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Primary hyperparathyroidism, a common endocrine disorder, is associated with familial disease in about 10% of cases. These syndromes include multiple endocrine neoplasia types 1, 2A and 4 (MEN1, MEN2A, MEN4), familial isolated hyperparathyroidism (FIHP), and the hyperparathyroidism jaw tumor (HPT-JT) syndrome. HPT-JT syndrome, an autosomal dominant disease with incomplete penetrance, results from a germline inactivating mutation in the HRPT2 gene. HPT-JT manifests with about 20% of patients having multiple enlarged parathyroid glands and/or parathyroid carcinoma. Furthermore, 28% of patients will have a recurrence during follow-up. Since these patients have a high rate of multiple enlarged parathyroid glands, parathyroid carcinoma, and recurrence, it is controversial as to what is the optimal initial surgical approach for parathyroidectomy. Clinical evidence for the optimal initial surgical approach for HPT-JT syndrome is limited to case series and retrospective small cohort studies. Furthermore, there is scant data on the clinical utility of localization studies to select the optimal operative approach. Only one study reported the results of localization studies and showed a lack of benefit due to high rates of multigland disease that would have been missed if a focused parathyroidectomy approach was used. Given the high rates of multigland disease, parathyroid carcinoma, risk of recurrence, and the possibility of missing additional enlarged glands not seen on preoperative localizing studies, bilateral neck exploration with identification of all four glands and removal of enlarged glands would be the best surgical approach given our current knowledge.

Germline genetic tests can be extremely helpful for clinical diagnosis of patients and their families when a known deleterious change is found, but there are many reasons why gene testing and interpretation is not straightforward. This chapter pertains to monogenic conditions in which the genetic contribution to a parathyroid disorder is well-established. These disorders include: familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, hyperparathyroidism-jaw tumor syndrome and parathyroid carcinoma and multiple endocrine neoplasia types 1, 2, and 4.

Familial hyperparathyroidism occurs in a handful of genetic syndromes including Multiple Endocrine Neoplasia (MEN) type 1 and 2A, Familial Hypocalciuric Hypercalcemia (FHH), and Hyperparathyroidism-Jaw Tumor Syndrome (HPT-JT). MEN 1 is characterized by a loss of function in the tumor suppressor gene, Menin, whereas MEN 2 is characterized by a gain of function mutation in the RET proto-oncogene. FHH is characterized by mutations that alter the calcium-sensing receptor in the kidney and parathyroid glands, resulting in mild hypercalcemia and elevated PTH levels. HPT-JT is characterized by hereditary predisposition to jaw tumors and benign and malignant tumors of the parathyroids. All four syndromes are autosomal dominant, with variable penetrance of degree of clinical hyperparathyroidism. Each of these disorders requires careful evaluation, diagnostic testing, genetic analysis, and potentially, surgical management.