- Created by: MazzaW
- Created on: 29-11-19 11:57
Autosomal dominant mutation in MEN1 gene. Very rare.
Tumours: parathyroid (95%), gastroenteropancreatic tract (30-80%), anterior pituitary e.g. prolactinomas (15-90%)
Tumours usually occur in late teens, but Dx can be delayed until 30s-40s. Often presents with hyperparathyroidism (asymptomatic hypercalcaemia on routine screening).
Often have diffuse hyperplasia of parathyroid gland and pancreas. Functioning pituitary tumours will generally secrete either prolactin (hyperprolactinaemia), GH (acromegaly) or ACTH (Cushing's disease).
Dx: screening 1st and 2nd degree relatives, genetic testing
Activation of RET gene in later life.
MEN2A: medullary thyroid cancer, benign parathyroid hyperplasia, phaeochromocytoma
MEN2B: thick lips, tall slim build (Marfanoid), mucosal neuromas, ganglioneuromas of gut, medullary thyroid Ca, phaeochromocytoma. Very rare
Autosomal dominant. Causes breast Ca, ovarian Ca, melanoma, prostate Ca and pancreatic Ca
BRCA genes used for double stranded DNA repair- if not available then only have PARP to repair single stranded breaks. Tumour cells will have no functioning BRCA so can use PARP inhibitors to stop them from repairing DNA so cells die.
Overall risk of Ca higher with BRCA 1. BRCA2 more likely to cause male breast Ca.
Suspect if: Ashkenazi Jew, bilateral breast Ca, triple negative breast Ca, 1st degree relative with breast Ca before age 40, 2+ 1st or 2nd degree relatives with breast Ca, male relative with breast Ca, mixture of breast and ovarian Ca in several relatives
Offer genetic testing to someone if their combined risk of being a BRCA1 or 2 mutation carrier is 10% or more (BOADICEA or Manchester scoring system).
Mgmt: family screening, surveillance (yrly MRI 30-49 and yrly mammogram 40-69), chemoprevention (BRCA2- COCP, tamoxifen), offer bilateral mastectomy/salpingo-oophorectomy (need HRT if no ER+ breast Ca)
Familial Adenomatous Polyposis
Causes colorectal Ca via suppressor pathway. Germline mutations in APC gene.
Classic: 1000s of adenomas, 100% lifetime cancer risk (95% penetrant by 35)
Attenuated: 10-100 adenomas
Extracolonic features: gastric fundus/duodenal polyps, congenital hypertrophy/hyperplasia of retinal pigment epithelium (4+ highly specific for FAP), childhood hepatoblastoma, papillary thyroid Ca.
Dx: can do genetic testing, colonoscopy = diagnostic.
Mgmt: annual colonoscopy
Gardner's syndrome: FAP + osteomas, soft tissue tumours (sebaceous cysts, fibromas, desmoid tumours)
Turcot syndrome: FAP + brain tumours (commonly medulloblastoma)
Mutator pathway (adenoma progression). Mutation in MMR (mismatch repair) gene (MSH2- most common, MLH1, MSH6, PMS2). <100 adenomas, colorectal and endometrial Ca. Typically right-sided, large, non-fibrous tumours.
Muir Torre syndrome: Lynch + sebaceous skin tumours (sebaceous adenoma/epithelioma/ carcinoma, keratoacanthoma)
Turcot syndrome: Lynch + brain tumours (commonly glioblastoma).
Dx via Amsterdam criteria:
- positive FH (3 colorectal tumours across 2 generations, at least 1 diagnosed <50)
- tumour tissue positive for microsatellite instability
- tumour tissue negative for BRAF V600E
- immunohistochemistry to determine which MMR gene is mutated
Mgmt: surveillance (2 yrly colonoscopy, if positive FH then also 1-2yrly OGD and biliary USS), long-term 75mg aspirin OD, surgical prophylaxis (not recommended, if pt wants), screen family
Li Fraumeni syndrome
Germline mutation in TP53 (50% of sporadic Cas will have this mutation). Rare.
Tumours: early onset breast Ca (in 20s), childhood sarcoma, leukaemia, adrenocortical carcinoma, glioblastoma.
50% penetrant by age 30.
Criteria for Dx:
- sarcoma before age 35
- 1st degree relative with early cancer (before 45)
- another relative (1st or 2nd degree) with cancer before 35 or sarcoma at any age
Suggestive family and personal history- genetic tesing for TP53
Mgmt: screen other family members, annual full body MRI from 20-49, mammogram not recommended as pt at risk of so many cancers.
40% cases caused by hereditary mutation of RB1 on chromosome 13. Onset usually between 3 months gestation and 5 yrs old.
Suspect it is the hereditary form if it is bilateral disease, or if it is unilateral but occurs below the age of 1.
75% of germline mutations are de novo.
Pts with a germline mutation are at higher risk of other Cas (e.g. sarcoma)
Must rule this out in any babies with a squint (strabismus). Other signs include leukocoria (abnormal pupils, especially when a photo is taken/when testing fro red light reflex) and deterioration of vision.