatropic dysplasia: the combined phenotype of chondrodysplasia and neuropathy? Am. J. Med. Genet. 155A: 2860–2864, 2011. [PubMed: 21964829,]
6. Parastremmatic dwarfism: Langer, L. O., Jr., Petersen, D., Spranger, J. W. An unusual bone dysplasia: parastremmatic dwarfism. Am. J. Roentgen. Radium Ther. Nucl. Med. 110: 550–560, 1970. [PubMed: 4992387]; Nishimura, G., Dai, J., Lausch, E., Unger, S., Megarbane, A., Kitoh, H., Kim, O. H., Cho, T.‐J., Bedeschi, F., Benedicenti, F., Mendoza‐Londono, R., Silengo, M., Schmidt‐Rimpler, M., Spranger, J., Zabel, B., Ikegawa, S., Superti‐Furga, A. Spondylo‐epiphyseal dysplasia, Maroteaux type (pseudo‐Morquio syndrome type 2), are parastremmatic dysplasia are caused by TRPV4 mutations. Am. J. Med. Genet. 152A: 1443–1449, 2010. [PubMed: 20503319]; Rask, M. R. Morquio‐Brailsford osteochondrodystrophy and osteogenesis imperfecta: report of a patient with both conditions. J. Bone Joint Surg. Am. 45: 561–570, 1963; Sensenbrenner, J. A., Dorst, J. P., Hungerford, D. S. Parastremmatic dwarfism.In: Bergsma, D. : Skeletal Dysplasias. Amsterdam: Excerpta Medica (pub.) 1974. Pp. 425–429.
7. Scapuloperoneal spinal muscular atrophy: Berciano, J., Baets, J., Gallardo, E., Zimon, M., Garcia, A., Lopez‐Laso, E., Combarros, O., Infante, J., Timmerman, V., Jordanova, A., De Jonghe, P. Reduced penetrance in hereditary motor neuropathy caused by TRPV4 arg269‐to‐cys mutation. J. Neurol. 258: 1413–1421, 2011. [PubMed: 21336783]; DeLong, R., Siddique, T. A large New England kindred with autosomal dominant neurogenic scapuloperoneal amyotrophy with unique features. Arch. Neurol. 49: 905–908, 1992. [PubMed: 1520078,]
8. SED, Maroteaux type: Doman, A. N., Maroteaux, P., Lyne, E. D. Spondyloepiphyseal dysplasia of Maroteaux. J. Bone Joint Surg. Am. 72: 1364–1369, 1990. [PubMed: 2229114]; Megarbane, A., Maroteaux, P., Caillaud, C., Le Merrer, M. Spondyloepimetaphyseal dysplasia of Maroteaux (pseudo‐Morquio type II syndrome): report of a new patient and review of the literature. Am. J. Med. Genet. 125A: 61–66, 2004. [PubMed: 14755468]; Nishimura, G., Kizu, R., Kijima, Y., Sakai, K., Kawaguchi, Y., Kimura, T., Matsushita, I., Shirahama, S., Ikeda, T., Ikegawa, S., Hasegawa, T. Spondyloepiphyseal dysplasia Maroteaux type: report of three patients from two families and exclusion of type II collagen defects. Am. J. Med. Genet. 120A: 498–502, 2003.
9. Spinal muscular atrophy, distal, congenital, nonprogressive: Astrea, G., Brisca, G., Fiorillo, C., Valle, M., Tosetti, M., Bruno, C., Santorelli, F. M., Battini, R. Muscle MRI in TRPV4‐related congenital distal SMA. Neurology 78: 364–365, 2012. [PubMed: 22291064]; Berciano, J., Baets, J., Gallardo, E., Zimon, M., Garcia, A., Lopez‐Laso, E., Combarros, O., Infante, J., Timmerman, V., Jordanova, A., De Jonghe, P. Reduced penetrance in hereditary motor neuropathy caused by TRPV4 arg269‐to‐cys mutation. J. Neurol. 258: 1413–1421, 2011. [PubMed: 21336783]; Echaniz‐Laguna, A., Dubourg, O., Carlier, P., Carlier, R.‐Y., Sabouraud, P., Pereon, Y., Chapon, F., Thauvin‐Robinet, C., Laforet, P., Eymard, B., Latour, P., Stojkovic, T. Phenotypic spectrum and incidence of TRPV4 mutations in patients with inherited axonal neuropathy. Neurology 82: 1919–1926, 2014. [PubMed: 24789864]; Fleury, P., Hageman, G. A dominantly inherited lower motor neuron disorder presenting at birth with associated arthrogryposis. J. Neurol. Neurosurg. Psychiat. 48: 1037–1048, 1985. [PubMed: 4056805]; Reddel, S., Ouvrier, R. A., Nicholson, G., Dierick, I., Irobi, J., Timmerman, V., Ryan, M. M. Autosomal dominant congenital spinal muscular atrophy–a possible developmental deficiency of motor neurones? Neuromusc. Disord. 18: 530–535, 2008. [PubMed: 18579380]; van der Vleuten, A. J. W., van Ravenswaaij‐Arts, C. M. A., Frijns, C. J. M., Smits, A. P. T., Hageman, G., Padberg, G. W., Kremer, H. Localisation of the gene for a dominant congenital spinal muscular atrophy predominantly affecting the lower limbs to chromosome 12q23‐q24. Europ. J. Hum. Genet. 6: 376–382, 1998. [PubMed: 9781046,]
10. Spondylometaphyseal dysplasia, Kozlowski type: Dai, J., Kim, O.‐H., Cho, T.‐J., Schmidt‐Rimpler, M., Tonoki, H., Takikawa, K., Haga, N., Miyoshi, K., Kitoh, H., Yoo, W.‐J., Choi, I.‐H., Song, H.‐R., and 23 others. Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family. J. Med. Genet. 47: 704–709, 2010. [PubMed: 20577006]; Kozlowski, K., Maroteaux, P., Spranger, J. W. La dysostose spondylo‐metaphysaire. Presse Med. 75: 2769–2774, 1967.