Genetic Syndromes Associated with Primary Hyperparathyroidism

Abstract

A solitary benign adenoma is responsible for primary hyperparathyroidism (pHPT) in nearly 80% of the cases. The other 20% of pHPT occurs as a result of parathyroid multiglandular disease. A good proportion of these patients belong to familial forms of pHPT. In recent decades, mutations in specific genes have been identified as responsible for various hereditary types of pHPT [1]. All of them are inherited as an autosomal dominant trait, and, as opposed to the sporadic HPT, they occur in children or in young adults. Some of these forms arise in the context of a genetic syndrome, others are nonsyndromic. These forms include: multiple endocrine neoplasia (MEN) types 1, 2A, and 4; familial hypocalciuric hypercalcemia (FHH); autosomal dominant moderate hyperparathyroidism (ADMH); neonatal severe hyperparathyroidism (NSHPT); hyperparathyroidism-jaw tumor syndrome (HPT-JT); familial isolated hyperparathyroidism (FIHPT) (Tables 14.1 and 14.2). The accurate and prompt diagnosis of these genetic conditions is crucial to plan appropriate surveillance of the carriers of the genetic mutations and to perform the correct surgical management. Research on the mutations is also useful for the identification of the family members (theoretically 50% of the offspring) who do not harbor the mutation and can avoid unnecessary biochemical, radiological and instrumental investigations. The determination as to which patients with pHPT the mutational analysis should be recommended to is controversial. The current guidelines suggest that the following situations require mutational analysis: individuals with pHPT before 45 years of age; patients at any age with presence of other endocrine tumors; multiglandular parathyroid disease at any age; presence of a parathyroid carcinoma at any age. In Table 14.3, a flowchart for the approach to a selective mutational analysis on the basis of clinical, biochemical and pathological data is shown. If the mutation of the genes involved in hereditary pHPT is found, the genetic analysis should be offered to all the first-degree relatives [2, 3].