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RB Y2 Endocrine - 4 Adrenal > Genetics in Endocrine > Flashcards

Genetics in Endocrine Flashcards

1
Q

mendelian disease

A

rare, high penentrance

are only inherited maternally

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2
Q

monogenic disorders

A

single gene aetiology

evaluated through the studies of families

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3
Q

polygenic disorders

A

multiple gene aetiology, often environmental influences

they are evaluated by looking at large populations

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4
Q
A

autosomal recessive

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5
Q
A

mendelian inheritance - only maternal

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6
Q
A

x linked

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7
Q
A

x linked recessive

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8
Q
A

autosomal dominant

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9
Q

MEN

A

functioning hormone producing tumours in multiple organs

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10
Q

how are MEN inherited

A

autosomal dominant

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11
Q

what was MEN-1 originally known as

A

Wermer syndrome

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12
Q

aetiology of MEN-1

A

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

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13
Q

LOH

A

loss of heterozygosity

common genetic event in which one allele is lost

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

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14
Q

is there a phenotype genotype correlation in MEN-1

A

no

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15
Q

clinical features of MEN-1

A

Parathyroid hyperplasia/adenoma

Pancreas endocrine tumour

Pituitary prolactinoma/GH secreting tumour

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16
Q

what pancreas endocrine tumours are often seen in MEN-1

A

gastrinoma 70%

insulinoma, somatostatinoma, VIPoma, glucagonoma

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17
Q

what effect does MEN-1 have on morbidity and mortality

A

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

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18
Q

what is the leading cause of death in MEN-1

A

malignant pancreatic neuroendocrine tumour

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19
Q

psychological burden of MEN-1

A

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

20
Q

what imaging surveillance if performed in MEN-1

A

abdominal imaging every 1-2 years

21
Q

what does mutational analysis of the MEN-1 gene allow

A
  • 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 ​
22
Q

what is a phenocopy

A

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

– clinical status can be mistakenly assumed

23
Q

aetiology of MEN-2

A

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

the RET gene is a classic proto-oncogene

24
Q

RET mutations

A

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

cysteine 634 is the most common mutation

25
Q

is there a phenotype genotype correlation in MEN-2

A

yes, clear

26
Q

what does C634 mutation confer a risk of

A

high risk of adrenal medullary cancer (phaeochromocytoma)

also increased risk of hyperparathyroidism

27
Q

what was the original name for MEN-2a

A

sipple syndrome

28
Q

clinical features of MEN-2a

A

Thyroid: medullary thyroid carcinoma (100%)

Adrenal: phaeochromocytoma (50%)

Parathyroid hyperplasia (seen in 80%, only 20% have increased Calcium)

29
Q

what are the adrenal phaeochromocytomas like in MEN-2

A

usually benign and bilateral

30
Q

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

A

medullary thyroid carcinoma

31
Q

MEN-2b

A

has similar features to MEN-2a, plus mucosal neuromas, ganglioneuromas and Marfinoid appearance

but no hyperparathyroidism

32
Q

mucosal neuromas

A

seen in MEN-2b

consist of bumps on lips, cheeks, tongue, glottis and visible corneal nerves

33
Q

management of MEN-2

A

due to 100% risk of medullary thyroid carcinoma, perform prophlactic thyroidectomy

screening for phaeochromocytoma and parathyroid disease

34
Q

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

A

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

35
Q

at which age is screening for phaeochromocytoma and parathyroid disease performed

A

high risk of RET mutation: from 11 years

moderate risk: from 16 years

36
Q

clinical features of carney complex

A

spotty skin pigmentation

myxoma of skin, mucosa or heart (particularly atrial myxoma)

endocrine tumours: pituitary adenoma, adrenal hyperplasia, testicular tumour, thyroid carcinoma

PPNAD

37
Q

what often occurs in Carney Complex due to pituitary adenomas

A

secreting GH - acromegaly

38
Q

PPNAD

A

(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

39
Q

genetics of Carney Complex

A

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

40
Q

McCune-Albright Syndrome features

A

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

41
Q

precocious puberty

A

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

42
Q

genetics of McCune Albright Syndrome

A

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

43
Q

Von Hippel-Lindau

A

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

44
Q

what is the inheritance of Von Hippel-Lindau

A

autosomal dominant

family screening is vital

45
Q

HIF proteins

A

hypoxia inducible factors - transcription factors that respond to hypoxia

activated in Von Hippel-Lindau by VHL gene mutations and in SDH genes in phaeochromocytomas

46
Q

clinical features of neurofibromatosis type I

A

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

47
Q

genetics of Neurofibromata type I

A

caused by mutation in NEF 1 gene

RB Y2 Endocrine - 4 Adrenal (5 decks)

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