Mutations in the hyperparathyroidism type 2 (HRPT2/CDC73) gene and alterations in the parafibromin protein have been established in the majority of parathyroid carcinomas and in subsets of parathyroid adenomas.
The purpose of this study was to investigate the underlying HRPT2 defect in a young patient with symptomatic hyperparathyroidism due to an apparently sporadic parathyroid adenoma with cystic features.
We recommend that these be conducted at a younger age, preferably 5 to 10 years before the earliest diagnosis of hyperparathyroidism within the family, and potentially at birth in families with a known mutation of the CDC73 gene, in light of the malignant potential of the disease.
Patients 3 and 4 and their relatives did not have MEN1 mutations, but instead had familial hypocalciuric hypercalcaemia (FHH) due to a calcium-sensing receptor mutation (p.Arg680Cys), and the hyperparathyroidism-jaw tumour (HPT-JT) syndrome due to a hyperparathyroidism type 2 deletional-frameshift mutation (c.1239delA), respectively.
Inactivation of the HRPT2/CDC73 gene, encoding the putative tumor-suppressor protein parafibromin and discovered in the context of the hyperparathyroidism-jaw tumor (HPT-JT) syndrome, is a common, somatic event in most parathyroid cancers.
The development of parathyroid carcinoma has been associated with inactivating mutations of the Hyperparathyroidism type 2 (HRPT2) gene encoding parafibromin, a member of the human RNA Polymerase II-Associated Factor Complex (hPAF) and functionally linked to the Wingless type (Wnt) pathway.
Mutations in HRPT2, the gene responsible for hereditary hyperparathyroidism with jaw-tumor syndrome, were strongly associated with sporadic parathyroid carcinoma.
We recommended MEN1 gene analysis for patients having one of the following clinicopathological features: 1) age younger than 30 years old; 2) enlargement of multiple glands; 3) coexistence or presence of past history of MEN1-related tumors; or 4) family history of hyperparathyroidism or MEN1-related tumors.
We concluded that it is necessary to individualize the surgical approach for HRPT2-related hyperparathyroidism until we can gather a better phenotype-genotype correlation in larger series, to best define their treatment.
An unacceptable recurrence/persistence rate (80%) associated with increasingly difficult re-operations and risk of parathyroid carcinoma in the setting of germline mutations of HRPT2 gene with familial hyperparathyroidism suggest that a more aggressive operative approach should be undertaken in these patients.
To our knowledge, this is the first report of a patient with both MEN1 and BRCA2 mutations and with a personal history of hyperparathyroidism and pancreatic neuroendocrine tumors.
The parafibromin subunit of the hPAF complex is a product of the HRPT-2 (hereditary hyperparathyroidism type 2) tumor suppressor gene, which is mutated in the germ line of hyperparathyroidism-jaw tumor patients.
We therefore suggest that routine germline MEN1 mutation testing of all cases of "classical" MEN1, familial hyperparathyroidism, and sporadic hyperparathyroidism with one other MEN1 related condition is justified by national testing services.
Parafibromin is the 531-amino-acid protein product encoded by HRPT2, a putative tumor suppressor gene recently implicated in the autosomal dominant hyperparathyroidism-jaw tumor familial cancer syndrome, sporadic parathyroid cancer, and a minority of families with isolated hyperparathyroidism.
We therefore suggest that routine germline MEN1 mutation testing of all cases of "classical" MEN1, familial hyperparathyroidism, and sporadic hyperparathyroidism with one other MEN1 related condition is justified by national testing services.
The components of MEN-1 are hyperparathyroidism due to multiple parathyroid adenomas, pancreatic neuroendocrine tumors, and pituitary adenomas, in addition to some less common neoplastic manifestations.
Examination of the MEN1 gene may be valuable to make an accurate diagnosis and choose the appropriate therapy in some ESRD patients with hyperparathyroidism.
Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is a familial multi-tumor syndrome resulting from mutations in the HRPT2 tumor suppressor gene, which encodes a protein product named parafibromin.