Alternative titles; symbols
SNOMEDCT: 22764001; ORPHA: 2635; DO: 0111514;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q24.11 | Metatropic dysplasia | 156530 | Autosomal dominant | 3 | TRPV4 | 605427 |
A number sign (#) is used with this entry because of evidence that metatropic dysplasia (MTD) is caused by heterozygous mutation in the TRPV4 gene (605427) on chromosome 12q24.
Metatropic dysplasia (MTD) is characterized by short limbs with limitation and enlargement of joints and usually severe kyphoscoliosis. Radiologic features include severe platyspondyly, severe metaphyseal enlargement, and shortening of long bones (Genevieve et al., 2008).
Maroteaux et al. (1966) described a chondrodystrophy that at birth is likely to be called achondroplasia ('hyperplastic type') because of the short limbs and later in life Morquio syndrome because of the relatively short spine and severe scoliosis. The designation for the condition was chosen to convey the change or reversal in body proportions. The manifestations are already present at birth, with generalized epimetaphyseal disturbance of ossification. Kyphoscoliosis is progressive and severe. Anisospondyly, halberd-shaped pelvis, and hyperplastic femoral trochanters are features. The coccyx is unusually long, resulting in a tail. The ends of the femurs and humeri are trumpeted. The 2 brothers reported by Michail et al. (1956) probably had this condition.
Houston et al. (1972) suggested that 'hyperchondrogenesis' might be a good designation for this condition inasmuch as the histologic picture is characterized by exuberant cartilage formation in the trachea and bronchi, as well as in the growing ends of the bones. Some of the cases reported by Kaufmann (1892) and by MacCallum (1915) had metatropic dwarfism.
Boden et al. (1987) had an opportunity to study bone from an infant with metatropic dysplasia who died at 7 months of respiratory failure. The major findings were (1) the absence of formation of normal primary spongiosa in the metaphysis; and (2) the presence of a thin seal of bone at the chondroosseous junction, with abnormal metaphyseal vascular invasion and arrest of endochondral ring structures with persistence of circumferential growth. The findings suggested an uncoupling of endochondral and perichondral growth and offered an explanation for the dumbbell-shaped morphologic changes in the metaphysis.
Kannu et al. (2007) characterized the natural history of 11 patients (6 females and 5 males), ranging from 20 weeks' gestation to age 70 years, incorporating data collected over a 37-year period. The study included 1 father/daughter pair and 1 sib pair. The authors noted that complications such as upper respiratory obstruction secondary to laryngotracheal dysfunction need to be carefully monitored in infancy because this is a preventable cause of mortality. The progression of a thoracic kyphoscoliosis in the patients was often relentless and resistant to surgical treatment. Other causes of morbidity included cervical instability, hearing loss, and functional impairments resulting from degenerative joint deformity. Intellectual outcome in all surviving cases had been normal and final adult heights ranged from 107 to 135 cm.
Genevieve et al. (2008) reported the clinical and radiologic features of 19 novel metatropic patients (5 lethal or terminated pregnancies, and 14 living patients) that had been collected over 40 years. They described new radiologic features, including precocious calcification of hyoid and cricoid cartilage, irregular and squared-off calcaneal bones, severe hypoplasia of the anterior portion of the first cervical vertebrae, and erratic areas of microcalcifications in vertebral bodies and epiphyses.
Krakow et al. (2009) described 2 patients with metatropic dysplasia. Both were identified in the newborn period with high forehead and flat nasal bridge. Both had congenital scoliosis, contractures, and prominent joints. One had respiratory compromise. Radiographic findings showed odontoid hypoplasia in 1 patient, clavicular pseudoarthrosis in 1 patient, anterior rib splaying in both, platyspondyly in both, dense wafer vertebrae in both, no evidence of overfaced vertebral pedicles, flared iliac wings in 1, halberd pelvis in 2, irregular proximal femoral growth plate in 1, dumbbell-shaped femora/humeri in both, and phalangeal cone epiphyses in both. Krakow et al. (2009) noted phenotypic overlap with spondylometaphyseal dysplasia, Kozlowski type (SMDK; 184252).
Dai et al. (2010) provided a detailed radiographic review of 20 patients diagnosed with SMDK and 22 patients diagnosed with nonlethal metatropic dysplasia, noting that although some radiologic signs are shared by both disorders, the presence or absence of dumbbell-shaped femora ascertained distinction between MTD and SMDK, respectively. Unexpected findings included the fact that although narrow thorax, prominent joints, and coccygeal tail are considered to be clinical hallmarks of MTD, only prominent joints were consistently found in MTD, and these features were also occasionally found in SMDK. Evolution of body proportion with age, another hallmark of MTD, was not essential; several postpubertal MTD patients showed short limbs, not short trunks. MTD patients after infancy showed overfaced pedicles that were indistinguishable from those in SMDK patients. A small percentage of SMDK patients showed mild brachydactyly or mild epiphyseal dysplasia/premature degenerative joint disease, yet these cases were classified as SMDK based on the overall pattern of skeletal changes. Dai et al. (2010) concluded that accurate delineation of the total phenotypic spectrum in these disorders would require further accumulation of cases with radiographs taken at standard ages.
Camacho et al. (2010) performed histologic studies of bone derived from 2 patients with lethal metatropic dysplasia. There was abnormally thick cartilage with nodular proliferation, short diaphyses, and abnormal bone formation, indicating disrupted endochondral ossification. There was also evidence of abnormal chondrogenesis and abnormal differentiation of mesenchymal progenitors as well as lack of normal columns of chondrocytes. Camacho et al. (2010) suggested that the mechanism of disease may result from increased calcium in chondrocytes.
Unger et al. (2011) reported 4 patients, including a pair of monozygotic twins, with a severe lethal form of metatropic dysplasia associated with fetal akinesia. Three of the 4 were found to have absent movements, severe contractures, and features of metatropic dysplasia on prenatal ultrasound, and the pregnancies were terminated. The fourth patient presented with multiple joint contractures and absent limb movements at birth, consistent with fetal akinesia. Features of severe metatropic dysplasia in these patients included short long bones, cartilaginous joint expansion, narrow thorax, flat vertebral bodies, and sacrococcygeal tail. The fourth patient had a normal neonatal neurologic examination, except for restricted movements, but electromyography at age 3 months showed an absence of voluntary activity in the lower limbs. There was some residual activity in the upper limbs, and there were signs of a chronic axonal denervating process. These results were considered to be indicative of a neuropathic disorder. The baby died of respiratory complications at age 4 months.
Weinstein et al. (2016) identified a 22-month-old child with a diagnosis consistent with nonlethal metatropic dysplasia who had somatic mosaicism for a mutation in the TRPV4 gene. The skeletal dysplasia was noted at birth, and neonatal radiographs showed odontoid hypoplasia, platyspondyly with anterior rounding, shortened long bones with a clubbed appearance, and flattened acetabular roofs. MRI at age 5 months showed pronounced dextroscoliosis and kyphosis of the lumbosacral spine. On physical examination at 22 months of age, the child had midface hypoplasia with frontal bossing and protuberant knees. Spine radiographs showed flat, anteriorly rounded vertebral bodies, and scoliosis. Other radiographic findings included significant metaphyseal widening of the long bones of the upper and lower extremities, halberd-shaped proximal femurs, wide ilia, hypoplastic acetabular roofs, flat and hypoplastic epiphyses, and short and widened phalanges.
From personal observations and a review of the literature, Beck et al. (1983) suggested 3 types of metatropic dysplasia: (1) a nonlethal autosomal recessive form; (2) a nonlethal dominant form; and (3) a lethal form with death before or shortly after birth and with possible autosomal recessive inheritance. They illustrated the cases of brother and sister with type I, father and daughter with type II, and a stillborn fetus presumably with type III. Noteworthy is the father's age (45 years) in the last case.
Genevieve et al. (2005) reported clinical and radiologic findings of one of the sporadic original cases reported by Maroteaux et al. (1966), followed from 15 days to 30 years of age. At birth the radiologic manifestations of dumbbell aspect of long bones, severe platyspondyly, and severe scoliosis were consistent with the nonlethal autosomal recessive form of metatropic dwarfism. However, over time there was striking modification of the skeletal anomalies with amelioration of the size of the long bones and significant improvement of the platyspondyly resulting in almost normal vertebral bodies at 15 years of age, corresponding to a description of the autosomal dominant form of metatropic dwarfism. Genevieve et al. (2005) suggested that a distinction between 3 different types of the disorder, especially in isolated cases, is questionable.
Kannu et al. (2007) suggested that the clinical and radiologic findings show considerable overlap between the so-called mild, classic, and lethal forms of metatropic dysplasia and cannot reliably be separated. Furthermore, the radiologic and clinical findings in father/daughter and brother/sister cases were identical, suggesting a single mode of inheritance. In reported families, the ratio of affected to unaffected (close to 1:20) is not supportive of an autosomal recessive inheritance pattern. They therefore proposed that metatropic dysplasia represents a single gene dominant condition, and that the variable subtypes can be accounted for by variable expression and sib recurrence due to gonadal mosaicism.
Genevieve et al. (2008) supported the hypothesis of gonadal mosaicism by the observation of recurrence in half-sibs from an unrelated Chinese family with 2 different fathers.
In 2 sporadic cases of metatropic dysplasia, Krakow et al. (2009) identified heterozygosity for de novo missense mutations in the TRPV4 gene (605427.0006-605427.0007).
Dai et al. (2010) analyzed the TRPV4 gene in 22 MTD probands and 20 SMDK probands, and identified heterozygous TRPV4 mutations in all, except for 1 MTD proband. In the MTD patients, the recurrent P799L mutation (605427.0007) was found in 9 patients, and 4 more patients had 3 different substitutions at pro799 (605427.0013-605427.0015), which the authors designated a 'hot codon' for metatropic dysplasia. The remaining 8 MTD patients included 7 with novel missense mutations and 1 with a 3-bp deletion of a codon (F471del; 605427.0016), which Dai et al. (2010) stated was the first mutation other than a missense mutation to be reported in the TRPV4 gene.
Camacho et al. (2010) reported 10 patients with varying severity of metatropic dysplasia, all of whom carried a heterozygous mutation in the TRPV4 gene (see, e.g., 605427.0006-605427.0007, 605427.0023-605427.0024). The findings confirmed that metatropic dysplasia is a dominant disorder. Five patients had a lethal form of the disorder with death in the neonatal period or infancy, whereas 5 had a nonlethal disorder classified as mild, moderately severe, or severe. There was no clear relationship between the severity of the disorder and type of mutation or domain affected, but Camacho et al. (2010) suggested that the degree of constitutive activation of the mutant channels likely correlates with disease severity.
In 4 patients with a severe lethal form of metatropic dysplasia associated with fetal akinesia, Unger et al. (2011) identified 3 different heterozygous de novo missense mutations in the TRPV4 gene (605427.0027-605427.0029). Unger et al. (2011) noted that skeletal dysplasias do not generally cause arthrogryposis multiplex, as seen in these patients, and since electrophysiologic studies of 1 indicated a neuropathic process, these TRPV4 mutations may cause a combination of a severe skeletal dysplasia and a neurologic phenotype causing fetal akinesia.
In a cohort of 26 patients diagnosed with various skeletal dysplasias, including 15 with MTD, 9 with SMDK, and 2 with brachyolmia (BCYM3; 113500), Andreucci et al. (2011) sequenced the TRPV4 gene and identified heterozygosity for missense mutations in 14 of the 15 patients with MTD (see, e.g., 605427.0003, 605427.0007, and 605427.0014). Seven of the MTD patients previously were reported by Kannu et al. (2007), including a father/daughter pair (patients 2 and 3), of whom the father had been originally described by Beck et al. (1983). Andreucci et al. (2011) noted that within a family with an affected mother and 2 sons (patients 5, 6, and 7), one of the sons had radiologic features more consistent with MTD, whereas the other showed features more consistent with SMDK, thus illustrating the degree of intrafamilial variability within this spectrum of skeletal dysplasias. The 4 patients in whom no mutation was detected in TRPV4 all exhibited atypical features for their respective clinical diagnoses.
In a patient with nonlethal MTD, Weinstein et al. (2016) detected somatic mosaicism for a leu618-to-pro (L618P; 605427.0035) mutation in TRPV4. Sanger sequencing was negative for mutations in all of the coding exons of TRPV4, as well as of other genes consistent with the phenotype. Subsequent exome sequencing detected a c.1853T-C transition in 16 of 71 reads, consistent with somatic mosaicism. Parental exomes were negative for the mutation. This mutation had previously been detected in heterozygosity by Camacho et al. (2010) in a patient with lethal MTD. Comparing levels of the mutant allele in their patient with those of the patient of Camacho et al. (2010), Weinstein et al. (2016) found that 15% of alleles in blood cells contained the mutation, implying that about 30% of cells in the patient would be expected to be heterozygous for the L618P allele. However, the level of mosaicism in the target tissue (cartilage) could not be assessed directly because a sample was not available. Weinstein et al. (2016) noted that high-throughput sequencing can have higher sensitivity for the detection of mosaicism than Sanger sequence analysis.
Hall and Elcioglu (2004) attempted to classify the radiologic findings in 8 sporadic cases of lethal forms of metatropic dysplasia.
Andreucci, E., Aftimos, S., Alcausin, M., Haan, E., Hunter, W., Kannu, P., Kerr, B., McGillivray, G., McKinlay Gardner, R. J., Patricelli, M. G., Sillence, D., Thompson, E., Zacharin, M., Zankl, A., Lamande, S. R., Savarirayan, R. TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted by clinical, radiographic, and molecular studies in 21 new families. Orphanet J. Rare Dis. 6: 37, 2011. [PubMed: 21658220] [Full Text: https://doi.org/10.1186/1750-1172-6-37]
Beck, M., Roubicek, M., Rogers, J. G., Naumoff, P., Spranger, J. Heterogeneity of metatropic dysplasia. Europ. J. Pediat. 140: 231-237, 1983. [PubMed: 6628444] [Full Text: https://doi.org/10.1007/BF00443368]
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] [Full Text: https://doi.org/10.1002/ajmg.a.33392]
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] [Full Text: https://doi.org/10.1136/jmg.2009.075358]
Fox, R. R., Cray, D. D. Hereditary chondrodystrophy in the rabbit: genetics and pathology of a new mutant, a model for metatropic dwarfism. J. Hered. 66: 271-276, 1975. [PubMed: 1184951] [Full Text: https://doi.org/10.1093/oxfordjournals.jhered.a108628]
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] [Full Text: https://doi.org/10.1002/ajmg.a.32191]
Genevieve, D., Le Merrer, M., Munnich, A., Maroteaux, P., Cormier-Daire, V. Long-term follow-up in a patient with metatropic dysplasia. (Letter) Am. J. Med. Genet. 135A: 342-343, 2005. [PubMed: 15889420] [Full Text: https://doi.org/10.1002/ajmg.a.30710]
Hall, C. M., Elcioglu, N. H. Metatropic dysplasia lethal variants. Pediat. Radiol. 34: 66-74, 2004. [PubMed: 14566438] [Full Text: https://doi.org/10.1007/s00247-003-1063-x]
Houston, C. S., Awen, C. F., Kent, H. P. Fatal neonatal dwarfism. J. Canad. Assoc. Radiol. 23: 45-61, 1972. [PubMed: 5063132]
Jenkins, P., Smith, M. B., McKinnell, J. S. Metatropic dwarfism. Brit. J. Radiol. 43: 561-565, 1970. [PubMed: 5433366] [Full Text: https://doi.org/10.1259/0007-1285-43-512-561]
Kannu, P., Aftimos, S., Mayne, V., Donnan, L., Savarirayan, R. Metatropic dysplasia: clinical and radiologic findings in 11 patients demonstrating long-term natural history. Am. J. Med. Genet. 143A: 2512-2522, 2007. [PubMed: 17879966] [Full Text: https://doi.org/10.1002/ajmg.a.31941]
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] [Full Text: https://doi.org/10.1016/j.ajhg.2009.01.021]
Larose, J. H., Gay, B. B., Jr. Metatropic dwarfism. Am. J. Roentgen. Radium Ther. Nucl. Med. 106: 156-161, 1969. [PubMed: 5769297] [Full Text: https://doi.org/10.2214/ajr.106.1.156]
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] [Full Text: https://doi.org/10.1002/ajmg.a.34268]
Weinstein, M. M., Kang, T., Lachman, R. S., Bamshad, M., Nickerson, D. A., Krakow, D., Cohn, D. H. Somatic mosaicism for a lethal TRPV4 mutation results in non-lethal metatropic dysplasia. Am. J. Med. Genet. 170A: 3298-3302, 2016. [PubMed: 27530454] [Full Text: https://doi.org/10.1002/ajmg.a.37942]