Abnormalities of human development

Question 1

What are the different (broad) causes of abnormalities of development?

Answer 1

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

Question 2

What results from division or fusion of conceptuses?

Answer 2

Identical siblings – one conceptus splits into 2/3 identical individuals

Conjoined twins – Incomplete inner cell mass separation of one conceptus

Chimerism – two genetically distinct conceptuses fuse into one individual with different lineages (Chimeras may have visible blaschko’s lines if different skin colour lineages)

Question 3

What results from mosaicism?

Answer 3

Mosaicism – Non-disjunction, different chromosomal patterns between cells (some aneuploid)

Can compensate by distributing aneuploid cells into placenta while normal cells form the embryo itself (observed in some pregnancy)

Eye colour – Chromosome 15. Differentiation about day 22 pf (event must happen prior), will causes heterochromia

Question 4

What results from aneuploidy of the sex chromosomes?

Answer 4

Males
Klinefelter’s – XXY Infertility, learning difficulties
XXY – XXY Syndrome ‘Super males’ Learning difficulties

Females
Triple X syndrome – XXX Learning difficulties
(More of X and Y can be present – XXXX, XYYY etc – present more severely)

Also Turner’s Syndrome (X0) - infertility, NO learning difficulties (X0 is the ONLY chromosome loss aneuploidy compatible with life)

Question 5

What results from aneuploidy of autosomal chromosome?

Answer 5

Down’s syndrome (21) – 1/1000 live births, heart problems determine survival

Edward’s syndrome (18) – 1/6000 live births, most die pre-birth, lifespan <2 weeks

Patau’s syndrome (13) – 1/15,000 live births, more die pre-birth, lifespan <1 Year

All other autosomal chromosome aneuploidies have been detected in spontaneous pregnancy loss tissues, EXCEPT chromosome 1. Ch1 is largest most important chromosome in human, loss would lead to pregnancy loss within days post fertilisation (will not be detected)

Question 6

What can result from chromosomal translocation?

Answer 6

XX male – XY translocation, translocation of SRY gene, phenotypical male with XX

Autosomal translocation – Linked with tumour development
e.g. Burkitt’s lymphoma (Promotor translocated to oncogene)
CML (BCR-ABL from Philadelphia chromosome)

Question 7

Describe the result of KIT 1 Mutation

Answer 7

Characteristic piebaldism pattern

Question 8

Describe Holt-Oram syndrome

Answer 8

Holt-Oram syndrome (TBX 5 Mutation) – Heart/Hand defects
Atrial septum defects
Range of hand abnormalities (E.G. Thumb develops as finger)
Symptoms not identical (even within opposite hands in same individual)

Question 9

Describe achondroplasia

Answer 9

Achondroplasia – Gain of function mutation in FGFR3

Cartilage isn’t being converted to bone – Isn’t able to grow

Question 10

How common are major and minor dysmorphologies in development?

Answer 10

Major – 3% of pregnancies, 25% of infant deaths

Minor – 15% of pregnancies (little health impact)

Question 11

What infectious agents are teratogens? What do they cause?

Answer 11

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

Question 12

What physical agent is a teratogen? What does it cause?

Answer 12

Ionising radiation – Microcephaly, spina bifida, cleft palate, limb defects

Question 13

What chemical agents are teratogens? What do they cause?

Answer 13

Thalidomide – Limb defects, heart malformations
Lithium – Heart malformations
Amphetamines – Cleft lip/Palate, heart defects
Cocaine – Growth restriction, microcephaly, behavioural abnormalities
Alcohol – FAS, Maxillary hypoplasia, Heart defects

Question 14

When do teratogens tend to exert their effect? Why?

Answer 14

Early in development, most of the primary structures of the body’s systems are being formed early in development

Question 15

What is a malformation of the digits?

Answer 15

Polydactyly - Ordinarily forelimb bud appears d27/8 and hindlimb bud d29. From there five digital rays appear and develop into the digits, in many cases of polydactlyly extra digital rays appear and then undergo normal digit patterning (Formation is normal only quantity is abnormal)

If polydactyly due to abnormal polarisation (increased symmetry) then patterning will be abnormal - little finger may resemble thumb and extra webbing may be present. This occurs due to mutation of Sonic hedgehog (Shh) the polarising factor for upper limb development.

Question 16

What causes thalidomide’s malforming effects?

Answer 16

Caused deformed limbs, eyes, hearts, alimentary and urinary tracts as well as blindness and deafness all possible. (Upper limb most pronounced) 25 days pf – 28 pf it exerts its effects. This is due to prevention of BLOOD VESSEL formation.

Amelia – Prolonged exposure, rapidly developed blood vessels not forming leading to widespread cell death and signalling lost

Phocomelia – Short exposure, rapidly developed blood vessels not forming (short term) uniform cell death and partial loss of AER signalling – THIS RECOVERS

Question 17

What is the cause of spina bifida?

Answer 17

Faulty neurulation (posterior neuropore not closed) leads to incomplete fusion of spinal column, and vertebral column. Presents within 4 weeks post fertilisation

Question 18

What are the categories of spina bifida?

Answer 18

Spina bifeda occulta – Least severe, cluster of hair marks but neural tissue relatively unaffected

Meningocele – CSF filled protrusion due to incomplete vertebral column closure

Myelomeningocele – Spinal cord protrudes due to incomplete vertebral column closure

Question 19

What is the effect of folate on the incidence of spina bifida?

Answer 19

Folate decrease incidence by 70% - give 3 months before conception (final follicular development, ensures folate will be present in egg involved in fertilisation)

Question 20

What is anencephaly?

Answer 20

Anencephaly – 1-8/10,000 (More common in female foetus) Defect in skull and brain development (Anterior neuropore closure incomplete) 22-23 days post fertilisation.

Question 21

What causes a cleft lip or palate?

Answer 21

5 weeks Nasal pits lateral on front of face, eyes at side of face. Over next few weeks move medially and down.

Grooves exist in early maxillary prominence, in normal development furrow is filled in has the tissue moves to its final position, in abnormal development it persists (persistent labial groove) and as the medial nasal prominences merge the area of the of the philtrum lateral is made completely separate.

Cleft palate is due to abnormalities in fusion of halves of palate

Question 22

Why is surgery very successful in cleft lip?

Answer 22

Extremely quick cell proliferation in infants – wound healing is extremely effective (little scarring)

Question 23

What is Respiratory distress syndrome?

Answer 23

Respiratory distress syndrome (Surfactant deficiency syndrome)

Not enough surfactant – cannot open lungs

Surfactant produced 26 weeks post fertilisation (24 GA)

100% GA 24 Weeks have RDS
50% at 26-28 Weeks have RDS
25% at 30-31 Weeks have RDS

Question 24

How can respiratory distress syndrome be partly prevented?

Answer 24

1 injection of glucocorticoids 2-3 days before delivery increased in utero production of surfactant to reduce respiratory distress in preterm births