Familial Hypercalcemia Hypercalciuria Syndrome or Autosomal Dominant Moderate Hyperparathyroidism (ADMH)
Carling et al. reported a large family with 20 members, from different generations, affected by this syndrome (OMIM 601199) (Table I). These subjects did exhibit hypercalcemia and hy- percalciuria, with an inappropriately high serum PTH and magnesium levels and with nephrolithiasis in a subset of patients.
Pathology
Uni-, multi-glandular involvement of parathyroid glands was found and diffuse to nodular parathyroid neoplasia has been reported on pathological examination (Table III).
Molecular aspects
DNA test revealed the presence of an atypical inactivating mutation in the intra-cytoplasmic tail domain of CaSR in the germline of affected subjects (Table II). LOH analysis revealed allelic losses at various genetic loci, consistent with mono- or oligoclonality of parathyroid tumors.
Treatment of ADMH-PHPT manifestations
Differently than classical FHH cases, radical subtotal parathyroid resection with parathyroid remnants of 10-20 mg or total parathyroidectomy with autotransplantation (Table III) normalized calcemia in 60% of affected. A persistent hypercalcemia was noted in the 60% of patients (3/5) subjected to less radical parathyroid surgical procedures. However, after an average follow up of 5.1 years no patients with recurrent hypercalcemia have been reported.
Conclusions
In general, an inherited hyperparathyroid syndrome should be suspected in younger patients with PHPT, <40 years old or at least two decades earlier than the sporadic counterpart, and/or in patients with multiple parathyroid adenomas or hyperplasia at surgery as seen in MEN1 or FHH syndromes, atypical parathyroid adenomas, such as familial cystic parathyroid ade- nomatosis, or parathyroid carcinoma as reported in HPT-JT syndrome, and in presence of a family or past medical history pointing to one of the described syndromes. The availability of specific genetic testing for four of the syn-dromes has improved diagnostic accuracy and simplified family monitoring in many cases, but its current cost and limited accessibility require rationalization of its use. Moreover, the cloning of several genes responsible for familial PHPT syndrome has increased the possibilities for new basic and clinical researches. Functional studies have to be performed to understand the function of a specific gene, as also the mechanisms by which its mutations lead to parathyroid tumorigenesis. A great help will come from the creation of specific animal models that will provide the possibility to manipulate the mouse homologue of the gene(s).
The advent of intraoperative PTH evaluation, as a routine evaluation in many centers performing parathyroid surgery, may be helpful for an optimal outcome of parathyroid surgery for familial PHPT syndromes, although some controversies are still existing concerning the rate of possible false-positive results and the possibility of inadequate resection of parathyroid tissue in patients with multiglandular disease. In order to reduce the risk of false-positive results, specially in MEN1 patients, it has been suggested to apply more stringent criteria in the threshold value of percentage reduction of PTH circulating levels prior to establish an adequate excision of parathyroid tissue. However, further studies are needed to optimize rates of false-positive and -negative results in the setting of familial PHPT to guide an adequate extent of parathyroid tissue resection to achieve postoperative long-term eucalcemia.
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Finally, new acquisitions in the pathogenesis of familial PH- PT will be extremely useful to examine the role of specific genetic pathways in the sporadic counterparts. In particular, it will be important to understand how specific gene mutations, such as in HRPT2 gene, can contribute to malignant progression in a distinct subset of parathyroid tumors. Molecular techniques such as the microarray expression profile analysis may recognize the existence of a sort of molecular signatures distinguished for each subset of familial parathyroid tumors, also contributing to define a genotype-pheno- type correlation that could improve the clinical management of this disease.
Carling et al. reported a large family with 20 members, from different generations, affected by this syndrome (OMIM 601199) (Table I). These subjects did exhibit hypercalcemia and hy- percalciuria, with an inappropriately high serum PTH and magnesium levels and with nephrolithiasis in a subset of patients.
Pathology
Uni-, multi-glandular involvement of parathyroid glands was found and diffuse to nodular parathyroid neoplasia has been reported on pathological examination (Table III).
Molecular aspects
DNA test revealed the presence of an atypical inactivating mutation in the intra-cytoplasmic tail domain of CaSR in the germline of affected subjects (Table II). LOH analysis revealed allelic losses at various genetic loci, consistent with mono- or oligoclonality of parathyroid tumors.
Treatment of ADMH-PHPT manifestations
Differently than classical FHH cases, radical subtotal parathyroid resection with parathyroid remnants of 10-20 mg or total parathyroidectomy with autotransplantation (Table III) normalized calcemia in 60% of affected. A persistent hypercalcemia was noted in the 60% of patients (3/5) subjected to less radical parathyroid surgical procedures. However, after an average follow up of 5.1 years no patients with recurrent hypercalcemia have been reported.
Conclusions
In general, an inherited hyperparathyroid syndrome should be suspected in younger patients with PHPT, <40 years old or at least two decades earlier than the sporadic counterpart, and/or in patients with multiple parathyroid adenomas or hyperplasia at surgery as seen in MEN1 or FHH syndromes, atypical parathyroid adenomas, such as familial cystic parathyroid ade- nomatosis, or parathyroid carcinoma as reported in HPT-JT syndrome, and in presence of a family or past medical history pointing to one of the described syndromes. The availability of specific genetic testing for four of the syn-dromes has improved diagnostic accuracy and simplified family monitoring in many cases, but its current cost and limited accessibility require rationalization of its use. Moreover, the cloning of several genes responsible for familial PHPT syndrome has increased the possibilities for new basic and clinical researches. Functional studies have to be performed to understand the function of a specific gene, as also the mechanisms by which its mutations lead to parathyroid tumorigenesis. A great help will come from the creation of specific animal models that will provide the possibility to manipulate the mouse homologue of the gene(s).
The advent of intraoperative PTH evaluation, as a routine evaluation in many centers performing parathyroid surgery, may be helpful for an optimal outcome of parathyroid surgery for familial PHPT syndromes, although some controversies are still existing concerning the rate of possible false-positive results and the possibility of inadequate resection of parathyroid tissue in patients with multiglandular disease. In order to reduce the risk of false-positive results, specially in MEN1 patients, it has been suggested to apply more stringent criteria in the threshold value of percentage reduction of PTH circulating levels prior to establish an adequate excision of parathyroid tissue. However, further studies are needed to optimize rates of false-positive and -negative results in the setting of familial PHPT to guide an adequate extent of parathyroid tissue resection to achieve postoperative long-term eucalcemia.
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Finally, new acquisitions in the pathogenesis of familial PH- PT will be extremely useful to examine the role of specific genetic pathways in the sporadic counterparts. In particular, it will be important to understand how specific gene mutations, such as in HRPT2 gene, can contribute to malignant progression in a distinct subset of parathyroid tumors. Molecular techniques such as the microarray expression profile analysis may recognize the existence of a sort of molecular signatures distinguished for each subset of familial parathyroid tumors, also contributing to define a genotype-pheno- type correlation that could improve the clinical management of this disease.
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