PATH 201 - LECTURE 15

what is the most common congenital anomaly

heart defect

what are the types of abnormalities

malformation

disruption

deformation

dysplasia

sequence

syndrome

what is a malformation

a structural defect of a part of or an entire organ or body region

how do malformations come about

• primary errors of morphogenesis

• arise from an INTRINSICALLY abnormal developmental

what is morphogenesis

formation of the structure

what is an example of a malformation

• coloboma

what is a disruption

defect in an organ or a body part caused by a process that interferes with an originally normal development - EXTRINSIC DISTURBANCE

• The structure begins to develop normally but gets exposed to some sort of teratogen, which disrupts normal growth

what is an example of a disruption

• thalidomine induced phocomela

what is a deformation

• structural abnormality caused by mechanical forces

• extrinsic distrubance

what is an example of a deformation

• amniotic band constriction

what is a dysplasia

• abnormality of tissue caused by abnormal intrinsic developmental process

• incorrect pattern - grow in the wrong location or direction

what are some examples of dysplasia

• ectodermal dysplasia

• hip dysplasia - hips dont develop at the correct angle

what are the defects that involve more than one structure

• sequence

• syndrome

what is a sequence

• cascade of anomalies triggers by one initating abberation

what is an example of a sequence

oligohydramnios - potter sequence

describe potter sequnce/oligohydramnios

• leak in the amniotic sac or renal agenesis can cause oligohydramnios which causes fetal compression

• fetal compression can cause pulmonary hypoplasia, breech presentation etc

what is a syndrome

• a group of malformations of different structures due to a single primary cause acting through mutliple developmental pathways

what is an example of a syndrome

down syndrome

what are the two main causes of congential anomalies

• genetic and environmental

what are the geneticall based malformations caused by

• abnormalities of chromosomal division

• gene mutations

what is abnormal chromosome number called

aneuploidy

what is polyploidy

• higher multiple than 2x haploid number

what is the outcome of polyploidy pregnancies

usually spontaneously abort early on

what is triploidy

3 × 23 chromosomes

what is monosomy

lack of one member of a choromsome pair

what is trisomy

triplet instead of a pair of chromosomes

what causes triploidy

• polyspermy

• failed cytokinesis

• polar body not seperated during meiosis

how does polyspermy cause triploidy and how is it prevented

• multiple sperm = 3 pronuclei

• normally zona plucida becomes impermeable after first sperm is body

how does failed cytokinesis cause triploidy

• during mitosis, failed cytokinesis means that the germ cells dont seperate fully which means they can have two nuclei in them

• this can happen in the oocyte or the sperm

what is the outcome of monosomy of autosomes or sx chromosomes

• usually not viable but some do survive

what are some examples of syndromes causes by monosomy

• turner syndrome

• cri du chat syndrome

what is turner syndrome

• missing x chromosome

• female phenotype but sterile

what is cri du chat syndrome

• short arm of chromosome 5 missing

• distinctive cry that resembles cat mewing

• characteristic facial features, slow growth, microcephaly, psychomotor disability

what is trisomy 21

down syndrome

what is trisomy 13

patau syndrome

what is trisomy 18

edwards syndrome

what are some examples of sex chromosome trisomy syndromes

klinefelter syndrome

XXY

triple X syndrome

what is klinefelter syndrome

XXY - male phenotype, small testes, infertile

what is XYY

• male phenotype, tall, healthy, impulsive behaviour

what is triple X syndrome

• female phenotype, healthy, cognitive impairment, fertile

what causes trisomy

non disjunction during oocyte meiosis

what is achondroplasia

• morphologicaly abnormality caused by genetics

• fibroblast growth factor 3 receptor gene mutated - FGFR3

• also known as dwarfism

what is haemophilia

• morphologicaly abnormality caused by genetics

• mutations in genes for collting factors VIII, IX, XI

what is muscular dystrophy

30 different genetic disorders affecting geens that make muscle proteins

what are some examples of environmental causes of abnormalities

• maternal/placental infections

• maternal nutrition and disease

• drugs and chemicals

• hormones

how can maternal infections cause abnormalities

• can interfere with early development or destroy structures already formed

what are types of maternal infections

• transcervical

• transplacental

when do transcervical infections occur

around the time of birth

when do transplacental infections occur

• anytime

what are some examples of maternal/placental infections

• toxoplasmosis

• rubella

• zika

what nutrient deficiency causes abnormalities

• folate/folic acid

at what stage is folic acid deficiency dangerous

first month gestation

what can folate acid deficiency during gestation result in

neural tube defects

what are some examples of neural tube defects caused by folic acid deficiency

• anencephaly

• spina bifida

• maternal diabetes

what is anencephaly

• underdeveloped brain and incomplete skull

what is spina bifida

spinal cord fails to develop and close normally

what are some drugs and chemicals that cause defects

thalidamine

alcohol

cigarrettes

dioxins

what defects does thalidamide cause

• malformation of limbs ears face cardiovascualr and gastrointestinal systems

what defects does cigarrettes cause

low birth weight

when is cigarretes msot effectvie

• third trimester

how does dioxins cause defects

• possible link to human birth defects but inconclusive evidence

what hormones are known to cause birth defects

androgens

diethylstillbestrol

how does androgen cause defects

• masculinisation of female offspring

• accelerated genital development in male offsping

what was androgen initially used for

prrevent abortion and treat tumours

when is androgens naturally high

polyendocrine metabolic ovarian syndrome

what defects does diethylstilbestrol (syntehtic estrogen) cause

• cervical and uterine abnormalities

• crytporchidism in males

• cancers

what was diethylstillbestrol used for

• to prevent miscarriage

how is defects caused by hormones hereditary

• If the grandmother is exposed to it during the pregnancy while the germ cells of the fetus are still developing, then those germ cells go on to be the grandchild, and therefore carries on and can cause alterations in the children of the offspring that was orginally exposed

what are some risks of twin pregnancies

• premature birth

• foetal growth resitriction

• foetal mortality

• congenital abnormalities

what are the two types of twins

dizygotic - fraternal

monozygotic identical

what is a dichorionic pregnancy

• when each twin has its own placenta

what is a monochorionic pregnancy

• when the twins share a placneta

what is 2 ways that twinning can occur

1. 2 eggs ovulatted that are fertilised by 2 sperm

2. 1 egg that is ovulated by 1 sperm

describe twin pregnancies that originate from 2 eggs

• seperate pregnancies at the same time

• fraternal - dizygotic

• genetically different

• basically siblings

describe twin pregnancies that originate from 1 egg

• embryo is formed and then splits> 1 pregnancy turned into two offspring

• genetically the same - identical twins - monozygotic

are twin pregnancies that happen with 1 egg dichorionic or monochorionic

• if split happens early then dichorionic

• if it happens later then monochorionic

• more often mono - risky

describe the effect of older parental age

• older mothers have higher risk of complications including down syndrome

describe the effect of younger prenatal age of mothers and fathers

• increased risk of some pathologies such as asthma and schizophrena

• likely due to nutritional effects as teh parents themselves are still developing

what are the main types of diognosis of developmental pathologies

• preconception carrier screening

• preimplantation genetic screening/diagnosis

• prenatal

• neonatal

describe preconception carrier screening

• predictive not diagnostic

• genetic test for gene mutations - commonly inherited reessive and serious conditions

what are some examples of diseases that are tested for in precarrier screening

• cystic fibrosis

• fragile x syndrome

• spinal muscular atrophy

what is preimplantation genetic screening used for

• used in ART to test for aneuploidy

how is preimplantation genetic screening done

• biopsy from trophectoderm of blastocyst

FISH or NGS sued to determine chromosome copies

what is preimplantation genetic diagnosis used for

• serious inherited genetic disorders such as trisomy 21. CF, huntingtons, fragile X, muscular atrophy

what is important to do along side preimplantation genetic diagnosis

genetic counseling

what are examples of prenatal diagnostic techniques

ultrasound

foetal DNA testing

CVS - chronic villus sampling

describe prenatal ultrasound

11-14 weeks

measure fluid filled subcutaneous space at nape of neck for indication of downsyndrome and other abnormalities

also done at 18-20 weeks

describe prenatal foetal DNA testing

• circulating foetal cells or cell free DNA from foetus can be sampled from mothers blood

• can be done in 10th week of pregnancy

• next gen sequencing for chromsome anueploidy and copy number variatons

describe prenatal amniocentesis

• done if there is an abnormal ultrasodun after 15 weeks of gestation

• sample amniotic fluid which contains foetal cells to test for genetic disorders, chromosomal abnormalities and foetal maturitiy

what is the risk of prenantal amniocentesis

1% risk of micarriage

what is some examples of neonatal diagnosis

• apgar score

• physical exams

• hearing test

• guthrie test

what is teh apgar score

done 1-5 mins after birth to test msucle tone, appearance, pulse, respiration

what is included in neonatal examinations

• hip dysplasia

• undescended testes

• neural reflexes

• heart sounds

what is the guthrie test

• screens for metabolic disorders 48 hours after birth

what metabolic disorders does the guthrie test, test for

• amino acid disorders

• fatty acid oxidation disorders

• congential hypothyroidism

• congentia adrenal hyperplasia

• CF

• galactosaemia

• Severe combined immunodeficiency

• biotinidase deficiency