The phenotypes and outcome of MEN1-, MEN4- and HRPT2-related HPTH are briefly described, with a focus on the most recent literature data and is compared with familial hypocalciuric hypercalcemia.
<i>Parathyroid carcinoma.</i> Most parathyroid carcinomas are functional, resulting in hyperparathyroidism and a high serum calcium level; however, non-functioning parathyroid carcinomas are also rarely described in individuals with a <i>CDC73-</i>related disorder.
Screening for the mutated CDC73 confirmed carrier status in the proband's daughter and the biochemistry and ultrasonography led to pre-emptive surgery and resolution of the hyperparathyroidism.
We briefly review published childhood cases, consider the challenges in differentiating malignant from benign hyperparathyroidism in this age group, and discuss the association of CDC73 mutations with parathyroid carcinoma.
This case illustrates that the hyperparathyroidism and the fibro-osseous tumors are independent features of the persistent germline tumor suppressor gene (CDC73) mutation.
In 2002, germline HRPT2 (also known as CDC73) mutation was reported as the cause of hyperparathyroidism-jaw tumor (HPT-JT) syndrome, an autosomal dominant hereditary tumor syndrome associated with a lifetime risk of parathyroid carcinoma approaching 15 %.
Genetic analysis of the CDC73 gene [for Hyperparathyroidism-jaw tumor (HPT-JT)], MEN1 for Multiple Endocrine Neoplasia Type1, CDKN1B for MEN4, SDHB and SDHD for Paraganglioma/Pheochromocytoma susceptibility, VHL for von Hippel-Lindau Syndrome, BMPR1A and SMAD4 for Juvenile Polyposis Syndrome (JPS) (sequencing and MLPA), karyotype and array CGH (44 K) were all normal.
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.
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 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.
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.