Genetics in Endocrine

Question 1

mendelian disease

Answer 1

rare, high penentrance

are only inherited maternally

Question 2

monogenic disorders

Answer 2

single gene aetiology

evaluated through the studies of families

Question 3

polygenic disorders

Answer 3

multiple gene aetiology, often environmental influences

they are evaluated by looking at large populations

Question 4

Answer 4

autosomal recessive

Question 5

Answer 5

mendelian inheritance - only maternal

Question 6

Answer 6

x linked

Question 7

Answer 7

x linked recessive

Question 8

Answer 8

autosomal dominant

Question 9

MEN

Answer 9

functioning hormone producing tumours in multiple organs

Question 10

how are MEN inherited

Answer 10

autosomal dominant

Question 11

what was MEN-1 originally known as

Answer 11

Wermer syndrome

Question 12

aetiology of MEN-1

Answer 12

caused by inactivating germline mutations of MEN1 gene, which is located on chromosome 11q

the MEN1 gene is a tumour suppressor gene

biallelic inactivation of the MEN1 gene is required for the development of a tumour cell. LOH is frequently observed in MEN-1 assoicated tumours

Question 13

LOH

Answer 13

loss of heterozygosity

common genetic event in which one allele is lost

often is the second hit that unmasks a recessive tumour suppressor gene

Question 14

is there a phenotype genotype correlation in MEN-1

Answer 14

no

Question 15

clinical features of MEN-1

Answer 15

Parathyroid hyperplasia/adenoma

Pancreas endocrine tumour

Pituitary prolactinoma/GH secreting tumour

Question 16

what pancreas endocrine tumours are often seen in MEN-1

Answer 16

gastrinoma 70%

insulinoma, somatostatinoma, VIPoma, glucagonoma

Question 17

what effect does MEN-1 have on morbidity and mortality

Answer 17

results in premature morbidity and mortality, half of affected individuals will die prematurely as a direct result of the disease

Question 18

what is the leading cause of death in MEN-1

Answer 18

malignant pancreatic neuroendocrine tumour

Question 19

psychological burden of MEN-1

Answer 19

considerable, largely due to the uncertainty of being unable to predict the onset/timing or development of fatal aggressive tumours

Question 20

what imaging surveillance if performed in MEN-1

Answer 20

abdominal imaging every 1-2 years

Question 21

what does mutational analysis of the MEN-1 gene allow

Answer 21

• Identification of ‘at risk’ individuals
• Contract tracing of additional family members
• Reassurance to those without the familial MEN1 mutation
• Periodic screening and early tumour detection to those at risk
• Exclude presence of phenocopies ​

Question 22

what is a phenocopy

Answer 22

features characteristically typical of a genotype, but that are produced environmentally rather than genetically

– clinical status can be mistakenly assumed

Question 23

aetiology of MEN-2

Answer 23

gain of function mutation in RET gene, on chromosome 10q

the RET gene is a classic proto-oncogene

Question 24

RET mutations

Answer 24

affect specific cysteine residues, and mutations result in the activation of a receptor tyrosine kinase

cysteine 634 is the most common mutation

Question 25

is there a phenotype genotype correlation in MEN-2

Answer 25

yes, clear

Question 26

what does C634 mutation confer a risk of

Answer 26

high risk of adrenal medullary cancer (phaeochromocytoma) also increased risk of hyperparathyroidism

Question 27

what was the original name for MEN-2a

Answer 27

sipple syndrome

Question 28

clinical features of MEN-2a

Answer 28

Thyroid: medullary thyroid carcinoma (100%) Adrenal: phaeochromocytoma (50%) Parathyroid hyperplasia (seen in 80%, only 20% have increased Calcium)

Question 29

what are the adrenal phaeochromocytomas like in MEN-2

Answer 29

usually benign and bilateral

Question 30

what feature is seen in almost 100% of MEN-2a cases

Answer 30

medullary thyroid carcinoma

Question 31

MEN-2b

Answer 31

has similar features to MEN-2a, plus **mucosal neuromas, ganglioneuromas** and **Marfinoid appearance** but no hyperparathyroidism

Question 32

mucosal neuromas

Answer 32

seen in MEN-2b consist of bumps on lips, cheeks, tongue, glottis and visible corneal nerves

Question 33

management of MEN-2

Answer 33

due to 100% risk of medullary thyroid carcinoma, perform **prophlactic thyroidectomy** screening for phaeochromocytoma and parathyroid disease

Question 34

at what age is a prophylactic thyroidectomy performed in those with MEN-2

Answer 34

age at which it is perfomed depends on the risk level of *RET* mutation*:* highest risk: \<1 year of age high risk: \<5 years of age moderate risk: \>5 years of age, but perform regular screening

Question 35

at which age is screening for phaeochromocytoma and parathyroid disease performed

Answer 35

high risk of RET mutation: from 11 years moderate risk: from 16 years

Question 36

clinical features of carney complex

Answer 36

**spotty skin pigmentation** **myxoma** of skin, mucosa or heart (particularly atrial myxoma) endocrine tumours: pituitary adenoma, adrenal hyperplasia, **testicular tumour,** thyroid carcinoma **PPNAD**

Question 37

what often occurs in Carney Complex due to pituitary adenomas

Answer 37

secreting GH - acromegaly

Question 38

PPNAD

Answer 38

(Primary Pigmented Nodular Adrenocortical Disease) a form of **bilateral adrenocortical hyperplasia** causing the adrenal glands to produce an excess or **cortisol** leading to the development of Cushing's syndrome

Question 39

genetics of Carney Complex

Answer 39

caused by a mutation in **PRKAR1A** which results in a defective regulatory subunit, and aberrant **PKA signalling** as PKA regulates cAMP, autonomous cAMP production activates downstream signalling pathways and proliferative stimulation of tumour formation

Question 40

McCune-Albright Syndrome features

Answer 40

café-au-lait pigmentation ('Coast of Maine' appearance) polyostotic fibrous dysplasia (affecting more than one bone) precocious puberty thyroid nodules pitutiary - excess GH causes acromegaly features cushing's syndrome

Question 41

precocious puberty

Answer 41

refers to the appearance of physical and hormonal signs of pubertal development at an earlier age than is considered normal

Question 42

genetics of McCune Albright Syndrome

Answer 42

post-zygotic somatic mutation (ie not germline inherited) in ***GNAS,*** affecting cAMP signalling

Question 43

Von Hippel-Lindau

Answer 43

caused by a mutation in the ***VHL*** gene, which plays a role in oxygen sensing in the cell this leads to accumulationof **HIF proteins** and stimulation of **cellular proliferation as an abnormal response to hypoxia** note associated phaeochromocytomas

Question 44

what is the inheritance of Von Hippel-Lindau

Answer 44

autosomal dominant family screening is vital

Question 45

HIF proteins

Answer 45

hypoxia inducible factors - transcription factors that respond to hypoxia activated in Von Hippel-Lindau by *VHL* gene mutations and in *SDH* genes in phaeochromocytomas

Question 46

clinical features of neurofibromatosis type I

Answer 46

**Café-au-lait macules** occur from birth onwards (\>5 suggest genetic disease) **Neurofibromas** (soft neural tumours) Axillary or inguinal freckling Optic glioma \>2 Lisch nodules – dome shaped gelatinous masses developing on surface of iris. Scoliosis Learning difficulties in some Rarely, phaeochromocytoma *The more features a patient has the greater the certainty of the diagnosis*

Question 47

genetics of Neurofibromata type I

Answer 47

caused by mutation in NEF 1 gene