Syndromes Flashcards
MEN1
Wermer Syndrome
Rare and heritable with prevalence of 2 per 100,000.
autosomal dominant
mutations in the MEN1 gene, located on chromosome 11
MEN1 gene provides instructions for making a protein called menin, which is thought to play a role in regulating cell growth and division
o Characterised by abnormalities of the parathyroid, pancreas and pituitary (3 P’s).
Parathyroid:
Primary hyperparathyroidism most common (80-95% of patients). See both hyperplasia and adenomas.
elevated levels of parathyroid hormone (PTH) and hypercalcemia (high blood calcium levels)
o Pancreas - pancreatic NETs:
Aggressive endocrine tumours. Usually metastatic at time of diagnosis. Not uncommon to find multiple microadenomas throughout the pancreas.
Can present with Zollinger-Ellison syndrome (digestive disorder that results in too much gastric acid → ulcers, gastritis etc) in context of functional gastrinomas.
o Pituitary:
Prolactinoma most common. Some patients develop acromegaly from somatotropin secreting tumours.
MEN1 – transcription regulator. Can be ACTH, GH or prolactin secreting adenomas
o Others:
Duodenum – most common site of gastrinomas, far more common than the pancreas. Synchronous duodenal and pancreatic can be seen in the same patients
25% gastrinomas arise with other endocrine tumours as part of MEN1. Sporadic gastrinomas are usually single.
Thyroid and adrenocortical adenomas
Lipomas more common than in the general population.
also less commonly carcinoid, adrenal cortical lesions, meningioma, lipoma, breast ca, FNH, facial angiofibroma
MEN 2A
medullary thyroid (100%), parathyroid, pheochromocytoma
NB: As many as 25% of phaemochromocytomas arise in familial syndromes associated with germline mutations MEN 2A, 2B, NF-1, VHL, familial paraganglioma syndromes
Caused by gain of function mutations in RET (rearranged during transfection) proto-oncogenes.
Autosomal dominant
The RET gene provides instructions for making a protein that is involved in the development and maintenance of nerve cells and the formation of various tissues, including the endocrine glands. Mutations in the RET gene lead to the production of a malfunctioning RET protein, which can contribute to the development of tumors in certain endocrine tissues, such as the thyroid and adrenal glands.
MEN 2B
medullary thyroid (80%) (usually multifocal), phaeochromocytoma, mucosal neuroma, marfanoid body habitus.
NO parathyroid hyperplasia
neuromas and ganglioneuromas of skin, oral mucosa, eyes, respiratory tract, GIT.
Like MEN 2A, also associated with mutations in the RET proto-oncogene and is inherited in an autosomal dominant manner
Polyposis Syndromes
- Familial Adenomatous Polyposis (FAP)
- Peutz-Jegher
- Cronkhite-Canada Syndrome
- Juvenile Polyposis Syndrome
- Cowden syndrome:
Not a polyposis syndrome
Hereditary Non-Polyposis Colorectal Cancer (HNPCC) aka Lynch Syndrome
Familial Adenomatous Polyposis (FAP)
Autosomal dominant. 75% of cases are inherited. Remaining 25% are sporadic
o Ampulla of Vater and stomach are common sites for extracolonic involvement.
Additionally, non-gastrointestinal manifestations may include desmoid tumors (aggressive fibrous tumors), dental abnormalities, and certain skin and soft tissue tumors
Fundic gland polyps associated with FAP occur in the gastric body and fundus. Dysplasia and cancer may occur in FAP-associated fundic gland polyps, but sporadic fundic gland polyps carry no cancer risk.
Fundic gland polyps occur sporadically and in individuals with FAP. The prevalence of fundic gland polyps is increasing due to increasing use of PPI. These drugs inhibit acid production, which leads to increased gastrin secretion and, in turn, oxyntic gland growth.
Intestinal type gastric adenocarcinoma are generally associated with FAP
gastric adenocarcinoma is often separated morphologically into intestinal type, which tends to form bulky masses, and a diffuse type, which infiltrates the wall diffusely, thickens it, and is typically composed of signet ring cells
In contrast to diffuse gastric cancers, sporadic intestinal-type gastric cancers are strongly associated with mutations that result in increased signaling via the Wnt pathway. These include loss of- function mutations in the adenomatous polyposis coli (APC) tumor suppressor gene and gain-of-function mutations in the gene encoding β-catenin. Therefore FAP patients, who carry germline APC mutations, have an increased risk of intestinal-type gastric cancer.
Both intestinal and diffuse are associated with H. pylori.
o Numerous colorectal polyps occurring as teenagers.
o Somatic mutation in APC gene – regulator in Wnt pathway
o Colorectal carcinoma occurs in 100% of these patients. Always before age 50. Mostly prior to 30 yrs.
o FAP is caused by mutations in the APC (adenomatous polyposis coli) gene
o Associated with a defect in APC/Wnt pathway.
o APC gene is a tumour suppressor gene, and affects beta-cateninn, a protein that helps regulate the Wnt signaling pathway which is involved in cell division and differentiation
Mutation in APC ⇒ increased beta-catenin accumulation in cells → increased Wnt signalling → uncontrolled cell growth → uncontrolled polyp formation → accumulation of other mutations such as KRAS and other genetic changes → colorectal cancer
o Attenuated variants of FAP are associated with different mutations in APC and MUTYH repair genes which can lead to development of polyps and CRC after the age of 50
o On histology has a tubular villous appearance. Typical adenocarcinoma.
o Associations include:
Congenital hypertrophy of the retinal pigment epithelium
Gardner syndrome → FAP PLUS:
DOPE
Desmoid tumours/fibromatosis, abnormal dentition (supernumerary teeth, dentigerous cysts), duodenal/ampullary carcinomas
Osteomas (multiple) of the mandible, skull, long bones
Papillary thyroid cancer
Epidermal cysts
Turcot syndrome → intestinal polyposis (associated with APC mutation),
medulloblastomas and GBM.
Peutz-Jegher
AD. Presenting at median age of 11.
o STKI 1 mutation. AMP kinase related pathways.
o Hamartomatous polyps and mucocutaneous hyperpigmentation.
o Polyps occur most commonly in small intestine. Can occur in stomach and colon. Lower frequency in bladder and lungs.
o Large and pedunculated polyps with a nodular contour. Arborising connective tissue, smooth muscle, lamina propria and glands lined by normal appearaing intestinal epithelium. Increased risk of colonic adenocarcinoma.
o Pigmented macules, increased risk of colon, breast, lung, pancreatic and thyroid cancer.
lifetime risk of approx. 40%
Late childhood – gastric and small intestinal cancers
2nd and 3rd decades – colon, pancreatic, breast, lung, ovarian, uterine
Cronkhite-Canada Syndrome
Non-hereditary polyposis syndrome. Unknown aetiology.
o Harmatomatous polyps of the stomach, small intestine, colon,.
o Abnormalities seen in nonpolypoid mucosa
o See nail atrophy, hair loss, abnormal skin pigmentation, cachexia and anaemia
o Mean age at presentation > 50 yrs.
Juvenile Polyposis Syndrome
Mean age at presentation < 5 yrs
o Associated with SMAD4 and BMPR1A mutation. TGF- signalling pathway
o Juvenile polyps. Increased risk of gastric, small intestinal, colonic and pancreatic adenocarcinoma.
o Congenital malformations, digital clubbing
o vagues association with AVM (pulmonary, GIT, brain)
Cowden syndrome:
o Mean age at presentation is < 15 yrs
o Associated with PTEN mutation. PI3K/AKT pathway
o Hamartomatous inflammatory intestinal polyps, lipomas, ganglioneuromas
o Benign skin tumours, benign and malignant thyroid and breast lesions.
Increased association with breast and thyroid cancer
o Lhermitte-Duclos → cerebellar hamartomas
o No associated increase in GIT cancers.
Hereditary Non-Polyposis Colorectal Cancer (HNPCC) aka Lynch Syndrome
HNPCC is thought to account for 2% to 4% of all colorectal cancers, making it the most common syndromic form of colon cancer
caused by inherited mutations in genes that encode proteins responsible for the detection, excision, and repair of errors that occur during DNA replication
majority of patients with HNPCC have mutations in MSH2 or MLH1
Often occur in the RIGHT side of the colon, and at younger ages than sporadic
sites: colorectum, endometrium, stomach, ovary, ureters, brain, small bowel, hepatobiliary tract, pancreas, and skin
Percentage of breast malignancies attributable to BRCA mutations
BRCA 1 and 2 account for 80-90% of breast malignancies that can be attributed to single gene mutations and approx 3% of all breast cancers.
BRCA 1
(think of this as female centric – triple -ve breast, ovarian, fallopian tube)
Ch 17q21
More common than type 2
Increased risk of breast, ovary (more so than BRCA2), pancreatic, CRC, fallopian carcinoma, primary peritoneal serous carcinoma
72% breast Ca and 44% ovarian Ca risk.
Triple -ve is common with medullary breast Ca the most common subtype in BRCA 1
Also get fallopian tube, pancreas, colonic cancers
Associated with male breast (less so than BRCA 2), prostate and hi
BRCA2
male centric)
Ch 13q12-13
Male carriers have a higher risk of male breast cancer with BRCA 2
Increased risk of prostate in men (20x increased risk)
Increased risk of breast, ovary and various GI cancers.
69% breast Ca and 17% ovarian Ca risk.
Increased risk of fallopian (less so than BRCA1), pancreatic (5%), colonic, gallbladder, pharyngeal
BRCA2 mutation carriers are at increased risk for skin cancer, compared with BRCA1 carriers, in particular for basal cell carcinoma, also melanoma.
Association with FA - Biallelic germline mutations cause a rare form of Fanconi anaemia
Fanconi anemia (FA) is a rare genetic disorder that primarily affects the bone marrow, leading to a decrease in the production of all types of blood cells. It is a form of inherited bone marrow failure syndrome
BRCA associated Ovarian serous carcinoma peritoneal spread:
The nodular pattern of disease and presence of disease in the gastrohepatic ligament are associated with significantly higher odds of BRCA mutant disease.
Pattern of peritoneal disease: presence of peritoneal disease in gastrohepatic ligament, mesenteric involvement and supradiaphragmatic lymphadenopathy at CT are significantly associated with BRCA mutation status at univariate analysis and multiple regression.
Li-Fraumeni:
P53 doesn’t work leading to heap of rare cancers.
Hereditary cancer syndrome associated with TP53
Sarcomas:
Osteosarcoma
Rhabdomyosarcoma
CNS:
Gliomas
CPC
Medulloblastoma
Neuroectodermal tumours
Breast Ca
Adrenal cortical carcinoma
