Hereditary hyperparathyroidism

Introduction

Primary hyperparathyroidism (PHPT) is a disorder featured by an excessive and unregulated secretion of parathyroid hormone (PTH) from one or more parathyroid glands. Clinical diagnosis relies on the two major biochemical hallmarks of the disease: hypercalcemia and elevated circulating concentrations of PTH. Generally, PHPT can occur at any age, but it is seen most commonly in the sixth decade of life. Overall, PHPT has a prevalence of 3/1000 in the general population. The female:male ratio has been reported to be 3:1 and women may exhibit PHPT clinical expression in the first menopausal decade, between 50 and 60 years. PTH hypersecretion is generally determined by one or more parathyroid glands and the most frequent histopathological picture accounting for PHPT is represented by a solitary benign adenoma, nearly 80% of cases, and less frequently multiple adenomas, hyperplasia of all parathyroid glands, observed in 15-20% of PHPT patients, and carcinoma occur. The latter represents no more than 0.5% of PHPT cases. PHPT, usually, is a rare endocrine disease in children and young adults and when present in these subjects is quite always in the context of a hy- perparathyroidism familial syndrome. Contrarily to sporadic PHPT, parathyroid hyperplasia is commonly associated to hereditary forms of PHPT, such as Multiple Endocrine Neoplasia type 1 (MEN1) and type 2 (MEN2) syndromes, Familial Isolated Hyperparathyroidism syndrome (FIHPT), Hyper- parathyroidism-Jaw tumors syndrome (HPT-JT), Familial Hypocalciuria Hypercalcemia (FHH) syndrome, Neonatal Severe Hyperparathyroidism (NSHPT) syndrome and Autosomal Dominant Moderate hyperparathyroidism (ADMH) syndrome (Table I).


New important molecular insights on parathyroid tumorigenesis have been acquired in the last decade. This is particularly true for hereditary forms of primary hyperparathyroidism where mutations in specific genes, mainly anti-oncogenes, account for the parathyroid tissue outgrowth.
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Table I - Clinical syndromes of familial forms of primary hyperparathyroidism.
Multiple Endocrine Neoplasia type 1 (MEN1)
Multiple Endocrine Neoplasia type 2A (MEN2A)
Familial Isolated Primary hyperparathyroidism (FIHPT)
Hyperparathyroidism- Jaw tumors (HPT-JT)
Familial Hypocalciuric Hypercalcemia (FHH)/Neonatal Severe Hy- perparathyroidism (NSHPT)
Autosomal Dominant Moderate Hyperparathyroidism (ADMH)