Case 7 Flashcards
How long after ovulation can the oocyte be fertilised?
24hrs
How long can sperm remain viable in female tract?
24hrs
Capacitation
Removal of proteins by enzymes in plasma membrane of sperm.
Enables sperm to pass through coronal cells and undergo acrosome reaction.
Acrosome reaction
Enzymes released from acrosome of sperm, which digest coronal cells. Allows sperm fuses with oocyte membrane.
Where does fertilisation usually occur?
Ampullary region of uterine tube
Cortical reaction
Formation of a fertilisation membrane after one sperm has entered.
Prevents triploidy.
Cleavage
Rapid mitotic growth without growth.
How does a morula differ from a blastocyst?
Blastocyst has formed an inner cavity.
Inner cell mass will eventually become the..
Embryo
Trophoblast eventually becomes the…
Placenta
Blastocoele
Fluid filled space surrounded by trophoblast
Yolk sac
Morula
Spherical 16-cell mass
4-7 days post fertilisation
Blastocyst
Has a cavity inside the zona pellucida and an inner cell mass.
8-14 days post fertilisation
Attachment of blastocyst to uterine epithelium
Blastocyst hatches from surrounding zona pellucida.
L selectin on trophoblast of blastcyst attaches to CHO receptors on endometrial wall.
Function of syncytiotrophoblast
Invades endometrium causing spiral arteries to rupture
Cytotrophoblast
Immediately surrounding embryo
When does blastocyst reach the uterus?
6-7 days after fertilisation
Apposition/Adplantation
Blastocyst is pressed against endometrium at the Inner Cell Mass region
When is embryo completely surrounded by endometrium?
9-10 days after fertilisation
Complete Implantation
Apposition - blastocyst becomes pressed against endometrium at ICM region.
Adhesion between L-selectins on trophoblast cells and CHO receptors on endometrial wall.
Syncytiotrophoblast secretes enzymes which break down endometrial cells.
Decidual reaction
Stromal cells of uterine mucosa fill with glycogen.
Provides nourishment until placenta develops.
Majority of abnormal implantations occur in…
Uterine tubes
Placenta Previa
Low lying placenta.
Inserted into lower uterine segment.
Prevents natural birth.
Placenta accreta
Abnormal invasion of endometrium and myometrium
Gastrulation
Conversion of bilayered blastula into an embryo with 3 layers
Primitive streak cells synthesise….
FGF8 - controls migration and specification.
Mechanism for gastrulation
Cells of epiblast migrate towards primitive streak, moving away from epiblast and slipping beneath it.
Invagination and lateral migration of epiblast cells.
Ectoderm derived tissues:
CNS Pineal gland Epidermis Hair Enamel Inner ear Retina and lens
Mesoderm derived tissues:
Cranium Connective tissue Urogenital system Pericardium Heart Blood Lymphatics
Endoderm derived tissues:
Epithelium of GI tract, respiratory tract, urinary bladder, parathyroid gland
Important proteins involved in neurulation
Wnt
Shh
Wnt protein
Induces ecto and mesodermally derived tissues
Shh protein
Initially expressed in notochord.
Induces neural patterning.
Induces patterning of somites.
Neurulation
Cells in mesoderm just below primitive streak differentiate into notochord.
Induces formation of a thickening in ectoderm called the neural plate.
Neural plate cells dive into mesoderm and form a ring structure called the Neural Tube.
Neural tube formation induces cells from ectoderm to enter mesoderm - Neural crest cells.
Closure of neural tube occurs due to adhesion of which molecules:
E-cadherin
N-cadherin
E-cadherin is found in…
External epidermis of skin
N-cadherin is found in…
Neural crest cells
Neuropores
Openings in neural tube
Neural tube closure travels from…
Neck region and continues posteriorly
Molecules responsible for dorsalisation of CNS
BMP and Wnt
Molecules responsible for ventralisation of CNS
Shh
Molecules responsible for caudalisation of CNS
Wnt and Retinoic acid
When does gastrulation occur?
Week 3
Neural Crest cells
Temporary group of cells found in mesoderm.
Give rise to a number of different cells.
Neural Crest cells
Temporary group of cells found in mesoderm.
Give rise to a number of different cells.
Cranial neural crest
Carilage and bone Cranial neurons Glia and CT of face Bones of middle ear Tooth primordia
Trunk neural crest
Dorsal root ganglia and sensory neurons
Sympathetic ganglia
Melanocytes
Vagal and sacral neural crest
Parasympathetic nerves of gut
Cardiac neural crest
Melanocytes
Neurons
Division between aorta and pulmonary artery.
Somites
Paired blocks of mesoderm. Arranged at either side of neural tube.
Somitogenesis
Formation of whorls of concentric mesoderm cells, producing pairs of identical somites which differentiate into the same cell types.
Hox (Homeotic genes)
Inform somites of their position.
Somites differentiate into…
Cartilage and bone
Muscles of ribcage, limbs and back
CT of dermis
Giemsa stain
Stains all parts of DNA equally, generating patterns of light and dark due to different amounts of coiling.
Telomerase
Recaps ends of chromosome which fray during replication.
Trisomy 21
Down’s Syndrome
Why does nuchal translucency increase with Down’s Syndrome?
Abnormal venous drainage
Physical features seen in infants with Down’s Syndrome
Muscle hypotonia Large tongue Brushfield spots (white spots in iris) Single palmar crease Flattened nose Curved 5th finger Sandal gap deformity Low set ears Epicanthal folds
Features of Down’s Syndrome in later life
Developmental delay
Obesity
People with Down’s Syndrome are at an increased risk of…
Heart disease Thyroid disorders Conductive hearing loss Immune dysfunction Leukaemia Seizures (15%) Dementia (75% by 65yrs)
Trisomy 18
Edward’s Syndrome
Prognosis for Edwards syndrome
75% miscarried or stillborn
5-10% survive to 1 year
Common features of Edward’s Syndrome
Arthrogryposis (joint contractures) Rocker bottom foot with prominent calcaneus Clenched hands with index and 5th fingers overriding 3rd and 4th Skeletal defects Cleft lip/palate Heart and urogenital abnormality Seizures Developmental delay
Trisomy 13
Patau Syndrome
Prognosis for Patau Syndrome
20% survival at 1 year
Common features of Patau syndrome
Microcephaly Holoprosencephaly (failure of forebrain division) Cleft palate Cutis Aplasia (missing skin, usually scalp) Craniofacial defects Polydactyly Omphalocoele Urogenital and heart defects Seizures Developmental delay
Holoprosencephaly
Failure of forebrain division and midline formation.
Seen in Patau syndrome
Cutis Aplasia
Missing skin, usually on scalp, seen in Patau syndrome
Hypotelorism
Short distance between eyes, seen in Patau syndrome
Cyclopia
One eye
Seen in Patau syndrome
Proboscis
Tube rather than a nose
Seen in Patau syndrome
Polydactyly
Many fingers
Seen in Patau syndrome
Omphalocoele
Liver and intestines outside the body.
Seen in Patau syndrome
Mosaicism
When someone is composed of cells of 2 genetically different types.
Caused by errors in post-zygotic mitosis e.g. non dysjunction and trisomy rescue
Germline mosaicism
Mutated cells only found in testis or ovaries.
Asymptomatic but offspring may be affected.
Possible triploidies
69 XXX
69 XXY
69 XYY
Diandry
Egg fertilised by 2 sperm or a diploid sperm
Accounts for 60-80% of triploidy cases
Effect of diandry
Large placenta
Small foetus
Digyny
Diploid egg fertilised by 1 sperm
20-40% of cases
Effect of Digyny
Small placenta
Very small foetus
Features of troploidy
Misscarriage/Stillbirth Early neonatal death Prematurity Craniofacial dysmorphism Hypotonia Eye/gut/brain/cardiac/limb/GU abnormalities
Why are sex chromosome aneuploidies more mild?
Y chromosome is small and X chromosome can be inactivated
Barr body
Condensed, inactive X chromosome
47XXY
Klinefelter syndrome
Features of Klinefelter Syndrome
Hypogonadism and infertility Gynaecomastia Absent secondary sexual characteristics Small testes Tall stature Shy and apprehensive
People with Klinefelter syndrome are at higher risk of…
Female associated health problems e.g. Breast cancer, thyroid problems
Management of Klinefelter syndrome
Testosterone and fertility treatment
Treat gynaecomastia
Features of 47 XYY syndrome
Normal intelligence, testosterone and fertility.
Tall
Aggressive/antisocial
Severe acne
45X
Turner Syndrome
Visible features of Turner Syndrome
Neck webbing
Broad, flat chest with widely spaced nipples
Low set ears
Increased carrying angle of elbows
Sexual characteristics of Turner Syndrome
Streak ovaries
Lack of sexual development
Primary amenorrhoea
Infertile
Physiological characteristics of Turner Syndrome
Heart and kidney defects
Increased risk of IBD
Hypothyroidism
Management of Turner Syndrome
GH in childhood
Oestrogen in adolescence
Surgery for webbing
IVF/Egg donation
Risks of balanced reciprocal translocation
Infertility
Recurrent miscarriage
Ring chromosome
A chromosome whos arms have fused together to form a ring
Ring chromosome 20
Associated with Seizures
Robertsonian Translocations most commonly occur between..
Chromosome 13 and 14
45,XX,der(13:14)
Robertsonian Translocation between chromosome 13 and 14.
Combination of small arms of 13 and 14 have been lost.
Uniparental Disomy
2 copies of a chromosome come from the same parent.
May occur due to trisomy rescue (deletion of a third chromosome)
Risk of Down’s syndrome when mother carries the Robertsonian Translocation
10%
High risk as there is no competition between eggs.
Risk of Down’s Syndrome when father carries the Robertsonian translocation
<0.5%
Low risk since abnormal sperm are outcompeted
5p Deletion (deletion of short arm of chromosome 5)
Cri Du Chat
Interstitial Deletion 15q11-q13
Prader-Willi Syndrome
Angelman Syndrome
Features of Prader-WIlli Syndrome in the newborn
Weak feeding, hypotonia, slow development
Features of Prader-Willi Syndrome in a child
Constantly hungry Obesity (+diabetes) Narrow forehead Small hands and feet Short Intellectual and behavioural problems Hypogonadism
Features of Angelman Syndrome
Delayed development and intellectual disability Severe speech impairment Gait ataxia Epilepsy Microcephaly Excitable/Hyperactive Fair coloured skin and hair Scoliosis
Intersitial deletion 22q11.2
DiGeorge Syndrome
Inheritance pattern for DiGeorge Syndrome
Autosomal dominant
Features of DiGeorge Syndrome
Heart abnormalities (74%) Palate abnormalities (69%) Immun deficiencies (77%) Hypocalcaemia (50%) Learning disabilities (70-90%)
Use of Fluorescent In Situ Hybridisation (FISH)
For small changes in genes, too small to be seen by karyotyping (e.g. microdeletion 22q11.2)
Micro Array-Based Comparative Genomic Hybridisation
Detects changes in genes and chromosomes.
Used in most post and prenatal cytogenetic testing.
Problems with Array-CGH
Incidental findings e.g. Huntington’s
Malformations usually occur at what stage of gestation?
3-8wks
Disruptions
Alterations of pre existing structures due to destructive forces e.g. Amniotic band syndrome
Amniotic band syndrome
Foetus entangled in amniotic bands Decreased blood flow causing: Club hands Cleft lip/palate Syndactyly Amputation
Deformations are caused by…
Mechanical factors
Syndrome
Pattern of malformations occurring together that are thought to have a specific common cause
Teratogens
Disrupt embryonic or foetal development during critical periods.
Produce malformations/birth defects
Fragile X Syndrome
Fragile sites found in regions of CCG repeats.
Causes mental retardation, large ears, prominent jaw and autism
Effect of chemical agents during 1st trimester
Congenital malformations
Effect of chemical agents during 2nd/3rd trimester
Affect foetal growth and functional development
Effect of chemical agents near term/during labour
Adverse affects on labour and neonate after birth
Effect of thalidomide on foetus
Missing limbs
Facial, CV and CNS abnormalities
Increased risk of prematurity and spontaneous abortion
Effect of Isotretinoin (Analogue of Vit A used for acne) on foetus
Facial abnormalities
Low IQ
CNS and CV problems
Effect of Rubella infection during first trimester
Congenital Rubella Syndrome
Cataracts
Cardiac defects
Deafness
Mental retardation
Effect of rubella infection during weeks 13-16 gestation(Early 2nd trimester)
15% have deafness and retinopathy
Effect of Rubella infection after 16 weeks gestation
Normal development
SMALL risk of deafness and retinopathy
Why does alcohol intake by a pregnant woman have a detrimental effect on the foetus?
Foetal liver does not have alcohol or aldehyde dehydrogenase
Effect of alcohol intake during 1st trimester
Foetal Facial deformity
Smooth Philtrum Abnormal ear cartilage Wide set eyes/Epicanthal folds Small upper lip Microcephaly
Effect of alcohol intake during 2nd trimester
Increased risk of spontaneous abortion
Effect of alcohol intake during 3rd trimester
Effect weight, length and brain growth of baby.
Facial deformity seen in Foetal Alcohol Spectrum Disorders
Smooth Philtrum Abnormal ear cartilage Wide set eyes/Epicanthal folds Small upper lip Microcephaly
Effect of smoking during pregnancy
IUGR
2x more likely for premature delivery
Low birth weight (<5lb)
Why does smoking affect pregnancy?
Nicotine constricts blood vessels - reducing blood supply to foetus.
Nicotine can cross blood:placenta barrier - affects brain development and impairs cell growth
Effect of hyperthermia in pregnancy
Neural tube defects Micropthalmia (small eyes) Cataracts Microencephaly Craniofacial defects (clefts) Behavioural problems
Effect of cocaine use during pregnancy
Spontaneous miscarriage
Premature labour
Difficult delivery
Low birth weight and small head circumference
What screening do we carry out for pregnant women in Wales?
Hep B
Sickle cell anaemia + thalassaemia
Down’s Syndrome (NT)
Blood group + Ab
Features of trinucleotide repeat disorders
Symptoms of disorder become more severe/have an early onset with each generation
Trinucleotide repeat disorders
Myotonic Dystrophy
Huntington’s Disease
Fragile X Syndrome
Inheritance pattern for Myotonic Dystrophy
Autosomal Dominant
Inheritance pattern for Huntington’s Disease
Autosomal Dominant
Inheritance pattern for Fragile X Syndrome
X linked Dominant
Features Myotonic Dystrophy
Progressive muscle wasting and weakness Slurred speech Myotonia (unable to relax muscles after use e.g. Jaw locking) Cataracts Cardiac conduction defects
Breast cancer susceptibility genes
BRCA1 (20-30%)
BRCA2 (10-20%)
Phenocopy
Individual without the specific gene gets the condition
Non penetrance
Individual with the specific gene does not get the condition
Sex limitation
Male with specific gene for a condition only affecting females, does not get the condition
Variable expression
Example
Female with gene for breast cancer gets ovarian cancer
Hardy-Weinberg Equation
p2 + 2pq + q2 = 1
Where p+q=1
Somatic mosaicism
Some cells lack the mutation, therefore a more mild phenotype is expressed
Constitutional mutation
Inherited from a gamete (germline mutation) or occurs soon after fertilisation
Chimerism
One organism composed of 2 or more populations of genetically distinct cells, originating from different zygotes
Chimeric Singleton
Where one twin dies and becomes integrated with the other foetus
Therapeutic chimerism
Haemopoietic stem cell treatment
Placental anastomoses
Occurs in 8% of dizygotic twins. Gives rise to chimerism
Epigenetics
Changes in organisms caused by modification of gene expression rather than an alteration of the genetic code itself
Genetic Imprinting
Gene expression which depends on which parent the gene was inherited from.
Occurs as a result of epigenetics.
Maternal inheritance of 15q11-q13
Angelman Syndrome
Paternal inheritance of 15q11-q13
Prader Willi Syndrome
Why is folic acid given in pregnancy?
Reduces incidence of neural tube defects e.g. spina bifida, acrania, anencephaly
Folic acid treatment before/during pregnancy:
400 micrograms when trying to conceive and during first 12 weeks of pregnancy.
5mg for women at high risk (Hx of NTD or family Hx)
Haemolytic disease of newborn
Anaemia
Hyperbilirubinaemia
Kernicterus (bilirubin induced neurological deficit)
Prevention of Rhesus Disease
Anti-Rh given to rhesus positive mothers after birth and at sensitisation events (e.g. car accident)
Combined Test consists of:
US measurement of CRL and NT
Biochemical markers: beta hCG in blood and pregnancy associated plasma protein A
When must combined test be carried out?
10-14wks gestation
When is combined test less accurate?
Obese women
Quadruple test consists of:
US measurements of CRL and head circumference
Biochemical markers:
Foetal serum albumin (AFP), hCG, unconjugated estradiol (uE3) and inhibin A
Quadruple test results which would suggest high risk pregnancy
High AFP = neural tube defect
High hCG = T21
Low uE3 = T21
When is quadruple test indicated?
When time frame for Combined test is missed
Women with BMI > 40
Time frame for Quadruple Test
14-20wks gestation
What happens if QT/CT gives a high risk result?
Mother is offered diagnostic tests - CVS or amniocentesis
At what stage in gestation can CVS be carried out?
After 11 weeks
Risks of CVS
> 1% risk of miscarriage
Up to 5% of tests do not give a result
Chorionic Villus Sampling
Aspitation of chorionic villi through abdomen under US guidance
Amniocentesis
Aspiration of amniotic fluid
Risks of amniocentesis
1% risk of miscarriage
1% risk of infection
1% of tests do not give a result
At what stage in gestation can Amniocentesis be carried out?
After 15 weeks
What is the disadvantage of amniocentesis?
Takes place late in pregnancy.
If a termination is requested, treatment is:
Foeticide - injection of KCl into foetal heart
When is screening for Syphilis, Hep B and HIV carried out for a pregnant woman?
8-12 weeks
Can be at any time
When is screening for Sickle Cell Anaemia and Thalassaemia carried out for a pregnant woman?
0-10weeks
When is screening for blood group and rhesus disease carried out for a pregnant woman?
8-10 weeks
Can be at any time
NIFTY/NIPT
Diagnostic test examining maternal blood.
Low risk
Can be carried out on twin pregnancies (only give result for one foetus)
CVS and Amniocentesis do not give an accurate result for…
Twin/Multiple pregnancies - since there is already a higher risk of miscarriage
Features of Autosomal Dominant Inheritance
Multiple generations
Males and females affected equally
Incomplete penetrance i.e. unaffected carriers
Conditions with Autosomal Dominant Inheritance patterns
Huntington's FAP Familial Hypercholesterolaemia LQT Myotonic dystrophy Hereditary breast.ovarian cancer Marfan's Syndrome
Features of Autosomal Recessive Inheritance
Usually only one generation affected
Often childhood onset
Common in consanguinous families
Conditions with Autosomal Recessive Inheritance patterns
B-Thalassaemia Sickle Cell Phenylketonuria Tay Sachs Spinal Muscular Atrophy MYH Associated Polyposis
Recurrence risk after a couple has one child affected with an AR condition
25%
Features of X-Linked Recessive inheritance
Usually only affects males
Affected males can never transmit condition to their sons.
Daughters of affected males are always carriers
Examples of X-Linked Recessive conditions
Duchenne Muscular Dystrophy
Haemophilia A
Red-Green colour blindness
Penetrance
Frequency with which the characteristic controlled by a gene is seen in individuals possessing it
Pseudodominant
Where a recessive condition appears to transmit dominantly.
Usually occurs in consanguinous families
Features of X-linked dominant inheritance
Higher incidence in females
Affected male gives condition to all daughters and not to sons.
Affected female gives condition to half of her sons and half of her daughters
Examples of X-linked Dominant conditions
Vitamin D resistant rickets (hypophosphataemic)
Rett’s Syndrome
Fragile X syndrome
Incontinentia Pigmenti
X linked dominant.
Males die in utero. Females inactivate a chromosome and survive
Features of Incontinentia Pigmenti
Blistering (0-4 months) Wart like rash and hypopigmentation Alopecia Hypodontia (missing teeth) Dystrophic nails Retinal detachment Developmental delay/learning disability
Features of Y linked inheritance
Males only
Often affects fertility - unlikely to be passed on
Features of mitochondrial inheritance
Transmitted mother to child only
Examples of mitochondrial inherited conditions
Leber Hereditary optic neuropathy
Chronic progressive external opthalmoplegia
Leber Hereditary optic neuropathy
Sudden permanent vision loss due to optic atrophy in young adult
Mitochondrial inheritance
Low penetrance - only 50% of male carriers are symptomatic, only 15% of female carriers are symptomatic
Chronic progressive external opthalmalgia
Weakness of muscles of the eye
Loss of function of eye and eyelid movement.
Mitochondrial inheritance
Why does imprinting affect foetal growth?
Paternal genome wants to maximise resources for foetus.
Maternal genome wants to minimise resources for foetus.
Bechwith-Wiedmann Syndrome
Paternally inherited 11p15 mutation (imprinting)
Macroglossia Neonatal hyperinsulinism (large pancreas) Large limbs and body Wine stained skin Ear creases Increased risk of cancer
Silver Russell Syndrome
Maternally inherited 11p15 mutation (imprinting)
Small Feeding problems Hypoglycaemia Clinodactyly Hypospadias
Clinodactyly
Curved little finger (outward curvature)
Hypospadias
Urethral opening is in an abnormal position
Why is ibuprogen contraindicated in pregnancy?
Causes neonatal haemorrhage due to thrombocytopenia
Fundal height at 12 weeks gestation
Pubic symphysis
Fundal height at 20wks gestastion
Umbilicus
Fundal height at 36wks gestation
Xiphoid process of sternum
Quadruple test results suggesting high risk of Down Syndrome
High hCG and Inhibin A
Low AFP and Estriol
Protein responsible for dorsalisation of CNS
Wnt and BMP
Proteins responsible for caudalisation of CNS
Wnt and Retinoic acid
Proteins responsible for ventralisation of CNS
Shh
