**9. Familial isolated hyperparathyroidism (FIHP)**

By definition, FIHP is a non-syndromic category of familial HPT describing families that contain two or more members with HPT but which lack the specific features of MEN1, MEN2A, HPT-JT or FHH (**Figure 1**) [74]. FIHP is genetically heterogeneous and is a diagnosis of exclusion. While at the time of initial ascertainment germline mutation of *MEN1*, *CDC73*, or *CASR* may account for a fraction of kindreds with the FIHP phenotype [20, 34, 75–77], the majority of FIHP families lack mutations in these established HPT-susceptibility genes (**Figure 1**) [20, 75, 78].

Missense variants in GCM2, a transcription factor homologous to the Drosophila "glial cells missing" (gcm) gene and required for parathyroid gland development, were recently described in the germline DNA of eight unrelated families with FIHP [21]. Previous studies showed that germline dominant-negative and loss-of-function mutations in GCM2 were associated with autosomal dominant and autosomal recessive familial isolated hypoparathyroidism, respectively [79, 80]. The two rare germline *GCM2* genetic variants associated with FIHP act as gain-of-function mutations [21]. These missense mutations map to the C-terminal conserved inhibitory domain (CCID) of GCM2 and increase its transcriptional activity when measured *in vitro*, suggesting that *GCM2* in the context of FIHP is a parathyroid proto-oncogene. It has been estimated that approximately 18% of FIHP families harbor germline activating GCM2 mutations [21], leaving ~80% of FIHP families without a currently-identified genetic etiology [74]. Other clinical investigators have identified rare germline *GCM2* variants in a subset of FIHP kindreds [81]. Activating *GCM2* variants mapping to the CCID region have been found among patients with sporadic parathyroid tumors in low frequency and appear to be of low penetrance [82].
