Abstract
Spondylocarpotarsal synostosis syndrome (SCT) is a rare group of skeletal dysplasias, characterized by disproportionate short stature with a short trunk, abnormal segmentation of the spine with vertebral fusion, scoliosis and lordosis, carpal and tarsal synostosis, and mild facial dysmorphisms. While the majority of the cases show autosomal recessive inheritance, only a few cases of vertical transmissions, with MYH3 mutations, have been reported. Here we report a case with typical SCT, carrying a novel heterozygous mutation in MYH3. This observation supports the hypothesis of a pathogenic link between autosomal dominant SCT and heterozygous mutations in MYH3. Of note, our case showed basilar invagination on brain magnetic resonance imaging at the age of 10 years. Basilar invagination could be a rare complication of both autosomal recessive and dominant SCT, indicating that prompt investigation are warranted for SCT patients.
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Krakow D, Robertson SP, King LM, Morgan T, Sebald ET, Bertolotto C, et al. Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Nat Genet. 2004;36:405–10.
Isidor B, Cormier-Daire V, Le Merrer M, Lefrancois T, Hamel A, Le Caignec C, et al. Autosomal dominant spondylocarpotarsal synostosis syndrome: phenotypic homogeneity and genetic heterogeneity. Am J Med Genet A. 2008;146A:1593–1597.
Carapito R, Goldenberg A, Paul N, Pichot A, David A, Hamel A, et al. Protein-altering MYH3 variants are associated with a spectrum of phenotypes extending to spondylocarpotarsal synostosis syndrome. Eur J Hum Genet. 2016;24:1746–51.
Zieba J, Zhang W, Chong JX, Forlenza KN, Martin JH, Heard K, et al. A postnatal role for embryonic myosin revealed by MYH3 mutations that alter TGFβ signaling and cause autosomal dominant spondylocarpotarsal synostosis. Sci Rep. 2017;7:41803.
Takagi M, Dobashi K, Nagahara K, Kato M, Nishimura G, Fukuzawa R, et al. A novel de novo germline mutation Glu40Lys in AKT3 causes megalencephaly with growth hormone deficiency. Am J Med Genet A. 2017;173:1071–6.
Chong JX, Burrage LC, Beck AE, Marvin CT, McMillin MJ, Shively KM, et al. Autosomal-dominant multiple pterygium syndrome is caused by mutations in MYH3. Am J Hum Genet. 2015;96:841–9.
Toydemir RM, Rutherford A, Whitby FG, Jorde LB, Carey JC, Bamshad MJ. Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome. Nat Genet. 2006;38:561–5.
Tajsharghi H, Kimber E, Kroksmark AK, Jerre R, Tulinius M, Oldfors A. Embryonic myosin heavy-chain mutations cause distal arthrogryposis and developmental myosin myopathy that persists postnatally. Arch Neurol. 2008;65:1083–90.
Alvarado DM, Buchan JG, Gurnett CA, Dobbs MB. Exome sequencing identifies an MYH3 mutation in a family with distal arthrogryposis type 1. J Bone Jt Surg Am. 2011;93:1045–50.
Beck AE, McMillin MJ, Gildersleeve HI, Kezele PR, Shively KM, Carey JC, et al. Spectrum of mutations that cause distal arthrogryposis types 1 and 2B. Am J Med Genet A. 2013;161A:550–5.
Beck AE, McMillin MJ, Gildersleeve HI, Shively KM, Tang A, Bamshad MJ. Genotype-phenotype relationships in Freeman-Sheldon syndrome. Am J Med Genet A. 2014;164A:2808–13.
Brunetti-Pierri N, Esposito V, De Brasi D, Mattiacci DM, Krakow D, Lee B, et al. Spondylocarpotarsal synostosis: long-term follow-up of a case due to FLNB mutations. Am J Med Genet A. 2008;146A:1230–3.
Hague J, Delon I, Brugger K, Martin H, Abbs S, Park SM. Molecularly proven mosaicism in phenotypically normal parent of a girl with Freeman-Sheldon Syndrome caused by a pathogenic MYH3 mutation. Am J Med Genet A. 2016;170A:1608–12.
Acknowledgements
We thank the patient and their families for participation in this study. We also thank Yukihiro Hasegawa for fruitful discussion.
Funding
The Japan Society for the Promotion of Science (Number: 16K10007). Grant sponsors: Takeda Science Foundation and Foundation for Growth Science.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Takagi, M., Shimomura, S., Fukuzawa, R. et al. A novel truncating mutation in MYH3 causes spondylocarpotarsal synostosis syndrome with basilar invagination. J Hum Genet 63, 1277–1281 (2018). https://doi.org/10.1038/s10038-018-0513-0
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s10038-018-0513-0
This article is cited by
-
Expanding the mutation and phenotype spectrum of MYH3-associated skeletal disorders
npj Genomic Medicine (2022)
