Multiple Endocrine Neoplasia (MEN) syndrome - Overview

Most endocrine surgical problems occur in a sporadic fashion, but some tumours occur because of a genetic problem. When a patient develops several of these tumours, affecting a number of different endocrine glands at once, they may be part of a complex syndrome due to a genetic or inherited abnormality.

The most common of these clusters of tumours occur in the Multiple Endocrine Neoplasia syndromes (MEN syndromes), which are the subject of this section of the website.

What is MEN Syndrome?

There are four types of MEN syndromes described, which each have characteristic features: 

  • tumours in two or more endocrine glands
  • a specific genetic abnormality
  • distinct clusters of endocrine disease

 The clusters of endocrine disease are shown in the table below:

Genetics

Most patients when diagnosed with one of the MEN syndromes are concerned about what it means to have a genetic or inherited disease, that runs in families.

Every cell in the body has thousands of genes that make up a 'code book' for all of the body's functions. These genetic codes are transmitted from parents to their children, with each parent contributing half of their genes to each child. Like a lot of things that are 'lost in translation', the transmission of this genetic code can go wrong and an abnormality can occur in one specific gene - a mutation. People with certain genetic mutations, which are detailed below, can develop one of the MEN syndromes.

Fig.1: Diagram of the autosomal dominant inheritance patternThe mutation is normally quite specific, and passed on in a specific way by autosomal dominant inheritance (Fig. 1), which means that:

  • affected patients will only develop one type of MEN syndrome (related to their specific mutation)
  • there is a 50/50 chance of passing on this inherited abnormality to each child
  • the child can only develop the MEN syndrome if they inherit the mutation
  • the affected child can only develop the same MEN syndrome as their parent (again related to the specific mutation)
  • once diagnosed with one type of MEN syndrome, there is no increased risk of developing the other form of MEN syndrome in either the affected patient or their children
  • even if there is a family history, a parent cannot pass on the mutation unless they have it themselves (i.e: they have MEN syndrome themselves)

Of course, all genetic abnormalities have to start somewhere, so that a small percentage of patients will have no family history and be new mutations. In MEN2B nearly half of all cases arise as new mutations, but in the other types this figure is much lower.

Genetic testing is available to sort out whether a genetic mutation has occurred, which helps not only in the management of the condition, but also will determine the risk of passing on the abnormality to any children.

There are three types of MEN syndromes, which each have specific genetic abnormalities and certain clusters of endocrine diseases. They are MEN1, MEN2A and MEN2B.

MEN1

This syndrome was first described by a USA physician, Paul Wermer, in 1954, so it is sometimes known as 'Wermer's Syndrome'. It was not until 1997 however, that the MEN1 gene was identified on chromosome 11q13. Over 1000 mutations have been described in the MENIN gene (which codes for the menin protein), mutations being found in 90% of patients with MEN1 syndrome. This gene is found widely in the body in the cell nucleus.

This menin protein appears to have a tumour suppressor function, which is lost in the mutation, hence the development of a variety of tumours affecting parathyroid, pancreas and pituitary glands.

MEN2

MEN2 syndrome is divided into two subtypes MEN2A (95%) and MEN2B (5%), which have slightly different clinical manifestations, although the underlying genetic mutation is the same. MEN2A is also known as Sipple syndrome, after John H. Sipple, the American physician who described it in 1961.

Fig.2: RET proto-oncogene and codon abnormalities associated with MEN2 syndromesFamilial medullary thyroid cancer (FMTC) is a distinct variant of MEN2A, characterised by only one feature (MTC) of the syndrome.

The gene responsible for MEN2 is a proto-oncogene called RET (which codes for the tyrosine kinase RET protein subunit of a cell surface receptor). This abnormality is found in 98% of all patients with MEN2 syndromes. The mutation of the RET gene leads to activation of the receptor, with unfettered growth and overactivity of the target cells, and subsequent tumour formation.

In contrast to the MENIN gene of MEN1, RET is found on chromosome 10, and only in neural crest–derived cells, such as the C cells of the thyroid gland and the chromaffin cells in the adrenal gland. Neural crest cells are all in one place in the embryo, but spread out around the body later in development, which results in these cells being found in a variety of anatomically separate places in the adult. This explains the clinical syndrome of specific tumours in the thyroid (MTC) and adrenal (phaeochromocytoma).

Whether RET is also expressed in the parathyroid glands remains unknown, especially considering the low rate of hyperparathyroidism in patients with MEN2A and the lack of hyperparathyroidism in MEN2B. 

Codon abnormalities

MEN2A and FMTC have similar genetic mutation abnormalities so that determining the codons affected does not help to distinguish one from the other. In MEN2A and FMTC, more than 70% of patients have a mutation in codon 634 (exon 11). In MEN2B, the RET mutation is almost always in codon 918 (exon 16) (Fig. 2).

The vast majority of mutations that cause MEN2A affect the extracellular domain codons, particularly codon 634 (exon 11) in over 70%, or codons 609, 611, 618 and 620 (exon 10). They account for 98% of all mutations associated with MEN2A. In fact, a single mutation where a codon 634 cysteine is substituted for an arginine amino acid accounts for 50% of all MEN2A mutations.

In about half of FMTC families, mutations affect codons in exon 10 (mainly codons 618 and 620). In a limited number of families, mutations affect exon 11 (codons 630, 631 or 634). In an increasing proportion of FMTC families , mutations affect exon 13 (codons 768, 790 and 791), exon 14 (codons 804 and 844) and exon 15 (codon 891) in the intracellular domain of the gene.

There is a close relationship between the genetic abnormalities (genotype) and how the disease affects the patient (phenotype), reported initially by the International RET mutation consortium analysis, and summarised below:

  • phaeochromocytoma risk is 50% with a codon 634 or 918 mutation, 8% with a mutation in exon 10, and low in patients with mutations in codons 790, 791, 804 and 891
  • most families with parathyroid neoplasia and all families with cutaneous lichen amyloidosis syndrome have a codon 634 mutation
  • in contrast, only 30% of FMTC patients have a mutation at codon 634
  • mutations at codons 768 and 804 are thus far seen only with FMTC
  • families with MEN2A syndrome and Hirschsprung's disease have a mutation in codons 609, 618 or 620

MTC aggressiveness may be related to the particular mutation in the codon. The specific mutation in codon 634 in patients with MEN2A may have an impact on tumour aggressiveness.

A summary of the risks is shown in Table 1 below, recently published in the American Thyroid Association Guidelines for the Management of MTC (2015):

Table 1: Relationship of common RET mutations to the risk of aggressive MTC in MEN2A & 2B, and to the incidence of phaeochromocytoma (PHEO), hyperparathyroidism (HPTH), cutaneous lichen amyloidosis (CLA) and Hirschsprung's disease (HD). Source: ATA Guidelines on MTC Management

In subjects with a codon 634 mutation, the cumulative risk of MTC rises linearly with age, between under 2 years and 20 years of age. The mean age at diagnosis is 10 years among patients with MTC, and once malignant transformation has taken place, nodal metastases occur an average of six and a half years later. The identification of a single child with MTC and lymph node metastases at the age of 6 years has guided consensus recommendations for thyroidectomy at the age of 5 years. In subjects with an exon 10 mutation, MTC may occur later.

In subjects with mutations in exons 13, 14 or 15, the mean age at diagnosis is significantly older (16·6 years) and lymph node metastases may occur even later, and C cell disease has a less aggressive course. There are, however, always exceptions to these rules.

Screening in MEN

Genetic screening of family members of MEN1 and MEN2 patients is now the diagnostic test of choice, looking for the MENIN gene and RET oncogene respectively. The availability of such testing has made biochemical screening for early manifestations of either MEN syndrome largely obsolete.

Having children tested for genetic defects associated with MEN syndromes is a very individual decision. If children of a known MEN parent are tested, those unaffected can rest assured that no further investigations are required. Those who have inherited the gene can be comforted by the fact that testing and treatment patterns will determine as early as possible when intervention is required.

Thanks to this early detection by DNA test, complications from ulcers, kidney stones as a result of parathyroid tumours, and advanced pancreatic islet cell tumours in the case of MEN1, may be drastically reduced. For MEN2, complications from advanced medullary thyroid cancer, high blood pressure, stroke and heart failure due to adrenal tumours, and kidney stones as a result of parathyroid tumours, may be drastically reduced by early genetic testing.

Genetic testing for MEN1 may be offered to people who:

  • meet the clinical criteria for MEN1 by having at least two of the following: enlarged parathyroid glands, a pancreatic or duodenal endocrine tumour, or a pituitary tumour
  • don’t meet the clinical criteria but are suspected of having MEN1—for example, those who have multiple parathyroid tumours before age 30
  • are first-degree relatives of people with MEN1—children, brothers, or sisters— giving them a 50 percent chance of having inherited the mutation

Among affected family members of MEN2 patients, genetic testing for the RET mutation is the preferred method of diagnosis; the biochemical screening for MTC by calcitonin alone has been largely superseded. Annual screening for hyperparathyroidism and phaeochromocytoma should begin in early childhood and continue indefinitely. Screening for hyperparathyroidism is with annual measurement of serum calcium and PTH. Screening for phaeochromocytoma includes questions about symptoms, measurement of BP, and annual testing for urinary catecholamines.

Genetic counselling can assist family members in understanding how the test results may affect them individually and as a family. Genetic counselling may include a review and discussion of the psychosocial benefits and risks of genetic testing. Genetic testing results can affect the individual patient and their family members, so that genetic counselling can address issues related to how and with whom genetic test results will be shared and their possible effect on important matters such as health and life insurance coverage. A doctor, nurse, or genetics professional provides the genetic counselling.