Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Case Study
  • Published:

Familial isolated primary hyperparathyroidism caused by mutations of the MEN1 gene

Nature Clinical Practice Endocrinology & Metabolism volume 4, pages 53–58 (2008)Cite this article

Abstract

Background Familial isolated primary hyperparathyroidism (FIHP) is an autosomal dominant disorder that can represent an early stage of either the multiple endocrine neoplasia type 1 (MEN1) or hyperparathyroidism-jaw tumor (HPT-JT) syndromes; alternatively, the condition can be caused by an allelic variant of MEN1 or HRPT2 (hyperparathyroidism 2 gene), or caused by a distinct entity involving another locus. We have explored these possibilities in a patient with primary hyperparathyroidism, whose mother had a history of renal calculi and primary hyperparathyroidism.

Investigations Serum biochemistry and radiological investigations for primary hyperparathyroidism, MEN1 and HPT-JT, and genetic testing for MEN1 and HRPT2 mutations were undertaken.

Diagnosis FIHP with primary hyperparathyroidism as the sole endocrinopathy due to a previously unreported heterozygous missense germline MEN1 mutation, Tyr351Asn. In addition, another unreported heterozygous missense germline MEN1 mutation, Trp220Leu, was identified in an unrelated male patient with FIHP, whose mother and sister also had primary hyperparathyroidism. DNA from a parathyroid tumor from the sister revealed a loss of heterozygosity in which the mutant allele was retained. This is consistent with Knudson's 'two-hit' model of hereditary cancer and a tumor suppressor role for MEN1 in FIHP.

Management The patient underwent parathyroidectomy and has remained normocalcemic over a follow-up period of 6 years. The other four patients have remained normocalcemic for a follow-up period of 4–15 years following parathyroidectomy. None has developed abnormalities of the MEN1 syndrome, providing further support that FIHP is a distinct genetic variant of the MEN1 syndrome.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: DNA sequence analysis of MEN1 in two kindreds with FIHP.
Figure 2: Investigations for familial primary hyperparathyroidism.

References

  1. Thakker RV (2006) Multiple Endocrine Neoplasia Type 1. I. Endocrinology, 3509–3531 (Eds DeGroot LJ and Jameson JL) Philadelphia, PA: WB Saunders

  2. Bradley KJ et al. (2005) Uterine tumours are a phenotypic manifestation of the hyperparathyroidism-jaw tumour syndrome. J Intern Med 257: 18–26

    Article  CAS  Google Scholar 

  3. Hoff AO and Gagel RF (2006) Multiple Endocrine Neoplasia Type 2. I. Endocrinology, 3533–3550 (Eds DeGroot LJ and Jameson JL) Philadelphia, PA: WB Saunders

  4. Adami S et al. (2002) Epidemiology of primary hyperparathyroidism in Europe. J Bone Miner Res 17 (Suppl 2): N18–N23

    PubMed  Google Scholar 

  5. Pannett AA et al. (2003) Multiple endocrine neoplasia type 1 (MEN1) germline mutations in familial isolated primary hyperparathyroidism. Clin Endocrinol (Oxf) 58: 639–646

    Article  CAS  Google Scholar 

  6. Patracchini P et al. (1989) Sublocalization of the human protein C gene on chromosome 2q13-q14. Hum Genet 81: 191–192

    Article  CAS  Google Scholar 

  7. Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 68: 820–823

    Article  Google Scholar 

  8. Cetani F et al. (2004) Genetic analyses of the HRPT2 gene in primary hyperparathyroidism: germline and somatic mutations in familial and sporadic parathyroid tumors. J Clin Endocrinol Metab 89: 5583–5591

    Article  CAS  Google Scholar 

  9. Simonds WF et al. (2004) Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome. J Clin Endocrinol Metab 89: 96–102

    Article  CAS  Google Scholar 

  10. Villablanca A et al. (2004) Germline and de novo mutations in the HRPT2 tumour suppressor gene in familial isolated hyperparathyroidism (FIHP). J Med Genet 41: e32

    Article  CAS  Google Scholar 

  11. Bradley KJ et al. (2005) Utilisation of a cryptic non-canonical donor splice site of the gene encoding PARAFIBROMIN is associated with familial isolated primary hyperparathyroidism. J Med Genet 42: e51

    Article  CAS  Google Scholar 

  12. Bradley KJ et al. (2006) Parafibromin mutations in hereditary hyperparathyroidism syndromes and parathyroid tumours. Clin Endocrinol (Oxf) 64: 299–306

    Article  CAS  Google Scholar 

  13. Guarnieri V et al. (2006) Diagnosis of parathyroid tumors in familial isolated hyperparathyroidism with HRPT2 mutation: implications for cancer surveillance. J Clin Endocrinol Metab 91: 2827–2832

    Article  CAS  Google Scholar 

  14. Kelly TG et al. (2006) Surveillance for early detection of aggressive parathyroid disease: carcinoma and atypical adenoma in familial isolated hyperparathyroidism associated with a germline HRPT2 mutation. J Bone Miner Res 21: 1666–1671

    Article  CAS  Google Scholar 

  15. Mizusawa N et al. (2006) Genetic analyses in patients with familial isolated hyperparathyroidism and hyperparathyroidism-jaw tumour syndrome. Clin Endocrinol (Oxf) 65: 9–16

    Article  CAS  Google Scholar 

  16. Carpten JD et al. (2002) HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet 32: 676–680

    Article  CAS  Google Scholar 

  17. Simonds WF et al. (2002) Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds. Medicine (Baltimore) 81: 1–26

    Article  Google Scholar 

  18. Pollak MR et al. (1993) Mutations in the human Ca2-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 75: 1297–1303

    Article  CAS  Google Scholar 

  19. Thakker RV (2004) Diseases associated with the extracellular calcium-sensing receptor. Cell Calcium 35: 275–282

    Article  CAS  Google Scholar 

  20. Carling T et al. (2000) Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor. J Clin Endocrinol Metab 85: 2042–2047

    CAS  PubMed  Google Scholar 

  21. Warner J et al. (2004) Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications. J Med Genet 41: 155–160

    Article  CAS  Google Scholar 

  22. Miedlich S et al. (2001) Familial isolated primary hyperparathyroidism-a multiple endocrine neoplasia type 1 variant? Eur J Endocrinol 145: 155–160

    Article  CAS  Google Scholar 

  23. Brandi ML et al. (2001) Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86: 5658–5671

    Article  CAS  Google Scholar 

  24. Carneiro DM et al. (2002) Limited versus radical parathyroidectomy in familial isolated primary hyperparathyroidism. Surgery 132: 1050–1054

    Article  Google Scholar 

Download references

Acknowledgements

FM Hannan, MA Nesbit, PT Christie and RV Thakker are supported by the Medical Research Council (MRC), UK. FM Hannan is an MRC Clinical Research Training Fellow.

Author information

Authors and Affiliations

  1. FM Hannan is an MRC Clinical Research Training Fellow, MA Nesbit and PT Christie are postdoctoral scientists in Molecular Biology and RV Thakker is the May Professor of Clinical Medicine and leads the Academic Endocrine Unit, at the Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Churchill Hospital, Oxford, UK.,

    Fadil M Hannan, M Andrew Nesbit, Paul T Christie & Rajesh V Thakker

  2. C Fratter is a scientist at the Genetics Laboratory, Churchill Hospital. NE Dudley and GP Sadler are Consultant Endocrine Surgeons at the John Radcliffe Hospital, Oxford.,

    Carl Fratter, Nicholas E Dudley & Greg P Sadler

Authors
  1. Fadil M Hannan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Andrew Nesbit
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul T Christie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carl Fratter
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nicholas E Dudley
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Greg P Sadler
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rajesh V Thakker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rajesh V Thakker.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1

Representation of the steps required for DNA sequence analysis to detect a germline mutation. (DOC 741 kb)

Supplementary Figure 2

Schematic representation of the genomic organization of the multiple endocrine neoplasia type 1 gene (DOC 723 kb)

Supplementary Table 1

Disorders associated with forms of hereditary primary hyperparathyroidism. (DOC 27 kb)

Supplementary Table 2

MEN1, HRPT2 and CASR germline mutations detected in patients with FIHP (DOC 120 kb)

Supplementary Table 3

The major clinical features of the MEN1, MEN2, HPT-JT and FBHH syndromes. (DOC 49 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hannan, F., Nesbit, M., Christie, P. et al. Familial isolated primary hyperparathyroidism caused by mutations of the MEN1 gene. Nat Rev Endocrinol 4, 53–58 (2008). https://doi.org/10.1038/ncpendmet0718

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpendmet0718

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing