Familial or heritable hyperparathyroidism (FHPT) is seen in approximately 10–15 % of patients with primary hyperparathyroidism (PHPT) [1]. An increasing number of causative genes for sporadic PHPT have been identified through identification of the genetic cause of FHPT and the pathways affected. However, the real frequency of FHPT may be underestimated given variable penetrance and expressivity of the associated genes and de novo disease. Once the diagnosis of PHPT is established, consideration of heritable forms should be made in patients with positive family history, young onset, multi-glandular disease, and recurrent or persistent disease (Table 1).

FHPT is characterized by inappropriate and unchecked secretion of parathyroid hormone (PTH) by the parathyroid glands, driven by distinct heritable genetic mechanisms. PTH regulates calcium homeostasis through its effects on bone and kidney (Fig. 1). Majority of the genes known to cause FHPT are cancer-predisposing for instance, the tumor suppressor genes such as MEN1, CDKN1B, CDC73, FLCN, and the oncogenes/proto-oncogenes leading to increased cellular proliferation such as RET. While variants in some genes that regulate calcium set point and transport such as CASR, GNA11, AP2S1,and TRPV6 can result in FHPT, these genes appear to be rare causes of sporadic PHPT. Of note, FHPT caused by variants in genes that regulate calcium homeostasis do not typically result in target organ damage and do not benefit from surgical intervention. In contrast, patients with FHPT caused by cancer-predisposing genes often develop extra-parathyroidal manifestations necessitating surveillance or intervention. Thus, elucidation of genes and pathways causing PHPT can be clinically impactful.

FHPT encompasses both syndromic and non-syndromic forms (Fig. 2). Syndromic forms include multiple endocrine neoplasia (MEN) types 1, 2, 3 and 4, hyperparathyroidism-jaw tumor (HPT-JT) syndrome, hereditary pheochromocytoma and paraganglioma, and the more recently reported, Birt-Hogg-Dubé (BHD) syndrome and X-linked intellectual disability syndrome. Non-syndromic forms include familial hypocalciuric hypercalcemia (FHH)-types 1,2, and 3, neonatal severe hyperparathyroidism, GCM2-mediated hyperparathyroidism, transient neonatal hyperparathyroidism and familial isolated hyperparathyroidism (FIHP). In this review we aim to review the heritable forms of PHPT and highlight the important genetic insights and clinical implications (Table 2).