The clinical presentation of MEN is complex and numerous tumors may be seen [1] [2] [3] [5] [6] [7] [14]:

• Parathyroid tumors - MEN-1 is almost universally characterized by hyperparathyroidism (HPT), occurring in 90-100% of cases and hypercalcemia produced by primary HPT causes symptoms such as lethargy, depression, anorexia, nausea, vomiting, dehydration, development of kidney stones and a propensity toward pathological fractures. Primary hyperparathyroidism will develop in 20-30% of MEN-2a patients as well and it is used as a distinguishing feature from MEN-2b, in which absence of parathyroid disease and presence of a Marfanoid habitus, various musculoskeletal abnormalities (saber shins, bowing of the extremities), mucosal neuromas of the lips and tongue, and hypertrophy of the corneal nerve will be observed.
• Pituitary tumors - In 25% of MEN-1 cases, the initial symptoms of the disease arise from tumors of the hypophysis (prolactinomas and GH-secreting tumors are the most common) and peripheral vision loss, acromegaly, gigantism, menstrual cycle-related symptoms (such as amenorrhea and oligomenorrhea), and gynecomastia may be reported, depending on the location of the tumor and the hormone that is secreted due to its presence [6].
• Pancreatic neuroendocrine tumors (pNETs) - Gastrinomas, known for causing Zollinger-Ellison syndrome, appear in approximately 40% of all MEN-1 cases, are gastrin-secreting tumors that present with diarrhea, esophageal reflux, peptic ulcer disease, weight loss, vomiting, hematemesis, melena and other potentially severe complaints if untreated or not recognized on time. Insulinomas (hypoglycemia, headaches, confusion, convulsions, personality changes), glucagonomas (anorexia, glossitis, diarrhea, skin rash), VIPomas (watery diarrhea, hypokalemia, and achlorhydria) and somatostatinomas are other pNETs that have respective clinical findings.
• Carcinoid tumors - Various forms of this rare tumors exist, including thymic, bronchial and type II enterochromaffin-like carcinoids. Typical clinical presentation of diarrhea, flushing, wheezing and heart murmurs is rarely seen. They are diagnosed in about 10% of all MEN-1 cases, most frequently in an advanced stage of the disease.
• Adrenomedullary tumors - Bilateral pheochromocytoma is one of the main features of MEN-2a and MEN-2b, affecting about 50% of patients.
• Non-endocrine tumors - Angiofibromas, collagenomas, lipomas and melanomas are skin tumors that may be seen in MEN-1, while lesions of the central nervous system have been described as well (meningiomas, schwannomas, and ependymomas). In rare cases, leiomyomas and leiomyosarcomas have been documented.
• Medullary thyroid carcinoma (MTC) - Considered to be the cardinal feature of all forms of MEN-2 (including MEN-2a, MEN-2b, and FMTC), MTC is seen in virtually all patients with known RET proto-oncogene mutations.

• Weakness

  She complained of dizziness, occasional palpitation, weakness, hunger, sweating, and generalized tonic-clonic seizure that lasted for 5 minutes early in the morning. [ncbi.nlm.nih.gov]

  PTH), which is responsible for calcium metabolism in the body In MEN Syndrome Type 1, the parathyroid gland produces excess amounts of hormones, which results in high calcium levels in blood and urine, causing a thinning of the bones The bones become weak [dovemed.com]

  These symptoms can progress into further complications, such as muscle weakness, osteoporosis, kidney stones, mental and behavioural changes. [medic8.com]

  A person may have hyperparathyroidism for many years with no symptoms or have symptoms such as kidney stones, bone thinning, nausea and vomiting, high blood pressure (hypertension), weakness, and fatigue. [endocrineweb.com]

• Amyloidosis

  Cutaneous manifestations of MEN 2A syndrome include macular amyloidosis, whereas MEN 2B syndrome is traditionally linked to multiple mucosal neuromas. [ncbi.nlm.nih.gov]

  MEN2a mainly focuses on medullary thyroid carcinoma, pheochromocytoma, parathyroid hyperplasia or adenomas (causing hyperparathyroidism), and occasionally cutaneous lichen amyloidosis. [ronnyallan.net]

  MEN 2A involves primarily medullary thyroid carcinoma, pheochromocytoma, hyperplasia or sometimes adenomas of the parathyroid glands (with resultant hyperparathyroidism), and occasionally cutaneous lichen amyloidosis. [merckmanuals.com]

  An itchy skin condition known as cutaneous lichen amyloidosis may affect individuals with type 2. Additionally, medullary thyroid cancer is also common in these individuals. [news-medical.net]

• Fatigue

  However, most people with endocrine disease complain of fatigue and weakness. Blood and urine tests to check your hormone levels can help your doctors determine if you have an endocrine disorder. [webmd.com]

  We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: May 13, 2019 [patientslikeme.com]

  Systemic signs: renal (polyuria, hypercalciuria, nephrolithiasis) skeletal, neuromuscular (myopathy, chondrocalcinosis, arthritis), central nervous system (fatigue, cognitive changes), gastrointestinal (peptic ulcer, pancreatitis), cardiovascular (hypertension [iofbonehealth.org]

  A person may have hyperparathyroidism for many years with no symptoms or have symptoms such as kidney stones, bone thinning, nausea and vomiting, high blood pressure (hypertension), weakness, and fatigue. [endocrineweb.com]

• Thyroid Nodule

  […] carcinoma [FMTC] or pheochromocytoma) and family history Refer to testing algorithms for pheochromocytoma and thyroid nodules Laboratory Testing Genetic testing RET mutation analysis Confirms presence of mutation in patient with FMTC or pheochromocytoma [arupconsult.com]

  The two thyroid nodules were solid, irregular, heterogeneous, and had microcalcifications. Serum calcitonin was 1140 pg/ml (CLIA, NR < 12.0 pg/ml). [doi.org]

  Carney complex [ 12 ] Carney complex is a distinct rare type of MEN characterised by primary pigmented adrenocortical disease, pituitary adenoma, Sertoli-cell tumours, thyroid nodules and additional non-endocrine features. [patient.info]

• Short Stature

  In school-age children, additional signs and symptoms of MEN2B often include: A long, thin face (marfanoid facies) and slender body shape (may have short stature) Nodules in or on the lips, tongue or on the inside cheeks of the mouth (mucosal neuromas [chop.edu]

• Nausea

  A person may have hyperparathyroidism for many years with no symptoms or have symptoms such as kidney stones, bone thinning, nausea and vomiting, high blood pressure (hypertension), weakness, and fatigue. [endocrineweb.com]

  Abdominal pain Burning, aching, or hunger discomfort in the upper abdomen or lower chest that is relieved by antacids, milk, or food Black, tarry stools Nausea and vomiting Bloated feeling after meals Weakness Headache Vision problems Loss of coordination [uclahealth.org]

  Peptic ulcers can cause a burning pain in the stomach, diarrhea, nausea, vomiting and fatty, smelly stools. [rarediseases.org]

  Symptoms due to excessive parathyroid hormone production include: Tiredness, weakness Muscle or bone pain Nausea and vomiting Indigestion, constipation Recurrent fractures due to thinning of bone Kidney stone formation leading to back pain, blood in urine [dovemed.com]

  This can cause many other symptoms, including tiredness, weakness, muscle or bone pain, constipation, indigestion, nausea, loss of body hair, and loss of regular menstruation. [dartmouth-hitchcock.org]

• Abdominal Pain

  […] m oans (abdominal pain), and psychiatric overt ones (confusion). [medicalmediareview.com]

  […] diarrhea, abdominal pain Insulinoma (~10%) – pancreatic islet tumors; usually multiple Hypoglycemia and related symptoms Carcinoid tumors (~10%) – carcinoid syndrome Flushing, wheezing, diarrhea, carcinoid heart disease Vasoactive intestinal polypeptide [arupconsult.com]

  Abdominal pain Burning, aching, or hunger discomfort in the upper abdomen or lower chest that is relieved by antacids, milk, or food Black, tarry stools Nausea and vomiting Bloated feeling after meals Weakness Headache Vision problems Loss of coordination [uclahealth.org]

  The symptoms are very varied according to the type and extent of the glands affected and may include: Abdominal pain Amenorrhea Constipation or diarrhea Depression and anxiety Decreased libido Fatigue and weakness Headache Loss of appetite and weight [news-medical.net]

• Polydipsia

  Clinical Presentation Parathyroid tumors Primary hyperparathyroidism develops in ~100% of patients by age 50 Typically involves all four parathyroid glands (unlike sporadic disease) Signs – hypercalcemia, hyperparathyroidism Symptoms – fatigue, anorexia, polydipsia [arupconsult.com]

  The symptoms include: Heightened thirst and the need to drink fluids (polydipsia). The need for frequent urination (polyuria). Blocked bowels or constipation. Fatigue. [medic8.com]

  Hypercalcaemia may lead to constipation, polyuria, polydipsia, memory problems, depression, nephrolithiasis, glucose intolerance, gastro-oesophageal reflux and fatigue. [patient.info]

• Abdominal Distension

  Ganglioneuromatosis of the gastrointestinal tract is responsible for abdominal distension, megacolon, constipation or diarrhea. [ncbi.nlm.nih.gov]

  Associated symptoms include abdominal distension, megacolon, constipation, or diarrhea. [nature.com]

• Hypertension

  A 24 year old Caucasian man came to our attention for severe hypertension, resistant to anti-hypertensive polytherapy. At the age of twenty he had undergone total thyroidectomy with lymphadenectomy for medullary carcinoma. [ncbi.nlm.nih.gov]

  Severe, treatment-resistent hypertension (particularly paroxysmal in nature, with headaches, palpitations, and diaphoresis). MEN2B Marfanoid habitus Mucosal neuromas on lips, tongue and eyelids. Note that Abraham Lincoln was said (apocryphally?) [medicalmediareview.com]

  Hypertensive crisis is a severe increase in blood pressure that can damage blood vessels and lead to a stroke. [rarediseases.org]

  Prinzmetal: Pheochromocytoma with demonstration of pressor (adrenalin) substances in the blood preoperatively during hypertensive crises. Annals of Surgery, Philadelphia, 1937, 106: 85-91. J. H. [whonamedit.com]

• Palpitations

  Severe, treatment-resistent hypertension (particularly paroxysmal in nature, with headaches, palpitations, and diaphoresis). MEN2B Marfanoid habitus Mucosal neuromas on lips, tongue and eyelids. Note that Abraham Lincoln was said (apocryphally?) [medicalmediareview.com]

  She complained of dizziness, occasional palpitation, weakness, hunger, sweating, and generalized tonic-clonic seizure that lasted for 5 minutes early in the morning. [ncbi.nlm.nih.gov]

  Snapshot A 36-year-old women complains of severe episodes of headache, tremulousness, palpitations, and anxiety. The patient has noted a change in her voice and she has difficulty swallowing solids. [medbullets.com]

  headaches Usually bilateral Parathyroid tumors (~20-30%) – adenoma, hyperplasia Lichen planus amyloidosis MEN2B FMTC – childhood onset; aggressive; 100% of patients Pheochromocytoma (~50%) – paroxysmal hypertension, palpitations, headaches Multiple [arupconsult.com]

• Tachycardia

  They produce excessive adrenaline (epinephrine) secretion leading to tachycardia, palpitations, hypertension and headache. [patient.info]

  If patients develop tachycardia beta-blockade may be initiated. The preferred method of resection is laparoscopic adrenalectomy for tumors 8cm or suspicion for malignancy exists, an open procedure should be performed. [oncologynurseadvisor.com]

• Flushing

  • Carcinoid syndrome – rare – flushing attacks and dyspnea 19. Collagenomas and facial angiofibromas • Collagenomas >70 % cases – multiple, skin coloured cutaneous nodules. [slideshare.net]

  ~40% of patients develop carcinoid syndrome, which presents with: Flushing Diarrhoea Palpitations Hypotension Right sided heart failure This is due to extensive secretion of serotonin, prostaglandins, kinins, gastrin etc. [almostadoctor.co.uk]

  […] type Gastrinoma (~40%) – Zollinger-Ellison syndrome Peptic ulcer disease, recurrent diarrhea, abdominal pain Insulinoma (~10%) – pancreatic islet tumors; usually multiple Hypoglycemia and related symptoms Carcinoid tumors (~10%) – carcinoid syndrome Flushing [arupconsult.com]

• Skin Rash

  • Skin rash(necrolytic migratory erythema), venous thrombosis, anemia, diarrhea, anorexia, weight loss, stomatitis, hyperglycemia, hyperglucogonemia. 14. VIPomas • Rare. • WDHA syndrome. • Watery diarrhea, hypokalemia, achlorhydria. [slideshare.net]

  rash, anorexia, diarrhea Anterior pituitary tumors 10-60% of patients; symptoms depend on the pituitary hormone produced Prolactinoma (~20%) – most common Females – amenorrhea and galactorrhea Males – impotence or reduced libido Growth hormone tumor [arupconsult.com]

  One variant of MEN2A is associated with cutaneous lichen amyloidosis, a condition in which a scaly, itchy skin rash develops due to the accumulation of certain proteins (amyloids) in the skin. [rarediseases.org]

• Skin Disease

  Photo Credit Gracia Lam Personal Health A Little-Known Skin Disease That Can Disrupt People’s Sex Lives Patients deal with pain and itching and often encounter medical ignorance and mistreatment until affected tissues become irreparably scarred. [nytimes.com]

  Genetic testing is also important for people with a family history of the disease as early diagnosis and treatment will reduce the risk of thyroid cancer and death. See smartphone apps to check your skin. [dermnetnz.org]

• Pruritus

  In January 1998, he presented with flushing, pruritus, and watery diarrhea. [bcmj.org]

• Headache

  Severe, treatment-resistent hypertension (particularly paroxysmal in nature, with headaches, palpitations, and diaphoresis). MEN2B Marfanoid habitus Mucosal neuromas on lips, tongue and eyelids. Note that Abraham Lincoln was said (apocryphally?) [medicalmediareview.com]

  […] with this syndrome seek medical treatment because of one of the following: peptic ulcer disease, symptoms related to low blood sugar, symptoms related to high serum calcium levels or kidney stones, or symptoms related to pituitary problems (such as headache [uclahealth.org]

  Usually bilateral Parathyroid tumors (~20-30%) – adenoma, hyperplasia Lichen planus amyloidosis MEN2B FMTC – childhood onset; aggressive; 100% of patients Pheochromocytoma (~50%) – paroxysmal hypertension, palpitations, headaches Multiple and often bilateral [arupconsult.com]

  Snapshot A 36-year-old women complains of severe episodes of headache, tremulousness, palpitations, and anxiety. The patient has noted a change in her voice and she has difficulty swallowing solids. [medbullets.com]

If a clinical suspicion toward MEN is made based on a positive family history and findings from a meticulously performed physical examination, the diagnostic workup should be extensive and the following procedures should be performed [2] [6] [8] [9]:

• Parathyroid tumors - Serum levels of ionized calcium, phosphate, 24-hour urinary calcium and levels of parathyroid hormone (PTH).
• Pituitary tumors - Levels of prolactin (PRL), insulin-like growth factor 1 (IGF-1), and magnetic resonance imaging of the endocranium.
• pNETs and carcinoid tumors - Invasive imaging studies, such as endoscopic ultrasonography (EUS), are the most reliable methods of detection, as they have shown superior results over standard (CT, MRI, abdominal ultrasonography) and more advanced techniques (Gallium scanning and PET). Additionally, serum electrolytes (sodium, potassium, chloride) may be useful in patients with diarrhea.
• Adrenocortical tumors - Hyperaldosteronism will invariably cause changes in sodium and potassium levels as well, while ACTH and cortisol levels will be disturbed in the setting of hypercortisolism.
• Medullary thyroid carcinoma (MTC) - Because malignant cells secrete calcitonin, either pentagastrin or calcium stimulated serum calcitonin determination is the mainstay of MTC detection. Carcioembryonic antigen (CEA) is also a valid diagnostic marker.

If laboratory findings are strongly indicative of MEN, molecular analysis of DNA and identification of genetic mutations is used to confirm the diagnosis [1].

• Nephrolithiasis

  Patients may have asymptomatic hypercalcemia, nephrolithiasis, osteitis fibrosa cystica, vague symptoms associated with hypercalcemia, or occasionally peptic ulcers. [iofbonehealth.org]

  Hypercalcaemia may lead to constipation, polyuria, polydipsia, memory problems, depression, nephrolithiasis, glucose intolerance, gastro-oesophageal reflux and fatigue. [patient.info]

  Patients present with signs and symptoms consistent with sporadic PHPT, and include nephrolithiasis, abdominal pain, lethargy, psychiatric disturbances, fragility fractures and osteoporosis. [oncologynurseadvisor.com]

  Symptomatic manifestations of PHT are most commonly due to hypercalcemia, osteoporotic fractures or nephrolithiasis. Hypercalcemic pancreatitis is rare and is an uncommon first manifestation of PHT (4). [doi.org]

• Gastrin Increased

  […] hormone: increased production of cortisol Gastrin: increased risk of stomach ulcers Glucagon: increased risk of diabetes mellitus Parathyroid hormone: increased risk of hypercalcemia and kidney stones Vasoactive intestinal peptide: severe diarrhea Cause [news-medical.net]

  • Hypercalcemia may increase gastrin secretion from gastrinoma 10. [slideshare.net]

Hyperparathyroidism

Although malignant transformation of parathyroid tumors is quite rare, either total or subtotal parathyroidectomy involving 3 and 1/2 of the total parathyroid tissue, together with cervical thymectomy, should be performed [15], primarily because almost all parathyroid glands have proliferated abnormally and caused major symptoms, but also because there is a high chance of recurrence with insufficient gland removal [6] [8]. The main role of concomitant thymectomy is to prevent the potential development of thymic carcinoma [10]. There are disputes regarding the timing of surgery in MEN-1, however, as early surgery is more beneficial for the patient, whereas delaying the procedure may reduce the number of complications that occur during the operation as glands become larger and easier to remove [8]. Until recently, resection of parathyroid tissue and its transplantation to the non-dominant forearm was performed, but because of a high incidence of graft failure and consequent hypoparathyroidism, the procedure is not recommended anymore [8]. A conservative approach including calcimimetic agents, such as cinacalcet, has recently been implemented on a subset of HPT patients and good initial results were observed [8].

Pituitary tumors

Because prolactinomas are most common hypophyseal tumors in MEN, bromocriptine and cabergoline, two dopamine-2 (D2) receptor agonists, are the mainstay of therapy, while GH-secreting tumors are managed with somatostatin analogs lanreotide and octreotide [8]. Transsphenoidal surgery is performed when a curative effect can be achieved, but the development of permanent diabetes insipidus is a potential complication of this approach [8], which is why a careful preoperative assessment is necessary.

Neuroendocrine tumors

Insulinomas, VIPomas, glucagonomas and other rare functional NETs are almost always treated by surgical resection, but the role of invasive treatment in the setting of gastrinomas or non-functional NETs is still not solidified, as curative rates are much lower [8]. An additional reason is that the efficacy of pharmacologic therapy in managing excessive gastric acid secretion, diarrhea, and other associated symptoms with proton-pump inhibitors (PPIs) and histamine-2 receptor antagonists is very good and the risks of morbidity and mortality from surgery may outweigh its potential benefit [15].

Adrenal tumors

When it comes to management of phaeochromocytoma in MEN-2 patients, the initial recommendations suggested bilateral adrenalectomies with consequent Addisonian-like complications and life-long use of steroids, but adrenal-sparing surgery is now becoming the mainstay of therapy, primarily to reduce these complications and provide a better quality of life [16].

MTC

Medullary thyroid carcinoma must be treated aggressively through surgical removal of the thyroid gland, but the presence of a pheochromocytoma must be excluded prior to any invasive procedure due to a very high risk of sudden preoperative death due to abrupt changes in catecholamine secretion [13]. Management of metastatic MTC relies on symptomatic measures. Loperamide, codeine, and other anti-diarrheal agents are used, but the recent introduction of tyrosine kinase inhibitors vandetanib and cabozantinib have shown good results in clinical trials [8].

The prognosis of MEN of any type and subtype correlates with the time of diagnosis. Approximately 60% of duodenal gastrinomas or other neuroendocrine tumors have already metastasized at the time of diagnosis, which significantly reduces overall survival rates [1]. The presence of liver metastases, regardless of the origin of the primary tumor, is particularly associated with a poor prognosis in MEN-1 patients [8]. Additionally, the stage of MTC in MEN-2 patients is the single most important predictor of prognosis, as early recognition of this tumor markedly increases survival rates [1], ranging from 90% in localized disease to 40% in the presence of distant metastases, when observing a 10-year period from the diagnosis [8]. MEN-2b is a particularly dangerous clinical subtype characterized by an aggressive form of MTC that often develops in the first year of life and a 100% mortality rate before 30 years of age if untreated [8].

The cause of MEN varies depending on the underlying type, with different genes and mechanisms involved [1] [9]:

• MEN-1 - Different changes of menin protein, coded by the MEN-1 gene located on the long arm of chromosome 11 (11q13), is the underlying cause and the mutation is transferred by an autosomal dominant pattern of inheritance, but 10% of patients have shown to develop de novo mutations [3] [9] [10]. Menin is a tumor suppressor protein possessing various regulatory functions within the cell, but the exact pathophysiologic basis of disease remains unknown [9]. In a small number of MEN-1 patients, however, the characteristic MEN-1 gene mutation was not confirmed and an additional type MEN-4, was recently established due to the discovery of mutations in the cyclin-dependent kinase (CDK) inhibitor gene (CDKN1B), a tumor suppressor gene performing a similar role to MEN-1 gene [11].
• MEN-2 - Three distinct subtypes of MEN 2 exist - MEN-2a, MEN-2b and familial medullary thyroid carcinoma (FMTC) [12]. For all three subtypes, the principal pathological event is a mutation in the RET proto-oncogene with a variable penetrance [1]. This gene is located on chromosome 10, encoding a tyrosine kinase transmembrane receptor and more than 50 mutations have been identified so far [8]. This mutation is transferred from generation to generation in an autosomal dominant pattern of inheritance as well.

Prevalence rates of MEN-1 are estimated at around 2-3 per 100,000 individuals and studies have detected this disease post-mortem in around 0.25% of individuals [8]. In more than 80% of cases, the clinical onset of MEN-1 does not start before the third decade of life [8]. The most common manifestation, hyperparathyroidism, is most frequently recognized in individuals between 20-25 years of age [8]. Due to the very high penetrance of HPT in MEN-1 patients, all patients suffering from this syndrome will develop HPT by the age of 50 [8]. MEN-2, on the other hand, is less commonly encountered in clinical practice than MEN-1, with an incidence rate of 1 in 200,000 live births [4]. Although prevalence rates of exact subtypes are unknown, the prevalence of MEN-2b is estimated to be between 1 in 600,000 to 1 in 4 million cases [13]. MEN-2a comprises more than 50% of cases, whereas only 5-10% of patients are diagnosed with MEN-2b and the remaining 35% is attributed to FMTC [8].

In the setting of MEN-1, various aberrations of the MEN-1 tumor suppressor gene and consequent changes of the protein encoded by this gene, menin, are key steps in the pathogenesis [9]. Cell division, cell cycle control, regulation of gene transcription and genomic stability are all processes in which menin plays a key role [3]. An instability of the MEN-1 gene and hyperplasia of duodenal cells are thought to be the key events in a proliferation of duodenal gastrinomas [8], but the exact model is yet to be discovered. Studies have also confirmed that menin is a coregulator of estrogen receptors and it was suggested that it may play a role in the pathogenesis of breast cancer, as much higher rates of this malignancy are seen in MEN-1 patients compared to the general population [14]. The pathogenesis of MEN-2 stems from different genetic mutations. The RET proto-oncogene, encoding a transmembrane tyrosine kinase receptor, is a vital constituent of various signaling pathways, most notably during renal and enteric organogenesis [8]. Like in MEN-1, the exact mechanism remains unclear, but this genetic aberration invariably leads to malignancy of the parafollicular C cells in the thyroid gland, causing medullary thyroid carcinoma (MTC) [5]. Its role in the occurrence of other tumors is still a topic of research and the answer remains unclear.

Screening of at-risk patients is the main strategy in preventing MEN from reaching more advanced stages. MEN-1 screening is highly recommended for patients with 2 or more MEN-1 related tumors, those who experience recurrent HPT at a young age and all individuals having a positive family history [8]. In fact, approximately 80% of MEN-1 patients are identified through MEN-1 gene sequencing [8]. For this reason, all first and second-degree relatives of the diagnosed patient should be tested for MEN-1 mutations, so that they are aware of the potential risk and to allow early treatment [9].

Prophylactic screening for RET proto-oncogene mutations in MEN-2 patients and subsequent thyroidectomy at an earlier age is one of the key steps in reducing mortality rates from this type of MEN (especially MEN-2b subtype) when thyroidectomy should be performed within the first few years of life [15]. For FMTC-positive families, screening of children at age 21 and subsequent thyroidectomy is recommended, but post-operative follow-up evaluation of CEA and calcitonin levels, as well as regular CT scans, are mandatory to detect possible recurrence [10].

Multiple endocrine neoplasia is a clinical entity describing a group of genetic disorders in which development of two or more neoplasms occurs [1]. Two main types exist - MEN-1, with tumor proliferation stemming from mutations in the MEN-1 gene on chromosome 11 and subsequent alterations in menin, a tumor suppressor protein; and MEN-2, distinguished by mutations of the RET proto-oncogene located on chromosome 10 [2]; Both forms are transferred from parents to their children through an autosomal dominant pattern of inheritance, but in 10% of cases, however, de novo mutations have been described and the underlying cause is yet to be determined [3]. MEN is a rare syndrome, affecting 2-3 per 100,000 individuals in the case of MEN-1, whereas an even lower incidence rate of 1 in 200,000 live births is estimated for MEN-2 [4]. The clinical presentation of patients is diverse and significant variations exist depending on the type. Primary hyperparathyroidism (HPT) is seen in 90-100% of all MEN-1 patients and the two most frequent neoplasias accompanying HPT are pituitary tumors (most commonly prolactinomas and growth-hormone secreting tumors) and pancreatic neuroendocrine tumors of various classes (most commonly gastrinomas that produce Zollinger-Ellison syndrome) [5]. Consequently, symptoms related to hypercalcemia (lethargy, confusion, anorexia), pituitary changes (gynecomastia, amenorrhea/oligomenorrhea, or acromegaly) and the gastrointestinal tract (diarrhea, vomiting, bleeding, peptic ulcer disease) are most frequently encountered [6]. On the other hand, medullary thyroid carcinoma (MTC) is the principal finding of MEN-2, together with pheochromocytoma that is encountered in approximately 50% of cases. Three clinical subtypes of MEN-2 exist: MEN-2a (parathyroid disease develops in 20-30%), MEN-2b (early-onset of mucosal neuromas of the lips and tongue, a Marfanoid body habitus and distinctive facies with enlarged lips ) and familial MTC [7]. A myriad of tumors of both endocrine and non-endocrine etiology have been described in these patients, which is why the diagnosis of MEN may be difficult to attain, particularly without obvious evidence of positive family history. A complete laboratory and imaging workup is necessary in order to support clinical suspicion, while genetic studies are needed to confirm the diagnosis [6]. Treatment principles somewhat depend on the stage of the tumors at the diagnosis, but surgery is the most frequent modality. Subtotal or total parathyroidectomy, adrenal-sparing surgery in the setting of pheochromocytoma and thyroidectomy are frequently performed [1]. If surgery is not able to provide a curative effect, which may be the case for neuroendocrine tumors, or if conservative treatment is possible (in the case of smaller prolactinomas), alleviation of symptoms through the use of drugs is recommended, but the therapeutic process is complex and long-term monitoring of patients is necessary [1]. Several preventive strategies have been advised, such as screening of families with known RET proto-oncogene or MEN-1 gene mutations and prophylactic thyroidectomy of patients at risk for MEN-2b, but the main focus of prevention is early recognition of the disease, since almost all MEN types and subtypes carry a much poorer prognosis if diagnosed before reaching advanced stages of the disease [8].

Multiple endocrine neoplasia (MEN) is a term that encompasses a group of genetic disorders represented by the development of more than one tumor in the body. Two main forms exist: MEN-1, in which mutations of MEN-1 gene that codes for menin, a tumor suppressor protein, leads to tumors of the parathyroid glands, the pancreas, and the pituitary gland; and MEN-2, distinguished by mutations of the RET proto-oncogene, in whom malignant tumors of the thyroid gland (known as medullary thyroid carcinoma) are seen. Furthermore, MEN-2 is divided into MEN-2a, MEN-2b and familial medullary thyroid carcinoma (FMTC), each having some specific clinical features. Regardless of the type, MEN is a disease that is transmitted from parents to their children and due to the nature of the disease, a 50% chance of transfer exists if one parent is suffering from the disease. MEN is considered as a rare condition, as MEN-1 is seen in approximately 2-3 per 100,000 individuals and even lower rates are seen in the case of MEN-2. However, the diagnosis can be difficult to make, as numerous signs and symptoms may be seen, including gastrointestinal (diarrhea, abdominal pain, bleeding, vomiting, bloating, anorexia, esophageal reflux), musculoskeletal (weakness, increased risk of fractures, changes in the shape of extremities), constitutional (weight loss, confusion, altered mental state, dehydration, etc.) and various other. In addition to tumors that are regarded as essential features of MEN, a myriad of other neoplasias may be discovered in these patients, including those of the skin, central nervous system, muscles, kidneys and the breast. For this reason, it is necessary to perform a thorough clinical examination and obtain a detailed patient history to possibly find out about the presence of tumors within the family. Laboratory studies should include evaluation of serum electrolytes (calcium, sodium, potassium and chloride), pituitary hormones (prolactin and tests that indicate growth hormone levels), calcitonin (secreted by malignant cells of the thyroid gland) and parathyroid hormone, whereas invasive imaging studies such as endoscopic ultrasonography are considered to be the gold standard for discovering tumors confined to the gastrointestinal tract. For many tumors encountered in MEN, either partial or total surgical removal of the affected gland is recommended. Symptom management through the use of drugs is performed when the risks of surgery outweigh the benefits (in the case of pancreatic tumors), but an individualized approach is mandatory to ensure optimal outcomes. To prevent the risks and the harm these disorders may cause, screening of at-risk individuals for genetic mutations is highly advised, so that procedures including preventive removal of the thyroid gland may be performed in the setting of MEN-2b, a very aggressive form of the disease that carries a poor prognosis if not diagnosed early. It is imperative to obtain an early diagnosis of all MEN forms, in fact, as survival rates are significantly lower if the disease is recognized when tumor progression occurs. This may not be easy, however, as the clinical course of many tumors is insidious and often present with very few symptoms.

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