Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 702378002; ORPHA: 99880; DO: 13543;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q31.2 | Hyperparathyroidism-jaw tumor syndrome | 145001 | Autosomal dominant | 3 | CDC73 | 607393 |
| 1q31.2 | Parathyroid adenoma with cystic changes | 145001 | Autosomal dominant | 3 | CDC73 | 607393 |
A number sign (#) is used with this entry because of evidence that hyperparathyroidism-2 with jaw tumors (HRPT2), also known as hyperparathyroidism-jaw tumor syndrome, is caused by heterozygous mutation in the CDC73 gene (607393) on chromosome 1q31.
Hyperparathyroidism-2 with jaw tumors (HRPT2) is a rare autosomal dominant disorder characterized by synchronous or metachronous occurrence of primary hyperparathyroidism, ossifying fibroma of the maxilla and/or mandible, renal tumor, and uterine tumors. It is associated with increased risk of parathyroid cancer (summary by Shibata et al., 2015).
For a discussion of genetic heterogeneity of hyperparathyroidism, see HRPT1 (145000).
Although the most common familial form of primary hyperparathyroidism is parathyroid hyperplasia (HRPT1; 145000), a few families have manifested parathyroid adenomas. Mallette et al. (1987) described a family in which 4 members developed cystic parathyroid adenomas. Although calcium levels returned to normal after resection of the adenoma, a second adenoma often developed several years later; thus, Mallette et al. (1987) termed the condition adenomatosis. Each adenoma had a cystic histologic appearance, and 3 of the 4 normal-sized parathyroid glands also contained many cysts. No other endocrine tumors developed, but in 3 of the patients the hyperparathyroidism was complicated by fibrous maxillary or mandibular tumors that resembled ossifying fibromas rather than the brown tumors generally found in patients with hyperparathyroidism. Each patient with an adenoma was hypercalciuric, but 2 were considered obligate carriers of hypocalciuric hypercalcemia (145980). The adenomatosis occurred in a father and 3 sons. A brother and sister of the father had hypercalciuric hypercalcemia, as did the son of 1 of the 3 sons.
Jackson (1958) reported a family with hereditary hyperparathyroidism in which 4 of 5 of the affected members of the first generation had jaw tumors. Because 3 affected members of the third generation developed similar jaw tumors which progressed even after surgical correction of their hypercalcemia, the family was reinvestigated. The maxillary and mandibular tumors could be differentiated from the 'brown tumors' of hyperparathyroidism; they were histologically distinct fibroosseous lesions without giant cells. As far as is known, ossified fibrous tumors do not occur in areas other than the jaw, such as the knees or ribs which can be the site of 'brown tumors.' Parathyroid enlargement was mostly uniglandular with multiple tumors found only occasionally. Linkage studies in this and a second family with the same association demonstrated linkage to neither chromosome 11 markers (the site of the gene for MEN1; see 131100) nor markers on chromosome 10 (the site of the gene for MEN2; see 171400). (According to Jackson (1994), linkage studies in 5 families exclude the locus for this disorder, symbolized HRPT2, from the sites of MEN1 and MEN2.) Thus, hereditary hyperparathyroidism with multiple ossifying jaw fibromas may be a genetically distinct disorder. The family of Mallette et al. (1987) was included in the study of Jackson et al. (1990). Other families were reported by Kennett and Pollick (1971), Rosen and Palmer (1981), and Warnakulasuriya et al. (1985). Inoue et al. (1995) reported a 53-year-old Japanese woman diagnosed as having primary hyperparathyroidism caused by hyperplasia of the parathyroid glands and causing renal stones and hypercalcemia. One year after she underwent total parathyroidectomy and implantation of parathyroid tissue, she underwent surgery for a cementifying fibroma. A 19-year-old nephew was found to have elevated serum calcium levels and levels of serum parathyroid hormone and a parathyroid adenoma was removed at surgery.
Szabo et al. (1995) found no instance of parathyroid carcinoma in their families; 1 case of this malignancy had been reported by Dinnen et al. (1977). The occurrence of Wilms tumor in 2 female members of unrelated families in their study raised the possibility that Wilms tumor may be a component of the HPT-JT syndrome. Further evidence that parathyroid carcinoma and Wilms tumor are part of the HPT-JT syndrome came from a report by Kakinuma et al. (1994) in which one sib had parathyroid carcinoma, a second had parathyroid adenoma plus Wilms tumor, and a third had parathyroid adenoma plus jaw tumor. Szabo et al. (1995) studied 6 hereditary Wilms tumor families, including 29 affected members, and found no linkage to 1q markers closely linked with HRPT2. Furthermore, 9 parathyroid adenomas and one Wilms tumor from 9 members of 3 HPT-JT families showed no loss of heterozygosity at the HRPT2-linked loci.
Teh et al. (1996) reported 2 families with HPT-JT syndrome in which adult renal hamartomas or cystic kidney disease were prominent associated features, possibly representing a new phenotypic variant of the HPT-JT syndrome. In the first family, renal lesions were present in 5 of 6 affected individuals, whereas HPT and jaw tumors (JT) were seen in 4 and 2 cases, respectively. In the second family, JT was found in 3 of the 5 affected individuals, and 2 affected members also exhibited polycystic kidney disease. The possibility of the latter cosegregating as a separate autosomal dominant gene cannot be ruled out. A sex-dependent penetrance of primary HPT, resulting in predominantly male-affected cases was evident in the 2 families.
Pidwirny et al. (1995) found that the proband in the Canadian family reported by Kennett and Pollick (1971) had died of parathyroid carcinoma, that the family was a branch of a kindred reported by Rosen and Palmer (1981), and that a member of the second branch had also died of parathyroid cancer. This and other experiences established parathyroid cancer as part of the hyperparathyroidism-jaw tumor syndrome occurring in at least 1 patient in 5 (42%) of the 12 known families.
Fujikawa et al. (1998) described 2 sisters and a brother, young adults, with hyperparathyroidism due to multiple parathyroid adenomas without evidence of other endocrinologic abnormalities. A 22-year-old woman had 2 parathyroid adenomas complicated by multiple ossifying jaw fibromas. Her sister, aged 29, also suffered from primary hyperparathyroidism associated with 2 parathyroid adenomas, 1 of which was also suspected to be a carcinoma. These 2 woman had unusual multiple small uterine polyps, which were diagnosed as adenomyomatous polyps. Their brother, aged 17, had 2 parathyroid adenomas complicated by urolithiasis. Fujikawa et al. (1998) tabulated the findings in previously reported families. The tabulation indicated that parathyroid lesions tend to be malignant in familial idiopathic hyperparathyroidism.
The transmission pattern of HRPT2 in the families reported by Carpten et al. (2002) was consistent with autosomal dominant inheritance.
Szabo et al. (1995) performed genetic linkage studies in 5 families containing a total of 20 individuals with the hereditary hyperparathyroidism-jaw tumor syndrome. They mapped the HRPT2 locus to 1q21-q31 and found a maximum lod score of 6.10 at theta = 0.0 with marker D1S212.
Teh et al. (1996) determined that the disease in their 2 kindreds was linked to 5 markers in the 1q21-q32 region (lod scores: 3.2-4.2), whereas linkage to the MEN1 and MEN2 regions was excluded. Meiotic recombinations detected in affected individuals placed the locus telomeric of D1S215, thus narrowing the HRPT2 region from over 60 to approximately 34 cM. Loss of heterozygosity (LOH) was studied in 7 renal hamartomas from 2 affected individuals in the first family, as well as in a jaw tumor and a parathyroid tumor from the second family. All renal hamartomas showed LOH in the 1q21-q32 region. All losses involved the wildtype allele derived from the unaffected parent, suggesting the inactivation of a tumor suppressor gene in this region.
Hobbs et al. (1999) studied 2 HPT-JT families identified through the literature. These 2 expanded families and 2 previously reported families were investigated jointly for linkage with 21 new, closely linked markers. Multipoint linkage analysis resulted in a maximum lod score of 7.83 at a recombination fraction of 0.0 for markers D1S2848-D1S191. Recombination events in these families reduced the HRPT2 region to approximately 14.7 cM. In addition, 2 of the 4 families shared a 2.2-cM segment of their affected haplotype, indicating a possible common origin. Combining the linkage data and shared-haplotype data, Hobbs et al. (1999) proposed a 0.7-cM candidate region for HRPT2.
Haven et al. (2000) reported a large Dutch kindred in which 13 affected members presented with either parathyroid adenoma or carcinoma; in 5 affected individuals, cystic kidney disease was found. Additionally, pancreatic adenocarcinoma, renal cortical adenoma, papillary renal cell carcinoma, testicular mixed germ cell tumor with major seminoma component, and Hurthle cell thyroid adenoma were also identified. Linkage analysis of the family using MEN1-linked microsatellite markers and mutation analysis excluded the involvement of the MEN1 gene. Using markers from the HPT-JT region in 1q25-q31, cosegregation with the disease was found, with a maximum lod score of 2.41 obtained for 6 markers using the most conservative calculation. Meiotic telomeric recombination between D1S413 and D1S477 was identified in 3 affected individuals, and when combined with previous reports, delineated the HPT-JT region to 14 cM.
Carpten et al. (2002) further refined the HRPT2 region to a critical interval of 12 cM by genotyping in 26 affected kindreds.
Using a positional candidate approach, Carpten et al. (2002) identified a single gene, which they called HPRT2, in which 13 different heterozygous, germline, and activating mutations (e.g., 607393.0001) were found in 14 families with HPT-JT. The proposed role of this gene, also known as CDC73, as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified 3 somatic inactivating mutations, all located in exon 1. None of these mutations was detected in normal controls, and all were predicted to cause deficient or impaired protein function.
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]
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]
Fujikawa, M., Okamura, K., Sato, K., Mizokami, T., Tamaki, K., Yanagida, T., Fujishima, M. Familial isolated hyperparathyroidism due to multiple adenomas associated with ossifying jaw fibroma and multiple uterine adenomyomatous polyps. Europ. J. Endocr. 138: 557-561, 1998. [PubMed: 9625369] [Full Text: https://doi.org/10.1530/eje.0.1380557]
Haven, C. J., Wong, F. K., van Dam, E. W. C. M., van der Luijt, R., van Asperen, C., Jansen, J., Rosenberg, C., de Wit, M., Roijers, J., Hoppener, J., Lips, C. J., Larsson, C., Teh, B. T., Morreau, H. A genotypic and histopathological study of a large Dutch kindred with hyperparathyroidism-jaw tumor syndrome. J. Clin. Endocr. Metab. 85: 1449-1454, 2000. [PubMed: 10770180] [Full Text: https://doi.org/10.1210/jcem.85.4.6518]
Hobbs, M. R., Pole, A. R., Pidwirny, G. N., Rosen, I. B., Zarbo, R. J., Coon, H., Heath, H., III, Leppert, M., Jackson, C. E. Hyperparathyroidism-jaw tumor syndrome: the HRPT2 locus is within a 0.7-cM region on chromosome 1q. Am. J. Hum. Genet. 64: 518-525, 1999. [PubMed: 9973288] [Full Text: https://doi.org/10.1086/302259]
Hobbs, M. R., Rosen, I. B., Jackson, C. E. Revised 14.7-cM locus for the hyperparathyroidism-jaw tumor syndrome gene, HRPT2. (Letter) Am. J. Hum. Genet. 70: 1376-1377, 2002. [PubMed: 11951180] [Full Text: https://doi.org/10.1086/340093]
Inoue, H., Miki, H., Oshimo, K., Tanaka, K., Monden, Y., Yamamoto, A., Kagawa, S., Sano, N., Hayashi, E., Nagayama, M., Hayashi, Y. Familial hyperparathyroidism associated with jaw fibroma: case report and literature review. Clin. Endocr. 43: 225-229, 1995. [PubMed: 7554319] [Full Text: https://doi.org/10.1111/j.1365-2265.1995.tb01919.x]
Jackson, C. E., Norum, R. A., Boyd, S. B., Talpos, G. B., Wilson, S. D., Taggert, R. T., Mallette, L. E. Hereditary hyperparathyroidism and multiple ossifying jaw fibromas: a clinically and genetically distinct syndrome. Surgery 108: 1006-1013, 1990. [PubMed: 2123361]
Jackson, C. E. Hereditary hyperparathyroidism associated with recurrent pancreatitis. Ann. Intern. Med. 49: 829-836, 1958. [PubMed: 13583774] [Full Text: https://doi.org/10.7326/0003-4819-49-4-829]
Jackson, C. E. Personal Communication. Detroit, Mich. 1994.
Kakinuma, A., Morimoto, I., Nakano, Y., Fujimoto, R., Ishida, O., Okada, Y., Inokuchi, N., Fujihara, T., Eto, S. Familial primary hyperparathyroidism complicated with Wilms' tumor. Intern Med. 33: 123-126, 1994. [PubMed: 7912571] [Full Text: https://doi.org/10.2169/internalmedicine.33.123]
Kennett, S., Pollick, H. Jaw lesions in familial hyperparathyroidism. Oral Surg. Oral Med. Oral Path. 31: 502-510, 1971. [PubMed: 5279024] [Full Text: https://doi.org/10.1016/0030-4220(71)90347-1]
Mallette, L. E., Malini, S., Rappaport, M. P., Kirkland, J. L. Familial cystic parathyroid adenomatosis. Ann. Intern. Med. 107: 54-60, 1987. [PubMed: 3592449] [Full Text: https://doi.org/10.7326/0003-4819-107-1-54]
Pidwirny, G. N., Szabo, J., Hobbs, M., Heath, H., Jackson, C. E. Followup of two hyperparathyroidism-jaw tumor syndrome families reported in 1971 and 1981 reveals that they are related and that parathyroid cancer is a part of the syndrome. (Abstract) Am. J. Hum. Genet. 57: A75 only, 1995.
Rosen, I. B., Palmer, J. A. Fibroosseous tumors of the facial skeleton in association with primary hyperparathyroidism: an endocrine syndrome or coincidence? Am. J. Surg. 142: 494-498, 1981. [PubMed: 7283054] [Full Text: https://doi.org/10.1016/0002-9610(81)90382-2]
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]
Szabo, J., Heath, B., Hill, V. M., Jackson, C. E., Zarbo, R. J., Mallette, L. E., Chew, S. L., Besser, G. M., Thakker, R. V., Huff, V., Leppert, M. F., Heath, H., III. Hereditary hyperparathyroidism-jaw tumor syndrome: the endocrine tumor gene HRPT2 maps to chromosome 1q21-q31. Am. J. Hum. Genet. 56: 944-950, 1995. [PubMed: 7717405]
Teh, B. T., Farnebo, F., Kristoffersson, U., Sundelin, B., Cardinal, J., Axelson, R., Yap, A., Epstein, M., Heath, H., III, Cameron, D., Larsson, C. Autosomal dominant primary hyperparathyroidism and jaw tumor syndrome associated with renal hamartomas and cystic kidney disease: linkage to 1q21-q32 and loss of the wild type allele in renal hamartomas. J. Clin. Endocr. Metab. 81: 4204-4211, 1996. [PubMed: 8954016] [Full Text: https://doi.org/10.1210/jcem.81.12.8954016]
Warnakulasuriya, S., Markwell, B. D., Williams, D. M. Familial hyperparathyroidism associated with cementifying fibromas of the jaws in two siblings. Oral Surg. Oral Med. Oral Path. 59: 269-274, 1985. [PubMed: 3856818] [Full Text: https://doi.org/10.1016/0030-4220(85)90165-3]