Multiple endocrine neoplasia type 1

1. Introduction 

Multiple endocrine neoplasia type 1 (MEN-1) is a rare congenital disease but its genetic background offers a unique opportunity to understand a pathway of tumour genesis that may be common also for some sporadic tumours.

The classic clinical manifestation of MEN-1 is a composition of parathyroid hyperplasia, pancreatic endocrine tumour and pituitary adenoma [1]. Some patients, however, do not present all three tumours during their life span. Therefore, the definition of MEN-1 is the coincidence of at least two of the above mentioned tumours [1]. A diagnosis of familial MEN-1 requires, besides that, first-degree relative with at least one of the three tumours [1].

2. Clinical expressions of MEN-1 

Primary hyperparathyroidism is the most common clinical expression in affected patients, present in more than 90% of cases (Table 1). Multi-nodular hyperplasia of parathyroid glands is the most frequent, however solitary tumours (usually diagnosed as adenomas) are also seen. Interestingly, parathyroid carcinoma is less frequent than in sporadic cases of primary hyperparathyroidism. The onset age for MEN-1 associated parathyroid adenomas is about 25 years [2] in contrast to sporadic cases occurring mainly about the fifth decade of age [3].

Table 1. Tumours associated with MEN-1 and their penetrance

	Localization	Penetrance
	Endocrine
	Parathyroid	90%
	Enteropancreatic
	Gastrinoma	40%
	Insulinoma	10%
	Non-functioning	20%
	Other	2%
	Pituitary
	Prolactinoma	20%
	Other	17%
	Adrenal
	Non-functioning cortex	20%
	Pheochromocytoma	<1%
	Foregut neuroendocrine tumours
	Gastric	10%
	Thymic	2%
	Bronchial	2%
	Non-endocrine
	Facial angiofibromas	85%
	Collagenomas	70%
	Lipomas	30%
	Leiomyomas	10%
	Meningiomas	5%
	Ependymomas	1%

Enteropancreatic tumours are present in about 60% of patients. They are usually small and non-functional. The most common hormonally active ones are insulinomas or gastrinomas. The clinical presentation of a gastrinoma is the Zollinger–Ellison Syndrome due to gastrin over-production and subsequent gastric acid over-secretion. Ulcers in atypical locations and intestinal perforations may increase risk in these patients. Malignancies are the pre-dominant cause of increased mortality [4]. MEN-1 associated gastrinomas are typically multiple, located in small (<1 cm) nodules in duodenal sub-mucosa and, less frequently, in pancreas. Additionally, it is important to stress that MEN-1 gastrinoma is usually accompanied by other enteropancreatic tumours [5]. Insulinoma is rarely the first expression of MEN-1 as it occurs only in 10–30% of MEN-1 cases. Presentation is similar to that of sporadic cases with recurrent neuroglycopenia, mainly while fasting. Other hormonally active, rare enteropancreatic tumours observed in MEN-1 may secrete glucagon, somatostatin or vasoactive intestinal peptide (VIP) [6]. A limited number of tumours secreting growth hormone-releasing factor (GHRH), ACTH or parathyroid hormone-related peptide (PTHrP) were reported.

Pituitary adenomas affect approximately 30% of patients and usually they are prolactin-secreting micro-adenomas or “non-functional” tumours [7], [8]. Tumours secreting growth hormone or ACTH are less common. The symptoms and signs are similar to those in sporadic pituitary adenomas causing hyperprolactinemia, acromegaly or Cushing's disease, respectively.

Sporadic neuroendocrine tumour is most common in derivates of midgut [9]. In contrast, MEN-1 associated neuroendocrine tumour (carcinoid) originates mainly from the foregut structures (thymus, bronchus, stomach, pancreas, duodenum) [10] and is present in about 14% of MEN-1 cases.

Non-functional adrenal cortical enlargement was described in up to 40% of MEN-1 cases and diagnosed by radiological imaging [11]. Hypercortisolism, hyperaldosteronism or pheochromocytoma was rarely observed in MEN-1 [11].

Prevalence of MEN-1 syndrome in general population was estimated at 2.2 per 1000 in an autopsy series [12], and biochemical surveys suggested lower figures — 0.01–0.175 per 1000 [13], [14]. The fraction of MEN-1 in patients with primary hyperparathyroidism (HPT) is estimated at 1–5% [13], [15] and basing on HPT incidence the prevalence of MEN-1 can be calculated to be 0.15–0.3 per 1000 in general population.

3. MEN-1 gene function 

The MEN-1 gene is located at chromosome 11q13, spans 9.8 kb with 10 exons, and encodes a 610-amino-acid protein named menin [16]. Menin is an abundantly expressed 67-kDa protein which is located primarily in the nucleus [17] and is able to bind to DNA independently of the sequence [18]. It was co-localized with telomers in meiotic, but not in somatic cells [19]. Menin may bind directly or indirectly to the transcription, DNA processing or DNA repair factors and cytoskeleton-associated proteins [20], [21], [22].

The protein acts as a tumour suppressor, however its exact role was not fully elucidated. There are suggestions of increased DNA damage in cells lacking menin [23]. Inactivation of the MEN-1 gene increases proliferation rate and causes transition from G0/G1 to S phase in affected cells [24]. Consequently, over-expression of menin induced apoptosis and loss of this protein prevented apoptosis after other stimuli, such as UV irradiation or TNF-α stimulation. Supplementation of exogenous menin restored sensitivity to this stimulation [25]. Moreover in vitro partial suppression of the tumour phenotype in neoplastic cell lines with menin over-expression supports its role as a tumour suppressor [26], [27]. Most of the mutations present in MEN-1 cause absence or low availability of menin [28], [29]. Complete loss of menin has been identified in tumours from patients with MEN-1 or from mouse models of MEN-1 [30], [31].

Development of tumours in the MEN-1 syndrome is described by the two-hit hypothesis [32]. A carrier of the mutated, non-functioning allele develops a tumour after inactivation of the other allele, which allows clonal proliferation. Similarly, sporadic tumours may develop as the two alleles are subsequently inactivated.

A dysfunction of the MEN-1 gene may also be involved in the development of sporadic tumours. Loss of heterozygosity at menin locus was reported in sporadic parathyroid adenomas [33], [34], pancreatic [35], [36] and anterior pituitary tumours [37], [38], as well as in sporadic lung, thymic and gastric carcinoids [39], [40], lipomas [38], and cutaneous tumours [41]. Mutation of MEN-1 is present in sporadic endocrine tumours in a higher number of cases than of any other gene. Sporadic tumours with approximately 20% MEN-1 mutation include parathyroid adenoma, gastrinoma, insulinoma, and bronchial carcinoid [42], [43]. No correlation between MEN-1 genotype and the tumour phenotype or aggressiveness was found [44], prompting to point out that MEN-1 sequencing is not suggested for tumour staging.

4. Diagnosis of tumours in MEN-1 

It is recommended that the carriers of MEN-1 mutation should be screened biochemically every 1–3 years for hyperparathyroidism, prolactinoma, gastrinoma, insulinoma and other enteropancreatic tumours. Clinical manifestation is mostly mild for a long period of time and lack of regular screening may result in numerous complications [45].

Until recently total serum calcium concentration alone seemed satisfactory as a screening test for hyperparathyroidism in MEN-1 [46]. This was partly because maximal sensitivity for the earliest stages of parathyroid tumour or hyperplasia was not considered essential. However, recent observations of increased cardiovascular risk in patients with hyperparathyroidism even in the absence of hypercalcemia [47] may corroborate to include serum PTH concentration as a screening test as well. Inadequate high levels of PTH accompanied with high levels of calcium are required to diagnose hyperparathyroidism.

Fasting gastrin concentration is essential for gastrinoma screening, however hypochlorhydria and idiopathic peptic disease may give false positive results [48]. Hypochlorhydria may be excluded by measuring basic gastric acid output (BAO) [48]. Confirmation of gastrinoma may give secretin-stimulated gastrin levels [49]. Education about early symptoms of the Zollinger–Ellison Syndrome is important since these can occur in an interval between tests.

Fasting glucose concentration should be performed as screening for insulinoma [48]. If suspicion for insulinoma arises serum insulin concentration provides confirmation. Patients with insulinoma develop hypoglycaemia during supervised fasting. The test should be carried out until the hypoglycaemia occurs, not longer than 72-hours. Serum concentrations of glucose and insulin as well as pro-insulin and C-peptide should be measured at the time of hypoglycaemia [50]. During hypoglycaemia insulin concentration should not exceed 6 μl U/ml. Intake of sulfonyloureas may imitate symptoms and laboratory findings of insulinoma therefore the serum concentration of these medicaments should be measured.

The highest true positive rate for various enteropancreatic tumours in MEN-1 is provided by the test for chromogranin-A serum concentration, which was very high in all MEN-1 cases with radiologically detectable enteropancreatic tumours [51].

No biochemical test showed adequate sensitivity in MEN-1 associated neuroendocrine tumour to be useful. Computed tomography is the method of choice for screening for mediastinal or bronchial carcinoid, while gastric or duodenal neuroendocrine tumours could be recognized during endoscopy or endoscopic ultrasound investigation [48]. Scintigraphy aimed at somatostatin receptor may also be used for detecting neuroendocrine tumours if clinically reasonable.

Fasting prolactin concentration exceeding 20-fold the upper limit allows the diagnosis of prolactinoma [52], but pregnancy, lactation or use of dopamine antagonists may give false positive results. Breast manipulation or physical and mental stress may also increase prolactin concentration above normal values. Concentrations of other pituitary hormones should be assessed only upon more specific indications. The most sensitive imaging test for pituitary pathology is MRI.

5. Treatment of tumours in MEN-1 

Multiplicity of tumours is the main feature in MEN-1 and occurs as multiple tumours within one tissue as well as multiple tissues affected with tumourogenesis. Due to this, characteristic recurrence of tumours is common even after sub-total removal of a tissue. Nevertheless, MEN-1 related tumours are mostly subjected to surgical treatment.

In contrast to single gland resection in sporadic cases of primary hyperparathyroidism, total parathyroidectomy and thymectomy with autotransplantation of parathyroid tissue still remains the therapy of choice for primary hyperparathyroidism in MEN-1 [53]. The operation in MEN-1 related hyperparathyroidism is more difficult due to postoperative hypoparathyroidism and higher rates of recurrent or persistent HPT [53]. While malignancy in parathyroid tumours in MEN-1 is rare, pharmacological treatment is possible for a long period of time. Recent development of calcimimetics introduced a new effective treatment option for hyperparathyroidism [54]. Calcimimetics were also shown to inhibit parathyroid hyperplasia [55] so one may speculate they can allow slowing the progression of parathyroid tumours in MEN-1.

As the lesions in pancreas are mainly small and multiple there are controversies if surgery improves survival. In one retrospective analysis surgical treatment for MEN-1-associated pancreatic tumours <2 cm had no advantage over conservative treatment [56]. However analysis of other cohort of patients revealed that early detection and surgery is beneficial in MEN-1-associated pancreatic tumours [57].

Current pharmacological approach with proton pump inhibitors allows long-term pharmacological treatment for the gastrinoma-associated ZES [58]. The MEN-1 associated gastrinomas are multiple and small, therefore imaging techniques, including intra-operative ultrasound are not effective [59] and cure rates for Zollinger–Ellison Syndrome in MEN-1 are low [5]. Any gastrionoma treatment should include the assessment of liver metastases.

Also, insulinoma may be difficult to locate using endoscopic ultrasound or somatostatin receptor scintigraphy, however intra-operative ultrasound was shown to identify up to 90% of these tumours[60]. Arterial calcium stimulation with selective hepatic venous sampling was shown to be effective for localizing sources of hyperinsulinism not detected with pre-operative imaging techniques [61]. Prior to operation all MEN-1 patients should be evaluated for co-existing gastrinomas, neuroendocrine and other tumours as well as for the presence of metastases.

Treatment of pituitary tumours in MEN-1 does not differ from sporadic cases and include transsphenoidal surgical removal of the tumour [62]. Prolactinomas respond well to therapy with dopamine agonists, which may be used for a long period of time [63].

6. Learning points 

• Carriers of MEN-1 mutations require a thorough follow-up by an experienced endocrinologist.

• MEN-1 germ-line testing should be considered in both affected and unaffected relatives in a MEN-1 family. However, unlike the RET test in MEN-2, the positive result does not implicate intervention to prevent or cure malignancy.