What is family screening in MEN?

MEN of all types is an autosomal dominant genetic disorder therefore relatives of an affected individual are at an increased risk of developing the disorder. When an MEN patient is identified screening is offered to first and second degree relatives (e.g. siblings, offspring and cousins), who normally have no symptoms, where tests are carried out to see if they might show signs of carrying the gene and therefore having the disease.

The best way of checking this is to have a direct genetic test where the presence or absence of the mutated gene can be identified. Unfortunately for MEN, the structures of the genes responsible have not yet been elucidated, making direct gene analysis very difficult at present. Instead hormonal levels are measured:

MEN 1

Measurements are made of the various hormones and blood elements that may be raised in MEN 1. These include calcium, gastrin and prolactin. As hyperparathyroidism is the first part of the syndrome to manifest, monitoring of calcium levels yearly from the age of 5 is the best method. Tests on hormone levels such as gastrin and prolactin are costly and time-consuming therefore could not be considered for widespread screening programs. However once there is a suggestion of asymptomatic MEN 1 prolactin levels and pancreatic hormone levels should be continually assessed.

MEN 2a

Medullary thyroid carcinoma is the first manifestation of this syndrome screening is aimed at detecting the earliest signs of this. This involves the pentagastrin test (described in the section on symptoms and treatment of MEN2a) where the administration of pentagastrin causes raised levels of calcitonin within 2-3 minutes in affected individuals. This should be done in at risk individuals yearly from the age of 15 to 35-50 years of age (after which it does not arise).

Urinary catecholamine (adrenaline and noradrenaline) concentrations should also be obtained during a similar period of time to look for the development of phaeochromocytoma.

Calcium or parathyroid levels should also be obtained every 2 years.

For MEN 2a, once biochemical screening identifies the presence of the syndrome in a family, tests called linkage studies may be performed. These identify the mutation in the RET gene by using DNA markers that are very closely associated with the RET gene mutations. The structure of these markers are known, unlike the structure of the RET gene. The presence of different markers, as detected by genetic probe tests, indicates the presence of different mutations. Once the mutation in any given family is known, this itself can be tested for without having to put individuals through lengthy biochemical screening programs.

MEN 2b

This is essentially the same as for MEN 2a, except that screening for parathyroid abnormalities is not done. Therefore the pentagastrin test or medullary thyroid cancer and the urinary catecholamine tests are used. Linkage studies may also be done once the presence of MEN2b has been established in a family.