Aetiology
Type 1 multiple endocrine neoplasia (MEN1) and type 2 multiple endocrine neoplasia (MEN2) are caused by autosomal-dominant mutations that can be inherited or occur sporadically.
MEN1 gene mutations are responsible for over 75% of MEN1 cases and have a high penetrance.[8] Over 1300 different germline or somatic mutations have been reported in patients with MEN1, but genotype-to-phenotype correlations are weak.[3][8][20][21][22][23][24][25]
RET proto-oncogene mutations are responsible for almost all MEN2 cases and the phenotypes of the 3 main variants (MEN2A, MEN2B, and familial medullary thyroid cancer) are predicted by these mutations.[26][27][28] Different mutations confer different risks of medullary thyroid cancer aggressiveness and phaeochromocytoma penetrance. For example, mutations in codons 806, 883, and 918 confer a high risk of early aggressive medullary thyroid cancer in MEN2B, and mutations in codon 634 are associated with early phaeochromocytoma.[5] Codons 630, 768, 791, and 891 have not been associated with phaeochromocytoma at all.[29]
For MEN4, too few cases with a relatively wide range of mutations have been described to draw conclusions about genotype-phenotype correlations.[19]
Pathophysiology
Hormonal hypersecretion (dependent on tumour type) leads to specific MEN symptoms.
Hypersecretion of parathyroid hormone (from multigland parathyroid hyperplasia) can cause increased intestinal calcium absorption and mobilisation of calcium from bones resulting in increased risk of osteoporosis and nephrolithiasis. Hypercalcaemia can also occur as a result of thyrotoxicosis and phaeochromocytoma (and adrenal insufficiency).
Hypersecretion of prolactin (from prolactinoma pituitary adenomas) can cause menstrual and fertility problems due to the suppressive effects of elevated prolactin on gonadotrophin-releasing hormone.
Hypersecretion of growth hormone (from growth hormone-secreting pituitary adenomas) can cause excessive production of insulin-like growth factor-1 and lead to acromegaly.
Normal hormone production can be disrupted by the pressure of non-functioning pituitary adenomas on the pituitary gland, leading to over-production of prolactin due to stalk effect and under-production of the other anterior pituitary hormones.
Hypersecretion of adrenocorticotrophic hormone (from adrenocorticotrophic hormone-secreting pituitary adenomas and late-stage medullary thyroid cancer) can cause adrenal stimulation and elevated corticosteroid levels, leading to Cushing's syndrome.
Hypersecretion of thyroid-stimulating hormone (TSH) (from TSH-secreting pituitary adenomas) can cause hypersecretion of L-thyroxine (T4) and triiodothyronine (T3), leading to thyrotoxicosis, which is often clinically mild or subclinical.
Hypersecretion of gastrin (from gastrinomas) can cause over-stimulation of hydrochloric acid-secreting cells of the stomach leading to Zollinger-Ellison syndrome. MEN1 gastrinomas are almost entirely duodenal and generally multicentric, and are likely to develop from multiple primary lesions.[30]
Hypersecretion of peptide hormones produced by intestinal neuroendocrine and pancreatic tumours can cause various syndromes/conditions specific to the hormone involved.
Hypersecretion of catecholamines (from phaeochromocytomas) can be chronic or episodic and cause features including sweating, headache, palpitations, and severe hypertension. In some patients, the catecholamines are converted to inactive metabolites within the tumour, making certain phaeochromocytomas symptomatically silent.
Hypersecretion of calcitonin can occur as a result of medullary thyroid cancer.
MEN1 genes make nuclear proteins called menin.
Menin forms complexes with and modulates the activity of sequence-specific DNA-binding factors (transcription factors).[31][32] MEN1 tumours result from somatic mutations, that disrupt the normal MEN1 alleles in susceptible cells.
All MEN1 tumours exhibit loss of normal MEN1 alleles along with germline mutations, implying that menin has tumour-suppressive roles.[33]
There is no demonstrated link between mutation site and family-specific tumour combination patterns, but evidence suggests that mutation types (missense or nonsense) may be relevant to phenotypes.[25] For example, patients with MEN1 mutations leading to loss of interaction with checkpoint kinase 1 (CHEK1) have a higher risk of malignant pancreatic neuroendocrine tumours, with an aggressive course of disease and disease-related death.[34]
RET proto-oncogenes encode large transmembrane proteins that transduce growth and differentiation signals in several developing tissues, including those derived from neural crests.
These proteins consist of extracellular regions with ligand-binding domains, cadherin-like domains, and cysteine-rich domains close to the cell membranes.
They have single transmembrane domains and intracellular regions with two tyrosine kinase subdomains. In normal function, kinase activity is turned on by ligand-induced dimerisation.
In MEN2A, extracellular domain mutations lead to ligand-independent dimerisation and activation.[35]
Catalytic domain mutations lead to constitutive kinase activity and more aggressive MEN2B tumours.[36]
The CDKN1B gene acts as a tumour suppressor gene.[2]
Classification
Multiple endocrine neoplasia syndromes
MEN syndromes are characterised according to tumour characteristics and can be classified into 4 main forms: MEN1; MEN2, which is divided into subtypes, MEN2A and MEN2B, (also known as MEN2 and MEN3); and MEN4.[1]
Carney's complex is an extremely rare multiple endocrine neoplastic condition distinct from MEN1 and MEN2. Inactivating mutations in the type 1 alpha regulatory subunit of protein kinase A (PKA; the PRKAR1A gene), which lead to dysregulation and activation of the PKA pathway, are the main genetic cause of this.[2]
MEN1
Tumours typically arise from mutations in the tumour suppressor gene MEN1, which encodes the protein menin.[3] Diagnosis is based on patients having 2 or more of the MEN1-associated tumours listed below, or 1 associated tumour and a first-degree relative with the condition, or on the basis of genetics alone with a diagnosed pathogenic mutation of MEN1.[3]
Endocrine
Parathyroid adenomas
Pituitary adenomas
Gastrinomas and other enteropancreatic tumours
Neuroendocrine/carcinoid tumours from bronchial/gastric/thymic origin
Adrenal cortical tumours
Central nervous system tumours, including meningiomas[3]
Thyroid tumours (although these may occur with similar frequency to the background population).[3]
Non-endocrine
Primary hyperparathyroidism is the most common feature associated with MEN1, occurring in around 90% of patients.[3] Primary hyperparathyroidism associated with MEN1 is diagnosed at an earlier age compared to sporadic cases (aged 20 to 25 years versus 55 years).[3]
MEN2
Tumours typically arise from RET proto-oncogene mutations causing medullary thyroid cancer and/or phaeochromocytoma. Subgroups of MEN2 include MEN2 and MEN2B (also referred to as MEN3), and familial medullary thyroid cancer (FMTC).
Patients with MEN2A (also known as Sipple's syndrome) may have:
Medullary thyroid cancer
Phaeochromocytoma
Multigland parathyroid adenomas with hyperparathyroidism
Hirschsprung's disease as an associated feature
Cutaneous lichen amyloidosis as an associated feature.[5]
Patients with MEN2B may have:
Medullary thyroid cancer
Phaeochromocytoma
Marfanoid body habitus
Mucosal intestinal ganglioneuromatosis.[6]
The American Thyroid Association recommends that FMTC should not be a distinct syndrome from MEN2A and MEN2B, rather a variant along the spectrum of disease expression in MEN2A.[7] Patients with FMTC may have:
Family patterns of isolated medullary thyroid cancers
Pedigrees of multiple carriers >50 years of age
No other MEN2 manifestations (pheochromocytoma, hyperparathyroidism).[5]
MEN4
MEN4 is rare and is caused by inactivating mutations in the CDKN1B gene. Patients with MEN4 may have:
Parathyroid adenomas
Pituitary adenomas
Adrenal, renal, and reproductive organ tumours
Gastrointestinal neuroendocrine tumours, though they appear to be less prevalent in MEN4 than in MEN1.[2]
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