**7. The hyperparathyroidism-jaw tumor syndrome (HPT-JT)**

HPT-JT is a familial syndrome with variable and incomplete penetrance transmitted in an autosomal dominant fashion. The key clinical features of HPT-JT include HPT, jaw tumors (fibro-osseous tumors involving the maxilla and/or mandible, formally classified as cemento-ossifying fibromas [42], and distinct from so called "brown" tumors sometimes associated with HPT), renal cysts or tumors and uterine tumors in women [43–45]. HPT is the most penetrant feature of HPT-JT and is usually the presenting manifestation. In contrast to MEN1, parathyroid cancer is frequent in HPT-JT, affecting some 20% or more of those with HPT [43–46].

In the majority of HPT-JT kindreds, a germline loss-of-function mutation of the *CDC73* gene (formerly called *HRPT2*) can be identified [19, 47]. The majority of such *CDC73* mutations are predicted to inactivate gene function via frameshift or nonsense mutation, and only a minority of the mutations are missense [48]. Patients and kindreds with partial or complete deletion of the *CDC73* gene in the germline have also been described [49–52]. The *CDC73* gene encodes a 531-residue protein named parafibromin [47]. Because germline mutation predicted to cause loss-of-function of the *CDC73* gene predisposes to the neoplastic expressions

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*CDKN1B* mutation [72].

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

initially asymptomatic carriers is recommended [59].

**8. Multiple endocrine neoplasia type 4 (MEN4)**

MEN4/MENX kindred described who manifested HPT [60].

MEN4 is a syndrome originally described by Pellegata and coworkers in a multigenerational family with features resembling MEN1, including a proband with a growth hormone-secreting pituitary adenoma and HPT, but lacking germline *MEN1* mutation [60, 61]. A germline heterozygous truncation mutation in *CDKN1B* was identified in the proband and several members of this kindred [60]. *CDKN1B* encodes the cyclin dependent-kinase inhibitor p27 (Kip1). Attention to the *CDKN1B* locus was a consequence of a previous genetic analysis of rats with the MenX phenotype, a recessively inherited condition caused by a frameshift mutation in *Cdkn1b* [60, 62]. The MenX phenotype in rats was manifest by the development of bilateral pheochromocytomas, paragangliomas, parathyroid adenomas and thyroid C cell hyperplasia [60, 62]. In the study by Pellegata et al., the proband was the only member of the

Following the original report by Pellegata et al. [60], several groups have investigated a possible role for *CDKN1B* mutation in parathyroid tumorigenesis. None of the earlier reports of *MEN1* mutation-negative families harboring germline mutation in *CDKN1B*, and expressing MEN1-like tumors and thus classified as MEN4, had included families with more than one member with HPT proven to track with the *CDKN1B* mutation [60, 63–71], apart from the demonstration of HPT linked to *CDKN1B* mutation in monozygotic twins [64]. That was true until a more recent report by Frederiksen et al. describing a large Danish family in which HPT occurred in 13 members, spanning two generations, who carried a germline frameshift

Recent evidence supports the characterization of *CDKN1B* as a susceptibility gene for the development of primary parathyroid tumors [69, 72, 73]. This evidence validates the inclusion of germline *CDKN1B* mutation in the differential diagnosis

of HPT-JT, parafibromin is considered to be a tumor suppressor protein. Mixed epithelial tumor of the kidney (MEST), a rare type of renal tumor (formerly classified as cystic hamartoma of the renal pelvis, leiomyomatous renal hamartoma, or adult type mesoblastic nephroma), has been associated with HPT-JT and appears to correlate with a specific *CDC73* genotype, namely the Met1ILe missense mutation replacing the initiator methionine of parafibromin with isoleucine [47, 53, 54]. Somatic mutation of the *CDC73* tumor suppressor gene is uncommon in sporadic parathyroid adenomas [55]. In contrast to the results of analyses in benign parathyroid tumors, mutations of *CDC73* are quite frequently seen in apparently sporadic cases of parathyroid cancer [56–58]. Interestingly, recurrent somatic mutations in *CDC73* have been documented by exome sequence analysis of tumor DNA from parathyroid cancers [40, 41]. Selective amplification of the mutant copy of *CDC73* has been demonstrated in a subset of parathyroid carcinomas [40]. Approximately 25% of cases of seemingly sporadic parathyroid carcinoma may possess germline loss-of-function alterations in *CDC73*, suggesting that such patients may in fact have previously unrecognized, or *formes frustes* of, HPT-JT [19, 57, 58]. A minority of patients and families classified as FIHP can be shown to carry *CDC73* mutation in the germline, suggesting that this inherited disorder may in some cases be phenocopied by incompletely penetrant HPT-JT (see below and **Figure 1**). Approximately 20% of genetically confirmed or obligate *CDC73* mutation-positive family members lack HPT, fibro-osseous jaw tumors, or other manifestations of HPT-JT when their kindred is initially ascertained. Because the penetrance of the manifestations of HPT-JT increases with age among *CDC73* mutation carriers, lifelong surveillance of

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

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

**7. The hyperparathyroidism-jaw tumor syndrome (HPT-JT)**

*of overlap between circles has any quantitative significance.*

*The relationship among familial forms of hyperparathyroidism that may present as familial isolated hyperparathyroidism (FIHP) as a Venn diagram. The dashed circle represents the set of patients that can present with a provisional diagnosis of FIHP at the time of initial ascertainment. This includes patients with FIHP who have been evaluated for, but lack findings diagnostic of, MEN1, FHH and HPT-JT (nonsyndromic FIHP; in a solid circle). Approximately 18% of nonsyndromic FIHP kindreds harbor germline gain-of-function mutations in GCM2 (see text), whereas the remainder have currently unknown genetic etiologies. Subsets of patients with incomplete expression of MEN1, FHH and HPT-JT (the total set of patients in each syndrome represented by a solid circle) can also present with the FIHP phenotype (and thus overlap with the dashed circle). The distinction between the nonsyndromic FIHP category and the syndromic categories arbitrarily depends on the thoroughness of evaluation and the sensitivity of diagnostic tests used to detect the syndrome that can include germline gene mutational testing. MEN2A is a familial form of hyperparathyroidism that seldom if ever presents as FIHP. Within each circle representing a defined syndrome are included the genetic locus (or loci in the case of FHH; see text) of the syndromic trait and the associated gene product. The causative gene for HPT-JT encoding parafibromin is CDC73, formerly called HRPT2. The relationship among the patient sets illustrated as circles in this diagram is intended to be qualitative and neither the area of each circle nor the area* 

HPT-JT is a familial syndrome with variable and incomplete penetrance transmitted in an autosomal dominant fashion. The key clinical features of HPT-JT include HPT, jaw tumors (fibro-osseous tumors involving the maxilla and/or mandible, formally classified as cemento-ossifying fibromas [42], and distinct from so called "brown" tumors sometimes associated with HPT), renal cysts or tumors and uterine tumors in women [43–45]. HPT is the most penetrant feature of HPT-JT and is usually the presenting manifestation. In contrast to MEN1, parathyroid cancer is frequent in HPT-JT, affecting some 20% or more of those with HPT [43–46]. In the majority of HPT-JT kindreds, a germline loss-of-function mutation of the *CDC73* gene (formerly called *HRPT2*) can be identified [19, 47]. The majority of such *CDC73* mutations are predicted to inactivate gene function via frameshift or nonsense mutation, and only a minority of the mutations are missense [48]. Patients and kindreds with partial or complete deletion of the *CDC73* gene in the germline have also been described [49–52]. The *CDC73* gene encodes a 531-residue protein named parafibromin [47]. Because germline mutation predicted to cause loss-of-function of the *CDC73* gene predisposes to the neoplastic expressions

**118**

**Figure 1.**

of HPT-JT, parafibromin is considered to be a tumor suppressor protein. Mixed epithelial tumor of the kidney (MEST), a rare type of renal tumor (formerly classified as cystic hamartoma of the renal pelvis, leiomyomatous renal hamartoma, or adult type mesoblastic nephroma), has been associated with HPT-JT and appears to correlate with a specific *CDC73* genotype, namely the Met1ILe missense mutation replacing the initiator methionine of parafibromin with isoleucine [47, 53, 54]. Somatic mutation of the *CDC73* tumor suppressor gene is uncommon in sporadic parathyroid adenomas [55]. In contrast to the results of analyses in benign parathyroid tumors, mutations of *CDC73* are quite frequently seen in apparently sporadic cases of parathyroid cancer [56–58]. Interestingly, recurrent somatic mutations in *CDC73* have been documented by exome sequence analysis of tumor DNA from parathyroid cancers [40, 41]. Selective amplification of the mutant copy of *CDC73* has been demonstrated in a subset of parathyroid carcinomas [40]. Approximately 25% of cases of seemingly sporadic parathyroid carcinoma may possess germline loss-of-function alterations in *CDC73*, suggesting that such patients may in fact have previously unrecognized, or *formes frustes* of, HPT-JT [19, 57, 58]. A minority of patients and families classified as FIHP can be shown to carry *CDC73* mutation in the germline, suggesting that this inherited disorder may in some cases be phenocopied by incompletely penetrant HPT-JT (see below and **Figure 1**). Approximately 20% of genetically confirmed or obligate *CDC73* mutation-positive family members lack HPT, fibro-osseous jaw tumors, or other manifestations of HPT-JT when their kindred is initially ascertained. Because the penetrance of the manifestations of HPT-JT increases with age among *CDC73* mutation carriers, lifelong surveillance of initially asymptomatic carriers is recommended [59].
