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

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

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 *CDKN1B* mutation [72].

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 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 Frederiksen and co-workers [72].
