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.
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.
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.
In addition, genome-wide patterns of somatic DNA alterations, including disparate roles for MEN1 gene inactivation, indicate that markedly different molecular pathogenetic processes exist for clonal outgrowth in severe uremic hyperparathyroidism versus common parathyroid adenomas.
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.
We suggest that the bi-allelic somatic loss of MEN1 wild-type gene expression is involved in the pathogenesis of a clinically yet undefined subset of sporadic primary HP adenomas.
Mutations in HRPT2, the gene responsible for hereditary hyperparathyroidism with jaw-tumor syndrome, were strongly associated with sporadic parathyroid carcinoma.
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.
Extensive screening for MEN 1 in the presence of HPT will be conducted only when the familial history is suggestive, when parathyroid glands are hyperplastic or when multiple parathyroid adenomas have been found at surgery.
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.
Surgery plays an important role in the management of hyperparathyroidism in both MEN 1 and MEN 2A,although the timing and extent of surgery are areas of controversy.Long-term follow-up reveals a high rate of recurrent hyperparathyroidism in MEN 1 despite surgical intervention.
Clinical and pathological characteristics of hyperparathyroidism were unrelated to the presence or absence of loss of heterozygosity on 11q13 and MEN1 gene mutations.
These include chromosomal deletions of the MEN1 locus on 11q in sporadic and MEN1 associated primary HPT, of RB1 on 13q in carcinomas, and of the FHH gene located on 3q in sporadic primary and secondary HPT.
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.
No correlations were observed with the development of MEN1-related tumors such as hyperparathyroidism, pituitary adenomas, and enteropancreatic and adrenocortical tumors.
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 %.