Top

Published in:

Open Access 01-12-2016 | Research article

Lethal multiple pterygium syndrome, the extreme end of the RYR1 spectrum

Authors: Ariana Kariminejad, Siavash Ghaderi-Sohi, Hamid Hossein-Nejad Nedai, Vahid Varasteh, Ali-Reza Moslemi, Homa Tajsharghi

Published in: BMC Musculoskeletal Disorders | Issue 1/2016

Abstract

Background

Lethal multiple pterygium syndrome (LMPS, OMIM 253290), is a fatal disorder associated with anomalies of the skin, muscles and skeleton. It is characterised by prenatal growth failure with pterygium present in multiple areas and akinesia, leading to muscle weakness and severe arthrogryposis. Foetal hydrops with cystic hygroma develops in affected foetuses with LMPS. This study aimed to uncover the aetiology of LMPS in a family with two affected foetuses.

Methods and results

Whole exome sequencing studies have identified novel compound heterozygous mutations in RYR1 in two affected foetuses with pterygium, severe arthrogryposis and foetal hydrops with cystic hygroma, characteristic features compatible with LMPS. The result was confirmed by Sanger sequencing and restriction fragment length polymorphism analysis.

Conclusions

RYR1 encodes the skeletal muscle isoform ryanodine receptor 1, an intracellular calcium channel with a central role in muscle contraction. Mutations in RYR1 have been associated with congenital myopathies, which form a continuous spectrum of pathological features including a severe variant with onset in utero with fetal akinesia and arthrogryposis. Here, the results indicate that LMPS can be considered as the extreme end of the RYR1-related neonatal myopathy spectrum. This further supports the concept that LMPS is a severe disorder associated with defects in the process known as excitation-contraction coupling.

Hall JG. The lethal multiple pterygium syndromes. Am J Med Genet. 1984;17(4):803–7.CrossRefPubMed

Chen H, Immken L, Lachman R, Yang S, Rimoin DL, Rightmire D, Eteson D, Stewart F, Beemer FA, Opitz JM et al. Syndrome of multiple pterygia, camptodactyly, facial anomalies, hypoplastic lungs and heart, cystic hygroma, and skeletal anomalies: delineation of a new entity and review of lethal forms of multiple pterygium syndrome. Am J Med Genet. 1984;17(4):809–26.

Vogt J, Harrison BJ, Spearman H, Cossins J, Vermeer S, ten Cate LN, Morgan NV, Beeson D, Maher ER. Mutation analysis of CHRNA1, CHRNB1, CHRND, and RAPSN genes in multiple pterygium syndrome/fetal akinesia patients. Am J Hum Genet. 2008;82(1):222–7.

Froster UG, Stallmach T, Wisser J, Hebisch G, Robbiani MB, Huch R, Huch A. Lethal multiple pterygium syndrome: suggestion for a consistent pathological workup and review of reported cases. Am J Med Genet. 1997;68(1):82–5.

Moessinger AC. Fetal akinesia deformation sequence: an animal model. Pediatrics. 1983;72(6):857–63.PubMed

Ravenscroft G, Sollis E, Charles AK, North KN, Baynam G, Laing NG. Fetal akinesia: review of the genetics of the neuromuscular causes. J Med Genet. 2011;48(12):793–801.CrossRefPubMed

Michalk A, Stricker S, Becker J, Rupps R, Pantzar T, Miertus J, Botta G, Naretto VG, Janetzki C, Yaqoob N et al. Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. Am J Hum Genet. 2008;82(2):464–76.

Morgan NV, Brueton LA, Cox P, Greally MT, Tolmie J, Pasha S, Aligianis IA, van Bokhoven H, Marton T, Al-Gazali L et al. Mutations in the embryonal subunit of the acetylcholine receptor (CHRNG) cause lethal and Escobar variants of multiple pterygium syndrome. Am J Hum Genet. 2006;79(2):390–5.

Vogt J, Morgan NV, Marton T, Maxwell S, Harrison BJ, Beeson D, Maher ER. Germline mutation in DOK7 associated with fetal akinesia deformation sequence. J Med Genet. 2009;46(5):338–40.

10.

Wilbe M, Ekvall S, Eurenius K, Ericson K, Casar-Borota O, Klar J, Dahl N, Ameur A, Anneren G, Bondeson ML. MuSK: a new target for lethal fetal akinesia deformation sequence (FADS). J Med Genet. 2015;52(3):195–202.

11.

Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25(14):1754–60.CrossRefPubMedPubMedCentral

12.

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R. The sequence alignment/Map format and SAMtools. Bioinformatics. 2009;25(16):2078–9.

13.

McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M et al. The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20(9):1297–303.

14.

Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38(16):e164.CrossRefPubMedPubMedCentral

15.

Fredfeldt KE, Holm HH, Pedersen JF. Three-dimensional ultrasonic scanning. Acta Radiol Diagn (Stockh). 1984;25(3):237–41.

16.

McKie AB, Al-Saedi A, Vogt J, Stuurman KE, Weiss MM, Shakeel H, Tee L, Morgan NV, Nikkels PG, van Haaften G et al. Germline mutations in RYR1 are associated with foetal akinesia deformation sequence/lethal multiple pterygium syndrome. Acta Neuropathol Commun. 2014;2(1):148.

17.

Ellard S, Kivuva E, Turnpenny P, Stals K, Johnson M, Xie W, Caswell R, Lango Allen H. An exome sequencing strategy to diagnose lethal autosomal recessive disorders. Eur J Hum Genet. 2015;23(3):401–4.

18.

Monnier N, Romero NB, Lerale J, Nivoche Y, Qi D, MacLennan DH, Fardeau M, Lunardi J. An autosomal dominant congenital myopathy with cores and rods is associated with a neomutation in the RYR1 gene encoding the skeletal muscle ryanodine receptor. Hum Mol Genet. 2000;9(18):2599–608.

19.

Fujii J, Otsu K, Zorzato F, de Leon S, Khanna VK, Weiler JE, O'Brien PJ, MacLennan DH. Identification of a mutation in porcine ryanodine receptor associated with malignant hyperthermia. Science. 1991;253(5018):448–51.

20.

Romero NB, Monnier N, Viollet L, Cortey A, Chevallay M, Leroy JP, Lunardi J, Fardeau M. Dominant and recessive central core disease associated with RYR1 mutations and fetal akinesia. Brain. 2003;126(Pt 11):2341–9.

21.

Robinson LK, O’Brien NC, Puckett MC, Cox MA. Multiple pterygium syndrome: a case complicated by malignant hyperthermia. Clin Genet. 1987;32(1):5–9.CrossRefPubMed

Title: Lethal multiple pterygium syndrome, the extreme end of the RYR1 spectrum
Authors: Ariana Kariminejad
Siavash Ghaderi-Sohi
Hamid Hossein-Nejad Nedai
Vahid Varasteh
Ali-Reza Moslemi
Homa Tajsharghi
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: BMC Musculoskeletal Disorders / Issue 1/2016
Electronic ISSN: 1471-2474
DOI: https://doi.org/10.1186/s12891-016-0947-5

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Lethal multiple pterygium syndrome, the extreme end of the RYR1 spectrum

Abstract

Background

Methods and results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods and results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2016

Accuracy of magnetic resonance imaging in detecting lumbo-sacral nerve root compromise: a systematic literature review

Hypersensitivity reactions to metal implants: laboratory options

The effect of clinical features and glucocorticoids on biopsy findings in giant cell arteritis

The fusion rate of demineralized bone matrix compared with autogenous iliac bone graft for long multi-segment posterolateral spinal fusion

Association of a rare NOTCH4 coding variant with systemic sclerosis: a family-based whole exome sequencing study

Illness perceptions of gout patients and the use of allopurinol in primary care: baseline findings from a prospective cohort study