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 ... 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 can not 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.
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 were found in 14 families with HPT-JT. The proposed role of this ... 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 were found in 14 families with HPT-JT. The proposed role of this gene, CDC73 (607393), 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.