primary hyperparathyroidism is rarely a part of multiple endocrine neoplasia type 1 ( men-1 ) syndrome with familial occurrence .
the genetic background of this syndrome offers a unique opportunity to review a pathomechanism of tumourigenesis that may be also operative in some sporadic tumours .
the classic clinical manifestation of men-1 is a composition of parathyroid hyperplasia , pancreatic endocrine tumour , and pituitary adenoma     .
all three tumours , however , do not develop in all affected patients during their life span . therefore , the contemporary definition of men-1 is the coincidence of at least two of the above - mentioned tumours     .
a diagnosis of familial men-1 requires , besides that , a first - degree relative with at least one of the three tumours     . in an autopsy series , prevalence of the men-1 syndrome
was estimated at 2.2 per 1000 in the general population , but biochemical surveys suggested lower figures0.010.175 per 1000     [ 3 , 4 ] . in patients with primary hyperparathyroidism ( hpt ) approximately 15% is associated with the men-1 syndrome     [ 3 , 5 ] . combining this data with hpt incidence
, the prevalence of men-1 can be estimated to be 1030 per 100,000 in the general population . in about 60% of men-1 patients
moreover , it is important to stress that other enteropancreatic tumours usually accompany gastrinoma in men-1     .
insulinoma is found in 1030% of men-1 cases with the classic clinical presentation with recurrent neuroglycopenia , mainly in fasting , similar to that of sporadic cases .
other rare enteropancreatic tumours diagnosed in men-1 may secrete somatostatin , glucagon , vasoactive intestinal peptide ( vip ) , growth hormone - releasing factor ( ghrh ) , acth , or parathyroid hormone - related peptide ( pthrp )     . in approximately 30% of men-1 patients prolactin - secreting microadenomas or 
tumours secreting growth hormone or acth are less frequent , with the signs and symptoms equivalent to those in sporadic cases .
neuroendocrine tumour ( carcinoid ) , found in about 14% of men-1 cases , originates mainly from the foregut ( thymus , bronchus , stomach , pancreas , duodenum ) , in contrast to sporadic cases originating mainly from midgut . in up to 40% of men-1 cases
the localization of the tumours in the men-1 syndrome can not be explained by the ubiquitous expression pattern of the mutated gene men-1 and its encoded protein , menin .
the interaction of menin with mixed - lineage leukaemia protein - containing histone methyl transferase ( mll - hmt ) complex mediates tissue - selective tumour - suppressing and tumour - promoting effects and may be responsible for the tissue susceptibility to tumourigenesis in men-1 .
the men-1 gene is 9.8  kb in 10 exons located on chromosome 11q13 and encodes a 610-amino acid 67-kda protein menin     .
menin is ubiquitously expressed , located primarily in the nucleus   and is able to bind to the dna independently of the sequence     . in meiosis
menin is able to bind directly or indirectly to the proteins regulating transcription , dna processing , or dna repair as well as cytoskeleton - associated proteins     [ 1921 ] .
although its exact role is not fully understood , menin acts as a tumour suppressor .
inactivation of the men-1 gene causes cell transition from g0/g1 to s phase and increases their proliferation     .
loss of this protein prevents apoptosis which normally occurs in cells exposed to uv irradiation or tnf- , and exogenous supplementation of menin restores sensitivity to these stimuli     .
moreover , in vitro menin overexpression partially suppresses tumour phenotype in neoplastic cell lines supporting its role as a tumour suppressor     [ 25 , 26 ] . up to now
most of the mutations identified in men-1 subjects cause either absence or low availability of menin     [ 28 , 29 ] .
a complete loss of menin has been described in tumours from patients with men-1 or from mouse models of men-1     [ 30 , 31 ] .
a  two - hit  hypothesis is applied to describe the development of tumours in men-1 . in a germline carrier of the mutated , nonfunctioning allele a tumour develops after local inactivation of the other allele , allowing clonal initiation and promotion .
sporadic tumours may develop in a similar mechanism as the two alleles are subsequently inactivated in a cell line . in line with this hypothesis in the sporadic cases of parathyroid adenomas     [ 33 , 34 ] , pancreatic     [ 35 , 36 ] and anterior pituitary tumours     [ 37 , 38 ] , as well as in carcinoids of lung , thymus and stomach     [ 39 , 40 ] ,
lipomas     , and skin tumours   loss of heterozygosity at the menin locus has been described .
mutation of the men-1 gene is the most predominant genetic aberration observed in sporadic endocrine tumours . in approximately 20% of sporadic parathyroid adenoma , gastrinoma , insulinoma , and bronchial carcinoid an men-1 mutation
no correlation between men-1 genotype and the tumour phenotype or aggressiveness has been found     , therefore men-1 sequencing is not useful for tumour staging .
primary hyperparathyroidism ( phpt ) is the most prevalent clinical expression in men-1 mutation carriers , present in more than 90% of cases ( table 1 ) .
most frequently multinodular hyperplasia of parathyroid glands is present ; however solitary tumours ( usually diagnosed as adenomas ) have also been observed .
although the defective men-1 gene is a tumour suppressor , the parathyroid carcinoma is diagnosed in the smaller proportion of patients than in sporadic primary hyperparathyroidism .
mild hypercalcemia with normal range serum pth concentration can usually be detected during the second decade of life .
typically the men-1-associated parathyroid adenomas are diagnosed at the age of about 25 years     in a considerably younger population compared to the sporadic cases , occurring mainly about the fifth decade of life .
a point to be mentioned is the high frequency of supernumerary ( up to 20% ) and ectopic parathyroid glands , usually localized within the thyroid gland , in the anterior mediastinum and exceptionally in the pericardium in men-1 patients     . until now
the main clinical manifestation of men-1-associated phpt is progressing demineralisation   and/or recurrent kidney stones     [ 50 , 51 ] .
it was shown that 44% of patients with uncontrolled men-1-associated phpt had severe osteopenia ( t score , < 2.0 ) by 35 years of age .
recurrent kidney stones are less frequently reported in men-1 families     [ 50 , 51 ] .
unusually men-1 patients develop chronic kidney disease in the course of nephrolithiasis , interstitial nephritis and unrelated to the syndrome diabetes as the most frequent cause of chronic kidney disease all over the world     [ 51 , 52 ] .
it is recommended that biochemical screening for hyperparathyroidism , as well as for the other tumours , should be performed every 13 years in the carriers of men-1 mutation . for a long period of time
clinical manifestation is mild , and the lack of regular screening may result in the delay of diagnosis and numerous complications .
total serum calcium concentration corrected for albumin level or ionized calcium fraction has been considered the single sufficient screening test for hyperparathyroidism in men-1 , partly because identifying the earliest stages of parathyroid growth has not been considered essential . recently , however , increased cardiovascular risk has been observed in patients with mild hyperparathyroidism even in the absence of hypercalcemia     .
this may argue for inclusion of serum pth concentration measurement as a screening test as well .
diagnosis of hyperparathyroidism requires levels of pth inadequately high for the parallel calcium levels . at present
second generation of kits , measuring concentrations of the so - called  intact pth  ( ipth ) , are in the general usage .
these tests assess not only the concentration 1 - 84-pth , but also of a truncated pth fragment which was deprived of the first 16 n - terminal amino acids that do not stimulate pth receptor .
until now superiority of the third generation of pth kits , measuring only the concentration of  native  1 - 84-pth , has not been proven for diagnosis of primary hyperparathyroidism , at least in patients without chronic kidney disease .  
routine testing for men-1 mutation in young patients with primary hyperparathyroidism is not recommended , as these mutations are rare in unselected patients even below 40 years of age     .
the testing should be considered in patients with additional risk factors such as multiple gland disease , past history , or coexistence of other tumours characteristic for men-1 , family history of hyperparathyroidism or men-1 tumours .
total parathyroidectomy and thymectomy with autotransplantation of parathyroid tissue is the therapy of choice for primary hyperparathyroidism in men-1 in contrast to single gland - resection in sporadic cases     [ 57 , 58 ] .
the surgery in men-1-related hyperparathyroidism ( hpt ) bears also more difficulties : postoperative hypoparathyroidism and higher rates of recurrent or persistent hpt .
recurrence is usually located in preserved parathyroid tissue  either a previously normal gland or a remnant     .
subtotal parathyroidectomy or total parathyroidectomy with thymectomy and autotransplantation is associated with fewer recurrences than selective gland excision .
the recurrence rate is strongly influenced by proceeding the operation diagnosis of men-1 , the surgeon 's experience , and the possibility to perform an intraoperative histological examination and quick pth assessment .
the main role of intraoperative pth assessment is to confirm the removal of all the functional parathyroid tissue before parathyroid autotransplantation .
it is not established if the guidelines for the asymptomatic phpt are applicable for men-1-associated phpt .
some experts advocate early parathyroidectomy to control even mild hyperparathyroidism as uncontrolled disease is associated with a progressive decline of bone mineral density and the increased risk for kidney stones     [ 61 , 62 ] . in addition
burgess emphasises education of the patient in respect to hyperparathyroidism recurrence and possible reoperations in the years to come .   because malignancies in men-1 parathyroid tumours are uncommon , pharmacological treatment is hypothetically feasible .
the development of calcimimetics brought a new effective , however expensive , and until now unlicensed therapeutic option for both sporadic and men-1-associated phpt     [ 63 , 64 ] .
thus , such a therapy seems the only option when surgery is not possible or has been ineffective .
additionally calcimimetics have been shown to inhibit parathyroid hyperplasia      so one may speculate that they could slow the progression of parathyroid tumours in men-1 .
carriers of men-1 mutations require regular screening at least in 3-year intervals regardless of the current presence of hyperparathyroidism from the second decade of life .
surgery remains the main method of primary hyperparathyroidism management despite of high recurrence rate and the necessity of repeated procedures .
calcimimetic agents emerge as new therapeutic option if surgery is not possible or has been ineffective .
 primary hyperparathyroidism may occur as a part of an inherited syndrome in a combination with pancreatic endocrine tumours and/or pituitary adenoma , which is classified as multiple endocrine neoplasia type 1 ( men-1 ) . 
 this syndrome is caused by a germline mutation in men-1 gene encoding a tumour - suppressor protein , menin . 
 primary hyperparathyroidism is the most frequent clinical presentation of men-1 , which usually appears in the second decade of life as an asymptomatic hypercalcemia and progresses through the next decades . 
 the most frequent clinical presentation of men-1-associated primary hyperparathyroidism is bone demineralisation and recurrent kidney stones rarely followed by chronic kidney disease . 
 the aim of this paper is to present the pathomechanism , screening procedures , diagnosis , and management of primary hyperparathyroidism in the men-1 syndrome . 
 it also summarises the recent advances in the pharmacological therapy with a new group of drugs  calcimimetics . 
1. Introduction
2. MEN-1 Gene Function
3. Primary Hyperparathyroidism in MEN-1
4. Screening for Primary Hyperparathyroidism in MEN-1
5. Treatment of MEN-1 Associated Hyperparathyroidism
6. Conclusion