New Concepts About Familial Isolated Hyperparathyroidism

Context Familial isolated hyperparathyroidism (FIHP) is defined as familial primary hyperparathyroidism (FH) without a characteristic extraparathyroidal feature of a more complex hyperparathyroid syndrome. New concepts of FIHP have been developed within this definition. FIHP has been difficult to study due to small kindreds and mildly symptomatic cases. Evidence Acquisition Searches were through PubMed for FIHP, other FH syndromes, and the gene(s) mutated in each. Evidence Synthesis Within its definition, the current concept of FIHP has clinical and mutational components that can include incomplete expressions of multiple endocrine neoplasia type 1 (MEN1) familial hypocalciuric hypercalcemia, hyperparathyroidism-jaw tumor syndromes, or their mutations. Newest concepts of FIHP focus on kindreds without mutation of the MEN1, CASR, or CDC73 genes; 17% have germline activating mutation of the gene for the GCM2 transcription factor. The FIHP kindreds with or without GCM2 mutation contain a median of only two cases of primary hyperparathyroidism. The small kindred size in both subgroups of FIHP is probably caused by a low rate of screening among relatives. Persons with FIHP and GCM2 mutation present as adults with mild hypercalcemia and multiple parathyroid tumors. Conclusion The current concept of FIHP led to a focus on small kindreds without mutation of MEN1, CASR, or CDC73. These assisted in identifying germline activating GCM2 mutations in 17% of kindreds. Clinical and mutational characterization in more cases is needed to determine if there are any unique clinical features of FIHP, with or without mutation of GCM2.