Four individuals from the same family spanning three generations were noted to have a history of moderate hypercalcaemia (2.5-2.78 mmol/L) secondary to primary hyperparathyroidism (PHPT) treated with at least two parathyroidectomies. The histology was unknown in many of the samples although there were two confirmed parathyroid adenomas. Two individuals also had renal stone disease and another had history of renal cell carcinoma. There was no history of osteoporosis and surveillance for other tumours had not yet been done. With the discovery of multiple family members having parathyroid adenomas, genetic counselling was undertaken as to whether there could be an underlying familial endocrine syndrome. Two of the individuals underwent genetic screening for multiple endocrine neoplasia (MEN) type 1, which were negative, and then subsequently underwent testing for another novel mutation, CDC73, which was found to be positive.
CDC73 mutations have been associated with hyperparathyroidism-jaw tumour syndrome (HPT-JT) and familial isolated hyperparathyroidism (FIHP), both of which are rare forms of familial hyperparathyroidism. HPT-JT is an autosomal dominant syndrome with incomplete penetrance, characterised by PHPT due to one or multiple parathyroid adenomas or carcinomas, benign tumours of the mandible and the maxilla, and less commonly tumours of the kidney and uterus.
CDC73 is a tumour suppressor gene localised to the long arm of chromosome 1, in the region 1q21-q31, which encodes for an amino acid protein called parafibromin. The development of HPT-JT is caused by inactivating germline mutations leading to unregulated cell proliferation and subsequent tumour formation.
As CDC73 related conditions such as HPT-JT are inherited in an autosomal dominant manner, children of an individual have a 50% chance of inheriting the pathogenic gene. This has implications for families with regards to genetic counselling and screening, management of PHPT and surveillance for other tumours associated with this condition.