Clinical Features, Treatment, and Surveillance of Hyperparathyroidism-Jaw Tumor Syndrome: An Up-to-Date and Review of the Literature

Abstract

Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is an autosomal dominant disorder characterized by parathyroid tumors in association with fibro-osseous jaw tumors and uterine and renal lesions. HPT-JT syndrome is caused by germline mutations of the cell division cycle 73 (CDC73) gene that encodes the parafibromin, a 531-amino acid protein with antiproliferative activity. Primary hyperparathyroidism is the main finding of HPT-JT syndrome, usually caused by a single-gland parathyroid involvement (80% of cases), at variance with other variants of hereditary hyperparathyroidism, in which a multiglandular involvement is more frequent. Moreover, parathyroid carcinoma may occur in approximately 20% of cases. Surgery is the treatment of choice for primary hyperparathyroidism, but the extent of surgery remains controversial, varying between bilateral neck and focused exploration, with subtotal or limited parathyroidectomy. Recently, more limited approaches and parathyroid excisions have been suggested in order to decrease the risk of permanent hypoparathyroidism, the main surgical morbidity following more extensive surgical approaches. Ossifying fibromas of the mandible or maxilla may present only in a minority of cases and, even if benign, they should be surgically treated to avoid tumor growth and subsequent functional limitations. Benign and malignant uterine involvement (including leiomyomas, endometrial hyperplasia, adenomyosis, multiple adenomyomatous polyps, and adenosarcomas) is the second most common clinical feature of the syndrome, affecting more than 50% of CDC73-carrier women. Genetic testing should be performed in all family members of affected individuals, in young patients undergoing surgery for primary hyperparathyroidism, or in presence of other associated tumors, allowing early diagnosis and prompt treatment with more tailored surgery. Moreover, CDC73 mutation carriers should be also periodically screened for primary hyperparathyroidism and the other associated tumors. The present review was aimed to summarize the main clinical features of HPT-JT syndrome, focusing on genetic screening and surgical treatment, and to revise the available literature.

Genomics and Epigenomics in Parathyroid Neoplasia: from Bench to Surgical Pathology Practice

“…In MEN2A, most patients (> 90%) develop medullary thyroid carcinoma and pheochromocytoma (50%), whereas PHPT is more uncommon, occurring in 15–30% of patients [ 8 , 38 ]. For HPT-JT kindred, 70–80% develop PHPT, whereas approximately 10% of patients also develop ossifying fibromas of the mandible or maxilla [ 8 , 39 ]. PHPT in MEN1 usually presents as multiglandular disease that may develop in synchronous or metachronous settings and may be asymmetric.…”

Hyperparathyroidism-Jaw Tumor Syndrome

“…HPT-JT is caused by germline mutations of the cell division cycle 73 ( CDC73 ) gene that encodes the parafibroma, an amino acid protein with antiproliferative action. Although 75% of patients with HPT-JT have germline mutations within the coding region, 25% of HPT-JT patients may have abnormalities in CDC73 promoter regions, whole-exon or gene deletions, or mutations in epigenetic modifications or in unidentified genes [ 4 , 5 , 6 , 7 ]. This syndrome classically presents with parathyroid adenoma, ossifying tumors of the mandible, and renal or uterine neoplasms [ 5 ].…”

“…Early recognition and treatment are important as the hypercalcemia tends to be more severe than with spontaneous parathyroid adenomas or MEN1 [ 6 ]. A single parathyroid adenoma is the most common presentation, and surgical resection is often curative of hyperparathyroidism [ 4 , 7 ]. Our patient had an allele mutation associated with HPT-JT, a young age at onset for hyperparathyroidism, and a family history suggestive of an inherited calcium metabolism disorder.…”

“…Many patients are treated with hysterectomy at an early age. Women should undergo routine gynecologic care and pelvic imaging when clinically indicated at the onset of menarche, although there is no established guideline on this [ 4 ]. In this case, the patient had symptoms of menorrhagia and no evidence of uterine tumor on pelvic ultrasonography.…”

Familial Hyperparathyroidism

“…HPT is the most penetrant feature of HPT-JT and is the manifestation that most often brings carriers to medical attention. Besides HPT, the key clinical features of HPT-JT include cemento-ossifying fibromas restricted to the maxilla and mandible (as described above), renal lesions, and uterine tumors in women (90,(95)(96)(97). In contrast to sporadic HPT and MEN1, parathyroid cancer is relatively frequent in the context of HPT-JT, and affects~20% of those with HPT (90,95,96,98,99).…”