Should all patients with hyperparathyroidism be screened for a CDC73 mutation?

Abstract

SummaryPrimary hyperparathyroidism (PH) is a common endocrine abnormality and may occur as part of a genetic syndrome. Inactivating mutations of the tumour suppressor gene CDC73 have been identified as accounting for a large percentage of hyperparathyroidism-jaw tumour syndrome (HPT-JT) cases and to a lesser degree account for familial isolated hyperparathyroidism (FIHP) cases. Reports of CDC73 whole gene deletions are exceedingly rare. We report the case of a 39 year-old woman with PH secondary to a parathyroid adenoma associated with a large chromosomal deletion (2.5 Mb) encompassing the entire CDC73 gene detected years after parathyroidectomy. This case highlights the necessity to screen young patients with hyperparathyroidism for an underlying genetic aetiology. It also demonstrates that molecular testing for this disorder should contain techniques that can detect large deletions.Learning points:Necessity of genetic screening for young people with hyperparathyroidism.Importance of screening for large, including whole gene CDC73 deletions.Surveillance for patients with CDC73 gene mutations includes regular calcium and parathyroid hormone levels, dental assessments and imaging for uterine and renal tumours.

Hyperparathyroidism-jaw tumor syndrome: A rare disorder with significant clinical features

“…Strikingly, 65-80% of these mutations are predominantly located in exons 1, 2 and 7, howbeit they can be scattered out along the whole coding area 9,16,18,20 . Also, as it has been shown by numerous studies, in 1/3 of the cases a gross deletion of whole exons, that might even expand beyond CDC73 gene, is observed, yet without being necessarily linked to more severe clinical features 11,23,[27][28][29][30][31][32] .…”

“…pHPT in HPT-JT syndrome is usually mild and appears as a prolonged moderate hypercalcemia, that might even go unnoticed, with the total serum calcium levels ranging below or equal to 12 mg/dL 7,8,14,29,32 . However, in case of multiglandular involvement, calcium levels might exceed the limit of 12 mg/dL, whilst, in presence of PC, a severe hypercalcemic crisis with nausea, vomiting, fatigue and bone pain can be observed 15,23,30,35,38 .…”

“…Furthermore, it has been underscored that gross deletions expanding beyond the 1q25-32 region, where the CDC73 gene is located at and, hence, affect other genes, may be associated with development delay syndromes in children. However, these observations have been made in only two case reports so far and, thus, more research is required in order to elucidate whether there is a true association between development delay and children bearing a CDC73 gene deletion 31,32 .…”

“…Diagnosis can be achieved only via genetic screening for mutations in CDC73 gene and this remains the gold standard for corroborating the existence of HPT-JT syndrome 8,14 -Multiglandular disease and persistent recurrence of pHPT 2,4,7,8,15,25,32 .…”

“…It has been suggested that genetic testing should start before the age of ten, as the youngest patient reported with HPT-JT syndrome, so far, is 7 years old 8,9,25,29 . It is important to stress that if direct DNA sequencing for point mutations is negative in an individual suspicious for CDC73 germline mutations, the deployment of more advanced techniques (qPCR) for detection of whole gene deletion is crucial 23,24,27,28,32 .…”