Table 1.

Genes implicated in syndromic and sporadic parathyroid tumorigenesis, and related syndromes

Gene	Protein encoded	Associated hyperparathyroid syndrome: main syndromic manifestations	Features of syndromic parathyroid tumors	Defect in sporadic parathyroid tumors
MEN1	Menin	Multiple endocrine neoplasia type 1 (MEN1): anterior pituitary, parathyroid, enteropancreatic, foregut carcinoid tumors	Multiple, asymmetric tumors typical (> 99% benign)	Inactivation in ~25–35% of benign tumors; mutation exceedingly rare in cancer
CDC73/HRPT2	Parafibromin	Hyperparathyroidism-jaw tumor syndrome: fibro-osseous jaw, parathyroid, uterine tumors; renal cysts	Single tumor common (~15% malignant)	Inactivation in ~70% of cancers; mutation rare in sporadic adenomas
CDKN1B	P27(Kip1)	Multiple endocrine neoplasia type 4 (MEN4): anterior pituitary, other involvement varies	Single to multiple glands (benign in reports to date); can be recurrent	Loss-of-function mutation in ~5% of sporadic adenomas; including germline mutation in sporadic presentation
CASR	Calcium-sensing receptor	Familial hypocalciuric hypercalcemia type 1 (FHH1) with heterozygous inactivation; neonatal severe hyperparathyroidism (NSHPT) with homozygous inactivation	FHH1: near-normal size and surgical pathology; altered serum calcium set-point for PTH release NSHPT: Marked enlargement of multiple glands by polyclonal (non-neoplastic) mechanism	Decreased expression common; mutation exceedingly rare
GNA11	G protein subunit α11	Familial hypocalciuric hypercalcemia type 2 (FHH2)	ND	ND
AP2S1	adaptor protein-2 sigma subunit	Familial hypocalciuric hypercalcemia type 3 (FHH3): hypercalcemia more severe than in FHH1	ND	ND
RET	c-Ret	Multiple endocrine neoplasia type 2A: medullary thyroid cancer, pheochromocytoma, parathyroid tumors	Single tumor common (> 99% benign)	Mutation exceedingly rare
CCND1/PRAD1	Cyclin D1	NA	NA	Overexpression results from DNA rearrangement involving PTH gene

NA, not applicable

ND, not determined due to lack of relevant published studies