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
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
References
Thakker RV (2006) Multiple Endocrine Neoplasia Type 1. I. Endocrinology, 3509–3531 (Eds DeGroot LJ and Jameson JL) Philadelphia, PA: WB Saunders
Bradley KJ et al. (2005) Uterine tumours are a phenotypic manifestation of the hyperparathyroidism-jaw tumour syndrome. J Intern Med 257: 18–26
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
Adami S et al. (2002) Epidemiology of primary hyperparathyroidism in Europe. J Bone Miner Res 17 (Suppl 2): N18–N23
Pannett AA et al. (2003) Multiple endocrine neoplasia type 1 (MEN1) germline mutations in familial isolated primary hyperparathyroidism. Clin Endocrinol (Oxf) 58: 639–646
Patracchini P et al. (1989) Sublocalization of the human protein C gene on chromosome 2q13-q14. Hum Genet 81: 191–192
Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 68: 820–823
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
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
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
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
Bradley KJ et al. (2006) Parafibromin mutations in hereditary hyperparathyroidism syndromes and parathyroid tumours. Clin Endocrinol (Oxf) 64: 299–306
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
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
Mizusawa N et al. (2006) Genetic analyses in patients with familial isolated hyperparathyroidism and hyperparathyroidism-jaw tumour syndrome. Clin Endocrinol (Oxf) 65: 9–16
Carpten JD et al. (2002) HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet 32: 676–680
Simonds WF et al. (2002) Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds. Medicine (Baltimore) 81: 1–26
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
Thakker RV (2004) Diseases associated with the extracellular calcium-sensing receptor. Cell Calcium 35: 275–282
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
Warner J et al. (2004) Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications. J Med Genet 41: 155–160
Miedlich S et al. (2001) Familial isolated primary hyperparathyroidism-a multiple endocrine neoplasia type 1 variant? Eur J Endocrinol 145: 155–160
Brandi ML et al. (2001) Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86: 5658–5671
Carneiro DM et al. (2002) Limited versus radical parathyroidectomy in familial isolated primary hyperparathyroidism. Surgery 132: 1050–1054
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
Corresponding author
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
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ncpendmet0718
This article is cited by
-
Stepwise CaSR, AP2S1, and GNA11 sequencing in patients with suspected familial hypocalciuric hypercalcemia
Endocrine (2017)
-
Genetic basis of familial isolated hyperparathyroidism: a case series and a narrative review of the literature
Journal of Bone and Mineral Metabolism (2014)
-
Familial isolated primary hyperparathyroidism due to HRPT2 mutation
Hormones (2013)
-
Diagnosis and management of parathyroid cancer
Nature Reviews Endocrinology (2012)