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Y3 Lecture weeks > GI genetics > Flashcards

GI genetics Flashcards

1
Q

What’s pattern of inheritance and gene of Peutz-Jeghers syndrome?

A

Peutz- Jeghers

  • AD inheritance
  • responsible gene encodes serine-threonine kinase LKB1 or STK11
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2
Q

What’s prognosis for Peutz- Jeghers syndrome?

A

Peutz-Jeghers syndrome

Prognosis:

  • around 50% of patients die from GI cancer before the age of 60
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3
Q

Characteristics/clinical features of Peutz - Jeghers syndrome

A

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

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4
Q

Management of Peutz Jeghers syndrome

A

Conservative, unless complications develop

Examples:

  • resection of polyps if serious bleeding or intussusception occur
  • resection of intestinal segments
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5
Q

DIagnosis of Peutz- Jeghers syndrome

A

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

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6
Q

A pattern of inheritance of Multiple Endocrine Neoplasia (MEN)

A

Autosomal dominant

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7
Q

MEN I

  • cancers involved
  • gene involved
  • the most common presentation
A

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

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8
Q

MEN II a

  • cancers involved
  • mutation
A

MEN II a

Cancers involved

  • Medullary thyroid cancer (70%)

2 P’s

  • Parathyroid (60%)
  • Phaeochromocytoma

RET oncogene

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9
Q

MEN II b

  • cancers involved
  • features
  • mutation
A

MEN IIb

Cancers:

  • Medullary thyroid cancer

1 P

  • Phaeochromocytoma

Features: Marfanoid body habitus, Neuromas

Mutation: RET oncogene

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10
Q

What’s Multiple Endocrine Neoplasia (MEN) in general?

A

MEN

  • several distinct syndromes -> tumours of endocrine glands
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11
Q

What’s polygenic inheritance?

A

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.

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12
Q

What’s a variable expression (genetics)?

A

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

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13
Q

What’s the clinical example of variable expression (disease)?

A

Neurofibromatosis

  • patients with the same genetic mutations show different symptoms and signs of the disease
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14
Q

What’s an incomplete penetrance and its examples?

* clinical example (disease)

A

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.

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15
Q

What’s anisocytosis?

A

Anisocytosis - variation in size

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16
Q

What’s poikilocytosis?

A

Poikilocytosis - variation in shape

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17
Q

What’s that?

*comment on the appearance

A

Hypochromic microcytic anaemia

  • variation in size (anisocytosis)
  • variation in shape (poikilocytosis)
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18
Q

Red flags for iron deficiency anaemia

A
  • GI blood loss
  • rectal bleeding (maybe rectal carcinoma)
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19
Q

The commonest causes of the iron deficiency

A
  • dietary
  • anaemia of chronic disease
  • blood loss

* red flags e.g. rectal bleeding

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20
Q

What’s that?

*comment on appearance

A

Appearance:

  • tear-drop poikilocytes (different shapes)
  • target red cells
  • normal iron studies - problem with globin synthesis

This is thalassemia

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21
Q

Genetic problem in alpha thalassemia

A

Alpha-thalassaemia

  • deficiency of alpha chains in haemoglobin

Overview

  • 2 separate alpha-globulin genes are located on each chromosome 16
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22
Q

Beta- thalassemia major

  • what is the genetic defect?
A

Beta thalassemia major

  • absence of beta chains
  • chromosome 11
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23
Q

Features and clinical presentation of beta thalassemia major

A

Features

  • presents in first year of life with failure to thrive and hepatosplenomegaly
  • microcytic anaemia
  • HbA2 & HbF raised
  • HbA absent
24
Q

Management of beta- thalassemia major

A

Beta - thalassemia major

  • repeated transfusion → iron overload
  • s/c infusion of desferrioxamine (to manage iron overdose)
25
Q

What is thalassemia? (in general)

A

Thalassaemias

  • group of genetic disorders characterised by a reduced production rate of either alpha or beta chains
26
Q

What’s ‘beta thalassemia trait’?

*inheritance pattern

* characteristics

A

Beta-thalassaemia trait :

  • autosomal recessive condition
  • mild hypochromic, microcytic anaemia
  • usually asymptomatic
27
Q

What is the other name for Hereditary Haemorrhagic Telangiectasia?

A

Hereditary Haemorrhagic Telangiectasia = Osler- Weber- Rendu syndrome

28
Q

Hereditary Haemorrhagic Telangiectasia

  • inheritance pattern
  • characteristics
A

Hereditary Haemorrhagic Telangiectasia

  • autosomal dominant condition
  • multiple telangiectasia over the skin and mucous membranes
  • 20% of cases occur spontaneously without prior family history
29
Q

Diagnosis of Hereditary Haemorrhagic Telangiectasia

(criteria)

A
  • 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
30
Q

Pathophysiology of telangiectasia

A

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
31
Q

Treatment of Hereditary Haemorrhagic Telangiectasia

A

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)
32
Q

What happens to the vessels in Hereditary Haemorrhagic Telangiectasia?

A

HHT

  • abnormal connection between the arteriole and collecting vein (artero-vascular malformation)
  • blood flows at higher pressure -> dileted vessel
33
Q

What is important to remember in Hereditary Haemorrhagic Telangiectasia?

A

That need to look for AVM in other organs -> prevent complications

34
Q

What can you see on this x ray?

A

White shadowing in the R peripheral mid zone -> pulmonary AVN (associated with Hereditary Haemorrhagic Telangiectasia)

35
Q

What are the complications of pulmonary?

A

Complication:

  • high output cardiac failure -> as cardiac output is lost in AVN (blood shunting)
  • respiratory distress
36
Q

Treatment of pulmonary AVM associated with Hereditary Haemorrhagic Telangiectasia or an incidental finding

A
  • embolisation of AVM side
37
Q

Why is it important to identify Hereditary Haemorrhagic Telangiectasia?

A

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
38
Q

Differential diagnosis for Hereditary Haemorrhagic Telangiectasia

A

There are number of conditions that present with telangiectasia

*pregnancy = oestrogen increased

39
Q

What is the problem with hamartomatous polyps in Peutz- Jeghers syndrome?

A

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
40
Q

What is the sign of intussusception?

A

Raspberry jelly (mucous) passed in a child’s nappy

41
Q

Types of cancers with Peutz- Jeghers syndrome

A
  • pancreas
  • ovarian ca
  • breast ca
  • teratoma of the testes
  • GI ca - due to malignant transformation of hamartomatous polyps
42
Q

Hereditary pancreatitis

A

Hereditary Pancreatitis

  • mutation in trypsinogen gene -> trypsinogen cannot be inactivated -> it will digest pancreatic tissues (episodes of acute inflammation - leads to chronic pancreatitis)
43
Q

What other condition apart from Hereditary Pancreatitis may cause pancreatitis?

(apart from GET SHMASHED)

A

CF -> ducts of pancreas are blocked -> pancreatic insufficiency -> chronic pancreatitis

44
Q

Familiar gastric cancer

  • what gene is involved?
  • management
A

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)

45
Q

Familial Polyposis Coli

- pattern of inheritance

  • what’s mutated?
A

Familial Polyposis Coli/ aka familial adematous polyposis

  • AD inheritance
  • mutation in APC gene (gene involved in cell adhesion)
46
Q

What happens in Familial Adenomatous Polyposis? (FAP)

A
  • 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)

47
Q

Management of Familiar Polyposis Coli

A

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)
48
Q

What’s Gardner syndrome?

A

FAP (Familial Adenomatous Polyposis) + growths outside bowel (in bone) and skin

  • AD inheritance
  • APC gene
49
Q

Another name for Lynch syndrome?

A

Lynch Syndrome = HNPCC

(Hereditary nonpolyposis colorectal cancer)

50
Q

What is genetic behind Lynch syndrome?

  • inheritance pattern
  • mutation
A

Lynch syndrome

  • AD inheritance
  • germline mutation in DNA mismatch repair gene
51
Q

Cancers associated with Lynch syndrome

A

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
52
Q

Mx of Lynch syndrome

A
  • Colonoscopy every 1-2 years from age 25
  • Consideration of prophylactic surgery
  • Extra colonic surveillance recommended
53
Q

Is it essential to remove an organ in Lynch syndrome?

A

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

54
Q

What happens/clinical presentaiton in Gilbert’s syndrome?

A

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

55
Q

Findings on LFTs in Gilbert syndrome

A

Unconjugated hyperbilirubinaemia + otherwise normal LFTs

56
Q

Management of Gilbert’s syndrome

A

Mx: no Rx required -> just to be aware so doctors do nto get worried on elevated LFTs

Y3 Lecture weeks (65 decks)

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