DNA‐based test: when and why to apply it to primary hyperparathyroidism clinical phenotypes

Abstract

. Several cancer‐related genes have been discovered and molecular test for the cancer genetic risk assessment has been widely increasing. Disorders such as Multiple Endocrine Neoplasia syndromes have received benefits from the identification of the responsible genes whose mutations account for the genetic susceptibility to develop endocrine tumours. Primary hyperparathyroidism (PHPT)is a clinical phenotype frequently associated to Multiple Endocrine Neoplasia syndromes, but it can also represent the unique endocrinopathy recurring as a familial cluster. In recent years, care options have been made available to patients and families with hereditary PHPT, and the process of systematically assessing the genetic risk has been becoming increasingly important. This review aims to help health providers not frequently dealing with genetic testing use and it will introduce some general concepts concerning genetic diagnosis issues. As an example the role and the practical usefulness of DNA‐based diagnosis in patients affected by different forms of congenital PHPT is described, with a close look on why, when and how genetic testing should be performed in these subjects and their relatives. Some practical recommendations and suggestions concerning on how to deal when a suspect or known case of familial PHPT has to be faced conclude this manuscript.

Hereditary hyperparathyroidism—a consensus report of the European Society of Endocrine Surgeons (ESES)

“…Alternatively, pHPT may be due to a de novo germline mutation in the patient (with subsequent absent family history but increased risk of hereditary pHPT in the children of the patient) or because of the incomplete penetrance and variable expressivity of the putative gene [2,140].…”

“…Genetic testing has a pivotal role for early identification of mutation carriers, the earlier identification of associated tumours, appropriate clinical and biochemical surveillance, timing and surgical strategy, early identification of healthy and/or asymptomatic mutation carriers among relatives (with subsequent earlier surgical treatment) and identification of relatives who do not harbour the familial germline mutation and can be excluded from follow-up, with the associated lower costs and disease-related anxiety [2,9,140]. Ideally, whenever possible, genetic confirmation should be performed preoperatively because the results could impact the surgical strategy [3].…”

A novel germline inactivating mutation in the CASR gene in an Italian kindred affected by familial hypocalciuric hypercalcemia

“…Today, CASR genetic test may be used for diagnostic testing in the symptomatic individual (proband) and in presymptomatic subjects (19). The problem is still how to suspect the FHH syndrome.…”

Molecular genetics in primary hyperparathyroidism: the role of genetic tests in differential diagnosis, disease prevention strategy, and therapeutic planning. A 2017 update

“…Activating CaSR mutations induce an increased sensitisation of receptor to extracellular calcium that, at parathyroid level, is responsible for the induction of a chronic hypocalcemia, and, at kidney level, determines a minor reabsorption of calcium with subsequent constant hypercalciuria and risk of renal stones and nephrocalcinosis. Twenty-seven polymorphisms have been identified within the CaSR gene locus, but no definitive results are available about their possible role in susceptibility to FHH1 and/or sporadic form of PHPT or ADH (23). FHH2 has been originally mapped to chromosome 19p.…”

“…Parathyroid tumours occur in about 95% of patients and they are typically the first clinical manifestation of the syndrome. PHPT in HPT-JT is characterised by aggressive behaviour (severe hypercalcaemia with likelihood of hypercalcaemic crisis) and it is usually associated with parathyroid carcinoma in about 10-15% of cases (23). Inactivating germline mutations of the tumour suppressor CDC73 gene (cell division cycle 73 gene, known also as HRPT2 gene; locus 1q31.2, OMIM gene 607393, encoding parafibromin) have been described in over 50% of HPT-JT families and in about 20% of apparently sporadic parathyroid carcinoma (26).…”