Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 786037006; ORPHA: 99879; DO: 13543;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q31.2 | Hyperparathyroidism, familial primary | 145000 | Autosomal dominant | 3 | CDC73 | 607393 |
A number sign (#) is used with this entry because familial isolated hyperparathyroidism-1 (FIHP, HRPT1) is caused by heterozygous mutation in the CDC73 gene (607393) on chromosome 1q31.
Familial isolated primary hyperparathyroidism is an autosomal dominant hypercalcemic disorder caused by inappropriate oversecretion of parathyroid hormone (PTH) from parathyroid adenomas, hyperplasia, and carcinomas (summary by Shibata et al., 2015).
Genetic Heterogeneity of Familial Hyperparathyroidism
Hyperparathyroidism-2 with jaw tumors (HRPT2; 145001), also known as the hyperparathyroidism-jaw tumor syndrome (HPT-JT), is also caused by mutation in the CDC73 gene. A locus for HRPT (HRPT3; 610071) has been mapped to chromosome 2p14-p13.3. HRPT4 (617343) is caused by mutation in the GCM2 gene (603716) on chromosome 6p24. Neonatal severe hyperparathyroidism (NSHPT; 239200) is caused by mutation in the CASR gene (601199) on chromosome 3q.
Familial isolated primary hyperparathyroidism occasionally results from incomplete expression of multiple endocrine neoplasia (see MEN1, 131100).
Familial hypocalciuric hypercalcemia (see 145980) can be confused with familial primary hyperparathyroidism.
Cutler et al. (1964) and others emphasized that chief cell hyperplasia rather than adenoma may be the characteristic histologic change in familial cases of hyperparathyroidism. The 2 types of changes are often distinguished with difficulty.
Jackson and Boonstra (1967) studied 8 families, each with multiple cases (55 in all) of parathyroid adenoma. In at least 3 kindreds some individuals had other endocrine adenomata.
Familial hyperparathyroidism occurs as part of multiple endocrine neoplasia (see MEN1, 131100). Families with multiple cases of parathyroid adenoma were described by Cassidy and Anderson (1960), Jackson et al. (1960), and others. Although such families may have had multiple endocrine neoplasia, the possibility of a separate and distinct dominantly inherited entity could not be excluded (Cutler et al., 1964).
Boey et al. (1975) found associated endocrine disease indicative of multiple endocrine adenomatosis in 21 of 119 cases of primary hyperparathyroidism. The clinical pattern of hypercalcemia was the same in the 21 as in the others, but MEN was found more often in patients with several diseased parathyroid glands.
Marx et al. (1977) concluded that primary parathyroid hyperplasia is separate from multiple endocrine neoplasia type I. In the former disorder, close to half the offspring of affected persons show hypercalcemia in the first 2 decades, nephrolithiasis and peptic ulcer disease are unusual, and concentrations of peptic hormones other than parathyroid hormone are normal. The distinctness of 'pure' hyperparathyroidism was supported by the findings of Goldsmith et al. (1976) in an extensively affected kindred.
Thymic and nonthymic carcinoid tumors have been reported with MEN I and with hereditary hyperparathyroidism (Lokich and Li, 1978).
In 1 member of a family in which 19 members had isolated hyperparathyroidism, Wassif et al. (1993) found a parathyroid carcinoma after postsurgical recurrence of hypercalcemia. Because parathyroid carcinoma has been reported in other families with primary hyperparathyroidism (Dinnen et al., 1977; Frayha et al., 1972; Leborgne et al., 1975; Streeten et al., 1992), malignant hyperparathyroid disease is clearly a risk in these families.
Stefenelli et al. (1997) found a high incidence of left ventricular hypertrophy (82%) and aortic and/or mitral valve calcifications (46 and 39%, respectively) in patients with primary hyperparathyroidism. Follow-up at 1 year and at 41 months after successful parathyroidectomy showed regression of hypertrophy. While no comments were made regarding inclusion of familial cases in their study, their findings indicate that parathyroid hormone per se may play an important role in myocardial hypertrophy and that these cardiac complications may also occur in familial cases.
Gasperi et al. (2002) studied 18 patients with primary hyperparathyroidism due to solitary parathyroid adenoma. Mean serum IGF1 (147440) levels in primary hyperparathyroidism were lower than in normal controls, and in 6 patients individual serum IGF1 levels were below the age-related normal range. The mean peak GH (139250) response to arginine alone in patients was significantly lower than in normal subjects. The authors concluded that primary hyperparathyroidism patients have a reduction in both spontaneous and stimulated GH secretion.
Origin of Parathyroid Adenomas
Arnold et al. (1988) presented evidence for the clonal origin of parathyroid adenomas. They found tumor-cell-specific restriction fragment-length alterations involving the parathyroid hormone gene (168450) in 2 parathyroid adenomas. Furthermore, using a RFLP related to HRPT, they found that of 8 adenomas in women, 6 had the DNA hybridization pattern indicative of monoclonality, and the other 2 had an equivocal pattern. None of 5 hyperplastic parathyroid glands showed a monoclonal pattern. Six of the patients had documented hypercalciuria, and 4 had a history of nephrolithiasis.
Cases of apparently isolated familial hyperparathyroidism were reported by Cameron et al. (1966), Cutler et al. (1964), and Peters et al. (1966), among others. The pedigrees have usually been consistent with autosomal dominant inheritance.
Law et al. (1983) reported a family in which hyperparathyroidism was present in 2 sisters and their brother; their parents, 10 sibs, 2 offspring of 1 of the affected sisters, and many paternal and maternal aunts and uncles were unaffected. The parents were unrelated. Autosomal recessive inheritance was proposed by the authors for this apparently unique family; McKusick (1983) thought this much less likely than gonadal mosaicism of one of the parents. The 3 affected persons had adenomatous hyperparathyroidism which became symptomatic in their twenties.
Teh et al. (1998) reported 3 families with familial primary hyperparathyroidism and evaluated their clinical, pathologic, and genetic profiles. In 2 families with a total of 10 affected cases and 3 female obligate carriers, there was no evidence of jaw or renal lesions despite careful radiologic investigations. In both families, the disease was linked to the 1q21-q32 region with lod scores of 3.10 and 3.43 for markers D1S222 and D1S249, respectively, at recombination fractions of 0. In 1 family, 2 types of parathyroid pathology were found: 3 of chief cell type and 1 of oxyphil/oncocytic cell type. Two chief cell tumors and 1 oxyphil tumor were found to have LOH involving loss of the wildtype alleles for chromosome 1q markers. In the third family, with 4 affected sibs, a parathyroid carcinoma and 2 cases of polycystic kidney disease were found. The parathyroid carcinoma also showed LOH in the 1q region. Teh et al. (1998) interpreted these findings as indicating that a subset of familial isolated hyperparathyroidism families represent a variant of the hyperparathyroidism-jaw tumor syndrome (HPT-JT) and that the gene involved is a tumor suppressor gene.
Teh et al. (1998) described a family in which members of 2 generations had familial isolated hyperparathyroidism. They proposed that FIHP can be divided into at least 2 forms on the basis of histopathologic and genetic findings. The MEN1 variant is characterized by multiglandular hypoplastic disease resulting from a MEN1 mutation, with the Knudson 2-hit model being responsible for the development of the parathyroid tumors, and clinically by a milder course of hyperparathyroidism. The HPT-JT variant characterized by solitary adenomas is linked to the HRPT2 (CDC73; 607393) locus on 1q21-q32 and more frequently presents with profound hypercalcemia or hypercalcemic crisis.
Heterogeneity
Kassem et al. (1994) suggested that familial primary hyperparathyroidism may be caused by mutation in a gene located in the MEN1 region on 11q13, possibly the MEN1 locus. They studied a large family in which 7 patients had previously been operated on for HRPT. Through family studies, 4 new patients with HRPT and 2 with probable HRPT were found. No clinical or biochemical evidence of MEN syndromes could be detected. However, DNA marker D11S97, located at 11q13, gave a maximum 2-point lod score of 2.12 at a recombination fraction of 0.05.
Yoshimoto et al. (1998) presented 4 patients from a single family with FIHP. The 27-year-old proband died of parathyroid carcinoma with metastases of the lungs and chest wall. Sixteen years later, his 34-year-old sister presented with a neck tumor and primary hyperparathyroidism. Family screening revealed parathyroid tumors in his 36-year-old sister and 29-year-old cousin. Histologic examination of resected tumors showed parathyroid carcinoma and adenoma in the 34-year-old sister, a parathyroid adenoma in the 36-year-old sister, and an atypical parathyroid adenoma in the cousin. Autopsy of the proband ruled out MEN1, and the 3 patients who underwent parathyroidectomy did not exhibit any abnormalities in the pancreas or the pituitary gland. Analysis of tumor DNA from 1 parathyroid carcinoma, the atypical parathyroid adenoma, and 2 parathyroid adenomas showed limited loss of heterozygosity on 13p12.3-q32 in 1 of the adenomas, and of 9p22-p21 and 13q12.3-q32 in the adenoma of the other patient. These results suggested a possible contribution of the tumor suppressor genes RB1 (614041) and BRCA2 (600185), both located on the proximal part of 13q, to parathyroid tumors in this family.
In patients with primary hyperparathyroidism, bone (particularly cortical bone) is reduced by increased bone turnover. Chow et al. (2003) studied the effect of bisphosphonate therapy on bone mineral density (BMD) in patients with primary hyperparathyroidism. Forty postmenopausal women with primary hyperparathyroidism were randomized to receive alendronate 10 mg/d or placebo for 48 weeks, followed by treatment withdrawal for 24 weeks. The mean changes in BMD at femoral neck and lumbar spine were significantly higher with alendronate at 48 weeks. Serum calcium was reduced with alendronate but not placebo. Serum bone-specific alkaline phosphatase activity was lower with alendronate from 12 weeks onward and increased 24 weeks after treatment withdrawal. The authors concluded that alendronate improves BMD and reduces bone turnover markers in postmenopausal women with primary hyperparathyroidism.
Most hyperparathyroidism is nonfamilial. The frequency of familial primary hyperparathyroidism was estimated to be 0.14 per thousand by Jackson and Boonstra (1967) and 0.13 per thousand by Christensson (1976).
In a kindred with familial isolated hyperparathyroidism, Carpten et al. (2002) found a germline leu64-to-pro (L64P; 607393.0006) mutation in exon 2 of the CDC73 gene.
In the proband and 2 affected members of a family with familial isolated hyperparathyroidism, Cetani et al. (2004) identified heterozygosity for a germline in the donor splice site of intron 1 of the CDC73 gene (607393.0010). This mutation was also found as a somatic change in a sporadic parathyroid adenoma
Associations Pending Confirmation
See 168450.0004 for discussion of a possible association between primary hyperparathyroidism and mutation in the PTH gene (168450).
Exclusion Studies
To establish whether familial isolated hyperparathyroidism is a distinct disease entity or a variant of one of the multiple endocrine neoplasia syndromes, Wassif et al. (1993) tested 19 members of a large family in which the disease had been transmitted through 4 generations in an autosomal dominant fashion. Location of the causative mutation on chromosome 11 in the vicinity of the MEN1 locus (131100) or on chromosome 10 in the vicinity of the MEN2A locus (171400) was excluded by linkage study, as was also linkage to the parathyroid hormone gene (PTH; 168450).
In connection with a study of germline mutations in the MEN1 gene in familial multiple endocrine neoplasia type I, Agarwal et al. (1997) studied the DNA of the probands from 5 families with familial hyperparathyroidism. No MEN1 germline mutation was found in any of them, suggesting that familial hyperparathyroidism is often caused by mutation in another gene or genes.
Agarwal, S. K., Kester, M. B., Debelenko, L. V., Heppner, C., Emmert-Buck, M. R., Skarulis, M. C., Doppman, J. L., Kim, Y. S., Lubensky, I. A., Zhuang, Z., Green, J. S., Guru, S. C., Manickam, P., Olufemi, S.-E., Liotta, L. A., Chandrasekharappa, S. C., Collins, F. S., Spiegel, A. M., Burns, A. L., Marx, S. J. Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. Hum. Molec. Genet. 6: 1169-1175, 1997. [PubMed: 9215689] [Full Text: https://doi.org/10.1093/hmg/6.7.1169]
Arnold, A., Staunton, C. E., Kim, H. G., Gaz, R. D., Kronenberg, H. M. Monoclonality and abnormal parathyroid hormone genes in parathyroid adenomas. New Eng. J. Med. 318: 658-662, 1988. [PubMed: 3344017] [Full Text: https://doi.org/10.1056/NEJM198803173181102]
Boey, J. H., Cooke, T. J. C., Gilbert, G. M., Sweeney, E. C., Taylor, S. Occurrence of other endocrine tumours in primary hyperparathyroidism. Lancet 306: 781-784, 1975. Note: Originally Volume II. [PubMed: 78151] [Full Text: https://doi.org/10.1016/s0140-6736(75)80002-x]
Cameron, K. M., Ogg, C. S., Harrison, A. R. Familial hyperparathyroidism. Lancet 288: 1006-1007, 1966. Note: Originally Volume II.
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., Agarwal, S. K., Sood, R., and 17 others. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nature Genet. 32: 676-680, 2002. [PubMed: 12434154] [Full Text: https://doi.org/10.1038/ng1048]
Cassidy, C. E., Anderson, A. S. A familial occurrence of hyperparathyroidism caused by multiple parathyroid adenomas. Metabolism 9: 1152-1158, 1960. [PubMed: 13691344]
Cetani, F., Pardi, E., Borsari, S., Viacava, P., Dipollina, G., Cianferotti, L., Ambrogini, E., Gazzerro, E., Colussi, G., Berti, P., Miccoli, P., Pinchera, A., Marcocci, C. Genetic analyses of the HRPT2 gene in primary hyperparathyroidism: germline and somatic mutations in familial and sporadic parathyroid tumors. J. Clin. Endocr. Metab. 89: 5583-5591, 2004. [PubMed: 15531515] [Full Text: https://doi.org/10.1210/jc.2004-0294]
Chow, C. C., Chan, W. B., Li, J. K. Y ., Chan, N. N., Chan, M. H. M., Ko, G. T. C., Lo, K. W., Cockram, C. S. Oral alendronate increases bone mineral density in postmenopausal women with primary hyperparathyroidism. J. Clin. Endocr. Metab. 88: 581-587, 2003. [PubMed: 12574184] [Full Text: https://doi.org/10.1210/jc.2002-020890]
Christensson, T. Familial hyperparathyroidism. (Letter) Ann. Intern. Med. 85: 614-615, 1976. [PubMed: 984613] [Full Text: https://doi.org/10.7326/0003-4819-85-5-614]
Cutler, R. E., Reiss, E., Ackerman, L. V. Familial hyperparathyroidism: a kindred involving eleven cases, with a discussion of primary chief-cell hyperplasia. New Eng. J. Med. 270: 859-865, 1964. [PubMed: 14110030] [Full Text: https://doi.org/10.1056/NEJM196404232701701]
Dinnen, J. S., Greenwood, R. H., Jones, J. H., Walker, D. A., Williams, E. D. Parathyroid carcinoma in familial hyperparathyroidism. J. Clin. Path. 30: 966-975, 1977. [PubMed: 412876] [Full Text: https://doi.org/10.1136/jcp.30.10.966]
Frayha, R. A., Nassar, V. H., Dagher, F., Salti, I. S. Familial parathyroid carcinoma. J. Med. Liban. 25: 299-309, 1972. [PubMed: 4657413]
Gasperi, M., Cecconi, E., Grasso, L., Bartalena, L., Centoni, R., Aimaretti, G., Broglio, F., Miccoli, P., Marcocci, C., Ghigo, E., Martino, E. GH secretion is impaired in patients with primary hyperparathyroidism. J. Clin. Endocr. Metab. 87: 1961-1964, 2002. [PubMed: 11994325] [Full Text: https://doi.org/10.1210/jcem.87.5.8451]
Goldsmith, R. E., Sizemore, G. W., Chen, I.-W., Zalme, E., Altemeier, W. A. Familial hyperparathyroidism: description of a large kindred with physiologic observations and a review of the literature. Ann. Intern. Med. 84: 36-43, 1976. [PubMed: 1244790] [Full Text: https://doi.org/10.7326/0003-4819-84-1-36]
Graber, A. L., Jacobs, K. Familial hyperparathyroidism: medical and surgical considerations. JAMA 204: 542-544, 1968. [PubMed: 5694438] [Full Text: https://doi.org/10.1001/jama.204.6.542]
Grevsten, S., Grimelius, L., Thoren, L. Familial hyperparathyroidism. Upsala J. Med. Sci. 79: 109-115, 1974. [PubMed: 4135089] [Full Text: https://doi.org/10.3109/03009737409178978]
Jackson, C. E., Boonstra, C. E. The relationship of hereditary hyperparathyroidism to endocrine adenomatosis. Am. J. Med. 43: 727-734, 1967. [PubMed: 4383267] [Full Text: https://doi.org/10.1016/0002-9343(67)90114-3]
Jackson, C. E., Talbert, P. C., Taylor, H. D. Hereditary hyperparathyroidism. J. Indiana Med. Assoc. 53: 1313-1316, 1960.
Kassem, M., Zhang, X., Brask, S., Eriksen, E. F., Mosekilde, L., Kruse, T. A. Familial isolated primary hyperparathyroidism. Clin. Endocr. 41: 415-420, 1994. [PubMed: 7955451] [Full Text: https://doi.org/10.1111/j.1365-2265.1994.tb02570.x]
Law, W. M., Jr., Hodgson, S. F., Heath, H., III. Autosomal recessive inheritance of familial hyperparathyroidism. New Eng. J. Med. 309: 650-653, 1983. [PubMed: 6888431] [Full Text: https://doi.org/10.1056/NEJM198309153091107]
Leborgne, J., Le Neel, J.-C., Buzelin, F., Malvy, P. Cancer familial des parathyroides: interet de l'angiographie dans le diagnostic des recidives loco-regionales--considerations a propos de deux cas. J. Chir. (Paris) 109: 315-326, 1975. [PubMed: 1176554]
Lokich, J. J., Li, F. P. Carcinoid of the thymus with hereditary hyperparathyroidism. Ann. Intern. Med. 89: 364-365, 1978. [PubMed: 686552] [Full Text: https://doi.org/10.7326/0003-4819-89-3-364]
Mallette, L. E., Bilezikian, J. P., Ketcham, A. S., Aurbach, G. D. Parathyroid carcinoma in familial hyperparathyroidism. Am. J. Med. 57: 642-648, 1974. [PubMed: 4372885] [Full Text: https://doi.org/10.1016/0002-9343(74)90018-7]
Marx, S. J., Spiegel, A. M., Brown, E. M., Aurbach, G. D. Family studies in patients with primary parathyroid hyperplasia. Am. J. Med. 62: 698-706, 1977. [PubMed: 871127] [Full Text: https://doi.org/10.1016/0002-9343(77)90873-7]
McKusick, V. A. Personal Communication. Baltimore, Md. 1983.
Peters, N., Chalmers, T. M., Rack, J. H., Truscott, B. M., Adams, P. H. Familial hyperparathyroidism. Postgrad. Med. J. 42: 228-233, 1966. [PubMed: 5938607] [Full Text: https://doi.org/10.1136/pgmj.42.486.228]
Sandler, L. M., Moncrieff, M. W. Familial hyperparathyroidism. Arch. Dis. Child. 55: 146-157, 1980. [PubMed: 7377835] [Full Text: https://doi.org/10.1136/adc.55.2.146]
Shibata, Y., Yamazaki, M., Takei, M., Uchino, S., Sakurai, A., Komatsu, M. Early-onset, severe, and recurrent primary hyperparathyroidism associated with a novel CDC73 mutation. Endocr. J. 62: 627-632, 2015. [PubMed: 25959515] [Full Text: https://doi.org/10.1507/endocrj.EJ15-0057]
Stefenelli, T., Abela, C., Frank, H., Koller-Strametz, J., Globits, S., Bergler-Klein, J., Niederle, B. Cardiac abnormalities in patients with primary hyperparathyroidism: implications for follow-up. J. Clin. Endocr. Metab. 82: 106-112, 1997. [PubMed: 8989242] [Full Text: https://doi.org/10.1210/jcem.82.1.3666]
Streeten, E. A., Weinstein, L. S., Norton, J. A., Mulvihill, J. J., White, B. J., Friedman, E., Jaffe, G., Brandi, M. L., Stewart, K., Zimering, M. B., Spiegel, A. M., Aurbach, G. D., Marx, S. J. Studies in a kindred with parathyroid carcinoma. J. Clin. Endocr. Metab. 75: 362-366, 1992. [PubMed: 1639936] [Full Text: https://doi.org/10.1210/jcem.75.2.1639936]
Teh, B. T., Esapa, C. T., Houlston, R., Grandell, U., Farnebo, F., Nordenskjold, 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. (Letter) Am. J. Hum. Genet. 63: 1544-1549, 1998. [PubMed: 9792884] [Full Text: https://doi.org/10.1086/302097]
Teh, B. T., Farnebo, F., Twigg, S., Hoog, A., Kytola, S., Korpi-Hyovalti, E., Wong, F. K., Nordenstrom, J., Grimelius, L., Sandelin, K., Robinson, B., Farnebo, L.-O., Larsson, C. Familial isolated hyperparathyroidism maps to the hyperparathyroidism-jaw tumor locus in 1q21-q32 in a subset of families. J. Clin. Endocr. Metab. 83: 2114-2120, 1998. [PubMed: 9626148] [Full Text: https://doi.org/10.1210/jcem.83.6.4896]
Wassif, W. S., Moniz, C. F., Friedman, E., Wong, S., Weber, G., Nordenskjold, M., Peters, T. J., Larsson, C. Familial isolated hyperparathyroidism: a distinct genetic entity with an increased risk of parathyroid cancer. J. Clin. Endocr. Metab. 77: 1485-1489, 1993. [PubMed: 7903311] [Full Text: https://doi.org/10.1210/jcem.77.6.7903311]
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. Endocr. 48: 67-72, 1998. [PubMed: 9509070] [Full Text: https://doi.org/10.1046/j.1365-2265.1998.00354.x]