HYPERPARATHYROIDISM–JAW TUMOURS SYNDROME
Hyperparathyroidism-jaw Tumours syndrome (HPT-JT) is an autosomal dominant disorder characterized by parathyroid adenoma or carcinoma, ossifying fibroma of the mandible and/or maxilla, and renal cysts, adenomas, and carcinomas. Germline mutations in HRPT2, currently known as CDC73, encoding parafibromin, are associated with HPT-JT (Carpten et al. 2002; Newey et al. 2010). Typically, HPT-JT patients present with solitary parathyroid adenomas or carcinomas. Rarely, they present with double neoplasias. Parathyroid carcinomas are extremely rare and are not components of any other heritable syndrome. So its presence should raise the genetic differential diagnosis of HPT-JT. Approximately 80 % of HPT-JT patients present with hyperparathyroidism (HPT). Parathyroid carcinoma, manifesting as primary hyperparathyroidism, occurs in approximately 10–15 % of affected individuals. A unique pathologic feature of parathyroid lesions in HPT-JT is the high frequency of cystic changes. About 30 % of patients also develop fibro-osseous lesions, primarily in the mandible and/or maxilla. Kidney lesions have been reported including bilateral cysts, renal adenoma, hamartomas, and papillary or chromophobe RCC. It is important to be aware that in some families, only parathyroid lesions are present (FIHP). Thus, HPT-JT (>50–80 % of patients), parathyroid carcinoma (20 % of all apparently sporadic cases), and familial isolated hyperparathyroidism (FIHP; 15 %) associated with germline mutations in CDC73 are under the umbrella term CDC73-related disorders (Newey et al. 2010).
Germline mutations in CDC73, located on 1q25–q31, cause HPT-JT (Teh et al. 1996; Carpten et al. 2002). CDC73 has 17 exons spanning 18.5 kb of genomic distance. HPT-JT-associated mutations are truncating, mainly (>80
%) frameshift and nonsense, with the majority occurring in exon 1 (Carpten et al. 2002; Newey et al. 2010). Recently, a germline large deletion in CDC73 was reported (Cascon et al. 2011) Because this gene was recently identified, it remains unknown whether a genotype-phenotype association exists. The penetrance for HPT is 80 %, which mainly will develop by the late teens. The CDC73 transcript is 2.7 kb and is predicted to encode a 531-amino acid protein. While the gene is ubiquitously expressed, its function remained unknown for some time. Subsequently, parafibromin was shown to bind RNA Pol II as part of the PAF1 transcriptional regulatory complex (Yart et al. 2005) and importantly was found to mediate histone H3 K9 methylation which silences cyclin D1 expression (Yang et al. 2010).
Individuals and families who have or are suspected of having HPT-JT should be offered clinical cancer genetic consultation, which includes genetic counseling. When HPT-JT is suspected in a family or individual, DNA-based testing may be offered to establish the diagnosis and for medical management. Because CDC73 has been identified, molecular-based differentiation of the various complex syndromes associated with hereditary primary HPT has become possible. Clinical surveillance and prophylactic maneuvers in HPT-JT are based on expert opinion. Annual blood-based biochemical tests for ionized calcium and intact parathyroid hormone levels beginning by or slightly after age 10 have been advocated. Following the example of multiple endocrine neoplasia type 1 (MEN 1), some believe that surgical intervention should occur once serum levels confirm the presence of HPT. Parathyroid disease in HPT-JT is typically asynchronous adenomas although the potential for malignancy needs to be seriously considered (Howell et al. 2003; Shattuck et al. 2003). While some groups advocate removal only of the enlarged parathyroid gland with continued regular monitoring, the alternative approach would be complete parathyroidectomy with fresh parathyroid autotransplantation to the forearm (or sternocleidomastoid) (Marx et al. 2002; Chen et al. 2003). Because of the unclear frequencies of jaw manifestations and renal neoplasias, it is unknown if surveillance for these component features would prove useful. The more aggressive among HPT-JT exponents would suggest orthopentography of the jaw every 3 years as well as abdominal ultrasound or CT scan with and without contrast at least every 5 years after syndrome diagnosis to screen for polycystic disease, Wilms Tumours or carcinoma, and renal hamartomas (Chen et al. 2003; Newey et al. 2010).