Endocrine Genetics

Question 1

Describe monogenic disorders

Answer 1

Single gene aetiology with 6 pattern of inheritance (refer to monogenic pattern document):
• Autosomal dominant
• Autosomal recessive
• X-linked dominant
• X-linked recessive
• Y-linked 
• Mitochondrial 

Mostly identified by studying families

Question 2

Describe polygenic disorders

Answer 2

Multiple genes and there are often environmental influences

Evaluated by studying large populations

Question 3

What is MEN1?

Answer 3

Multiple Endocrine Neoplasia type 1 is caused an autosomal dominant mutation in the MEN1 gene (11q), which is a classic tumour suppressor

There is bi-allelic inactivation and loss of heterozygosity

Question 4

Benign tumours and/or hormonal excess in MEN1?

Answer 4

• Islet non-secreting
• Pituitary non-secreting
• Adrenal cortex
• PTH hormone, gastrin, insulin, prolactin, GH and ACTH

Question 5

Malignant tumours and/or hormonal excess in MEN1?

Answer 5

• Foregut carcinoid

* Gastrin, glucagon, VIP and pancreatic polypeptide

Question 6

Non-hormonal neoplasia in MEN1?

Answer 6

• Angiofibroma
• Collagenoma
• Lipoma
• Leiomyoma
• Meningioma
• Ependymoma

Question 7

What is MEN2?

Answer 7

Multiple Endocrine Neoplasia type 2 is an autosomal dominant mutation in the RET gene (10q), which is a classic proto-oncogene

Question 8

Benign tumours and/or hormonal excess in MEN2?

Answer 8

• C-cell cancer
• Adrenal chromaffin
• Calcitonin, catecholamine and PTH

Question 9

Malignant tumours and/or hormonal excess in MEN2?

Answer 9

• C-cell cancer
• Adrenal chromaffin
• Calcitonin and catecholamine

Question 10

Non-hormonal neoplasia in MEN2?

Answer 10

Neuroma

Question 11

Difference between MEN1 and MEN2?

Answer 11

Not related in any way except that they are both tumour predispositon syndrome and both have parathyroid tumours

Question 12

Tumour spectrum in MEN1?

Answer 12

Parathyroid adenoma (most common)

Pituitary adenoma, usually a prolactinoma (could be others)

Assoc. tumours:
• Adrenal cortical tumour
• Phaeochromocytoma (part of many genetic disorders)
• Angiofibroma (common)
• Collagenoma (common)

There are many more potential tumours

Question 13

Phenotype correlation with the genotype in MEN1?

Answer 13

Mutations occur throughout the coding region in MEN1 and these result in loss/reduced protein function

There is NO PHENOTYPE-GENOTYPE CORRELATION (disease is not predictable)

Question 14

Phenotype correlation with the genotype in MEN2?

Answer 14

RET mutations affect specific cysteine residues and these cause activation of receptor tyrosine kinase

There is a CLEAR PHENOTYPE-GENOTYPE CORRELATION (the type of mutation can help predict disease outcome)

Question 15

Tumours that occur in MEN2?

Answer 15

Parathyroid tumour

Medullary thyroid cancer (MOST IMPORTANT)

Phaeochromocytoma

Question 16

Morbidity and mortality assoc. with MEN1?

Answer 16

1/2 of patients will die as a DIRECT result of the disease, leading cause being:
• Malignant pancreatic neuroendocrine tumour
• Thymic carcinoids

Question 17

Typical tumours in MEN1 (MUST KNOW)?

Answer 17

1. Pituitary adenoma
2. Parathyroid hyperplasia
3. Pancreatic tumours

Question 18

Typical tumours in MEN2A?

Answer 18

1. Parathyroid hyperplasia
2. Medullary thyroid carcinoma (MTC)
3. Phaeochromocytoma

Question 19

Typical tumours and issues in MEN2B?

Answer 19

1. Mucosal neuromas
2. Marfanoid body habitus
3. MTC
4. Phaeochromocytoma

Question 20

Risk of MTC in MEN2?

Answer 20

Depends on age:
• Highest risk <1 year
• High risk <5 years
• Moderate risk >5 years but regular screening

Question 21

Risk of phaeochromocytoma in MEN2?

Answer 21

Higher and high risk from 11 years

Moderate risk from 16 years

Question 22

Risk of parathyroid disease in MEN2?

Answer 22

High risk from 11 years

Moderate risk from 16 years

Question 23

Treatment of MTC in MEN2?

Answer 23

MTC treatment - prophylactic thyroidectomy

Question 24

What is Carney complex?

Answer 24

Autosomal dominant mutation in PRK1R1A, causing a defective regulatory sub-unit and aberrant protein kinase A signalling; this leads to uncontrolled proliferation

Question 25

Manifestations of Carney complex?

Answer 25

Spotty skin pigmentation with a typical distribution, i.e: lips, conjunctiva and inner/outer canthi, vaginal and penile mucosa PPNAD Acromegaly (due to GH producing adenoma) Thyroid carcinoma (AT ANY AGE)

Question 26

What is PPNAD?

Answer 26

Primary Pigmented Nodular Adrenocortical Disease Causes adrenal glands to produce excess cortisol, leading to Cushing's syndrome

Question 27

What is McCune-Albright syndrome?

Answer 27

Genetic disorder affecting the bone, skin, and endocrine systems There is a post-zygotic somatic, i.e: acquired not germline, GNAS mutation that causes constitutive cAMP signalling

Question 28

Clinical manifestations of McCune-Albirght syndrome?

Answer 28

* Cafe-au-lait skin pigmentation ("Coast of Maine" appearance) * Polyostotic fibrous dysplasia (bones), causing scoliosis and lower limb issues * Precocious puberty, i.e: early (usually a manifestation in females) * Thyroid nodules * GH excess from the pituitary * Cushing's syndrome (Adrenal)

Question 29

What is Von-Hippel Lindau (VHL)?

Answer 29

Autosomal dominant mutation in the VHL gene that leads to accumulation of HIF proteins and stimulation of cellular proliferation

Question 30

Clinical manifestations of VHL?

Answer 30

A range of vascular tumours Retinal haemangiomas CNS haemangioblastomas Phaeochromocytoma Pancreatic cysts

Question 31

Vital management factor in VHL syndrome?

Answer 31

Family screening

Question 32

Clinical manifestations of neurofibromatosis type 1?

Answer 32

Axillary freckling, Cafe-au-Lait patches, neurofibromas Optic gliomas Scoliosis Learning difficulties in some Phaeochromocytoma (rare)

Question 33

Cause of NF type 1?

Answer 33

Mutation in NF1 gene Common condition

Question 34

Difference between phaeochromocytoma and paraganglioma?

Answer 34

Same tumours but in different places, i.e: • Phaeochromocyoma - in the adrenal gland • Paraganglioma - extra-adrenal and in the sympathetic chain

Question 35

Cause of paragangliomas?

Answer 35

Succinate dehydrogenase mutations cause a deficiency so succinate accumulates and their is activation of hypoxia pathways, i.e: • SDHD (head and neck paraganglioma) • SDHB (malignant paraganglioma)

Question 36

2 approaches in next generation sequencing?

Answer 36

Whole genome (WGS) Whole exome (WES)

Question 37

Differences between WGS and WES?

Answer 37

WGS produces a comprehensive data set that shows: • Non-coding changes • Chromosomal rearrangements • Copy Number Variants (CNVs) WES is a targeted approach that shows: • Coding and UTR variants But misses non-coding changes and rearrangements