Hyperparathyroidism -- Etiology, Diagnosis and Treatment

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

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Abstract

85% of sporadic hyperparathyroidism cases have a solitary adenoma. The remaining 15% of cases have multiple tumors. Adverse outcomes are increased in multigland disease and in cases with prior failed operation; the adverse outcomes include damage to important structures such as the recurrent laryngeal nerve(s), hypoparathyroidism, persistent hyperparathyroidism, and late recurrent hyperparathyroidism. Approximately half of new referrals to NIH have had prior failed neck exploration for hyperparathyroidism and are referred because of our expertise in such cases. The surgical success rate at NIH in these difficult cases has been 95%. This group is enriched for multi gland hyperparathyroidism and thus for hereditary causes. We have contributed to an intramural NIH collaboration that has cloned the MEN1 gene. We are continuing to explore its clinical and its basic implications. We find germline mutations in 70-80% of probands with familial MEN1 or at lower prevalence in cases with sporadic MEN1. In contrast, probands with familial isolated hyperparathyroidism have rare (about 5%) MEN1 mutations. Among the MEN1-like families without MEN1 mutation, a rare family shows mutation of the p27 cylclin dependent kinase inhibitor (CDKI) gene. p27 germline mutation in MEN1 is about 1% the frequency of MEN1 mutation. We have also found rare germline mutation of p15, p18, or p21 CDKIs. We have also found somatic MEN1 mutation in 15 to 35% of sporadic tumors of many endocrine organs. Thus MEN1 is the gene most frequently implicated in common endocrine tumors. We found p18 CDKI in a sporadic parathyroid adenoma. We will also determine the spectrum of pathologic states that the MEN1 or the CDKI genes contribute to through mutation and other mechanisms. Mutation of the cyclin D1 (PRAD1) gene accounts for about 3-4%. Sporadic (nonhereditary) mutation of the MEN1 gene is the most common known mutation, causing 25-30% of solitary and common variety adenomas. The ZFX gene is mutated in 6%. Of the 15% of cases with multigland disease, 5% (1/3 of 15%) have a familial form. 4% of the 5% have familial MEN1 or familial hypocalciuric hypercalcemia. About 1% have familial isolated hyperparathyroidism (FIHP). The underlying gene for FIHP is GCM2 (gain-of-function mutation) in approximately 20% of cases. The underlying gene(s)for the remaining 80% of FIHP are not known. Our work has also identified variants in FLCN gene as a cause of parathyroid cancer. We are working to identify and genotype-phenotype correlation in MEN1 and other genetic forms of primary hyperparathyroidism. Another disease of interest is Jansen Metaphyseal Chondrodysplasia (JMC), caused by constitutive activation of PTH1R. Our work has revealed that patients with JMC have a distinct facial appearance and have an increased predisposition to hearing loss, optic neuropathy, craniosynostosis, dentoskeletal malocclusion and airway compromise.