Genetics Flashcards
Monogenic Disorders
Single Gene Aetiology
6 patterns of inheritance
Polygenic Disorders
Multiple genes
Often environmental influences
Genetic Abnormalities leading to monogenic disorders
Single Nucleotide Variants (SNVs)
- missense amino acid change
- nonsense amino acid change
- splice site alteration
Small insertions and deletions
- in-frame
- out-of-frame
Loss of function typically results from
- nonsense
- frameshift
- coronical splice site mutations
Multiple endocrine neoplasia type 1 (MEN1)
Central to pathways disrupted in pancreatic NETs
Tumour Spectrum
- Parathyroid
- Pituitary
- Enteropancreatic
- Thymic/ bronchial carcinoids
- Gastric carcinoid
- Function/ Non-functioning adrenal
MEN1 clinical features
Primary hyperparathyroidism
- parathyroid adenoma/ hyperplasia
Pancreatic Neuroendocrine Tumours
- gastrinoma
- Insulinoma
Pituitary adenomas
Foregut neuroendocrine tumours
Adrenocrotical tumours
MEN1 clinical genetics
Autosomal dominant
‘Classic’ tumour suppressor in endocrine tissues
Mutations occur throughout MEN1 gene located on chromosome 11q13
Mutations typically result in loss/ reduced protein function
MEN1: Premature morbidity and mortality
50% of affected patients will die as a direct result
Leading causes of excess death
- malignant pancreatic neuroendocrine tumour
- thymic carcinoids
MEN1 Management
Management is difficult
- lack of genotype/ phenotype correlation
- variable age related penetrance
- inability to. predict course
- lack of specific therapies
Goal: Prevent premature morbidity and mortality from MEN1 associated tumours, whilst preserving quality of life
MEN1: Genetic testing
Clinical criteria for MEn1
Suspicion for MEN1
First degree relatives
-Aim to detect onset of tumours at an early stage
Multiple Endocrine Neoplasia Type 2 (MEN2)
Autosomal dominant
RET gene-10q
- RET tyrosine kinase receptor
Classic porto-oncogene
MEN2A + MEN2B
MEN2 Main cancer
Medullary thyroid cancer (MTC)
MEN2 Clinical features
MTC first manifestation in MEN2
-Derived from parafollicular C-cells in thyroid
Clinical presentation (i.e. neck mass) associated with metastatic disease and poor outcomes
Signs & Symptoms
- neck mass
- diarrhoea and flushing (metastatic)
- Ectopic ACTH and Cushing
MEN12 Diagnosis
Neck USS and FNA
Measure basal serum calcitonin
MEN2 treatment
Depends on stage of disease
Localised
- curative surgery (thyroidectomy)
Advanced
- Complex management (recent advent of tyrosine kinase inhibitors)
Opportunity from ‘prophylactic’ thyroidectomy in RET mutation carriers
Phaeochromocytoma
Occurs in 40-505 of MEN2
may occur in children and frequently bilateral
typically benign
