Genetics

Question 1

Monogenic Disorders

Answer 1

Single Gene Aetiology

6 patterns of inheritance

Question 2

Polygenic Disorders

Answer 2

Multiple genes

Often environmental influences

Question 3

Genetic Abnormalities leading to monogenic disorders

Answer 3

Single Nucleotide Variants (SNVs)

• missense amino acid change
• nonsense amino acid change
• splice site alteration

Small insertions and deletions

• in-frame
• out-of-frame

Loss of function typically results from

• nonsense
• frameshift
• coronical splice site mutations

Question 4

Multiple endocrine neoplasia type 1 (MEN1)

Answer 4

Central to pathways disrupted in pancreatic NETs

Tumour Spectrum

• Parathyroid
• Pituitary
• Enteropancreatic
• Thymic/ bronchial carcinoids
• Gastric carcinoid
• Function/ Non-functioning adrenal

Question 5

MEN1 clinical features

Answer 5

Primary hyperparathyroidism
- parathyroid adenoma/ hyperplasia

Pancreatic Neuroendocrine Tumours

• gastrinoma
• Insulinoma

Pituitary adenomas

Foregut neuroendocrine tumours

Adrenocrotical tumours

Question 6

MEN1 clinical genetics

Answer 6

Autosomal dominant

‘Classic’ tumour suppressor in endocrine tissues

Mutations occur throughout MEN1 gene located on chromosome 11q13

Mutations typically result in loss/ reduced protein function

Question 7

MEN1: Premature morbidity and mortality

Answer 7

50% of affected patients will die as a direct result

Leading causes of excess death

• malignant pancreatic neuroendocrine tumour
• thymic carcinoids

Question 8

MEN1 Management

Answer 8

Management is difficult

• lack of genotype/ phenotype correlation
• variable age related penetrance
• inability to. predict course
• lack of specific therapies

Goal: Prevent premature morbidity and mortality from MEN1 associated tumours, whilst preserving quality of life

Question 9

MEN1: Genetic testing

Answer 9

Clinical criteria for MEn1
Suspicion for MEN1
First degree relatives

-Aim to detect onset of tumours at an early stage

Question 10

Multiple Endocrine Neoplasia Type 2 (MEN2)

Answer 10

Autosomal dominant

RET gene-10q
- RET tyrosine kinase receptor
Classic porto-oncogene

MEN2A + MEN2B

Question 11

MEN2 Main cancer

Answer 11

Medullary thyroid cancer (MTC)

Question 12

MEN2 Clinical features

Answer 12

MTC first manifestation in MEN2
-Derived from parafollicular C-cells in thyroid

Clinical presentation (i.e. neck mass) associated with metastatic disease and poor outcomes

Signs & Symptoms

• neck mass
• diarrhoea and flushing (metastatic)
• Ectopic ACTH and Cushing

Question 13

MEN12 Diagnosis

Answer 13

Neck USS and FNA

Measure basal serum calcitonin

Question 14

MEN2 treatment

Answer 14

Depends on stage of disease

Localised
- curative surgery (thyroidectomy)

Advanced
- Complex management (recent advent of tyrosine kinase inhibitors)

Opportunity from ‘prophylactic’ thyroidectomy in RET mutation carriers

Question 15

Phaeochromocytoma

Answer 15

Occurs in 40-505 of MEN2
may occur in children and frequently bilateral
typically benign

Question 16

Phaeochromocytoma diagnosis.

Answer 16

Elevated urinary or plasma metanephrines

Question 17

Phaeochromocytoma treatment

Answer 17

Surgical

Appropriate pre-operative management

Question 18

Primary hyperparathyroidism

Answer 18

Occurs in ~30% of MEN2

Treatment
- Surgical removal of enlarged/ overactive thyroid glands

Question 19

Neurofibromatosis Type 1

• Gene
• Endocrine Tumours (1)
• Non-endocrine features (5)

Answer 19

Gene: NF1

Endocrine Tumours
- Phaeochromocytoma

Non-endocrine features

• Axillary freckling
• neurofibromas
• optic gliomas
• skeletal abnormalities
• GISTs

Question 20

Von Hippel - Lindae (VHL)

• Gene
• endocrine tumours (2)
• Non-endocrine features (4)

Answer 20

Gene: VHL

Endocrine Tumours

• Phaeochromocytoma
• Pancreatic NET

Non-endocrine features

• Renal Cell Carcinoma
• Renal Cysts
• Haemangioblastomas
• Pancreatic Cysts

Question 21

Carney Complex

• Gene
• Endocrine Tumours (3)
• Non-endocrine features (3)

Answer 21

Gene: PPKAR1A (defective regulatory subunit)

Endocrine Tumours

• PPNAD
• Thyroid tumours
• Pituitary Adenoma

Non-endocrine Features

• Lentigines
• Atrial myxomas
• Sertoli cell tumours

Question 22

McCune Albright Syndrome

Answer 22

Gene: GNAS

mutation occurs during early embryonic development