**10. Familial hypocalciuric hypercalcemia (FHH)**

FHH is a condition of PTH-dependent hypercalcemia, often resembling HPT, that is clinically benign and genetically heterogeneous (**Table 1**) [22]. Following partial or subtotal parathyroidectomy, affected patients from FHH kindreds almost always remain hypercalcemic. FHH is transmitted in an autosomal dominant fashion and usually causes mild hypercalcemia with relative hypocalciuria. The hypercalcemia seen in FHH is highly penetrant across all ages, including in infants [22, 83]. The majority of cases of FHH result from heterozygous germline inactivating mutation of the *CASR* gene on the long arm of chromosome 3 that encodes the calcium-sensing receptor [10, 84], and is classified as type 1 FHH (FHH1). Neonatal severe hyperparathyroidism (NSHPT), a rare autosomal recessive disorder typically presenting with severe hypercalcemia occurring in the first 6 months of life, most often results from the compound heterozygous or homozygous inheritance of two loss-of-function mutant *CASR* alleles [85]. Rather than the cellular monoclonality that would be expected in true parathyroid tumors, molecular genetic analysis of the hyperfunctioning parathyroid glands removed from a patient with NSHPT

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MEN2A [98].

*Familial Syndromes of Primary Hyperparathyroidism DOI: http://dx.doi.org/10.5772/intechopen.93036*

mutation [86].

reported [88, 89].

demonstrated generalized polyclonal hyperplasia, underscoring the non-neoplastic nature of the abnormal parathyroid glands associated with *CASR* inactivating

Loss of surface expression of the CASR protein has been documented in parathyroid adenomas and may contribute to the altered calcium set point and impaired calcium-mediated negative feedback on the release of PTH typical of such adenomas. Decreased *CASR* mRNA expression, but not LOH at the *CASR* locus, has been documented in parathyroid adenomas [87]. In sporadic parathyroid tumors studied to date, somatic inactivation of the *CASR* gene has not been

Type 2 FHH (FHH2) resulting from germline loss-of-function mutation of *GNA11*, encoding the G protein α11 subunit [90, 91], and type 3 FHH (FHH3) resulting from germline inactivating mutation in *AP2S1*, the gene that encodes an adaptor protein involved in endocytosis mediated by clathrin [92–95], have also been described. In studies of sporadic parathyroid tumors, somatic inactivating

MEN2A is a familial cancer syndrome characterized by a predisposition to the development of medullary thyroid cancer (MTC), pheochromocytoma (typically benign and often bilateral), and primary HPT. In the context of MEN2A, HPT is usually mild and resembles sporadic HPT. HPT in MEN2A is almost always results from benign parathyroid disease. MEN2A is an autosomal dominant disorder that results from germline gain-of-function mutation in the *RET* proto-oncogene at chromosomal location 10q11. *RET* encodes a receptor tyrosine kinase that binds the ligand glial derived neurotrophic factor, together with a glycosylphosphatidylinosi-

Germline oncogenic mutations of *RET* are associated with three distinct familial endocrine neoplasia syndromes, all associated with MTC: MEN2A, multiple endocrine neoplasia type 2B (MEN2B), and familial medullary thyroid cancer (FMTC). The disease spectrum of typical MEN2B or FMTC does not include parathyroid tumors and HPT. Genotype–phenotype correlations based on particular *RET* mutations are apparent and account for the distinct patterns of disease. Some 95% of MEN2A cases are due to the presence in the germline of nonsynonymous variants affecting the RET receptor's extracellular cysteine-rich domain, namely missense mutations of *RET* codons 609, 611, 618, 620, or 634 [97]. In fact, germline missense alteration of RET residue cysteine-634 accounts for approximately 85% of cases of

**12. Parathyroid tumorigenesis involving the CCND1 oncogene**

The discovery of the *CCND1* (or *PRAD1*, for parathyroid adenomatosis 1) oncogene resulted from the analysis of several large, non-familial, parathyroid adenomas that harbored DNA re-arrangements that involved the PTH gene locus [99–101]. A breakpoint resulting from the pericentromeric inversion of chromosome 11 DNA was identified just upstream of the *CCND1/PRAD1* oncogene [101]. The inversion positioned the PTH gene regulatory region, that is normally located on the short arm of chromosome 11, just upstream of the *CCND1/PRAD1* protooncogene located on 11q [99–101]. The product encoded by the proto-oncogene

mutations of *GNA11* and *AP2S1* have so far not been reported.

**11. Multiple endocrine neoplasia type 2A (MEN2A)**

tol-anchored protein co-receptor Gfra1 [96].

*Familial Syndromes of Primary Hyperparathyroidism DOI: http://dx.doi.org/10.5772/intechopen.93036*

*Mineral Deficiencies - Electrolyte Disturbances, Genes, Diet and Disease Interface*

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

**10. Familial hypocalciuric hypercalcemia (FHH)**

FHH is a condition of PTH-dependent hypercalcemia, often resembling HPT, that is clinically benign and genetically heterogeneous (**Table 1**) [22]. Following partial or subtotal parathyroidectomy, affected patients from FHH kindreds almost always remain hypercalcemic. FHH is transmitted in an autosomal dominant fashion and usually causes mild hypercalcemia with relative hypocalciuria. The hypercalcemia seen in FHH is highly penetrant across all ages, including in infants [22, 83]. The majority of cases of FHH result from heterozygous germline inactivating mutation of the *CASR* gene on the long arm of chromosome 3 that encodes the calcium-sensing receptor [10, 84], and is classified as type 1 FHH (FHH1). Neonatal severe hyperparathyroidism (NSHPT), a rare autosomal recessive disorder typically presenting with severe hypercalcemia occurring in the first 6 months of life, most often results from the compound heterozygous or homozygous inheritance of two loss-of-function mutant *CASR* alleles [85]. Rather than the cellular monoclonality that would be expected in true parathyroid tumors, molecular genetic analysis of the hyperfunctioning parathyroid glands removed from a patient with NSHPT

Frederiksen and co-workers [72].

of familial HPT, particularly in the evaluation of germline *MEN1* mutation-negative families who yet have MEN1-like features. The strongest justification for this follows from consideration of the Danish kindred in which 13 unique family members manifest HPT linked to germline inactivating mutation of *CDKN1B*, described by

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

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penetrance [82].

demonstrated generalized polyclonal hyperplasia, underscoring the non-neoplastic nature of the abnormal parathyroid glands associated with *CASR* inactivating mutation [86].

Loss of surface expression of the CASR protein has been documented in parathyroid adenomas and may contribute to the altered calcium set point and impaired calcium-mediated negative feedback on the release of PTH typical of such adenomas. Decreased *CASR* mRNA expression, but not LOH at the *CASR* locus, has been documented in parathyroid adenomas [87]. In sporadic parathyroid tumors studied to date, somatic inactivation of the *CASR* gene has not been reported [88, 89].

Type 2 FHH (FHH2) resulting from germline loss-of-function mutation of *GNA11*, encoding the G protein α11 subunit [90, 91], and type 3 FHH (FHH3) resulting from germline inactivating mutation in *AP2S1*, the gene that encodes an adaptor protein involved in endocytosis mediated by clathrin [92–95], have also been described. In studies of sporadic parathyroid tumors, somatic inactivating mutations of *GNA11* and *AP2S1* have so far not been reported.
