Familial Syndromes

Several genetic (familial) syndromes predispose to neuroendocrine tumors. These are important to recognize for three reasons. First, because these genetic syndromes are caused by genetic changes that can be inherited, other family members may be at risk. Second, these genetic syndromes predispose to (increase the risk of) more than one tumor type. Individuals with one of these syndromes therefore have an increased risk of developing neuroendocrine tumors in more than one organ. Finally, these syndromes are important because they provide insight into the biology of pancreatic neuroendocrine tumors. Because the genes that cause these genetic syndromes are known, scientists can understand the cellular pathways which lead to the development of pancreatic neuroendocrine neoplasms. The hope is that a better understanding of these pathways will lead to better treatments.

Multiple Endocrine Neoplasia, Type 1, abbreviated MEN 1, is a familial syndrome caused by inherited mutations in the MEN1 gene on chromosome 11. The MEN1 gene codes for the menin protein, and patients with an inherited mutation in the MEN1 gene are predisposed to develop tumors of the pituitary (the small "master" gland at the base of the brain), the parathyroids (four small glands in neck which help control blood calcium levels), and the pancreas.

Multiple Endocrine Neoplasia, Type 2, abbreviated MEN2, is a familial syndrome caused by inherited mutations in the RET gene on chromosome 10. Patients with an inherited mutation in the RET gene are predisposed to develop tumors of the  parathyroids (four small glands in neck which help control blood calcium levels), the adrenals and the thyroid (medullary carcinoma). Of these tumors, the medullary carcinomas of the thyroid tend to be the most aggressive.

von Hippel-Lindau Syndrome, abbreviated VHL, is a familial syndrome caused by inherited mutations in the VHL gene on chromosome 3. Patients with von Hippel-Lindau are predisposed to developing tumors in a number of organs including the the brain (hemagioblastoma), the eye (hemagioblastoma), the kidney (renal cell carcinoma), the pancreas (pancreatic neuroendocrine tumors) and the adrenals (pheochromocytoma). Pancreatic disease may be the first manifestation of VHL, and most patients with VHL eventually develop a pancreatic tumor. The pancreatic tumors in patients with VHL are interesting because they can have unique appearances. Some have a "clear" appearance under the microscope, and others are mixed tumors.

Tuberous Sclerosis Complex (TSC) also predisposes to  neuroendocrine neoplasms (http://www.tsalliance.org/index.aspx). Tuberous sclerosis complex is caused by inherited mutations in one of two genes- TSC1 or TSC2. The TSC1 gene is on chromosome 9 and it codes for the protein hamartin. The TSC2 gene is on chromosome 16 and it codes for the protein tuberin. Patients with tuberous sclerosis complex can suffer from developmental delay, mental retardation and even autism, and they are predisposed to develop a number of different tumors, including three different brain lesions- "tubers," subependymal giant cell astrocytomas and subependymal nodules. In fact, the name tuberous sclerosis comes from the brain lesions that these patients develop- Tuber in Latin means swelling and skleros in Greek means hard. They also can develop distinctive lesions of the skin (hypomelanotic macules and facial angiofibromas), kidney (angiomyolipomas), lungs (lymphangioleiomatosis), heart (rhabdomyomas), and eye tumors ( hamartomas). Most of these are entirely benign growths, but they can cause symptoms depending on their location. Although less common than the other manifestations of tuberous sclerosis, several patients with tuberous sclerosis complex have been reported who developed pancreatic neuroendocrine tumors.

Neurofibromatosis type 1, also known as von Recklinghausen disease, is a familial syndrome caused by inherited mutations in the NF1 gene on chromosome 17 (http://ghr.nlm.nih.gov/condition/neurofibromatosis-type-1). The NF1 gene codes for the protein neurofibromin. Patients with neurofibromatosis develop dark patches of skin (café-au-lait spots), and benign (non-cancerous) and malignant (cancerous) tumors of the nervous system. The benign nerous system tumors include neurofibromas, and the malignant the "malignant peripheral nerve sheath tumor." They can also develop distinctive eye lesions called Lisch nodules, and a small percentage develops somatostatinomas of the pancreas/duodenum.

Clinical genetic testing is now available for these syndromes, but such testing is best done with the help of a trained genetic counselor. Individuals found to have one of these genetic syndromes may benefit from increased screening for early tumors, and, it is our hope, that a better understanding of the genetics of these syndromes will lead to novel gene-specific therapies in the future.