Genetic Syndromes

Question 1

FAP

Answer 1

Mutation of APC gene (adenomatous polyposis coli)

Autosomal dominant - chromosome 5q

100% risk of bowel cancer

Hudreds of adenomatous poylps (defintion >100, attenuated if 10-100)

Colonic microadenomas (not seen in HNPCC)

Duodenal adenomas

Desmoid tumours

Surveillacne: flexi-sig from age 13 annually, 5-yearly colonoscopy from 20, prophylatic surgery when finished school or if symptomatic

Question 2

Gardner

Answer 2

Gardner

Question 3

HNPCC / Lynch syndrome

Answer 3

Lynch syndrome: Germline mutation of MMR genes (usually MLH1, MSH2,MSH6,PMS2) or EPCAM gene

HNPCC if meets Amsterdam criteria

Autosomal dominant

2-3% of all colorectal cancer

and 3% of endometrial cancer

Commonest inherited bowel cancer syndrome

in CRC, 7% have sychronous tumours, and 2%/yr rate of metanchronous tumours

CRC features: younger, more right sided, synchronous lesions, poor differentiated, signet ring and medullary subtype,

Question 4

Amsterdam II criteria for HNPCC

Answer 4

3 relatives with Lynch syndrome associated cancers (colorectal, endometrial, small bowel, TCC of ureter and renal pelvis)

2 successive generations affected

1 colorectal cancer under 50 years

FAP excluded

Tumours verified by pathological examination

Sensitivity 22% Specificity 98%

Question 5

HNPCC cancers

Answer 5

Large bowel 30-75%

Endometrium 30-70%

Stomach 5-10%

Ovary 5-10%

Urothelium 5%

Small bowel, pancreas, brain

Question 6

MAP

Answer 6

MYH-associated polyposis

Autosomal recessive

Biallelic mutation of mutY human homologue gen (MYH)

Chromosome 1p

1:200 general population hetrozygus (minimal increased risk)

Multiple colonic poylps, however only 50% have >100

1–% risk of CRC by age 60

Average age of CRC 47 years

Duodenal polyps 20-30%

Increased risk of oesteoma, dental cys and breast cancer

No desmoids

Start surveillance 25, otherwise manage as per FAP

Question 7

Fam juvenile polyposis syndrome

Answer 7

Autosomal dominant

Multiple harmatomatous polyps colon and upper GI

Macrocephaly

Hereditary haemorrhagic telangiectasia

Congentigal heart disease

SMAD4 and BMPR1A genes

40% risk of CRC

Surveillance: Regular screening with upper and lower endoscopy

Prophylactic gastrectomy and collectomy occasionally performed

Question 8

MEN 1

Answer 8

aka Wermer’s syndrome

Autosomal dominant

MEN1 gene codes for tumour suppressor protein menin (chromosome 11)

3 Ps - primiary hyperParathyroidism, anterior Pituitary adenomas, enteroPancreatic endocrine cells but also adrenal cortical adenoma

Hyper parathyroidism - 100%by age 50, on average 20 years younger than sporadic, far more multiple tumours

Question 9

MEN 2a

Answer 9

X

Question 10

MEN 2b

Answer 10

x

Question 11

BRCA 1

Answer 11

BRCA 1

Question 12

BRCA 2

Answer 12

BRCA 2

Question 13

Von Hippel-Lindau

Answer 13

Von Hippel-Lindau

Question 14

Carney

Answer 14

Carney

Question 15

Neurofibromatosis

Answer 15

Neurofibromatosis

Question 16

Cowden disease

Answer 16

Mutation of the PTEN genen on chromosome 10q22

Gastro-intestinal harmatomas

Breast cancer

Thyroid cacner

Uterine and cervical cancer

Fibrocystic breast disease

Non-toxic goitre

Trichilemmomas and other mucocutaneous lesions

Question 17

Li fraumeni

Answer 17

Autosomal dominant

TP53 aka tumour protein p53 (chromosome 17p13)

aka SBLA syndrome: Sarcoma, Breast, Leukaemia, Adrenal

80% lifetime risk of malignancy, 40% more than one tumour

Typically under 45 years

soft tissue sarcoma, osteosarcoma, pre-menopausal breast cancer, brain tumor, adrenocortical carcinoma, leukemia, or lung bronchoalveolar cancer

Test all with choroid plexus carcinoma or adrenocorticocarcinoma and women 30 years or younger with breast cancer if BRCA -ve

Question 18

Peutz Jegher

Answer 18

Autosomal dominant - STK11 gene on chromosome 19p13

Mucocutaneous pigmentation with multiple gastrointestinal harmatomaous polyps

Common to have small bowel obstruction from polyp intussusception

Lifetime cancer risk:

●Colorectal – 39 percent

●Stomach – 29 percent

●Small bowel – 13 percent

●Pancreas – 11 to 36 percent

●Ovary 20%, Cervix 10%, Breast 30-50%,

●Sertoli cell testicular cancer 10%

Surveillance: Annual physical and Hb check, Upper/Lower and capsule endoscopy every 2-3 years

Annual breast surveillance from 25yrs (<50 MRI/US, >50 mammogram)