Endocrine 2

Question 1

Monogenic vs polygenic inheritance?

Answer 1

Monogenic disorders

• Single gene
• 6 patterns = AD, AR, XLD, y-linked, mitochondrial

Polygenic disorders

• Multiple genes
• Environmental influences

Question 2

Monogenic endocrine tumour syndromes? (5)

Answer 2

• Multiple endocrine neoplasia type 1 (MEN1)
• Multiple endocrine neoplasia type 2 (RET) - c cell cancer
• Carney complex - thyroxine excess
• McCune Albright syndrome - fibrous dysplasia of bone, cafe-au-lait spots, sarcoma
• Von-Hippel Lindau disease - catecholamine, renal cancer
• Neurofibromatosis type 1 - neurofibroma, cafe-au-lait spots, lisch nodules, freckling

Question 3

MEN1 associated with? (3)
Gene? (3)
MEN2 associated with?
Gene? (3)

Answer 3

MEN1 (3 P’s) - pituitary, parathyroid and pancreatic endocrine tumours

• Autosomal dominant
• MEN1 gene - 11q
• Tumour supressor gene

MEN2 - medullary thyroid cancers, phaeochromocytoma + parathyroid disease

• autosomal dominant
• RET gene - 10q
• Proto-oncogene

Question 4

Phenotype/genotype correlation in MEN1 vs MEN2?

Answer 4

MEN1

• mutations occur throughout coding region
• loss/reduced protein function
• no phenotype/genotype correlation

MEN2

• mutations affect specific cysteine residues
• mutations result in activation of receptor tyrosine kinase
• clear phenotype/genotype correlation

Question 5

Why is MEN1 important?

Answer 5

• 50% of individuals will die as a direct result of the disease

Question 6

MEN2 treatment? (3)

Answer 6

• Medullary thyroid cancer = prophylactic thyroidectomy
• Screening for phaeochromocytoma
• Screening for parathyroid disease

Question 7

Clinical features of carney complex? (3)

Answer 7

• Primary pigmented nodular adrenocortical disease (PPNAD) - causes adrenal glands to produce excess cortisol leading to cushing’s syndrome
• Acromegaly
• Thyroid carcinoma

Question 8

Ax Carney complex?

Answer 8

• Mutation in PRKAR1A
• Defective regulatory subunit
• Abnormal PKA signalling = uncontrolled proliferation

Question 9

McCune-Albright syndrome s/s/? (6)

Answer 9

• Café-au-lait skin pigmentation (‘Coast of Maine” appearance)
• Polyostotic fibrous dysplasia (bones)
• Precocious puberty (typically females)
• Thyroid nodules
• Pituitary – GH excess
• Cushing’s syndrome (adrenal)

Question 10

Ax McCune-Albright syndrome?

Answer 10

• Post-zygotic GNAS mutation (not germline)

* Excessive cAMP signalling

Question 11

Features of Von Hippel-Lindau? (7)

Answer 11

• Retinal hemangiomas
• CNS hamangioblastomas
• Sac tumours of middle ear
• Lung cysts
• Phaeochromocytoma
• Pancreatic cysts
• Kindey cysts

Question 12

Ax von hippel lindau syndrome?

Answer 12

• Mutation in VHL gene (autosomal dominant)
• Leads to accumulation of HIF proteins + cell prolif
• (range of vascular tumours)

Question 13

Neurofibromatosis type 1 s/s? (6)

Answer 13

• Axillary freckling
• Cafe-au-lait spots
• Neurofibromas
• Optic gliomas
• Scoliosis
• Phaeochormocytoma (rare)

Question 14

Ax neurofibromatosis?

Answer 14

Mutation in NF1 gene

Question 15

Genes associated with phaeochromocytoma?

Answer 15

• NF1
• RET (MEN2)
• VHL
• SDH genes (most common)

Question 16

What are succinate dehydrogenase genes (SDH) associated with?
What are they?

Answer 16

Phaechromocytoma + paraganglioma

* enzymes involved in Kreb’s cycle