Genetics (paeds)

Question 1

FAMILIARISE YOURSELF WITH PHOTOGRAPHS OF:

Answer 1

Downs, Edwards, patau
Williams 
Turners 
Fragile X 
Kleinfelters 
Duchenne and Becker 
Pradra-willi 
Angelmans

Question 2

What’s a rule of thumb for knowing whether a disorder is autosomal dominant or recessive?

Answer 2

AR = are all ‘metabolic’ e.g. CF, apart from inherited ataxias e.g. Friedreich’s ataxia

AD = all ‘structural’ e.g. HD, apart from Gilbert’s, hyperlipidaemia type 2 (though both can be recessive)

Question 3

What are all the physical features of common genetic conditions?

Answer 3

Downs (trisomy 21)
Slanting palpebral fissures
Flat occiput 
Epicampal folds 
flat zygomatic arches
upward/outward slanting eyes
small mouth with protruding tongue
small head/ears
short neck 

Wide short hands/fingers, single palmar groove; deep groove between 1st/2nd toes

Patau syndrome (trisomy 13)
Microcephalic, small eyes
Cleft lip/palate
Polydactyly
Scalp lesions

Edward's syndrome (trisomy 18)
Micrognathia
Low-set ears
Rocker bottom feet
Overlapping of fingers

Fragile X
Learning difficulties
Macrocephaly
Long face
Large ears
Macro-orchidism

Noonan syndrome
Webbed neck
Pectus excavatum
Short stature
Pulmonary stenosis

Pierre-Robin syndrome*
Micrognathia
Posterior displacement of the tongue (may result in upper airway obstruction)
Cleft palate

Prader-Willi syndrome
Hypotonia
Hypogonadism
Obesity

William's syndrome
Short stature
Learning difficulties
Friendly, extrovert personality
Transient neonatal hypercalcaemia
Supravalvular aortic stenosis

Question 4

What antenatal genetics tests can be done?

Answer 4

11-14wk scan - if consented to screen for Down’s/Edward’s/Patau’s, can comment on nuchal translucency - if likely changes - maternal blood test - if high risk (1/2-1/150 chance) then CVS (wk 11-14) or amniocentesis (wk 15) offered and karyotyping of foetal cells is done

20wks scan - more abnormalities detectable e.g. cardiac abnormalities, spina bifa, exomphalos etc - microarray testing may be offered to find other genetic conditions

Question 5

What are some chromosomal genetic conditions?

Answer 5

Can be an increase in number = polyploidy; decrease in number = aneuploidy

Translocations - balanced (may be phenotypcially normal as have correct number of chromosomes) or unbalanced (5% of Down’s have a robertsonian translocation between Ch21-14 - need to test parents here as may have balanced translocations)

Lots of changes are not survivable - cause for lots of miscarriages

Question 6

What are the three survivable trisomy’s?

Answer 6

Down’s - T21
Edward’s - T18
Patau’s - T13

Question 7

What are the features of Down syndrome?

Answer 7

775 babies/year/UK

Hypotonia + low birth weight/length

Face - flat zygomatic arches, upward/outward slanting eyes, small mouth with protruding tongue, small head/ears, short neck

Wide short hands/fingers, single palmar groove; deep groove between 1st/2nd toes

Global developmental delay

Short attention span/impulsivity/slow learning/variable communication

Question 8

What other conditions are associated with Down’s?

Answer 8

AVSD + other cardiac malformations

Coeliac, hirschprung’s, hypothyroidism, Alzheimer’s

Question 9

What are the features of Edward’s?

Answer 9

Mosaic and partial forms = less severe (only some cells are T18) - 7/10 will survive for at least 1yr and possibly into adulthood

Low birth weight, small head/jaw/mouth, long overlapping fingers with underdeveloped thumbs, low set ears, smooth feet, cleft lip/palate, exomphalos

Breathing/feeding/immunity problems, heart/kidney/bone problems

Question 10

What are the features of Patau’s?

Answer 10

Most die within 1st year; if mosaic or partial then may survive >1yr

Low birth weight, cleft lip/palate, small or absent eyes, microcephaly, ear and scalp malformation, polydactyly

Question 11

What are the key feature of autosomal dominant inheritance?

Answer 11

Each child has a 50% risk rate of inheriting mutation

No ‘skipped’ generations

M:F equally affected (unless sex limited)

M-M transmission possible

Possible variable penetrance (being expressed in the first place) + variable expression (the degree to which it is expressed when it is penetrant)

Possible gonadal mosaicism (some gametes changes, some dont)

2x unaffected patents - could be de novo mutation; if they have more than one affected child - could be gonadal moasic

Question 12

What are some examples of AD conditions?

Answer 12

Adult PKD 
Familial hypercholesterolaemia 
MArfan syndrome 
Huntington disease 
Familial breast and ovarian cancers

Question 13

What are the key features of autosomal recessive inheritance?

Answer 13

Two germline mutations (one from each parent) to inherit the disease - heterozygous carriers

1/4 recurrent risk for siblings

2/3 carrier risk for unaffected siblings

Unless Hx of consanguinity then often only one generation affected

Question 14

What are some examples of AR conditions?

Answer 14

CF - carrier prevalence = 1/25 therefore affected = 1/2500; most picked up on heel prick

Haemochromatosis
Phenylketonuria (PKU)

Question 15

What are the features of X-linked inheritance?

Answer 15

Genes on X chromosome

M>F affected

F = carriers - 50% sons affected + 50% daughters are carriers

All daughters of affected males are obligate carriers

None of the offspring of affected males have the disorder

Possible de novo mutation + gonadal mosaics

Question 16

What are some examples of X-linked recessive inheritance?

Answer 16

Duchenne + Becker Muscular dystrophy (although X-linked, female carriers are still affected, just to a lesser degree); Becker = in-frame deletion so less severe, no premature stop codons unlike Duchenne’s

Haemophilia (A = 1/5,000-10,000, factor VIII; B = 1/40,000, factor IX)

Fragile X

Question 17

What is Turner’s syndrome?

Answer 17

45 X0 - part or complete absence of X chromosome in women

Physical features: short, webbed neck, low set ears, low hairline, cubitus valgus (forearm angled away from body a greater degree than normal), swollen hands and feet as newborn

Reproductive features: amenorrhoea, no breast development, infertility

Cardiac: bicuspid aortic valve, coarctation (most common), aortic valve stenosis

Other: horseshoe kidney, ADHD, hypothyroidism, DMT1

Question 18

What is Fragile X syndrome?

Answer 18

X-linked dominant inheritance

1/2000 males (80% undiagnosed), 1/6000 carriers; females dont always have clinical features but may have some LD

Trinucleotide expansion in FMR1 gene - fails to produce enough fragile X mental retardation protein which is required for the development of normal connections between neurons

Physical features: large protruding ears, long face, high arched palate, hyper-extensible joints, flat feet, hypotonia

Psych/neuro: spectrum from severe LD-normal IQ, related to number of repeats; memory problems; strong associations with ASD (15-60%) and ADHD; increased seizure risk seizures

Question 19

What is Klinefeler syndrome?

Answer 19

47, XXY

Symptoms are subtle but may present with hypotonia and weakness as infants; taller with less muscle coordination with age

Puberty - less testosterone produced = less muscular, less facial and body hair, broader hips, breast tissue, smaller testicles weaker bones, lower energy

Often infertile

Question 20

What is multifactorial inheritance and an example?

Answer 20

Genes + environment = condition

Probably lots of diseases are multifactorial in this way

e.g. neural tube defects - increased risk if affected parents and siblings but not very large (2-10% relative risk) + environmental factors e.g. low maternal folic acid or maternal DM = increased risk

Question 21

What is genomic imprinting?

Answer 21

Mostly, both copies of genes are expressed, in some they are maternally or paternally expressed = imprinting

Question 22

What is Prader-Wili syndrome?

Answer 22

Deletion of a region on Ch15q from the paternal inherited chromosome, or due to maternal uniparental disomy (child inherits both of mums Ch15’s, not one of each)

Presentation: neonatal hypotonia, poor feeding; moderate mental retardation, hyperphagia + obesity, small genitals

Question 23

What is Angelman’s syndrome?

Answer 23

Deletion of a region on Ch15q from the maternal inherited chromosome, or due to paternal uniparental disomy (child inherits both of dad’s Ch15’s, not one of each)

Presentation: ‘happy pupet’ = unprovoked laughing and clapping, microcephaly, mental retardation, seizures, ataxia, broad gait

Question 25

What are the features of mitochondrial inheritance?

Answer 25

All Mt come from mother

All off spring of an affected or carrier female at risk of being affected

All daughters of an affected or carrier female are at risk of being a carrier

Affected males cannot pass to children

Example: MELAS (mitochondrial encephalopathy, Lactic acidosis, stroke-like episodes)

Question 26

What is the process of predictive genetic testing?

Answer 26

Not generally done in children as not autonomous

Should be done over several visits in a 3-stage protocol = interview about motivations then blood test then a discussion of results

May want to test in known familial adenomous polyposis (FAP) as polyps that eventually turn cancerous are known to start developing young and children may need prophylactic surgery

Question 26

What is Williams syndrome?

Answer 26

Cocktail party personality

Dysmorphic features - ‘Elvin’ appearance

Mostly Caucasian with blue eyes