Endocrine Genetics Flashcards
what are monogenic disorders and how can they be inherited?
single gene aetiology 6 patters - AD - AR - XLD - XLR - Y linked - mitochondrial
what are polygenic disorders and what can cause them?
multiple genes
often involved environmental influences
X linked dominant inheritance?
male can only give to females
females can pass to males and females
always causes disease
X linked recessive?
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
2 characteristics of mandelian disease?
very rare
high penetrance
what factors indicate a possible genetic disease?
childhood/early onset
familial history
presence of features consistent with genetic syndrome
disease specific indications
what can affect the value of genetic testing?
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
when might genetic testing be worth while?
if high penetrance and high disease severity
endocrine and non endocrine features of MEN1?
endocrine - pancreatic, parathyroid, pituitary tumours - adrenocortical tumours non endocrine - lipomas - collagenomas - angiofibromas - meningiomas
endocrine and non endocrine features of MEN2?
endocrine: - medullary thyroid cancer - phaeochromocytoma - parathyroid tumours non endocrine - lichen amyloidosis - hirsprung disease - mucosal neuromas
von hippel Lindau
endocrine - phaeochromocytoma - pancreatic NET non endocrine - renal cell carcinoma - renal cysts - haemangioblastoma - pancreatic cysts
MEN1 features?
pituitary
parathyroid
pancreatic
(3 Ps)
what is MEN1?
autosomal dominant inheritance of MEN1 gene (11q) mutation (tumour suppressor gene)
Bi-allelic inactivation and LOH
what is MEN2?
autosomal dominant inheritance of RET gene (10q) mutation (classic proto-oncogene)
what are the features of MEN2?
medullary thyroid cancer
phaeochromocytoma
parathyroid tumours in type A
describe the genotype/phenotype correlation in MEN1
no correlation
MEN1 mutations scattered evenly throughout the coding region of DNA
describe genotype/phenotype correlation in MEN2?
clear correlation
RET mutations affect specific cysteine residues
what do MEN1 and RET mutations cause?
MEN1 = loss/reduced protein function RET = activation of receptor tyrosine kinase
describe mortality in MEN1
50% will die as a direct result of disease
high premature mortality
leading causes of death
- malignant pancreatic neuroendocrine tumour
- thymic carcinoids
what happens in MEN1?
bi-allelic inactivation of the MEN1 gene
indications for MEN1 testing?
if meeting clinical criteria for MEN1
if first degree relative affected
MEN1 features present
what 3 glands are affected in MEN1?
pituitary adenoma
parathyroid hyperplasia
pancreatic tumours
what glands are affected in MEN2A?
parathyroid hyperplasia
medullary thyroid carcinoma
Pheochromocytoma
what glands are affected in MEN2B?
mucosal neuromas
marfanoid body habitus
medullary thyroid carcinoma
pheochromocytoma
how is medullary thyroid cancer from MEN2 managed?
prophylactic thyroidectomy risk depends on age - highest = <1 - high = <5 - moderate = >5
when is risk highest for pheochromocytoma?
from 11 years old
moderate = from 16 yrs
when is risk highest for parathyroid disease?
from 1 years
moderate risk = from 16 years
what causes carney complex?
defect in protein kinase A regulatory subunit due to mutation in PRKAR1A
what happens in carney complex?
aberrant PKA signalling from GPCR resulting in uncontrolled proliferation
- skin pigmentation
- tumours
- acromegaly
- etc
what is McCune-Albright Syndrome?
café-au-lait skin pigmentation polyostotic fibrous dysplasia (bones) precocious puberty thyroid nodules pituitary - GH excess cushings syndrome (adrenal)
what causes McCune Albright Syndrome?
post zygotic GNAS mutation (not germline)
constitutive cAMP signalling
what are the features of von hippel-lindau?
retinal haemangiomas
CNA haemangioblastomas
pancreas - cysts
kidneys - cysts, clear cell renal cell carcinomas
epididymal (male) or broad ligament papillary cystadenomas
what causes von hippel-lindau syndrome?
mutation in VHL gene
autosomal dominant inheritance
mutation leads to accumulation of HIF proteins and stimulation of cellular proliferation
results in vascular tumours
is family screening needed in VHL?
yes
what causes neurofibromatosis type 1 and what are the features?
NF1 gene mutation axillary freckling café-au-lait patches neurofibromas optic gliomas scoliosis some have learning difficulties rarely phaeochromocytomas
are phaeochromocytomas inherited?
10% are familial
6 features of McCune Albright Syndrome?
café au lait ("coast of maine" appearance)
polyostotic fibrous dysplasia (bones)
precocious puberty (mainly females)
thyroid nodules
pituitary- GH excess
cushings syndrome (adrenal)what causes McCune Albright syndrome?
post zygotic mutation of GNAS (not germline)
constitutive cAMP signalling
what genes are involved in the development of phaeochromocytoma?
succinate dehydrogenase (B, C and D) D = head and neck paraganglioma B = malignant paraganglioma
what does succinate dehydrogenase do?
key mitochondrial enzymes involved in succinate metabolism and krebs cycle
accumulation of succinate and activation of hypoxia pathways - stabilise HIF 1a
