Hereditary hyperparathyroidism: Molecular aspects

Germline inactivating mutations of MEN1 gene have been found in most of the affected from MEN1 kindreds (Table II). Recent advances on pathophysiological roles of menin, the protein product of MEN1 gene, disclose the existence of an intricate network composed by several molecular partners interacting with menin: Smad3, TGFP, JUND, GFAP, vimentin, NF- kB, NM23H1, ERK, JUNK, Elk-1 and c-Fos. However, it is still completely unknown how mutations in menin cause tumorigenesis, nor is the function of menin. Menin may play different roles in different tissues interacting with such different proteins, but also the interacting proteins of such a molecular network may have a role in both the onset and progression of MEN1-associated tumors.
However, MEN1 parathyroid tumorigenesis has been widely demonstrated to progress through the inactivation of the "wild type" allele of MEN1 gene, a tumor suppressor gene, at somatic level indirectly evidenced as loss of heterozygosity (LOH) at 11q13 or intragenic DNA markers. After the cloning of MEN1 gene the early detection of asymptomatic carriers dra-matically decreases the morbidity and mortality of MEN1 syndrome, providing the opportunity to initiate appropriate treatment at early stages.


Treatment of MEN1-PHPT manifestations

Neck surgery still represents the elective treatment of this form of PHTP. However, the use of bone anti-resorptive agents should be considered prior to surgery, in order to both reduce hypercalcemia and limit PTH-dependent bone resorption. No general consensus has been reached on which technique could be the optimal surgical approach in MEN1-associated PH- PT. It may be treated with either subtotal parathyroidectomy (removal of 7/8 of the parathyroid tissue) or cryopreservation of parathyroid tissue or total parathyroidectomy and autotransplan- tation of parathyroid tissue (Table III). As above mentioned, it has been determined that eight to twelve years after successful subtotal parathyroidectomy, PHPT recurred in as many as 50% of euparathyroid individuals with MEN1 syndrome, likely as the result of either new neoplasia arising in residual normal tissue, or neoplasia progressing in the residual tissue. Elaraj et al. showed that subtotal and total parathyroidectomy resulted in longer recurrence-free intervals compared with lesser resection. Cumulative recurrence rates for procedures considering a less than subtotal parathyroid resection were 8%, 31 %, and 63% at one, five, and ten years, respectively, while for more extensive parathyroid resection, subtotal or total, the cumulative recurrence rates were 0%, 20%, and 39% at one, five, and ten years, respectively. Severe hypoparathyroidism exhibits a higher incidence after total parathyroidectomy, supporting the use of subtotal parathyroidectomy as the initial procedure of choice in MEN1 syndrome. Biochemical assessment of serum concentration of PTH on the first day following subtotal or total parathyroidectomy may result as a good predictor of residual parathyroid function. However, repeated measurements of serum calcium concentration are also useful and less expensive than measurement of the serum concentration of PTH. If auto-transplantation of the parathyroid glands has been performed, the serum concentration of PTH should be assessed no earlier than two months post-operatively and then once a year thereafter; serum concentration of PTH should be measured in separate, but simultaneous, blood samples, one from the arm without and one from the arm with the parathyroid tissue auto-transplantation. This procedure allows the physician both to assess the function of the transplanted parathyroid tissue and monitor for possible recurrence of hyperparathy- roidism. Postoperative parathyroid localizing studies may be helpful if hyperparathyroidism recurs.
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Table III - Main clinical features of various forms of hereditary hyperparathyroidism.

Syndrome	Age of onset (yr)	Parathyroid glands involvement	Pathology	Treatment
MEN1	20-25	Multiglandular	Hyperplasia/ Adenoma(s)	SPTX or TPTX with autologous reimplantation + transcervical thymectomy
MEN2A	>30	Single/ Multiglandular	Multiple adenomas/ Hyperplasia	Resection of only enlarged glands, SPTX, TPTX with autologous reimplantation
FIHPT	N. R.	Single/ Multiglandular	Single, Multiple adenoma(s)	Single disease: parathyroid adenomectomy Multiglandular disease: SPTX or TPTX with autologous reimplantation
HPT-JT	>30 [(average age 32 (ref. 28)]	Single/ Multiglandular (generally two glands)	Single or double adenoma (cystic parathyroid adenomatosis). Parathyroid carcinoma in approximately 10-15% of affected individuals	Single disease: parathyroid adenomectomy Multiglandular disease: SPTX or TPTX with autologous reimplantation. Carcinoma: Neck surgery, specifically an en bloc resection of primary tumor, as the only curative treatment
FHH/NSHPT	All ages/ at birth or within the first 6 months	Multiglandular	Mildly enlarged parathyroid glands/Markedly hyperplastic parathyroid glands	FHH: patients do not benefit from surgery of parathyroid lesions, but subtotal parathyroidectomy can be performed in subjects developing symptomatic PHPT NSHPT: TPTX
ADMH	44.5±3.9 (ref. 99)	Single/ Multiglandular	Diffuse to nodular parathyroid neoplasia	Radical subtotal parathyroid resection with parathyroid remnants of 10-20 mg or TPTX with autologous reimplantation