Genetic Disorders

Question 1

What are 3 trisomy chromosomal syndromes and their names?

Answer 1

Trisomy 13 - Patau’s

Trisomy 18 - Edward’s

Trisomy 21 = Down’s

Question 2

What are some features of Patau’s syndrome?

How would you Ix for Patau’s and what is it’s prognosis?

Answer 2

Patau’s = Trisomy 13 (1:14000)
-> 80% die in 1st month of life, 90% by 1 year old

Features:

• Microcephaly and brain defects
• Micropthalmia (small eyes) and other eye defects
• Cleft lip/palate
• Polydactyl
• Omphalocele/Gastroschisis

Ix:

• > USS analysis in 2nd trimester, combined test in T1
• > Chromosomal analysis from amniocentesis/cffDNA (NIPT)

Question 3

What are some features of Edward’s syndrome?

How would you Ix for it and what is its prognosis?

Answer 3

Edwards = Trisomy 18 (1:14,000)
-> Many die in infancy but prolonged survival is possible

Features:

• LBW
• Small mouth and chin
• Low set ears
• “Rocker bottom” feet
• Overlapping fingers
• Intellectual disability
• Cardiac, renal and GI abnormalities
• Associated with omphalocele/gastroschisis

Ix:

• > USS analysis in 2nd trimester
• > chromosomal analysis fro cffDNA/amniocentesis (NIPT)

Question 4

What are some features of Down’s syndrome?

What is the risk of Down’s and the cause of the chromosomal pathogenesis?

Answer 4

Trisomy 21 = Down’s

• > Risk increases as maternal age increases (i.e. 1:1500 in 20yM vs 1:100 in 40yM)
• > Most common genetic cause of intellectual disability

Features:

• Characteristic facies (up slanted palpebral fissures, epicanthic folds, flat occiput and nasal bridge, brushfield spots in iris)
• Congenital cardiac abnormalities in 40% (commonly AVSDs)
• Sandal gap
• Single palmar crease
• Hypotonia and short neck
• Short stature
• Omphalocele/Gastroschisis

Cause:
> 94% due to meiotic non-disjunction
> 5% due to translocation (Robertsonian, usually of X21 to X14)
> 1% due to mosaicism (milder phenotype as some cells normal and some w T21)

Question 5

What are the medical problems that children with Down’s syndrome may present with i) at birth, ii) later in life

Answer 5

i) at birth
- > Congenital heart defects (40%, AVSD)
- > Duodenal atresia
- > Hirschprung’s disease
- > Omphalocele/Gastroschisis
- > Associated congenital conditions = Bloom, Kostmann’s, NF1, Li Fraumeni, Fanconi

ii) later in life
- > Learning difficulty, delayed motor milestones
- > Secretory otitis media (75%)
- > Obstructive sleep apnoea (50-75%)
- > Visual impairment (25-50%)
- > Joint laxity (Atlanta-axial instability - NOTE to screen for this if they are doing high risk sports)

-> Increased chance of: Leukaemia (AML&raquo_space;» ALL), Epilepsy, Hypothyroidism, Early onset Alzheimer’s

Question 6

How would you manage Down’s syndrome? (immediate, later and support)

Answer 6

Mx:

Immediate:

• > ECHO for AVSD and evaluation by paediatricians for duodenal atresia
• > Genetic counselling (review results and further pregnancy risk)
• > Early intervention programmes if developmental delay present (physio, OT for fine motor and self care, SALT for speech)

Later:

• > Annual hearing tests, thyroid function, ophthalmic evaluation until 5y, then every 2y
• > Educational support measures and plans
• > Hb monitoring for IDA
• > Monitoring for OSA symptoms and growth patterns

Support:
-> Local DS Clinic, parent support groups, DS association

Question 7

What is imprinting and what are 2 examples of genetic imprinting syndromes? How may it occur?

Answer 7

Imprinting = when the expression of a gene is influenced by the sex of the parent who has transmitted it

Prader-Willi –> lack of PATERNAL PWS region on X15 (del15q)
Angelmann –> lack of maternal PWS region on X15

Causes:

• De novo deletion in the child of maternal or paternal chromosome 15
• Uniparental disomy 2 copies of X15 from mother or father only

Question 8

How does Prader-Willi syndrome present?

What are some features of Angelmann syndrome?

Answer 8

Prader-Willi:

• > Hypotonia
• > Hyperphagia (+Obesity)
• > Hypogonadism
• > Learning disability
• > Epicanthal folds, flat nasal bridge, upturned nose

note: Mx can involve growth hormone if evidence of growth failure and management of feeding and obesity

Angelmann:

• > cognitive impairment
• > ataxia
• > epilepsy (myoclonic seizures)
• > abnormal facial appearance

Question 9

What is Turners syndrome and its features?

What are some aspects of management, and how may they present in the neonatal period?

Answer 9

X0 (45)
-> 1:2500 - over 95% result in early miscarriage

May present in neonatal period with:

• > Pyloric stenosis
• > Cardiac problems (aortic coarctation, bicuspid aortic valve)
• > Renal anomalies
• > Cystic hygroma (back of neck)

Mx = growth hormone therapy and oestrogen replacement at time of puberty

Features:

• Short stature
• Webbed neck
• Cubitus valgus (wide carrying angle)
• Infertility
• Cardiac abnormalities (BISCUSPID AORTIC VALVE > AORTIC COARCTATION - hear ESM over aortic valve, weak fems)
• Low IQ
• Delayed puberty
• Hypothyroidism
• Omphalocele/Gastroschisis

Question 10

What is Klinefelter’s syndrome and its features?

Answer 10

XXY (47)
-> 1/2:1000 males

Features:

• Tall stature
• Gynaecomastia
• Infertility
• Hypogonadism (small testicles)
• Normal IQ and appearance

Question 11

What is Fragile X syndrome and its features?

What is the aetiology?

Answer 11

X-linked

• > 1:4000
• > CGG Trinucleotide repeat-expansion mutation of FMR1 gene
• > Exhibits genetic anticipation where can be more severe as it gets passed down generations

Features:

• Macrocephaly and characteristic facies (large, low-set ears, long, thin face, prominent forehead)
• Macroorchidism
• ADHD, autism
• Complications = MITRAL VALVE prolapse
• Low IQ of 20-80 (2nd most common genetic cause after Down’s)