Genetics in Endocrine Flashcards
mendelian disease
rare, high penentrance
are only inherited maternally
monogenic disorders
single gene aetiology
evaluated through the studies of families
polygenic disorders
multiple gene aetiology, often environmental influences
they are evaluated by looking at large populations
autosomal recessive
mendelian inheritance - only maternal
x linked
x linked recessive
autosomal dominant
MEN
functioning hormone producing tumours in multiple organs
how are MEN inherited
autosomal dominant
what was MEN-1 originally known as
Wermer syndrome
aetiology of MEN-1
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
LOH
loss of heterozygosity
common genetic event in which one allele is lost
often is the second hit that unmasks a recessive tumour suppressor gene
is there a phenotype genotype correlation in MEN-1
no
clinical features of MEN-1
Parathyroid hyperplasia/adenoma
Pancreas endocrine tumour
Pituitary prolactinoma/GH secreting tumour
what pancreas endocrine tumours are often seen in MEN-1
gastrinoma 70%
insulinoma, somatostatinoma, VIPoma, glucagonoma
what effect does MEN-1 have on morbidity and mortality
results in premature morbidity and mortality, half of affected individuals will die prematurely as a direct result of the disease
what is the leading cause of death in MEN-1
malignant pancreatic neuroendocrine tumour
psychological burden of MEN-1
considerable, largely due to the uncertainty of being unable to predict the onset/timing or development of fatal aggressive tumours
what imaging surveillance if performed in MEN-1
abdominal imaging every 1-2 years
what does mutational analysis of the MEN-1 gene allow
- 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
what is a phenocopy
features characteristically typical of a genotype, but that are produced environmentally rather than genetically
– clinical status can be mistakenly assumed
aetiology of MEN-2
gain of function mutation in RET gene, on chromosome 10q
the RET gene is a classic proto-oncogene
RET mutations
affect specific cysteine residues, and mutations result in the activation of a receptor tyrosine kinase
cysteine 634 is the most common mutation
is there a phenotype genotype correlation in MEN-2
yes, clear
what does C634 mutation confer a risk of
high risk of adrenal medullary cancer (phaeochromocytoma)
also increased risk of hyperparathyroidism
what was the original name for MEN-2a
sipple syndrome
clinical features of MEN-2a
Thyroid: medullary thyroid carcinoma (100%)
Adrenal: phaeochromocytoma (50%)
Parathyroid hyperplasia (seen in 80%, only 20% have increased Calcium)
what are the adrenal phaeochromocytomas like in MEN-2
usually benign and bilateral
what feature is seen in almost 100% of MEN-2a cases
medullary thyroid carcinoma
MEN-2b
has similar features to MEN-2a, plus mucosal neuromas, ganglioneuromas and Marfinoid appearance
but no hyperparathyroidism
mucosal neuromas
seen in MEN-2b
consist of bumps on lips, cheeks, tongue, glottis and visible corneal nerves
management of MEN-2
due to 100% risk of medullary thyroid carcinoma, perform prophlactic thyroidectomy
screening for phaeochromocytoma and parathyroid disease
at what age is a prophylactic thyroidectomy performed in those with MEN-2
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
at which age is screening for phaeochromocytoma and parathyroid disease performed
high risk of RET mutation: from 11 years
moderate risk: from 16 years
clinical features of carney complex
spotty skin pigmentation
myxoma of skin, mucosa or heart (particularly atrial myxoma)
endocrine tumours: pituitary adenoma, adrenal hyperplasia, testicular tumour, thyroid carcinoma
PPNAD
what often occurs in Carney Complex due to pituitary adenomas
secreting GH - acromegaly
PPNAD
(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
genetics of Carney Complex
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
McCune-Albright Syndrome features
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
precocious puberty
refers to the appearance of physical and hormonal signs of pubertal development at an earlier age than is considered normal
genetics of McCune Albright Syndrome
post-zygotic somatic mutation (ie not germline inherited) in GNAS, affecting cAMP signalling
Von Hippel-Lindau
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
what is the inheritance of Von Hippel-Lindau
autosomal dominant
family screening is vital
HIF proteins
hypoxia inducible factors - transcription factors that respond to hypoxia
activated in Von Hippel-Lindau by VHL gene mutations and in SDH genes in phaeochromocytomas
clinical features of neurofibromatosis type I
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
genetics of Neurofibromata type I
caused by mutation in NEF 1 gene
