Endocrine Genetics

Question 1

what are monogenic disorders and how can they be inherited?

Answer 1

single gene aetiology
6 patters
- AD
- AR
- XLD
- XLR
- Y linked
- mitochondrial

Question 2

what are polygenic disorders and what can cause them?

Answer 2

multiple genes

often involved environmental influences

Question 3

X linked dominant inheritance?

Answer 3

male can only give to females
females can pass to males and females
always causes disease

Question 4

X linked recessive?

Answer 4

only females can have the disorder (need 2 genes)
females can pass gene to males and make them carriers
females can be carriers if only 1 parent affected

Question 5

2 characteristics of mandelian disease?

Answer 5

very rare

high penetrance

Question 6

what factors indicate a possible genetic disease?

Answer 6

childhood/early onset
familial history
presence of features consistent with genetic syndrome
disease specific indications

Question 7

what can affect the value of genetic testing?

Answer 7

disease severity and typical penetrance of disorder
potential utility of disorder
- intervention /screening based on result
- value of test results to first degree relatives
- prenatal diagnosis/genetic counselling

Question 8

when might genetic testing be worth while?

Answer 8

if high penetrance and high disease severity

Question 9

endocrine and non endocrine features of MEN1?

Answer 9

endocrine
- pancreatic, parathyroid, pituitary tumours
- adrenocortical tumours
non endocrine
- lipomas
- collagenomas
- angiofibromas
- meningiomas

Question 10

endocrine and non endocrine features of MEN2?

Answer 10

endocrine:
- medullary thyroid cancer
- phaeochromocytoma
- parathyroid tumours
non endocrine
- lichen amyloidosis
- hirsprung disease
- mucosal neuromas

Question 11

von hippel Lindau

Answer 11

endocrine
- phaeochromocytoma
- pancreatic NET
non endocrine
- renal cell carcinoma
- renal cysts
- haemangioblastoma
- pancreatic cysts

Question 12

MEN1 features?

Answer 12

pituitary
parathyroid
pancreatic
(3 Ps)

Question 13

what is MEN1?

Answer 13

autosomal dominant inheritance of MEN1 gene (11q) mutation (tumour suppressor gene)
Bi-allelic inactivation and LOH

Question 14

what is MEN2?

Answer 14

autosomal dominant inheritance of RET gene (10q) mutation (classic proto-oncogene)

Question 15

what are the features of MEN2?

Answer 15

medullary thyroid cancer
phaeochromocytoma
parathyroid tumours in type A

Question 16

describe the genotype/phenotype correlation in MEN1

Answer 16

no correlation

MEN1 mutations scattered evenly throughout the coding region of DNA

Question 17

describe genotype/phenotype correlation in MEN2?

Answer 17

clear correlation

RET mutations affect specific cysteine residues

Question 18

what do MEN1 and RET mutations cause?

Answer 18

MEN1 = loss/reduced protein function
RET = activation of receptor tyrosine kinase

Question 19

describe mortality in MEN1

Answer 19

50% will die as a direct result of disease
high premature mortality
leading causes of death
- malignant pancreatic neuroendocrine tumour
- thymic carcinoids

Question 20

what happens in MEN1?

Answer 20

bi-allelic inactivation of the MEN1 gene

Question 21

indications for MEN1 testing?

Answer 21

if meeting clinical criteria for MEN1
if first degree relative affected
MEN1 features present

Question 22

what 3 glands are affected in MEN1?

Answer 22

pituitary adenoma
parathyroid hyperplasia
pancreatic tumours

Question 23

what glands are affected in MEN2A?

Answer 23

parathyroid hyperplasia
medullary thyroid carcinoma
Pheochromocytoma

Question 24

what glands are affected in MEN2B?

Answer 24

mucosal neuromas
marfanoid body habitus
medullary thyroid carcinoma
pheochromocytoma

Question 25

how is medullary thyroid cancer from MEN2 managed?

Answer 25

``` prophylactic thyroidectomy risk depends on age - highest = <1 - high = <5 - moderate = >5 ```

Question 26

when is risk highest for pheochromocytoma?

Answer 26

from 11 years old | moderate = from 16 yrs

Question 27

when is risk highest for parathyroid disease?

Answer 27

from 1 years | moderate risk = from 16 years

Question 28

what causes carney complex?

Answer 28

defect in protein kinase A regulatory subunit due to mutation in PRKAR1A

Question 29

what happens in carney complex?

Answer 29

aberrant PKA signalling from GPCR resulting in uncontrolled proliferation - skin pigmentation - tumours - acromegaly - etc

Question 30

what is McCune-Albright Syndrome?

Answer 30

``` café-au-lait skin pigmentation polyostotic fibrous dysplasia (bones) precocious puberty thyroid nodules pituitary - GH excess cushings syndrome (adrenal) ```

Question 31

what causes McCune Albright Syndrome?

Answer 31

post zygotic GNAS mutation (not germline) | constitutive cAMP signalling

Question 32

what are the features of von hippel-lindau?

Answer 32

retinal haemangiomas CNA haemangioblastomas pancreas - cysts kidneys - cysts, clear cell renal cell carcinomas epididymal (male) or broad ligament papillary cystadenomas

Question 33

what causes von hippel-lindau syndrome?

Answer 33

mutation in VHL gene autosomal dominant inheritance mutation leads to accumulation of HIF proteins and stimulation of cellular proliferation results in vascular tumours

Question 34

is family screening needed in VHL?

Answer 34

yes

Question 35

what causes neurofibromatosis type 1 and what are the features?

Answer 35

``` NF1 gene mutation axillary freckling café-au-lait patches neurofibromas optic gliomas scoliosis some have learning difficulties rarely phaeochromocytomas ```

Question 36

are phaeochromocytomas inherited?

Answer 36

10% are familial

Question 37

6 features of McCune Albright Syndrome?

Answer 37

``` café au lait ("coast of maine" appearance) polyostotic fibrous dysplasia (bones) precocious puberty (mainly females) thyroid nodules pituitary- GH excess cushings syndrome (adrenal) ```

Question 38

what causes McCune Albright syndrome?

Answer 38

post zygotic mutation of GNAS (not germline) | constitutive cAMP signalling

Question 39

what genes are involved in the development of phaeochromocytoma?

Answer 39

``` succinate dehydrogenase (B, C and D) D = head and neck paraganglioma B = malignant paraganglioma ```

Question 40

what does succinate dehydrogenase do?

Answer 40

key mitochondrial enzymes involved in succinate metabolism and krebs cycle accumulation of succinate and activation of hypoxia pathways - stabilise HIF 1a