Familial syndromes

Question 1

What is Li Fraumeni syndrome?

Answer 1

Autosomal dominant mutation in the tp53 gene (a tumour suppressor gene)
Chromosome 17p13
SLBA: sarcoma, leukaemia, breast, adrenal
Increased risk of phyllodes tumour
Radiation-associated cancers more frequent (risk normally <0.5%)
- 4-7% annual risk of contralateral breast cancer (2x BRCA carriers); more likely HER2+,
- adrenocortical carcinoma

Diagnosis
- sarcoma <45y and
- FDR any SLBA cancer <45y and
- FDR or SDR any SLBA <45y or sarcoma at any age

Question 2

What is BRCA1 syndrome?

Answer 2

Autosomal dominant mutation in BRCA1 gene (DNA repair)
<1% of the population
Confers 60% risk of breast cancer, 40% risk of ovarian cancer
10% lifetime risk of prostate cancer

Question 3

What is BRCA2 syndrome?

Answer 3

Autosomal dominant mutation in BRCA2 gene (DNA repair)
<1% population
Confers 60% risk breast cancer,20% risk ovarian cancer
10% lifetime risk of male breast cancer, pancreatic cancer, prostate cancer

Question 4

What is von Hippel Lindau syndrome?

Answer 4

Autosomal dominant inherited mutation of the VHL gene on chromosome 3p25 (a tumour suppressor gene)
1:36,000
Cancers: pancreatic cysts (SCN) and NET in 77% patients
Phaeochromocytoma in young patients, testicular/broad ligament cystadenoma, renal clear cell cancer, carotid body tumour

Question 5

What is tylosis?

Answer 5

An autosomal dominant inherited mutation of the RHBDF2 gene
Cancers: palmoplantar keratoderma, oesophageal SCC

Question 6

What is neurofibromatosis type 1?

Answer 6

An autosomal dominant inherited mutation in the NF1 gene coding for neurofibrin on chromosome 17q (tumour suppressor gene)
Mutation weakens neurofibrin so rapid cell growth in nervous system
1:2600
Neurofibromas, cafe-au-lait spots, Lisch nodules, GIST, phaeochromocytoma, carotid body tumour

Question 7

What is MEN1?

Answer 7

An autosomal dominant inherited mutation in the MEN1 gene, coding for menin, on chr 11q13 (a tumour suppressor gene)

Parathyroid hyperplasia
Pituitary adenoma
Pancreas NET (gastrinoma in upto 61% patients, insulinoma, glucagonoma)
Thymic, gastric or bronchial carcinoid
Breast cancer
Lipoma
Small bowel NET

Question 8

What is MEN2a?

Answer 8

An autosomal dominant inherited mutation in the RET proto-oncogene on chromosome 10, causing multicentric tumour formation in all organs where RET is expressed
Represents 96% of all MEN2 syndrome

Medullary thyroid cancer (8-35y)
Parathyroid hyperplasia
Phaeochromocytoma

Hirshsprungs disease
Lichen amyloidosis
Carotid body tumour

Question 9

What is MEN2b?

Answer 9

An autosomal dominant inherited mutation in the RET proto-oncogene on chromosome 10, causing multicentric tumour formation in all organs where RET is expressed

Medullary thyroid cancer in <1yo, 100% patients
Phaeochromocytoma in 50% patients (bilateral in 30%)

Megacolon
Mucosal neuromas
Bowel wall neuromas - gut dysmotility
Marfanoid habitus

Question 10

What familial syndromes are associated with GIST?

Answer 10

Primary familial GIST syndrome
Neurofibromatosis type 1
Carney Stratakis syndrome
Carney triad (paraganglioma, pulmonary chondroma, GIST)

Question 11

What is Gorlin’s syndrome?

Answer 11

An AD mutation in the PTCH gene on chr 9
A tumour suppressor gene
Phenotype: BCCs from 2 years old

Question 12

What is familial adenomatous polyposis?

Answer 12

An AD mutation in the APC gene on chr 5q21
A tumour suppressor gene
Phenotype: near complete penetrance of 100s of colonic polyps
Extracolonic manifestations:
- fundic gland polyps
- duodenal adenomas (Spigelman staging)
- desmoid tumours in 15%
- thyroid nodules and papillary thyroid cancer

Question 13

What is MYH-associated polyposis (MAP or MUTYH)?

Answer 13

Patients who present with FAP phenotype but no identifiable APC mutation
Have an autosomal recessive mutation in MYH gene
Polyps from <100 to thousands
Lifetime risk of colorectal cancer 100% by age 60
Predominantly right-sided cancers

Question 14

What is Lynch syndrome?

Answer 14

An autosomal dominant inherited condition associated with increased risk of colorectal cancer. The hallmark is microsatellite instability
Genes involved are MLH1, MSH2, MSH6, EPCAM, PMS1, PMS2

Question 15

What is Peutz Jeghers syndrome?

Answer 15

An autosomal dominant mutation of the STK11 gene on chromosome 19
It’s a tumour suppressor gene
Hallmark is mucocutaneous pigmentation and multiple hamartomas

Key manifestations:
- choledochal cysts
- colorectal cancer
- small bowel cancer
- stomach cancer
- pancreatic cancer
- breast, ovarian and cervical cancer
- Sertoli cell tumours