Genetic endocrinology Flashcards
(31 cards)
1
Q
What are the reasons there may be clinical suspicion for an inherited disorder?
A
- Early age of onset of disease
- Abnormal growth or metabolic abnormalities
- Multiple or aggressive primary tumours
- Bilateral tumours in paired organs
- Same or related tumour types clustering on the same side of the family
- Rare tumour types consistent with a specific diagnosis (e.g., medullary thyroid cancer in MEN2)
- Or conditions associated with congenital malformations
Take detailed family history. 3 generation family history, with both paternal and maternal histories.
2
Q
Outline Multiple Endocrine Neoplasia (MEN), what do they cause?
A
MEN I: 3 Ps
- Pituitary
- Parathyroid
- Pancreatic
MEN 2A: 2Ps, 1 M
- MTC
- Pheochromocytoma
- Parathyroid
MEN 2B: 2Ms, 1 P
- MTC
- Marfanoid habitus/ Mucosal neuroma
- Pheochromocytoma
3
Q
Describe MEN I
A
Also called multiple endocrine adenomatosis or Wermer’s syndrome
Caused by mutations in MEN1 gene, which is a tumour suppressor gene
Results in unregulated cell division that leads to tumour formation
Autosomal dominant
All children of a parent with MEN1 have 50% chance of developing the disease
4
Q
What causes type 1 MEN?
A
MENIN gene responsible for type 1 MEN has been localised to chromosome band 11q13
Produces a nuclear protein called menin, a tumour suppressor
5
Q
Describe neuroendocrine tumours
A
- Heterogenous group of neoplasms
- Share certain characteristic features
- Originate from neuroendocrine cells
- Have secretory characteristics
- Frequently present with hypersecretory syndromes
6
Q
Describe the incidence, diagnosis and imaging for primary hyperparathyroidism
A
- 100% penetrance – earliest / most common manifestation
- 1-2 % all hyperparathyroidism is MEN-1
- Multiglandular involvement
Clinically
- Stones, bones, groans, mental overtones
Diagnosis
- High serum calcium with high PTH
Imaging
- USS
- Sestamibi
- Bone densitometry
7
Q
Describe the prevalence, pathology, presentation, diagnosis and treatment of Anterior pituitary tumours
A
- Prevalence in MEN-1 ranges 15-60% in different series
- First clinical manifestation in up 25% of cases
- Two-thirds are microadenomas (<1cm) majority functioning tumours
- Prolactinomas 60%
- Somatotrophinomas 20%
- Corticotrophinomas
- Null cell tumors 15%
- Presentation related to hormone production
- Amenorrhea
- Galactorrhea
- Infertility
- Impotence in men
- Acromegaly
- Cushing’s disease
Diagnosis
- Check PRL, IGF-1, FSH, LH, Testosterone
- MRI
Treatment
Trans-sphenoidal resection of pituitary tumor or medical management in case of Prolactinoma
8
Q
Describe entero-pancreatic tumours, its presentation, symptoms
A
- Lesions tend to be multicentric and small
- Micro/macroadenomas → invasive → metastic carcinoma
- Malignant potential of entero-pancreatic lesions is the primary life-threatening manifestation of the syndrome
Presentation:
Asymptomatic - Present with obstructive symptoms
Symptomatic - Usually due to liver metastases, release of hormones into circulation e.g. serotonin and other gut peptides
Mostly functioning in MEN1 due to production of gut peptides:
- Gastrinomas - Multiple peptic ulcers
- Insulinomas - Hypoglycaemia
- Glucagonomas - Hyperglycaemia and necrotizing erytema
- VIPomas
- Somatostatinomas
- Pancreatic Polypeptide-Producing tumors
Symptoms:
- Intermittent abdominal pain
- Diarrhoea
- Flushing
- Lacrimation
- Rhinorrhoea
- Episodic palpitations
- Wheezing
- Pellagra
9
Q
Describe migratory necrolytic erythema, its diagnosis, imaging and treatment
A
Diagnosis:
- Clincial symptoms
- Hormone concentrations - gut peptides
- Radiology
- Histology - GOLD STANDARD
Imaging:
- Ultrasound
- CT
- MRI
- 68 Gallium DOTATATE Scan
- Endoscopic USS for tissue histology
- Lesion <2cm solitary low incidence of metastasis
Treatment:
- Surgery
- Curative
- Resection of primary and mesenteric lymph nodes despite liver metastasis
- Somatostatin analogues (e.g. Octreotide)
- Chemotherapy
- Hepatic artery embolisation
- Radionucleotide therapy
- Symptomatic
- PPI
- Anti Diarrhoeal
- K supplement
10
Q
Describe MEN II and its facial features
A
- Autosomal dominant
- 3 recognised clinical variant
- MEN2A
- MEN2B (MEN 3)
- Familial thyroid medullary carcinoma (FMTC)
- All varieties show high penetrance of MTC
- 90% MEN2 will show evidence of MTC
Facial features:
- Marfanoid face
- Mucosal neuromas
11
Q
What causes type 2 MEN?
A
- RET gene is responsible for type 2 MEN proto-oncogene, located on band 10q11.2
- RET leads to hyperplasia of target cells in vivo and tumour development
12
Q
Describe Medullary Thyroid Carcinoma
A
- First neoplastic manifestation of MEN2 and significant cause of death
- Rare tumour of the C cells of the thyroid gland
- Multifocal C cell hyperplasia → MTC
- Progression from C cell hyperplasia to carcinoma is variable
- Metastasis common
- Seretory product of C cell hyperplasia/MTC is calcitonin
- High lvls calcitonin important as tumour marker
13
Q
Describe Phaeochromocytoma
A
- Tumour of Chromaffin cells in adrenal medulla (unilateral or bilateral)
- Chromaffin cells produce catecholamines - adrenaline, NORAD
- Ability to suddenly produce large amounts of catecholamines → rise in BP
- Patients present with headaches, sweating, tachycardia, palpitations, in rare cases sudden death
- Usually presents after MTC
- Only present in MEN2A and 2B
14
Q
Describe clinical variants of MEN 2
A
- Cutaneous lichen amyloidosis occurs in 10% of families with MEN2.
- Hirschsprung disease (the absence of autonomic ganglion cells of the gastrointestinal tract caused by a failure of enteric ganglion cells to migrate completely during intestinal development) occurs in approximately 7% of patients with MEN2.
- Familial MTC (FMTC) is a variant of MEN2 in which MTCs occur in isolation due to a decreased penetrance for PC and primary hyperparathyroidism. It typically has a later age of onset.
15
Q
Describe the clinical presentation of MEN2
A
- MTC may present with thyroid lump
- Symptoms of calcitonin excess, including diarrhoea and flushing
- Hoarseness
- Prognosis in MEN2 determined principally by MTC, most lethal component of MEN2
- Pheochromocytoma can present with classic triad of palpitations, headache and diaphoresis but may be asymptomatic on diagnosis
- More likely to be bilateral, and those with a unilateral presentation frequently develop a contralateral PC within 10 years
- Rarely malignant
- Hyperparathyroidism in MEN2 is usually asymptomatic and diagonsed concurrently with the diagnosis of MTC
16
Q
Describe the biochemical diagnosis of MTC, Phaechromocytoma and Parathyroid adenoma
A
MTC:
- Plasma calcitonin concentration is measured before, 2, and 5 mins after IV administration of Ca
- Positive test = stimulated lvl is >3 times the basal level (or >300ng/L)
Phaechromocytoma:
- Elevated levels of catecholamines and catecholamine metabolites in 24hr urine collection
Parathyroid adenoma:
- Stimultaneously elevated serum concentrations of calcium and PTH
17
Q
How is MTC treated?
A
If localised:
- Total thyroidectomy
- Success depends on degree of malignant progression, should be performed before age of possible metastases
- Often curative and good prognosis if thyroid removed before metastasis
If metastasised:
- Difficult and ineffective with standard chemotherapy, X-ray, thermal radiation
- Genetic testing allows for earlier identification of at risk individuals → Prophylactic thyroidectomy
Those who have negative test reassured that they (and offspring) are unlikely to develop MTC
Prognosis (5 year survial):
- 50% overall
- 75% without metastasis or invasion
- 25% with metastasis or invasion
18
Q
Describe MEN4
A
Clinical presentation
- MEN4 was first reported in 2006 and has limited data due to very small numbers of case reports
- Patients develop MEN1-associated tumours, including parathyroid tumours and anterior pituitary tumours, which may occur in association with tumours of the kidneys, adrenals and reproductive organs.
- The most common phenotypic features are parathyroid neoplasia (80% of patients) and pituitary adenomas, which tend to be smaller and less aggressive than MEN1-associated pituitary adenomas.
- Pancreatic NET, including gastrinomas, have also been observed in MEN4
- Adrenal tumours and primary ovarian insufficiency have also been described.
- This autosomal dominant disorder is associated with CDNK1B mutations in patients who are MEN 1 mutation negative.
19
Q
Define primary hyperparathyoidism
A
- Peristent hypercalcaemia togehter with an elevated serum PTH concentration
- Benign solitary adenoma (80%)
- Hyperplasia of all 4 parathyroid glands (15-20%)
- Carcinoma (<1%)
20
Q
What are the familial forms of primary hyperparathyroidism?
A
- MEN1
- MEN2
- FHH (familial hypocalciuric hypercalcaemia)
- Neonatal severe Hyperparathyoidism (NSHPT)
- Hyperparathyoidism-Jaw Tumours syndrome (HPT-JT)
- Familial Isolated Primary Hyperparathyroidism (FIPH)
21
Q
Describe FHH
A
- Autosomal dominant trait, usaully causing mild HPT with relative hypocalciuria
- Hypercalcaemia in FHH is highly penetrant at all ages, even in prenatal peiod (64)
- Mild hypermagnesemia sometimes seen in FHH but unusual in other forms of primary HPT
- FHH cases almost always remain hypercalcemic following standard subtotal parathyroidectomy
- Most cases FHH result from loss-of-function mutation in gene encoding calcium-sensing receptor (CaSR 3)
22
Q
Describe PGL
A
- Paragangliomas (PGL) - Neuroendocrine tumour that forms near certain blood vessels and nerves outside of the adrenal gland as neural crest cells also migrate to form the SNS
- Benign, slow growing tumours
- Distributed throughout head and neck
- Can also be found in orbit, larynx, and along course of CNX
23
Q
Describe catecholamine metabolism
A
- Norepinephrine and dopamine can be synthesised by SNS
- Enzyme needed for synthesis of epinephrine is exclusive to adrenal medulla
24
Q
Describe the clinical presentation of Paraglinomas
A
- Headache, palpitations, sweating - Most common symptoms
- Other symptoms include hyperglycaemia, weight loss, lactic acidosis
- Adults most often have paroxysmal hypertension (50%) while children have sustained hypertension (70-90%)
- 20% children will be normotensive at diagnosis
25
Describe gene panel analysis for endocrine genetic disorders
- NGS of FH (fumarate hydratase), SHGB, SDHC, SDHD, SDHAF2, RET, MAX, TMEM127, VHL genes
- In absence of family history, genetics recommended:
- Hereditary PGL/Phaeo syndrome - Autosomal dominant syndrome
- SDHD
- Imprinted gene
- “Switched on” only when inherited from father
- 30% lifetime risk phaeo, 70% risk head/neck PGL
- SDHB
- 50% lifetime risk phaeo, 30% risk head/neck PGL
- 14% lifetime risk renal cell carcinoma
- All patients with PGL should be offered genetic testing
26
Describe localisation of endocrine tumours
- MIBG iodine-123 scintigraphy was used
- Although MIBG scan specific, has low sensitivity (41.6-60%) in mapping metastatic paragangliomas
- Gadolinium-68-DOTA-octreotate (68Ga-DOTATATE)/ CT scanning has been shown to have higher diagnostic accuracy and sensitivity in mapping paraganglioma metastases
- Contrast-enhanced MRI fluorine-18 fluorodeoxyglucose PET/CT
27
How are endocrine tumours managed?
- Medical
- Alpha and Beta adrenergic blockers
- Intraoperative hypertensive crisis can be expected each time catecholamine-secreting paraganglioma handled
- Close communications b/w surgeons and anaesthetists means episodes can be predicted and treated with fast-acting antihypertensives
- Surgical
- Radiotherapy
28
Describe Von Hippel-Lindau (VHL) syndrome
- Autosomal dominant
- Multi-organ
- Familial neoplastic syndrome
- Caused by genetic aberrations of the tumour supressor gene VHL
29
What are the most common VHL-associated tumours?
- Hemangioblastomas involving brain, spinal cord, and retina
- Retinal angiomas - Dilated, tortuous vessels leading to and away of the vascular tumour. Lesions can be peripheral. Fluroescein angiography typically shows early leakage and marked hyperfluorescence. Macular edema can be associated with lesions
- Clear cell renal cell carcinoma (RCC)
- Pheochromocytomas and Paragangliomas
- Pancreatic neuroendocrine tumours (PNETs)
30
Describe the molecular biology of the VHL gene
- VHL gene is a tumour suppressor gene, located on short arm of chromosome 3
- Regulates transcription factor HIF
- HIF-1 helps normal tissues as well as tumours to survive under hypoxic conditions
- Results in rapid proliferations, tumorigenesis, and angiogenesis
31
Describe the management of VHL-associated tumours
- Needs multidisciplinary approach
- Advances in genetic testing have lead to early diagnosis of the syndrome
- Surveillance
- Since early interventions can help prevent adverse outcomes
