Endocrine Genetics Flashcards
Describe monogenic disorders
Single gene aetiology with 6 pattern of inheritance (refer to monogenic pattern document): • Autosomal dominant • Autosomal recessive • X-linked dominant • X-linked recessive • Y-linked • Mitochondrial
Mostly identified by studying families
Describe polygenic disorders
Multiple genes and there are often environmental influences
Evaluated by studying large populations
What is MEN1?
Multiple Endocrine Neoplasia type 1 is caused an autosomal dominant mutation in the MEN1 gene (11q), which is a classic tumour suppressor
There is bi-allelic inactivation and loss of heterozygosity
Benign tumours and/or hormonal excess in MEN1?
- Islet non-secreting
- Pituitary non-secreting
- Adrenal cortex
- PTH hormone, gastrin, insulin, prolactin, GH and ACTH
Malignant tumours and/or hormonal excess in MEN1?
- Foregut carcinoid
* Gastrin, glucagon, VIP and pancreatic polypeptide
Non-hormonal neoplasia in MEN1?
- Angiofibroma
- Collagenoma
- Lipoma
- Leiomyoma
- Meningioma
- Ependymoma
What is MEN2?
Multiple Endocrine Neoplasia type 2 is an autosomal dominant mutation in the RET gene (10q), which is a classic proto-oncogene
Benign tumours and/or hormonal excess in MEN2?
- C-cell cancer
- Adrenal chromaffin
- Calcitonin, catecholamine and PTH
Malignant tumours and/or hormonal excess in MEN2?
- C-cell cancer
- Adrenal chromaffin
- Calcitonin and catecholamine
Non-hormonal neoplasia in MEN2?
Neuroma
Difference between MEN1 and MEN2?
Not related in any way except that they are both tumour predispositon syndrome and both have parathyroid tumours
Tumour spectrum in MEN1?
Parathyroid adenoma (most common)
Pituitary adenoma, usually a prolactinoma (could be others)
Assoc. tumours: • Adrenal cortical tumour • Phaeochromocytoma (part of many genetic disorders) • Angiofibroma (common) • Collagenoma (common)
There are many more potential tumours
Phenotype correlation with the genotype in MEN1?
Mutations occur throughout the coding region in MEN1 and these result in loss/reduced protein function
There is NO PHENOTYPE-GENOTYPE CORRELATION (disease is not predictable)
Phenotype correlation with the genotype in MEN2?
RET mutations affect specific cysteine residues and these cause activation of receptor tyrosine kinase
There is a CLEAR PHENOTYPE-GENOTYPE CORRELATION (the type of mutation can help predict disease outcome)
Tumours that occur in MEN2?
Parathyroid tumour
Medullary thyroid cancer (MOST IMPORTANT)
Phaeochromocytoma
Morbidity and mortality assoc. with MEN1?
1/2 of patients will die as a DIRECT result of the disease, leading cause being:
• Malignant pancreatic neuroendocrine tumour
• Thymic carcinoids
Typical tumours in MEN1 (MUST KNOW)?
- Pituitary adenoma
- Parathyroid hyperplasia
- Pancreatic tumours
Typical tumours in MEN2A?
- Parathyroid hyperplasia
- Medullary thyroid carcinoma (MTC)
- Phaeochromocytoma
Typical tumours and issues in MEN2B?
- Mucosal neuromas
- Marfanoid body habitus
- MTC
- Phaeochromocytoma
Risk of MTC in MEN2?
Depends on age:
• Highest risk <1 year
• High risk <5 years
• Moderate risk >5 years but regular screening
Risk of phaeochromocytoma in MEN2?
Higher and high risk from 11 years
Moderate risk from 16 years
Risk of parathyroid disease in MEN2?
High risk from 11 years
Moderate risk from 16 years
Treatment of MTC in MEN2?
MTC treatment - prophylactic thyroidectomy
What is Carney complex?
Autosomal dominant mutation in PRK1R1A, causing a defective regulatory sub-unit and aberrant protein kinase A signalling; this leads to uncontrolled proliferation
Manifestations of Carney complex?
Spotty skin pigmentation with a typical distribution, i.e: lips, conjunctiva and inner/outer canthi, vaginal and penile mucosa
PPNAD
Acromegaly (due to GH producing adenoma)
Thyroid carcinoma (AT ANY AGE)
What is PPNAD?
Primary Pigmented Nodular Adrenocortical Disease
Causes adrenal glands to produce excess cortisol, leading to Cushing’s syndrome
What is McCune-Albright syndrome?
Genetic disorder affecting the bone, skin, and endocrine systems
There is a post-zygotic somatic, i.e: acquired not germline, GNAS mutation that causes constitutive cAMP signalling
Clinical manifestations of McCune-Albirght syndrome?
- Cafe-au-lait skin pigmentation (“Coast of Maine” appearance)
- Polyostotic fibrous dysplasia (bones), causing scoliosis and lower limb issues
- Precocious puberty, i.e: early (usually a manifestation in females)
- Thyroid nodules
- GH excess from the pituitary
- Cushing’s syndrome (Adrenal)
What is Von-Hippel Lindau (VHL)?
Autosomal dominant mutation in the VHL gene that leads to accumulation of HIF proteins and stimulation of cellular proliferation
Clinical manifestations of VHL?
A range of vascular tumours
Retinal haemangiomas
CNS haemangioblastomas
Phaeochromocytoma
Pancreatic cysts
Vital management factor in VHL syndrome?
Family screening
Clinical manifestations of neurofibromatosis type 1?
Axillary freckling, Cafe-au-Lait patches, neurofibromas
Optic gliomas
Scoliosis
Learning difficulties in some
Phaeochromocytoma (rare)
Cause of NF type 1?
Mutation in NF1 gene
Common condition
Difference between phaeochromocytoma and paraganglioma?
Same tumours but in different places, i.e:
• Phaeochromocyoma - in the adrenal gland
• Paraganglioma - extra-adrenal and in the sympathetic chain
Cause of paragangliomas?
Succinate dehydrogenase mutations cause a deficiency so succinate accumulates and their is activation of hypoxia pathways, i.e:
• SDHD (head and neck paraganglioma)
• SDHB (malignant paraganglioma)
2 approaches in next generation sequencing?
Whole genome (WGS)
Whole exome (WES)
Differences between WGS and WES?
WGS produces a comprehensive data set that shows:
• Non-coding changes
• Chromosomal rearrangements
• Copy Number Variants (CNVs)
WES is a targeted approach that shows:
• Coding and UTR variants
But misses non-coding changes and rearrangements
