Hereditary hyperparathyroidism: Genetic aspects in familial forms of PHPT

Molecular genetics strongly contributed to clearly evidence that PHPT may also occur as a familial cluster (Table I). In Table II familial hyperparathyroid disorders with their main genetic features are briefly summarized. In any case, each of the following described syndromes should be clinically approached through a differential diagnosis. In deed, a differential diagnosis will include an integrating approach to all the hereditary forms of PH- PT.

MEN1

MEN1 (OMIM 131100) is a complex tumor-predisposing disorder inherited in an autosomal dominant manner with a high degree of penetrance, nearly 100% within 50 years of age. The syndrome exhibits a high grade of clinical variability, also in members from the same affected family. More than 20 combinations of both endocrine and nonendocrine tumors have been reported in MEN1 patients, with three endocrine localizations constituting the "typical" clinical features of this syndrome: multiple tumors of parathyroid glands (generally all the parathyroid glands), pituitary adenomas and tumors of the neuroendocrine cells in the gastroenteric tract. Advances in molecular biology and genetics have led to the identification of the specific genetic defect, at chromosome 11q13 (Table II), improving the understanding and ability to early diagnosis this syndrome.

MEN1-associated PHPT

MEN1-PHPT represents the most common endocrinopathy associated to MEN1 syndrome, accounting for the 2-4% of global PHPT forms and it represents the first clinical expression of MEN1 syndrome in approximately 90% of individuals. It does not exhibit sex prevalence and its age onset is typically between 20 and 25 years (Table II), three decades earlier than the sporadic cases of PHPT. Its penetrance reaches 100% with age and all MEN1 affected individuals are expected to have hypercalcemia by age 50 years.

MEN1-PHPT is often mild and asymptomatic with biochemical evidence of hypercalcemia often detected in the course of evaluation of individuals known to have or be at risk for MEN1 syndrome. However, even if the MEN1-associated PHPT is frequently asymptomatic for a long period of time, a reduced bone mass can be observed in hyperparathyroid women as early as 35 years of age.

Table II - Chromosomal localization and genetic defects underlying each familial form of hereditary hyperparathyroidism.

Syndrome/OMIM#°	Chromosomal localization	Gene/activity	Type of germline mutation
MEN1/131100	11q13	MEN1/oncosoppressor	Inactivating
MEN2A/171400	10q11.1	RET/proto-oncogene	Activating
FIHPT/145000	11q13*, 1q25-q31*, 3q13.3-q21*, and still unknown loci	MEN1/oncosoppressor, HRPT2/oncosoppressor, CaSR/GPCR and still unknown genes	Inactivating for MEN1, HRPT2, and CaSR genes
HPT-JT/607393	1q25-q31	HRPT2/oncosoppressor	Inactivating
FHH-NSHPT/145980-239200	3q13.3-q21	CaSR/GPCR	Inactivating
ADMH/601199	3q13.3-q21	CaSR/GPCR	Atypical inactivating

The common clinical manifestations of hypercalcemia are similar to those observed in nonhereditary sporadic form of PHPT. However, it must be taken into account that hypercalcemia may increase the secretion of gastrin from a gastrinoma, precipitating and/or exacerbating symptoms of Zollinger-Ellison syndrome, a clinical picture frequently associated to MEN1 syndrome.

Pathology

MEN1 affected subjects generally exhibit a multiglandular parathyroid disease with the enlargement of all the parathyroid glands, rather than a single adenoma (Table II); they are considered to be tumors of clonal origin. Asymmetric and asynchronic parathyroid outgrowth involves all parathyroid glands in these patients and after 8-10 years from sub-total parathyroidectomy a 50% of recurrence of PHPT has been observed. This could be due to an onset of a new tumor in the context of the parathyroid tissue remnant or, alternatively, to the growth of an unremoved tumor. Malignant progression of parathyroid tumors is not a clinical feature observed in "classic" MEN1 syndrome.
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