Rare genetic endocrine conditions

Question 1

What does MEN stand for?

Answer 1

Multiple Endocrine Neoplasia

Question 2

What is MEN1?

Answer 2

MEN 1 is a multiple tumour syndrome, causing a spectrum of tumour types, from neuroendocrine tumours to non-neuroendocrine tumours

Question 3

What are the main 3 tumours formed in MEN1?

Answer 3

3Ps:
- Parathyroid tumours
- Pituitary adenomas
- entero-Pancreatic neuroendocrine tumours

Question 4

What are some other tumours that can form in MEN1?

Answer 4

• Thymic/bronchial NETs
• Functioning/Non-functioning adrenal tumours
• Lipomas
• Meningiomas
• Collagenomas

Question 5

Describe the genetics of MEN1

Answer 5

Autosomal dominant
Follows double hit hypothesis to MEN1 genes
MEN1 genes code for menin, which helps in DNA damage response, chromatin remodelling and cell signalling

Question 6

How is MEN1 managed?

Answer 6

Surveillance and waiting for problems to arise

Treat problems when they do arise

Screening is constant throughout the patients lifetime with blood testing and radiological testing

Question 7

What are the main cancers formed in MEN2?

Answer 7

• Parathyroid tumours
• Medullary thyroid cancer
• Phaeochromocytoma

Question 8

What is MEN2?

Answer 8

Rare familial cancer syndrome caused by mutations in the RET proto-oncogene

Question 9

What are some other features of MEN2?

Answer 9

Cutaneous lichen amyloidosis
Hirschprung disease

Question 10

Describe the genetics of MEN2

Answer 10

Autosomal dominant
Mutation in RET gene (Proto-onco gene)
Affects cysteine residues, resulting in activation of tyrosine kinase receptor

Question 11

What are the 2 classes of MEN2?

Answer 11

MEN2A
MEN2B

Question 12

What is MEN2A?

Answer 12

Simple syndrome
Accounts for 90-95% of MEN2
Medullary thyroid cancer, phaeochromocytoma and parathyroid tumours

Question 13

What is MEN2B?

Answer 13

Severe MEN2 varient
Medullary thyroid cancer, phaeochromocytoma and:
- Marfanoid habitus
- Mucosal neuroma
- Medullated corneal fibres
- Intestinal autonomic ganglion dysfunction

Question 14

What is Von Hippel-Lindau syndrome?

Answer 14

Inherited disorder causing multiple tumours, both benign and malignant, in the central nervous system (CNS) and viscera

Question 15

What are the main 2 tumours formed in Von Hippel-Lindau syndrome?

Answer 15

• Phaeochromocytoma
• Pancreatic NETs

Question 16

What are some other conditions that can occur in VHL?

Answer 16

• Renal cell carcinoma
• Renal cysts
• Haemangioblastomas
• Pancreatic cysts
• Endolymphatic sac tumours of the middle ear

Question 17

Describe the genetics of Von Hippel-Lindau syndrome

Answer 17

Autosomal dominant
Mutation in VHL gene
Leads to accumulation of HIF proteins and stimulation of cellular proliferation

Question 18

How is VHL managed?

Answer 18

Family screening
Lifelong surveillance for tumours
Manage tumours appropriately

Question 19

What is neurofibromatosis-1?

Answer 19

Genetic condition that causes tumours along the nervous system

Question 20

What are the diagnostic criteria for neurofibromatosis (Features)?

Answer 20

≳2 of the following is diagnostic:

• ≳6 cafe-au-lait macules
• ≳ neurofibromas of any type, or one plexiform neurofibroma - the neurofibroma is the major NF-1 associated tumour
• Axillary or inguinal freckling
• Optic glioma
• ≳2 Lisch nodules
• Distinctive osseous lesion e.g. sphenoid dysplasia or thinning of long bone cortex, with or without pseudoarthrosis
• First degree relative with NF1

Question 21

What are some other associated conditions of neurofibromatosis-1?

Answer 21

Scoliosis
Learning difficulties
Phaeochromocytoma (Rare)

Question 22

Describe the genetics of neurofibromatosis-1

Answer 22

Mutation in NF1 gene

Question 23

What is Carney complex?

Answer 23

Rare genetic disorder characterized by multiple benign tumours (multiple neoplasia)

Question 24

What organs or systems are most commonly affected by Carney complex?

Answer 24

Heart
Skin (And skin pigmentation)
Endocrine system

Question 25

Describe the genetics of Carney complex?

Answer 25

Mutation in PRKAR1A
Causes defective regulatory sub-unit, allowing aberrant PKA signalling and thus uncontrolled proliferation

Question 26

What are some manifestations of Carney complex?

Answer 26

Spotty skin pigmentation
Myxoma (Cardiac, breast, mucosal)
PPNAD
Acromegaly
Thyroid carcinoma
Blue naevi formation
Osteochrondromyxoma
Psammomatous melanotic schwannoma

Question 27

What is PPNAD?

Answer 27

Primary pigmented nodular adrenocortical disease
Causes adrenal glands to produce excess cortisol, leading to Cushing’s

Question 28

What is McCune-Albright?

Answer 28

Complex genetic disorder affecting the bone, skin and endocrine systems

Question 29

Describe the genetics of McCune-Albright

Answer 29

Post-zygotic somatic GNAS mutation (not germline) resulting in mosaicism
Results in constitutive adenylyl cyclase signalling and overproduction of several hormones

Question 30

How does McCune-Albright present?

Answer 30

• Cafe-au-lait skin pigmentation
• Polyostotic fibrous dysplasia
• Precocious puberty (typically females)
• Thyroid nodules
• GH excess
• Cushing’s syndrome