Endocrinology and Genetics Flashcards
What are the typical features of monogenic disorders?
Single gene, 6 patterns of inheritance (AD, AR, XLD, XLR, Y-linked, mitochondrial), identified through studies of families
What are the typical features of polygenic disorders?
Multiple genes, often environmental influences, evaluated by looking at large population (GWAS studies)
What are the indicators of a possible genetic disease?
Childhood/early onset, familial setting, features consistent with genetic disease, disease-specific indications
What determines the value of genetic testing?
Disease severity and typical penetrance, potential utility of result (interventions, implications for relatives, pre-natal diagnosis)
What kind of disorder is multiple endocrine neoplasia (MEN)?
Monogenic
What are some features of MEN1?
Autosomal dominant, mutation in MEN1 gene (11q), classic tumour suppressor, bi-lateral allelic inactivation and LOH
What are some features of MEN2?
Autosomal dominant, RET gene (10q), classic proto-oncogene
Where do MEN1 mutations occur?
Throughout the coding region = mutations result in lost/reduced protein function, no phenotype/genotype correlation
Where do RET mutations occur?
Affect specific cysteine residues = mutations result in activation of receptor tyrosine kinase, clear phenotype/genotype correlation
Why is MEN1 important?
Premature mortality and morbidity = malignant pancreatic neuroendocrine tumour, thymic carcinoid
Considerable psychological burden
What are indications for MEN1 testing?
Meets clinical criteria or suspicion of MEN1
First degree relative with known MEN1 mutation
Test should be taken as early as possible
What conditions occur due to MEN2 mutations?
Medullary thyroid cancer, pheochromocytoma, parathyroid disease
How should medullary thyroid cancer be managed?
Diagnosed by calcitonin measurement and thyroid USS
Prophylactic thyroidectomy,
What is the risk associated with medullary thyroid cancer?
Age depends on risk level of RET mutation:
Highest risk <1 year of age
High risk <5 years of age
Moderate risk >5 years old but regular screening
What is the risk of RET mutation in patients with pheochromocytomas and parathyroid disease?
High risk from age 11
Moderate risk from age 16
What is the Carney complex?
Autosomal dominant condition = characterised by spotty skin pigmentation, endocrine overactivity and myxomas
What does primary pigmented nodular adrenocortical disease (PPNAD) cause?
Causes adrenal glands to produce excess cortisol leading to Cushing’s syndrome
What causes the Carney complex?
Mutation in PRKARIA = defective subunit, aberrant PKA signalling casing uncontrolled proliferation
What may Von Lindau Syndrome cause?
Neuroendocrine rumours of the pancreas and vascular tumours = family screening vital
What causes Von Lindau Syndrome?
Autosomal dominant mutation in VHL gene = leads to accumulation of HIF proteins and stimulation of cellular proliferation
What causes neurofibromatosis type 1?
Mutation in NF1 gene
What are some features of Neurofibromatosis type 1?
Axillary frecking, cafe au lait patches, neurofibromas, optic gliomas, scoliosis, phaechromocytomas (rare)
What causes McCune Albright syndrome?
Post zygotic somatic GNAS mutation = constitutive cAMP signalling
What are some features of McCune Albright syndrome?
Cafe au lait patches, polyostotic fibrous dysplasia, precocious puberty (typically female), thyroid nodules, GH excess, Cushing’s syndrome
What is the inheritance of phaechromocytomas?
10% have familial basis, 25% may have germline mutation
What genes are affected to cause phaechromocytomas and paragangliomas?
Succinate dehydrogenase hormone genes = key mitochondrial enzymes make your involved in succinate metabolism and Krebs cycle
Typically SDHs B,C and D
What do succinate dehydrogenase genes mutations cause?
Accumulation of succinate and activation of hypoxia pathways
50% have extra-adrenal manifestations
Where do paragangliomas form?
SDHD = head and neck paragangliomas SDHB = malignant paragangliomas
What can next generation sequencing be used for?
Identification of genes associated with hereditary disorders and genes where high prevalence of recurrent mutations associated with specific conditions
New insights into disease pathogenesis and treatment
Identification of at risk individuals
What are some features of Sangar sequencing?
1-10 genes, labour intensive, low content, simple interpretation, cost/base high, 1-10kb
What are some features of disease targeted gene panels?
5-100 genes, low content, simple interpretation, cost/base medium, 5-100kb
What are some features of whole scone sequencing?
30000 genes, high content, challenging interpretation, high risk VUS/IFs, cost/base low, 30Mb
What are some features of whole genome sequencing?
All coding and non-coding regions, very high content, challenging interpretation, high risk VUS/IFs, cost/base very low, 3Gb
