Parathyroid carcinomas are extremely rare, with an annual incidence of 0.5–1 per million of the population and account for only 1–2% of all cases of primary hyperparathyroidism. A rare familial syndrome of ossifying fibromas of the jaw, cystic and neoplastic renal tumours, uterine cancers and parathyroid cancers has been described. This familial hyperparathyroidism–jaw tumour syndrome is caused by a germline mutation in the HRPT2 tumour suppressor gene. It turns out that the majority of sporadic parathyroid cancers have somatic mutations of this same gene that encodes a protein parafibromin of uncertain function. A trawl through PubMed shows that research into the causes of parathyroid cancer reflects waxing and waning fashions in scientific research, but there is little that is likely to yield a true insight into this rare cancer. Non-coding RNAs, histone ubiquination and germline mutations in CDC73 are picked up in the net but inspection of the catch, to extend the clumsy metaphor, reveals tiddlers rather than trout.

Parathyroid cancers occur in the context of multiple endocrine neoplasia (MEN), which comprises a group of tumours whose clinical manifestations seem to delight old-fashioned physicians. In particular, the products they secrete give rise to many unusual syndromes. The majority of endocrine tumours are rare, with an incidence of 0.5 per million of the population per annum. But others are more common, such as carcinoid tumours, which have a reported incidence of 1.5 per 10⁵ of people per annum. These tumours, including parathyroid cancers, are frequently listed as occurring in the context of MEN. MENs are due to gene mutations. The MEN 1 gene is encoded at chromosome 11q13. The gene product is called, imaginatively, menin and encodes a nuclear protein that partners with JunD, NF-κB and many other proteins. The function of menin is, however, not known, but is lost in MEN 1. Mutations in MEN 2 lead to changes in the RET proto-oncogene. The RET gene encodes a receptor tyrosine kinase and mutations at different sites within the RET gene are associated with MEN type 2A and type 2B, Hirschsprung’s disease (congenital aganglionic megacolon) and medullary thyroid carcinoma. This one-gene source of multiple diseases is of course a blow to traditional paradigms of genetic disease but should perhaps be seen in the context of the shrinking genome. The number of genes postulated for the human genome has steadily fallen from the early days of the Human Genome Project, when it was speculated that 50,000–75,000 genes were present in the human genome, to the present “post-genomic” era, when estimates have decreased to 20,000 genes only. By comparison it requires 5000 components to make a Mercedes class C car.

Parathyroid cancers secrete parathormone (PTH), and for this reason the majority of patients present with hypercalcaemia. The hypercalcaemia is usually gross and, rather oddly, patients may be asymptomatic, with a calcium level that would normally be associated with death in the acute situation. The reason for this is that this condition generally has a long natural history and may have been present for many years prior to diagnosis. Calcium levels in excess of 4 mmol/L are frequently reported and the patient’s cellular processes will have adapted to this level of hypercalcaemia.

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Case Study: An achy Iranian woman in a chador.