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Familial tumoral calcinosis and hyperostosis–hyperphosphataemia syndrome are different manifestations of the same disease: novel missense mutations in GALNT3

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Abstract

Objective

To report on the biochemistry and clinical and genetic findings of two siblings, the younger sister presenting with recurrent bone pain of the radius and ulna, and medullary sclerosis, and the older brother with soft tissue calcific deposits (tumoral calcinosis) but who later developed bone pain. Both were found to be hyperphosphaturic.

Materials and methods

The index family comprised four individuals (father, mother, brother, sister). The affected siblings were the offspring of a non-consanguineous Indian family of Tamil origin. Bidirectional sequencing was performed on the DNA from the index family and on 160 alleles from a population of 80 unrelated unaffected control individuals of Tamil extraction and 72 alleles from individuals of non-Tamil origin.

Results

Two symptomatic siblings were found to harbour previously unreported compound heterozygous missense UDP-N-acetyl-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc-transferase; GALNT3) mutations in exon 4 c.842A>G and exon 5 c.1097T>G. This sequence variation was not detected in the control DNA. This is the first report of siblings exhibiting stigmata of familial tumoral calcinosis and hyperostosis–hyperphosphataemia syndrome with documented evidence of autosomal recessive missense GALNT3 mutations.

Conclusion

The findings from this family add further evidence to the literature that familial tumoral calcinosis and hyperostosis–hyperphosphataemia syndrome are manifestations of the same disease and highlight the importance of appropriate metabolic and genetic investigations.

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Acknowledgements

We are grateful to the families for participating in this research and to all those in Dr Joseph’s Ortho clinic who were involved in caring for these patients. The research was generously funded by Skeletal Cancer Action Trust (SCAT), UK. The work was also supported by the University College London Hospital/University College London (UCLH/UCL) Comprehensive Biomedical Research Centre. B.D.I. was funded by the Royal National Orthopaedic Hospital (RNOH) National Health Service (NHS) Trust. UCL is a partner of the EuroBoNeT consortium, a European Commission granted Network of Excellence for studying the pathology and genetics of bone tumours.

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, Vinodhagan Memorial Hospital and Dr. Joseph’s Ortho Clinic, Thanjavur, India

    Leo Joseph & Selvanayagam Joseph

  2. Department of Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, UK

    Sandra N. Hing, Bernadine D. Idowu, Adrienne Margaret Flanagan & David Delaney

  3. Department of Radiology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, UK

    Paul O’Donnell

  4. Cancer Institute, University College London (UCL), London, UK

    Nadege Presneau & Adrienne Margaret Flanagan

  5. Department of Histopathology, University College London Hospital (UCLH) NHS Trust, Rockefeller Building, London, UK

    Tim Diss & Adrienne Margaret Flanagan

  6. Institute of Orthopaedics and Musculoskeletal Science, University College London (UCL), Stanmore, UK

    Paul O’Donnell & Adrienne Margaret Flanagan

  7. Institute of Orthopaedics and Musculoskeletal Science, Stanmore, Middlesex, HA7 4LP, UK

    Adrienne Margaret Flanagan

  8. The Institute of Orthopaedics and Musculoskeletal Science, University College London (UCL), London, UK

    Paul O’Donnell

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  1. Leo Joseph
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  2. Sandra N. Hing
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  3. Nadege Presneau
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  4. Paul O’Donnell
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  5. Tim Diss
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  6. Bernadine D. Idowu
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  7. Selvanayagam Joseph
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  8. Adrienne Margaret Flanagan
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  9. David Delaney
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Corresponding author

Correspondence to Adrienne Margaret Flanagan.

Additional information

Leo Joseph and Sandra N. Hing contributed equally to this paper

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Joseph, L., Hing, S.N., Presneau, N. et al. Familial tumoral calcinosis and hyperostosis–hyperphosphataemia syndrome are different manifestations of the same disease: novel missense mutations in GALNT3 . Skeletal Radiol 39, 63–68 (2010). https://doi.org/10.1007/s00256-009-0808-5

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  • DOI: https://doi.org/10.1007/s00256-009-0808-5

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