Endocrinology and Genetics

Question 1

What are the typical features of monogenic disorders?

Answer 1

Single gene, 6 patterns of inheritance (AD, AR, XLD, XLR, Y-linked, mitochondrial), identified through studies of families

Question 2

What are the typical features of polygenic disorders?

Answer 2

Multiple genes, often environmental influences, evaluated by looking at large population (GWAS studies)

Question 3

What are the indicators of a possible genetic disease?

Answer 3

Childhood/early onset, familial setting, features consistent with genetic disease, disease-specific indications

Question 4

What determines the value of genetic testing?

Answer 4

Disease severity and typical penetrance, potential utility of result (interventions, implications for relatives, pre-natal diagnosis)

Question 5

What kind of disorder is multiple endocrine neoplasia (MEN)?

Answer 5

Monogenic

Question 6

What are some features of MEN1?

Answer 6

Autosomal dominant, mutation in MEN1 gene (11q), classic tumour suppressor, bi-lateral allelic inactivation and LOH

Question 7

What are some features of MEN2?

Answer 7

Autosomal dominant, RET gene (10q), classic proto-oncogene

Question 8

Where do MEN1 mutations occur?

Answer 8

Throughout the coding region = mutations result in lost/reduced protein function, no phenotype/genotype correlation

Question 9

Where do RET mutations occur?

Answer 9

Affect specific cysteine residues = mutations result in activation of receptor tyrosine kinase, clear phenotype/genotype correlation

Question 10

Why is MEN1 important?

Answer 10

Premature mortality and morbidity = malignant pancreatic neuroendocrine tumour, thymic carcinoid
Considerable psychological burden

Question 11

What are indications for MEN1 testing?

Answer 11

Meets clinical criteria or suspicion of MEN1
First degree relative with known MEN1 mutation
Test should be taken as early as possible

Question 12

What conditions occur due to MEN2 mutations?

Answer 12

Medullary thyroid cancer, pheochromocytoma, parathyroid disease

Question 13

How should medullary thyroid cancer be managed?

Answer 13

Diagnosed by calcitonin measurement and thyroid USS

Prophylactic thyroidectomy,

Question 14

What is the risk associated with medullary thyroid cancer?

Answer 14

Age depends on risk level of RET mutation:
Highest risk <1 year of age
High risk <5 years of age
Moderate risk >5 years old but regular screening

Question 15

What is the risk of RET mutation in patients with pheochromocytomas and parathyroid disease?

Answer 15

High risk from age 11

Moderate risk from age 16

Question 16

What is the Carney complex?

Answer 16

Autosomal dominant condition = characterised by spotty skin pigmentation, endocrine overactivity and myxomas

Question 17

What does primary pigmented nodular adrenocortical disease (PPNAD) cause?

Answer 17

Causes adrenal glands to produce excess cortisol leading to Cushing’s syndrome

Question 18

What causes the Carney complex?

Answer 18

Mutation in PRKARIA = defective subunit, aberrant PKA signalling casing uncontrolled proliferation

Question 19

What may Von Lindau Syndrome cause?

Answer 19

Neuroendocrine rumours of the pancreas and vascular tumours = family screening vital

Question 20

What causes Von Lindau Syndrome?

Answer 20

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

Question 21

What causes neurofibromatosis type 1?

Answer 21

Mutation in NF1 gene

Question 22

What are some features of Neurofibromatosis type 1?

Answer 22

Axillary frecking, cafe au lait patches, neurofibromas, optic gliomas, scoliosis, phaechromocytomas (rare)

Question 23

What causes McCune Albright syndrome?

Answer 23

Post zygotic somatic GNAS mutation = constitutive cAMP signalling

Question 24

What are some features of McCune Albright syndrome?

Answer 24

Cafe au lait patches, polyostotic fibrous dysplasia, precocious puberty (typically female), thyroid nodules, GH excess, Cushing’s syndrome

Question 25

What is the inheritance of phaechromocytomas?

Answer 25

10% have familial basis, 25% may have germline mutation

Question 26

What genes are affected to cause phaechromocytomas and paragangliomas?

Answer 26

Succinate dehydrogenase hormone genes = key mitochondrial enzymes make your involved in succinate metabolism and Krebs cycle
Typically SDHs B,C and D

Question 27

What do succinate dehydrogenase genes mutations cause?

Answer 27

Accumulation of succinate and activation of hypoxia pathways

50% have extra-adrenal manifestations

Question 28

Where do paragangliomas form?

Answer 28

SDHD = head and neck paragangliomas 
SDHB = malignant paragangliomas

Question 29

What can next generation sequencing be used for?

Answer 29

Identification of genes associated with hereditary disorders and genes where high prevalence of recurrent mutations associated with specific conditions
New insights into disease pathogenesis and treatment
Identification of at risk individuals

Question 30

What are some features of Sangar sequencing?

Answer 30

1-10 genes, labour intensive, low content, simple interpretation, cost/base high, 1-10kb

Question 31

What are some features of disease targeted gene panels?

Answer 31

5-100 genes, low content, simple interpretation, cost/base medium, 5-100kb

Question 32

What are some features of whole scone sequencing?

Answer 32

30000 genes, high content, challenging interpretation, high risk VUS/IFs, cost/base low, 30Mb

Question 33

What are some features of whole genome sequencing?

Answer 33

All coding and non-coding regions, very high content, challenging interpretation, high risk VUS/IFs, cost/base very low, 3Gb