Skip to main content
NCBI home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 2004 Mar;41(3):155–160. doi: 10.1136/jmg.2003.016725

Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications

J Warner 1, M Epstein 1, A Sweet 1, D Singh 1, J Burgess 1, S Stranks 1, P Hill 1, D Perry-Keene 1, D Learoyd 1, B Robinson 1, P Birdsey 1, E Mackenzie 1, B Teh 1, J Prins 1, J Cardinal 1
PMCID: PMC1735699  PMID: 14985373

Abstract

Familial hyperparathyroidism is not uncommon in clinical endocrine practice. It encompasses a spectrum of disorders including multiple endocrine neoplasia types 1 (MEN1) and 2A, hyperparathyroidism-jaw tumour syndrome (HPT-JT), familial hypocalciuric hypercalcaemia (FHH), and familial isolated hyperparathyroidism (FIHP). Distinguishing among the five syndromes is often difficult but has profound implications for the management of patient and family. The availability of specific genetic testing for four of the syndromes has improved diagnostic accuracy and simplified family monitoring in many cases but its current cost and limited accessibility require rationalisation of its use. No gene has yet been associated exclusively with FIHP. FIHP phenotypes have been associated with mutant MEN1 and calcium-sensing receptor (CASR) genotypes and, very recently, with mutation in the newly identified HRPT2 gene. The relative proportions of these are not yet clear. We report results of MEN1, CASR, and HRPT2 genotyping of 22 unrelated subjects with FIHP phenotypes. We found 5 (23%) with MEN1 mutations, four (18%) with CASR mutations, and none with an HRPT2 mutation. All those with mutations had multiglandular hyperparathyroidism. Of the subjects with CASR mutations, none were of the typical FHH phenotype. These findings strongly favour a recommendation for MEN1 and CASR genotyping of patients with multiglandular FIHP, irrespective of urinary calcium excretion. However, it appears that HRPT2 genotyping should be reserved for cases in which other features of the HPT-JT phenotype have occurred in the kindred. Also apparent is the need for further investigation to identify additional genes associated with FIHP.

Full Text

The Full Text of this article is available as a PDF (251.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bagnall R. D., Waseem N. H., Green P. M., Colvin B., Lee C., Giannelli F. Creation of a novel donor splice site in intron 1 of the factor VIII gene leads to activation of a 191 bp cryptic exon in two haemophilia A patients. Br J Haematol. 1999 Dec;107(4):766–771. doi: 10.1046/j.1365-2141.1999.01767.x. [DOI] [PubMed] [Google Scholar]
  2. Bilezikian John P., Potts John T., Jr, Fuleihan Ghada El-Hajj, Kleerekoper Michael, Neer Robert, Peacock Munro, Rastad Jonas, Silverberg Shonni J., Udelsman Robert, Wells Samuel A. Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Clin Endocrinol Metab. 2002 Dec;87(12):5353–5361. doi: 10.1210/jc.2002-021370. [DOI] [PubMed] [Google Scholar]
  3. Brandi M. L., Gagel R. F., Angeli A., Bilezikian J. P., Beck-Peccoz P., Bordi C., Conte-Devolx B., Falchetti A., Gheri R. G., Libroia A. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001 Dec;86(12):5658–5671. doi: 10.1210/jcem.86.12.8070. [DOI] [PubMed] [Google Scholar]
  4. Carling T., Szabo E., Bai M., Ridefelt P., Westin G., Gustavsson P., Trivedi S., Hellman P., Brown E. M., Dahl N. Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor. J Clin Endocrinol Metab. 2000 May;85(5):2042–2047. doi: 10.1210/jcem.85.5.6477. [DOI] [PubMed] [Google Scholar]
  5. Carpten J. D., Robbins C. M., Villablanca A., Forsberg L., Presciuttini S., Bailey-Wilson J., Simonds W. F., Gillanders E. M., Kennedy A. M., Chen J. D. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat Genet. 2002 Nov 18;32(4):676–680. doi: 10.1038/ng1048. [DOI] [PubMed] [Google Scholar]
  6. Chandrasekharappa S. C., Guru S. C., Manickam P., Olufemi S. E., Collins F. S., Emmert-Buck M. R., Debelenko L. V., Zhuang Z., Lubensky I. A., Liotta L. A. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997 Apr 18;276(5311):404–407. doi: 10.1126/science.276.5311.404. [DOI] [PubMed] [Google Scholar]
  7. Chou Y. H., Pollak M. R., Brandi M. L., Toss G., Arnqvist H., Atkinson A. B., Papapoulos S. E., Marx S., Brown E. M., Seidman J. G. Mutations in the human Ca(2+)-sensing-receptor gene that cause familial hypocalciuric hypercalcemia. Am J Hum Genet. 1995 May;56(5):1075–1079. [PMC free article] [PubMed] [Google Scholar]
  8. Conway G. S. Clinical manifestations of genetic defects affecting gonadotrophins and their receptors. Clin Endocrinol (Oxf) 1996 Dec;45(6):657–663. doi: 10.1046/j.1365-2265.1996.8680879.x. [DOI] [PubMed] [Google Scholar]
  9. Correa Pamela, Juhlin Christofer, Rastad Jonas, Akerström Göran, Westin Gunnar, Carling Tobias. Allelic loss in clinically and screening-detected primary hyperparathyroidism. Clin Endocrinol (Oxf) 2002 Jan;56(1):113–117. doi: 10.1046/j.0300-0664.2001.01436.x. [DOI] [PubMed] [Google Scholar]
  10. Eng C., Clayton D., Schuffenecker I., Lenoir G., Cote G., Gagel R. F., van Amstel H. K., Lips C. J., Nishisho I., Takai S. I. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA. 1996 Nov 20;276(19):1575–1579. [PubMed] [Google Scholar]
  11. Garcia de la Torre N., Wass J. A. H., Turner H. E. Parathyroid adenomas and cardiovascular risk. Endocr Relat Cancer. 2003 Jun;10(2):309–322. doi: 10.1677/erc.0.0100309. [DOI] [PubMed] [Google Scholar]
  12. Giraud S., Zhang C. X., Serova-Sinilnikova O., Wautot V., Salandre J., Buisson N., Waterlot C., Bauters C., Porchet N., Aubert J. P. Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. Am J Hum Genet. 1998 Aug;63(2):455–467. doi: 10.1086/301953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gunn I. R., Wallace J. R. Urine calcium and serum ionized calcium, total calcium and parathyroid hormone concentrations in the diagnosis of primary hyperparathyroidism and familial benign hypercalcaemia. Ann Clin Biochem. 1992 Jan;29(Pt 1):52–58. doi: 10.1177/000456329202900107. [DOI] [PubMed] [Google Scholar]
  14. Gökçe C., Gökçe O., Baydinç C., Ilhan N., Alaşehirli E., Ozkük F., Taşi M., Atilkeler M. K., Celebi H., Arslan N. Use of random urine samples to estimate total urinary calcium and phosphate excretion. Arch Intern Med. 1991 Aug;151(8):1587–1588. doi: 10.1001/archinte.1991.00400080083015. [DOI] [PubMed] [Google Scholar]
  15. Hanibuchi Noriyuki, Maruyama Takao, Menju Masakazu, Toyoshima Hiroyuki, Yamamoto Takehisa, Fukumoto Seiji, Konishi Ichiro. Marked hypercalcemia in a patient with hypocalciuric hypercalcemia without a mutation in the calcium-sensing receptor gene. Intern Med. 2002 Dec;41(12):1153–1157. doi: 10.2169/internalmedicine.41.1153. [DOI] [PubMed] [Google Scholar]
  16. Heath H., 3rd, Odelberg S., Jackson C. E., Teh B. T., Hayward N., Larsson C., Buist N. R., Krapcho K. J., Hung B. C., Capuano I. V. Clustered inactivating mutations and benign polymorphisms of the calcium receptor gene in familial benign hypocalciuric hypercalcemia suggest receptor functional domains. J Clin Endocrinol Metab. 1996 Apr;81(4):1312–1317. doi: 10.1210/jcem.81.4.8636323. [DOI] [PubMed] [Google Scholar]
  17. Hendy G. N., D'Souza-Li L., Yang B., Canaff L., Cole D. E. Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Hum Mutat. 2000 Oct;16(4):281–296. doi: 10.1002/1098-1004(200010)16:4<281::AID-HUMU1>3.0.CO;2-A. [DOI] [PubMed] [Google Scholar]
  18. Hinnie J., Bell E., McKillop E., Gallacher S. The prevalence of familial hypocalciuric hypercalcemia. Calcif Tissue Int. 2001 Apr 11;68(4):216–218. doi: 10.1007/s002230001201. [DOI] [PubMed] [Google Scholar]
  19. Howe J. R., Norton J. A., Wells S. A., Jr Prevalence of pheochromocytoma and hyperparathyroidism in multiple endocrine neoplasia type 2A: results of long-term follow-up. Surgery. 1993 Dec;114(6):1070–1077. [PubMed] [Google Scholar]
  20. Karges W., Jostarndt K., Maier S., Flemming A., Weitz M., Wissmann A., Feldmann B., Dralle H., Wagner P., Boehm B. O. Multiple endocrine neoplasia type 1 (MEN1) gene mutations in a subset of patients with sporadic and familial primary hyperparathyroidism target the coding sequence but spare the promoter region. J Endocrinol. 2000 Jul;166(1):1–9. doi: 10.1677/joe.0.1660001. [DOI] [PubMed] [Google Scholar]
  21. Kassem M., Kruse T. A., Wong F. K., Larsson C., Teh B. T. Familial isolated hyperparathyroidism as a variant of multiple endocrine neoplasia type 1 in a large Danish pedigree. J Clin Endocrinol Metab. 2000 Jan;85(1):165–167. doi: 10.1210/jcem.85.1.6299. [DOI] [PubMed] [Google Scholar]
  22. King Kathy, Flinter Frances A., Nihalani Vandana, Green Peter M. Unusual deep intronic mutations in the COL4A5 gene cause X linked Alport syndrome. Hum Genet. 2002 Sep 14;111(6):548–554. doi: 10.1007/s00439-002-0830-3. [DOI] [PubMed] [Google Scholar]
  23. Law W. M., Jr, Carney J. A., Heath H., 3rd Parathyroid glands in familial benign hypercalcemia (familial hypocalciuric hypercalcemia). Am J Med. 1984 Jun;76(6):1021–1026. doi: 10.1016/0002-9343(84)90852-0. [DOI] [PubMed] [Google Scholar]
  24. Marx S. J., Attie M. F., Levine M. A., Spiegel A. M., Downs R. W., Jr, Lasker R. D. The hypocalciuric or benign variant of familial hypercalcemia: clinical and biochemical features in fifteen kindreds. Medicine (Baltimore) 1981 Nov;60(6):397–412. doi: 10.1097/00005792-198111000-00002. [DOI] [PubMed] [Google Scholar]
  25. Matsuki T., Nishiura H., Jo Y., Kinoshita H., Morioka M., Tanaka H. [Familial isolated hyperparathyroidism: a report of two cases]. Nihon Hinyokika Gakkai Zasshi. 2000 Jan;91(1):33–36. doi: 10.5980/jpnjurol1989.91.33. [DOI] [PubMed] [Google Scholar]
  26. Mattick J. S. Non-coding RNAs: the architects of eukaryotic complexity. EMBO Rep. 2001 Nov;2(11):986–991. doi: 10.1093/embo-reports/kve230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Miller S. A., Dykes D. D., Polesky H. F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. doi: 10.1093/nar/16.3.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Mulligan L. M., Eng C., Attié T., Lyonnet S., Marsh D. J., Hyland V. J., Robinson B. G., Frilling A., Verellen-Dumoulin C., Safar A. Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene. Hum Mol Genet. 1994 Dec;3(12):2163–2167. doi: 10.1093/hmg/3.12.2163. [DOI] [PubMed] [Google Scholar]
  29. Ogawa Yoshihide, Yonou Hiroyuki, Hokama Sanehiro, Oda Masami, Morozumi Makoto, Sugaya Kimio. Urinary saturation and risk factors for calcium oxalate stone disease based on spot and 24-hour urine specimens. Front Biosci. 2003 Sep 1;8:a167–a176. doi: 10.2741/1139. [DOI] [PubMed] [Google Scholar]
  30. Palanisamy N., Imanishi Y., Rao P. H., Tahara H., Chaganti R. S., Arnold A. Novel chromosomal abnormalities identified by comparative genomic hybridization in parathyroid adenomas. J Clin Endocrinol Metab. 1998 May;83(5):1766–1770. doi: 10.1210/jcem.83.5.4806. [DOI] [PubMed] [Google Scholar]
  31. Pasieka J. L., Andersen M. A., Hanley D. A. Familial benign hypercalcaemia: hypercalciuria and hypocalciuria in affected members of a small kindred. Clin Endocrinol (Oxf) 1990 Oct;33(4):429–433. doi: 10.1111/j.1365-2265.1990.tb03881.x. [DOI] [PubMed] [Google Scholar]
  32. Pollak M. R., Brown E. M., Chou Y. H., Hebert S. C., Marx S. J., Steinmann B., Levi T., Seidman C. E., Seidman J. G. Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell. 1993 Dec 31;75(7):1297–1303. doi: 10.1016/0092-8674(93)90617-y. [DOI] [PubMed] [Google Scholar]
  33. Silverberg S. J., Shane E., Jacobs T. P., Siris E. S., Gartenberg F., Seldin D., Clemens T. L., Bilezikian J. P. Nephrolithiasis and bone involvement in primary hyperparathyroidism. Am J Med. 1990 Sep;89(3):327–334. doi: 10.1016/0002-9343(90)90346-f. [DOI] [PubMed] [Google Scholar]
  34. Simonds William F., James-Newton Laura A., Agarwal Sunita K., Yang Bing, Skarulis Monica C., Hendy Geoffrey N., Marx Stephen J. Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds. Medicine (Baltimore) 2002 Jan;81(1):1–26. doi: 10.1097/00005792-200201000-00001. [DOI] [PubMed] [Google Scholar]
  35. Tahara H., Smith A. P., Gas R. D., Cryns V. L., Arnold A. Genomic localization of novel candidate tumor suppressor gene loci in human parathyroid adenomas. Cancer Res. 1996 Feb 1;56(3):599–605. [PubMed] [Google Scholar]
  36. Teh B. T., Esapa C. T., Houlston R., Grandell U., Farnebo F., Nordenskjöld M., Pearce C. J., Carmichael D., Larsson C., Harris P. E. A family with isolated hyperparathyroidism segregating a missense MEN1 mutation and showing loss of the wild-type alleles in the parathyroid tumors. Am J Hum Genet. 1998 Nov;63(5):1544–1549. doi: 10.1086/302097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Teh B. T., Kytölä S., Farnebo F., Bergman L., Wong F. K., Weber G., Hayward N., Larsson C., Skogseid B., Beckers A. Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism. J Clin Endocrinol Metab. 1998 Aug;83(8):2621–2626. doi: 10.1210/jcem.83.8.5059. [DOI] [PubMed] [Google Scholar]
  38. Villablanca Andrea, Wassif Wassif S., Smith Thomas, Hög Anders, Vierimaa Outi, Kassem Moustapha, Dwight Trisha, Forsberg Lars, Du Quan, Learoyd Diana. Involvement of the MEN1 gene locus in familial isolated hyperparathyroidism. Eur J Endocrinol. 2002 Sep;147(3):313–322. doi: 10.1530/eje.0.1470313. [DOI] [PubMed] [Google Scholar]
  39. Wassif W. S., Moniz C. F., Friedman E., Wong S., Weber G., Nordenskjöld M., Peters T. J., Larsson C. Familial isolated hyperparathyroidism: a distinct genetic entity with an increased risk of parathyroid cancer. J Clin Endocrinol Metab. 1993 Dec;77(6):1485–1489. doi: 10.1210/jcem.77.6.7903311. [DOI] [PubMed] [Google Scholar]
  40. Yoshimoto K., Endo H., Tsuyuguchi M., Tanaka C., Kimura T., Iwahana H., Kato G., Sano T., Itakura M. Familial isolated primary hyperparathyroidism with parathyroid carcinomas: clinical and molecular features. Clin Endocrinol (Oxf) 1998 Jan;48(1):67–72. doi: 10.1046/j.1365-2265.1998.00354.x. [DOI] [PubMed] [Google Scholar]
  41. den Dunnen J. T., Antonarakis S. E. Nomenclature for the description of human sequence variations. Hum Genet. 2001 Jul;109(1):121–124. doi: 10.1007/s004390100505. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES