3. Abnormalities of human development

Question 1

What is a cleft palate and what are the problems associated with this?

Answer 1

There is a connection between the mouth and the nasal cavity, with the potential to cause problems with breathing, eating and drinking. Food or liquid could enter the sinuses of the face as well, and cause further problems.

Question 2

What does a cleft palate suggest about the mechanisms that are involved in normal development

Answer 2

The cleft palate suggests that the palate forms as two separate components on each side of the mouth, and grow to the centre, meet, and then fuse to form the usual roof of the mouth (hard palate)

Question 3

What is a teratology or dysmorphology?

Answer 3

A change in the basic structure of a tissue

Question 4

What can the causes of developmental abnormalities be classed as?

Answer 4

Genetic – 30%
Environmental – 15%
Multifactorial – 55%

Question 5

What are some examples of external causes that can cause abnormalities in development?

Answer 5

Teratogens
Infectious agents
Physical agents
Chemical agents

Question 6

What is a Teratogen?

Answer 6

Any agent that can disturb the development of an embryo or fetus

Question 7

Give examples of infectious agents that can cause developmental abnormalities. What does each agent cause?

Answer 7

o Rubella virus – Cataracts, glaucoma, heart defects, deafness
o Herpes simplex virus – Microphthalmia, microcephaly, retinal dysplasia
o HIV – Microcephaly, growth restriction
o Syphilis – Mental retardation, deafness
o Zika virus – microcephaly

Question 8

What are examples of physical agents that can cause developmental abnormalities and what would they cause?

Answer 8

X-rays & other ionising radiation – Microcephaly, spina bifida, cleft palate, limb defects

Question 9

Give examples of chemical agents that can cause developmental abnormalities. What does each agent cause?

Answer 9

o Thalidomide – Limb defects, heart malformations
o Lithium – Heart malformations
o Amphetamines – Cleft lip and palate, heart defects
o Cocaine – Growth restriction, microcephaly, behavioral abnormalities
o Alcohol – Fetal alcohol syndrome, maxillary hypoplasia, heart defects

Question 10

When are tissues most vulnerable during a pregnancy? What is an exception to this?

Answer 10

During the first trimester

The CNS remains vulnerable for the whole of development

Question 11

Why are the first few weeks of development unaffected by teratogens?

Answer 11

If teratogens affect development at this point, they completely derange development
The foetus would just be miscarried – this is not a teratogenic effect

Question 12

What are the three types of non disjunction of chromosomes?

Answer 12

Failure of a pair of homologous chromosomes to separate in meiosis I, failure of sister chromatids to separate during meiosis II, and failure of sister chromatids to separate during mitosis

Question 13

What is mosaicism?

Answer 13

Mosaicism (non disjunction) – differences in genetic makeup between cells within one individual
E.g. two different coloured eyes

Question 14

What is chimerism?

Answer 14

here, there are fused multiple zygotes (non-identical zygotes)
The individual that is born has two different chromosomal makeups

Question 15

What are some XY linked chromosome number abormalities?

Answer 15

· Klinefelter’s syndrome (XXY) – Decreased fertility. This is where boys are born with an extra X chromosome
· XXYY, XXXY, XXXYY, etc. – severe forms related to KS
· XYY (XYYY) – very variable (taller, learning problems)
· XXX – Limited effects, some mental changes
· XXXX, XXXXX – More severe effects

Question 16

What are some diseases caused by problems with autosomal chromosomes?

Answer 16

NOTE: these are all trisomies

• Down’s syndrome (ch21) – (affects 1/1000 live births) heart problems determine survival
• Edward’s syndrome (ch18) (1/6000 live births) – most die before birth, very few live-born, live ≤2 weeks
• Patau’s syndrome (ch13) (1/15,000 live births) – most die before birth, 80% live-born die within 1 year

Question 17

What happens if there are too few chromosomes (both XY and autosomal)?

Answer 17

XY linked
– Turner’s syndrome - X0
– Female, short stature, infertile
– Y0 is not viable – boys need the X chromosome

• Autosomal
– No complete losses are viable
– Partial chromosome loss syndromes are known and characterised

Question 18

What are XX males

Answer 18

XX males that are SRY-positive (have the sex determining region Y gene) have two X chromosomes, with one of them containing genetic material from the Y chromosome, making them phenotypically male but genetically female
Caused by an XY translocation with the SRY region joining an X chromosome

Question 19

What is Piebaldism?

Answer 19

A pale patch of skin on the abdomen, and a pale streak on the forehead
Caused by a mild mutation of the KIT receptor
The mutation is found in both humans and animals

Question 20

What is Holt Oram syndrome? What is it caused by?

Answer 20

The structure of the heart doesn’t develop properly. The divisions between the chambers of the heart do not develop properly. We see a lack of symmetry in the left and right hand
Due to a mutation in TBX5 (TF)

Question 21

What is Achondroplasia?

Answer 21

• Gain of function mutation in FGFR3
• Achondroplasia means “lack of cartilage”
• Defect is in conversion of cartilage to bone
• There is a lack of bone growth
• It gives rise to achondroplastic dwarfism. The long bones of the legs in particularly haven’t developed as they should

Question 22

What is polydactly?

Answer 22

Usually just an extra digit
The webbing between fingers may stay put in some instances of polydactyly. This indicates that the extra digit has formed too close to one of the digits
Some digits (e.g. the little finger) can look more like a thumb digit

Question 23

Outline the development of the limbs

Answer 23

The forelimb bud appears at day 27/28, and the hindlimb bud at day 29. The buds grow out from lateral plate mesoderm rapidly under the control of special signalling regions.
The digits are fully formed and patterned by day 56.

Question 24

How does a cleft lip/palate occur in development?

Answer 24

• Faces start developing with the eyes either side of the head (near to the ears)
• The nose also starts off developing relatively laterally
• The movement of structures medially means that clefting occurs in the middle of the face

Question 25

What can be done after birth about a cleft lip/ palate?

Answer 25

We can do something about the cleft lip after birth (surgical repair). The cleft palate MUST be mended: if you don’t, food can enter the nasal cavity, and potentially enter the lungs

Question 26

What is spina bifida?

Answer 26

- Literally means twin-spine - Generally, the parts of the body BELOW where the lesion is are most greatly affected - The nervous system is often involved, so the parts of the body below the lesion won’t function properly

Question 27

What are the three different forms of spina bifida?

Answer 27

1. There is a hidden form (spina bifida occulta), where the CNS is okay, but the spine itself hasn’t formed correctly. There may be a small patch of hair over the lesion. 2. There is a swelling that is fluid filled (seen in meningocele which is a sac protruding from the spinal cord but does not have any neural tissue) 3. A swelling that contains nervous tissue (in myelomeningocele). This is the SEVERE form. The nerves below this lesion will be damaged, and may not function very well (if at all).

Question 28

What happens during development to cause spina bifida?

Answer 28

- There is a bulge in the CNS, which stops the spine forming entirely over that region. This takes place within the first 4 weeks post-fertilisation - Formation of the CNS is the formation of a tubular structure but in spina bifida, the tube does not completely seal up (neurulation). - So spina bifida = faulty neurulation

Question 29

What can be given to decrease the incidence of spina bifida?

Answer 29

Folic acid - decreases incidence by 70%

Question 30

When should folic acid be given and why?

Answer 30

* Folic acid should be given 3 months prior to conception (12 weeks running up to pregnancy) * The egg does most of its development before it is selected as the main follicle within these 3 months * At this point, the egg is taking up nutrients and building its reserves for development

Question 31

What is anencephaly?

Answer 31

* Literally means no head * The top part of the head doesn’t develop properly * Female babies are affected more commonly than males

Question 32

How does anencephaly develop?

Answer 32

* Develops at around 23 days post fertilisation * The anterior neuropore can be seen at the top of the developing embryo. The posterior neuropore can be seen at the tail end. These are the two structures that do not fuse properly to develop the CNS tube. * This gives rise to either anencephaly or spina bifida, depending on which neuropore is affected

Question 33

What did thalidomide cause in neonates?

Answer 33

* The limbs were affected primarily (upper limbs more common, but lower limbs were also affected) * In addition, deformed eyes and hearts, deformed alimentary and urinary tracts, blindness and deafness

Question 34

What is thalidomide now used to treat?

Answer 34

It is now used in some leprosy and cancer treatments

Question 35

How did thalidomide cause these abnormalities?

Answer 35

* Thalidomide affects rapidly developing blood vessels, notably those of upper limbs * Therefore, the growing limb cannot grow. It is devoid of nutrients and truncates prematurely. If the exposure is short, it is PARTIAL limb loss that results. Longer exposure can result in complete limb loss * Blood vessel affects can be generic, hence the range of effects observed

Question 36

When was thalidomide taken during pregnancy?

Answer 36

Morning sickness is worst in the first trimester so this is when thalidomide was taken