Congenital Abnormalities.
- Apparent in 1/50 of newborn infants.
2. Accounts for 20-25% of all perinatal deaths and childhood (upto 10y/o)
How much do genetic factors account for congenital abnormalities?
40%
What are the classifications of congenital abnormalities?
- Malformation
- Disruption
- Deformation
- Dysplasia
- Sequence
- Syndrome
- Association
(MDDD single)
(SSA multiple)
What is malformation?
- Primary structural defect
2. Usually single organ showing multifactorial inheritance
What is disruption?
- Secondary structural defect of organ/tissue.
- Typically caused by ischaemia/infection/trauma
- Not genetic, but has predispositions
What is deformation?
- Distortion of a structure due to abnormal mechanical force.
- Occurs usually in late pregnancy - usually has good prognosis
What is syndrome?
- Consistent pattern of abnormalities with specific underlying cause.
What is a sequence?
- Multiple abnormalities caused by a primary factor.
2. Initial factor could be genetic
What is dysplasia?
- Abnormal organisation of cells in tissue
What is association?
- Non-random abnormalities that are not explained by a syndrome.
- Unknown cause.
What is metacentric?
If centromere in the middle exactly
What is submetacentric?
If centromere is just off middle
If the centromere is not on the middle, what is it called?
Acrocentric (small ends of chromatids called satellites\0
When chromosomes are stained, they become banded. What are the short and long arms called?
Short arm = p
Long arm = q
What are the types of chromosomal abnormalities?
- Numerical - aneuploidy - loss/gain of chromosome
- Structural - translocations/deletions/insertions/inversions/rings
- Mosaicism - different cell lines
What are the autosomal aneuploidies?
- Monosomy - loss of one chromosome - almost always lethal
- Trisomy - gain of a chromosome - tolerable
- Tetrasomy - gain of 2 chromosomes - tolerable
What is trisomy 21?
Down Syndrome
What are the clinical features of Down’s syndrome?
- Newborn period - severe hypotonia/sleepy/excess nuchal skin
- Craniofacial - big tongue, small ears, epicanthic folds, Brushfield spots, gap between upper and lower eyelids.
- Limbs - single palmar crease, wide gap between 1st and 2nd toes
- Cardiac - atrial & ventricular septal defects
- Short stature
What are 2 conditions that Down’s syndromes have increased risk of?
Leukaemia and Alzheimers.
What causes Down’s syndrome?
Non-disjunction of homologous chromosomes in meiosis 1.
What is the chromosomal abnormality spread of Down’s syndrome?
95% Trisomy (21)
4% Translocation (Robertsonian Translocation)
1% Mosaicism
If mosaicism is the cause of Down’s syndrome, how does this happen? How severe does it affect children?
- Mitotic non-disjunction in the zygote
2. Children less severely affected
Give an example of Monosomy X.
Turners Syndrome
Give 2 signs that can be detected in the 2nd trimester for Turners syndrome.
- Generalised oedema
2. Swelling in the neck
Give some clinical features of Turners syndrome.
- Short 4th metacarpals
- Webbed neck
- Aorta defect
- Normal intelligence
- Short stature in adults
- Ovarian failure
How is Turners treated?
With oestrogen replacement (2ndary sex characteristics and prevents osteoporosis)
How is Turners caused?
X/Y chromosome lost
Usually in paternal meiosis (80%)
Other causes include:
Ring chromosome
Single arm deletion
Mosaicism
Give an example of polysomy X in males.
Klinefelters
Describe Klinefelters.
1/1000 live Mal births
Clinical features:
- Clumsiness
- Verbal learning difficulty
- Tall
- 30% develop gynaecomastia.
- Risk of leg ulcers
- Osteoporosis
- Breast carcinoma in later life.
What is dosage compensation?
Process by which species equalise gene expression between different sexes.
How does dosage compensation work in humans?
In females, one X chromosome is inactivated.
What is a Barr body?
Region of density in a cell denoting a switched off X chromosome.
Explain how chromosome doesn’t equal gender.
- In embryonic stage of development, we are initially sexually indifferent.
- Whether we become males or females depends on SRY gene on Y chromosome.
- If SRY translocated from Y chromosome to X chromosome (during meiosis), there is an XX individual but male because one X chromosome has SRY.
- If SRY part of Y chromosome gets deleted, XY but female as no SRY.
Give examples of genomic disorders.
- Di George syndrome
2. Cri du Chat syndrome