GI genetics Flashcards
What’s pattern of inheritance and gene of Peutz-Jeghers syndrome?
Peutz- Jeghers
- AD inheritance
- responsible gene encodes serine-threonine kinase LKB1 or STK11
What’s prognosis for Peutz- Jeghers syndrome?
Peutz-Jeghers syndrome
Prognosis:
- around 50% of patients die from GI cancer before the age of 60
Characteristics/clinical features of Peutz - Jeghers syndrome
Peutz - Jeghers syndrome - characteristics:
- numerous hamartomatous * polyps
- pigmented freckles on the lips, soles, palms and hands
- intestinal obstruction e.g. intussusception
- gastrointestinal bleeding
*hamartomatous - focal malformations that consist of genetic mutations
Management of Peutz Jeghers syndrome
Conservative, unless complications develop
Examples:
- resection of polyps if serious bleeding or intussusception occur
- resection of intestinal segments
DIagnosis of Peutz- Jeghers syndrome
2 out of 3 of the following:
- Family history
- Mucocutaneous lesions - patches of hyperpigmentation in the mouth and on the hands and feet. The oral pigmentations are the first on the body to appear, and thus play an important part in early diagnosis.
- Hamartomatous polyps in the gastrointestinal tract. These are benign polyps with an extraordinarily low potential for malignancy.
*genetic testing can be performing -> looking for mutation in the STK11/LKB1 gene
A pattern of inheritance of Multiple Endocrine Neoplasia (MEN)
Autosomal dominant
MEN I
- cancers involved
- gene involved
- the most common presentation
MEN type I
3 P’s
- Parathyroid (95%): hyperparathyroidism due to parathyroid hyperplasia
- Pituitary (70%)
- Pancreas (50%): e.g. insulinoma, gastrinoma (leading to recurrent peptic ulceration)
- Also: adrenal and thyroid
MEN1 gene
Most common presentation = hypercalcaemia
MEN II a
- cancers involved
- mutation
MEN II a
Cancers involved
- Medullary thyroid cancer (70%)
2 P’s
- Parathyroid (60%)
- Phaeochromocytoma
RET oncogene
MEN II b
- cancers involved
- features
- mutation
MEN IIb
Cancers:
- Medullary thyroid cancer
1 P
- Phaeochromocytoma
Features: Marfanoid body habitus, Neuromas
Mutation: RET oncogene
What’s Multiple Endocrine Neoplasia (MEN) in general?
MEN
- several distinct syndromes -> tumours of endocrine glands
What’s polygenic inheritance?
Polygenic Inheritance
- occurs when one characteristic is controlled by two or more genes
- the genes are large in quantity but small in effect
Examples of human polygenic inheritance are height, skin color, eye color and weight.
What’s a variable expression (genetics)?
Variable expressivity
- a phenotype is expressed to a different degree among individuals with the same genotype
Example: individuals with the same allele for a gene involved in e.g. body height might have large variance (some are taller than others) -> prediction of the phenotype from a particular genotype alone difficult
What’s the clinical example of variable expression (disease)?
Neurofibromatosis
- patients with the same genetic mutations show different symptoms and signs of the disease
What’s an incomplete penetrance and its examples?
* clinical example (disease)
Incomplete or reduced penetrance
- some individuals will not express the trait even though they carry the allele
Example of an autosomal dominant condition showing incomplete penetrance is familial breast cancer due to mutations in the BRCA1 gene.
What’s anisocytosis?
Anisocytosis - variation in size
What’s poikilocytosis?
Poikilocytosis - variation in shape
What’s that?
*comment on the appearance
Hypochromic microcytic anaemia
- variation in size (anisocytosis)
- variation in shape (poikilocytosis)
Red flags for iron deficiency anaemia
- GI blood loss
- rectal bleeding (maybe rectal carcinoma)
The commonest causes of the iron deficiency
- dietary
- anaemia of chronic disease
- blood loss
* red flags e.g. rectal bleeding
What’s that?
*comment on appearance
Appearance:
- tear-drop poikilocytes (different shapes)
- target red cells
- normal iron studies - problem with globin synthesis
This is thalassemia
Genetic problem in alpha thalassemia
Alpha-thalassaemia
- deficiency of alpha chains in haemoglobin
Overview
- 2 separate alpha-globulin genes are located on each chromosome 16
Beta- thalassemia major
- what is the genetic defect?
Beta thalassemia major
- absence of beta chains
- chromosome 11
Features and clinical presentation of beta thalassemia major
Features
- presents in first year of life with failure to thrive and hepatosplenomegaly
- microcytic anaemia
- HbA2 & HbF raised
- HbA absent
Management of beta- thalassemia major
Beta - thalassemia major
- repeated transfusion → iron overload
- s/c infusion of desferrioxamine (to manage iron overdose)
What is thalassemia? (in general)
Thalassaemias
- group of genetic disorders characterised by a reduced production rate of either alpha or beta chains
What’s ‘beta thalassemia trait’?
*inheritance pattern
* characteristics
Beta-thalassaemia trait :
- autosomal recessive condition
- mild hypochromic, microcytic anaemia
- usually asymptomatic
What is the other name for Hereditary Haemorrhagic Telangiectasia?
Hereditary Haemorrhagic Telangiectasia = Osler- Weber- Rendu syndrome
Hereditary Haemorrhagic Telangiectasia
- inheritance pattern
- characteristics
Hereditary Haemorrhagic Telangiectasia
- autosomal dominant condition
- multiple telangiectasia over the skin and mucous membranes
- 20% of cases occur spontaneously without prior family history
Diagnosis of Hereditary Haemorrhagic Telangiectasia
(criteria)
- 4 main diagnostic criteria
- If the patient has 2 -> possible diagnosis of HHT
- 3 or more of the criteria -> definite diagnosis
Criteria:
- epistaxis : spontaneous, recurrent nosebleeds
- telangiectases: multiple at characteristic sites (lips, oral cavity, fingers, nose)
- visceral lesions: for example gastrointestinal telangiectasia (with or without bleeding), pulmonary arteriovenous malformations (AVM), hepatic AVM, cerebral AVM, spinal AVM
- family history: a first-degree relative with HHT
Pathophysiology of telangiectasia
Telangiectasia and arteriovenous malformations
- arise due to changes in angiogenesis, the development of blood vessels out of existing ones.
- The exact mechanism is unclear
(likely that they disrupt a balance between pro- and antiangiogenic signals in blood vessels)
- The wall of telangiectasias is unusually friable, which explains the tendency of these lesions to bleed
Treatment of Hereditary Haemorrhagic Telangiectasia
HHT treatment
- symptomatic treatment -> to reduce complications
- no therapy to stop telangiectasias and arterio-vascular malformations
- treat to reduce complications e.g. iron supplements, blood transfusion (if anaemia from chronic bleeds)
- concentrated treatment if a visceral organ is affected (e.g. lungs, liver)
What happens to the vessels in Hereditary Haemorrhagic Telangiectasia?
HHT
- abnormal connection between the arteriole and collecting vein (artero-vascular malformation)
- blood flows at higher pressure -> dileted vessel
What is important to remember in Hereditary Haemorrhagic Telangiectasia?
That need to look for AVM in other organs -> prevent complications
What can you see on this x ray?
White shadowing in the R peripheral mid zone -> pulmonary AVN (associated with Hereditary Haemorrhagic Telangiectasia)
What are the complications of pulmonary?
Complication:
- high output cardiac failure -> as cardiac output is lost in AVN (blood shunting)
- respiratory distress
Treatment of pulmonary AVM associated with Hereditary Haemorrhagic Telangiectasia or an incidental finding
- embolisation of AVM side
Why is it important to identify Hereditary Haemorrhagic Telangiectasia?
With HHT AVMs can happen in any organ -> this may lead to respiratory, cardiac failure, strokes etc (depends on the side of AVM)
- patients with HHT need to have specialist input and screened for AVMs
Differential diagnosis for Hereditary Haemorrhagic Telangiectasia
There are number of conditions that present with telangiectasia
*pregnancy = oestrogen increased
What is the problem with hamartomatous polyps in Peutz- Jeghers syndrome?
Hamartomatous polyps:
- histologically normal (benign) but in a wrong place
- jejunum, duodenum, ileum, stomach, urinary bladder, gallbladder
Complications:
- they are irritated by digestive enzymes -> can bleed
- can cause intussusception of the intestine
What is the sign of intussusception?
Raspberry jelly (mucous) passed in a child’s nappy
Types of cancers with Peutz- Jeghers syndrome
- pancreas
- ovarian ca
- breast ca
- teratoma of the testes
- GI ca - due to malignant transformation of hamartomatous polyps
Hereditary pancreatitis
Hereditary Pancreatitis
- mutation in trypsinogen gene -> trypsinogen cannot be inactivated -> it will digest pancreatic tissues (episodes of acute inflammation - leads to chronic pancreatitis)
What other condition apart from Hereditary Pancreatitis may cause pancreatitis?
(apart from GET SHMASHED)
CF -> ducts of pancreas are blocked -> pancreatic insufficiency -> chronic pancreatitis
Familiar gastric cancer
- what gene is involved?
- management
E-Cadherin gene
- cell adhesion gene
- it is related to malignancy and allows the malignancy to spread through the wall of the stomach
- it is AD
Management: prophylactic gastrectomy (before it develops into cancer, spreads and advance)
Familial Polyposis Coli
- pattern of inheritance
- what’s mutated?
Familial Polyposis Coli/ aka familial adematous polyposis
- AD inheritance
- mutation in APC gene (gene involved in cell adhesion)
What happens in Familial Adenomatous Polyposis? (FAP)
- multiple (hundreds/thousands) colonic polyps
- they will become dysplastic with time -> bowel cancer by age 30-40 (100% cancer risk)
Associated conditions:
Gastric fundal polyps (50%).
Duodenal polyps 90%.
If severe duodenal polyposis cancer risk of 30% at 10 years
Abdominal desmoid tumours (from abdominal wall/rectus abdominis)
Management of Familiar Polyposis Coli
FAP
- if known to be at risk then predictive genetic testing as teenager -> if known to be at risk
- annual flexible sigmoidoscopy from 15 years
- if no polyps found then 5 yearly colonoscopy started at age 20
- polyps found = resectional surgery (resection and pouch Vs sub total colectomy and IRA)
What’s Gardner syndrome?
FAP (Familial Adenomatous Polyposis) + growths outside bowel (in bone) and skin
- AD inheritance
- APC gene
Another name for Lynch syndrome?
Lynch Syndrome = HNPCC
(Hereditary nonpolyposis colorectal cancer)
What is genetic behind Lynch syndrome?
- inheritance pattern
- mutation
Lynch syndrome
- AD inheritance
- germline mutation in DNA mismatch repair gene
Cancers associated with Lynch syndrome
Lynch syndrome cancers: (increased risk of)
- colorectal, stomach, small bowel, liver, gallbladder, pancreas, upper urinary tract, brain and skin
- uterine and ovarian cancer in women
Mx of Lynch syndrome
- Colonoscopy every 1-2 years from age 25
- Consideration of prophylactic surgery
- Extra colonic surveillance recommended
Is it essential to remove an organ in Lynch syndrome?
Not at the beginning - we monitor the organs that have increased the risk of cancer (e.g. colon) -> if polyps found -> remove them as they have potential to become malignant -> then monitor pt regularly
What happens/clinical presentaiton in Gilbert’s syndrome?
Gilbert’s syndrome
- AR condition
Build up of unconjugated bilirubin in the blood stream
(defective bilirubin conjugation due to a deficiency of UDP glucuronyl transferase)
- episodic jaundice, often asymptomatic -> found on biochemistry
- triggers for jaundice: being tired, stressed, illness, infection
People are just slower to conjugate bilirubin
Findings on LFTs in Gilbert syndrome
Unconjugated hyperbilirubinaemia + otherwise normal LFTs
Management of Gilbert’s syndrome
Mx: no Rx required -> just to be aware so doctors do nto get worried on elevated LFTs
