Parathyroid neoplasias are very common; however, familial hyperparathyroidism occurs at a frequency of about 0.14 per 10,000 and, for the most part, occurs as part of the multiple endocrine neoplasia syndromes (MEN), with chief cell hyperplasia as the usual histological change. The genetic differential diagnosis of parathyroid hyperplasia or parathyroid adenoma includes MEN 1, caused by germline MEN1 mutations; MEN 2, caused by germline RET mutations; and hyperparathyroidism-jaw Tumours syndrome (HPT-JT), caused by germline mutations in HRPT2. Familial site-specific hyperparathyroidism can be caused by germline MEN1 mutations as well as due to HPT-JT (Teh et al. 1996; Kassem et al. 2000). Germline mutations in the calcium-sensing receptor gene have been identified in benign familial hypocalciuric hypercalcemia and, in homozygous form, cause neonatal severe hyperparathyroidism with parathyroid hyperplasia (Pollak et al. 1993). While parathyroid disease is very common in MEN 1 and often the first component neoplasia to manifest, hyperparathyroidism in MEN 2 occurs in 15–30 % of MEN 2A cases and likely manifests relatively later in life (Schuffenecker et al. 1998). Germline RET C634R is particularly associated with the development of hyperparathyroidism in MEN 2A (Mulligan et al. 1994; Eng et al. 1996a, b).
Parathyroid carcinoma is extremely rare, but it is an important component neoplasia of HPT-JT (Carpten et al. 2002). It is unclear, however, whether parathyroid carcinoma is a true component cancer of MEN 1 as well, but it does not appear to be so.
Somatic loss of heterozygosity (LOH) of markers on 11q13 and somatic MEN1 mutations have been described in parathyroid hyperplasias (Friedman et al. 1992). Somatic mutations in HRPT2 occur with a relatively high frequency in sporadic parathyroid carcinomas (Howell et al. 2003; Shattuck et al. 2003). Surprisingly, occult germline mutations in HRPT2 were found in 3 of the 15 apparently sporadic patients with parathyroid carcinoma (Shattuck et al. 2003).
Those at risk for parathyroid hyperplasia and/or adenoma should undergo routine clinical surveillance. Management for parathyroid disease for MEN 2.