Hereditary Tumor Syndromes

---

Tumors that frequently occur in a kindred are likely to have a hereditary background. Although modern medicine is beginning to understand the mechanisms responsible for the development of some of those diseases, many nexus are still unidentified. Individuals who carry a gene variant that is associated with a high likelihood to cause a specific tumor (in colloquial speech: mutation) need to have special surveillance and possibly different treatment approaches compared to patients with sporadic disease. 

MEN1 is a tumor syndrome that is caused by a mutation in the MEN1-gene that alterates the function of the encoded tumor suppressor protein menin. Patients with this syndrome are prone to developing multiple endocrine tumors of the pancreas, primary hyperparathyroidism and tumors of the anterior pituitary gland (3 "P": Pancreas, Parathyroid, Pituitary). Other (even rarer) tumors that are also associated with a dysfunctional menin protein are found in the thymus, bronchus, adrenal, thyroid and skin (multiple lipoma). It is important to bear in mind that every single cell of the body is affected by this genetic alteration. Therefore, the surgical approach to the pancreas (every endocrine cell in this organ may be a tumor precursor) and the parathyroid glands (always a multiglandular disease) needs to be tailored individually. 

MEN2 is caused by a mutation in the RET-proto-oncogene that affects the C-Cells of the thyroid and may lead to the development of medullary thyroid carcinoma (MTC). Furthermore katecholamine-producing cells in the adrenal medulla as well as the sympathetic trunk are frequently involved causing pheochromocytoma and paraganglioma, respectively. Depending on the type of mutation the onset of the disease may be as early as in childhood and other organs can also be affected, especially the parathyroid glands. MEN2 is therefore sub-classified into familial MTC-only variants, so-called fMTC; MEN2A (also simply called MEN2) if the type of mutation also affects the parathyroids and MEN 2B (or MEN3) that is associated with a marfanoid habitus and an aganglionic megacolon (Morbus Hirschsprung).

MEN4 is caused by a mutation in the cell cycle protein CDKN1B. It is amongst the rarest forms of familial tumor syndromes and resembles most manifestations found in MEN1.

VHL is a disease caused by a mutation in the VHL-tumor-suppressor gene. Manifestation are multifold and special care needs to be taken of katecholamin-producing adrenal tumors, renal cell carcinoma and pancreatic tumors.

NF1 or Morbus Recklinghausen is caused by a mutation in the gene coding the protein neurofibromin. In this disease (sub)cutaneous efflorescences typically lead to diagnosis and apart from neurological manifestation special surveillance is necessary with respect to development of (multiple) neuroendocrine tumors of the pancreas as well as katecholamine-producing tumors.

The succinate dehydrogenase is a complex of four enzymes that are necessary to produce energy within mitochondria of the cell. Mutations are known in each of the four subunits (SDH A-D) and are associated with katecholamine-producing tumors.