Paeds: Common chromosomal disorders

Question 1

Klinefelters syndrome: Affects

Answer 1

1/600-1/800 boys

Question 2

Klinefelters syndrome: Majority caused by

Answer 2

Non-disjunction during maternal oogenesis

Question 3

Klinefelters syndrome: Boys with Klinefelters syndrome

Answer 3

• Enter puberty normally, but by mid-puberty the testes begin to involute and the boys develop hypergonadotrophic hypogonadism with decreased testosterone production (often tall and may develop feminine body build).
• Testes are small in adult life and men with Klinefelter syndrome are generally infertile (azoospermia).
• Gynaecomastia develops at puberty in >50%
Boys with Klinefelter syndrome typically have an IQ ~15 points lower than their siblings.

Question 4

Klinefelters syndrome: Diagnosis by

Answer 4

• Chromosome analysis
Many boys remain undiagnosed throughout childhood, with the diagnosis only coming to light during investigation of infertility.

Question 5

Patau Syndrome (trisomy 13)

Incidence

Answer 5

1/6000 births

Question 6

Patau Syndrome (trisomy 13) Causes

Answer 6

75% caused by non-disjunction during maternal oogenesis
20% Robertsonian translocation
5% result from mosaicism

Question 7

Patau Syndrome (trisomy 13) Diagnosis

Answer 7

Trisomy 13 is usually diagnosed by antenatal US scan, since the majority of affected babies have multiple congenital anomalies

Question 8

Patau Syndrome (trisomy 13) Typical malformation sinclude

Answer 8

Holoprosecncephaly
SGA
Microcephalic 
Micophthalmia
Cleft lip/palate
Congenital heart disease e.g. ASD or VSD
Renal anomalies e.g. fused kidneys
Postaxial polydactyly
Together with severe/profound mental retardation

Question 9

Patau Syndrome (trisomy 13)Diagnosis is confirmed by

Answer 9

A chromosome analysis (additional chromosome 13)
Most cytogenetics laboratories are able to offer a rapid analysis e.g. interphase FISH, to confirm the diagnosis quickly.

Question 10

Edwards Syndrome (trisomy 18) Incidence

Answer 10

1/8000 births

Femal excess

Question 11

Edwards Syndrome (trisomy 18) Majority caused by

Answer 11

Non-disjunction during materanal oorgenesis

Question 12

Edwards Syndrome (trisomy 18) Presentation

Answer 12

Presentation

Question 13

Edwards Syndrome (trisomy 18) Other common features

Answer 13

Congenital heart disease usually VSD ± valve dysplasia
Short sternum
Overriding fingers
‘rocker-bottom feet’

Question 14

Edwards Syndrome (trisomy 18) Median life expectancy

Answer 14

4 days, although some affected babies life for several months

Question 15

Edwards Syndrome (trisomy 18) Diagnosis

Answer 15

Initial rapid interphase FISH testing followed by formal chromosome analysis (additional chromosome 18)

Question 16

Genetic disorders with cardiac features

Answer 16

Digeorge syndrome
Marfans syndromes
Noonans syndrome
Williams syndrome

Question 17

Genetic testing in cognitive impairment

Answer 17

Angelman syndrome (AS)
Fragile X syndrome (FRAXA)
Prader-Willi syndrome
Rett syndrome
Smith-Magenis syndrome
Wiliams syndrome

Question 18

Genetic disorders with neuromuscular features

Answer 18

Congenital myotonic dystrophy
Duchenne muscular dystrophy
Spinal musculal atrophy

Question 19

Genetic disorders with dermatological features

Answer 19

Ehlers-Danlos syndrome
Neurofibromatosis type §
X-linked hypohidrotic ectodermal dysplasia
Tuberous sclerosis

Question 20

Genetic disorders of growth

Answer 20

IUGR 
-	Silver-Russle syndrome
-	Cornelia de lange syndrome
Short stature Turners syndrome
Tall stature  marfans
Obesity 
-	Bardet-biedly syndrome
-	Prada-willi syndrome
Overgrowth
-	Beckwith-widemann syndrome
Sotos syndrome

Question 21

Turners Syndrome Affects

Answer 21

1/2500 females

Question 22

Turners Syndrome Genetic

Answer 22

Single X chromosome (45,X), usually due to non-disjunction

Question 23

Turners Syndrome Presentation

Answer 23

Short Stature
Typical phenotype: 
-	Broad neck
-	Ptosis
-	Wide carrying angle at elbows (cubitas valgus)
-	Widely spaced hypoplastic nipples
-	Low posterior hairline
-	Excessive pigmented naevi
Puffiness of the hands and feet is a common neonatal finding

Question 24

Turners syndrome

Associated abnormalities include

Answer 24

Congenital heart disease (15-50%)
Especially coarctation of the aorta and VASD
Structural renal anomalies (~30%) e.g. horseshoe kidney or unilateral renal agenesis
Hypoplastic ‘streak’ ovaries (1o amenorrhoea and infertility)

Question 25

Ehlers-Danlos Syndrome Incidence

Answer 25

1/5000 births

Question 26

Ehlers-Danlos Syndrome Inheritance

Answer 26

Autosomal dominant

Question 27

Ehlers-Danlos Syndrome All forms of Ehlers danlos are characterised by

Answer 27

Skin fragility
Unsightly bruising and scarring
Musculoskeletal discomfort
Susceptibility to osteoarthritis

Question 28

Angelmann Syndrome Incidence

Answer 28

1/40,000

Question 29

Angelmann Syndrome Caused by

Answer 29

Impaired or absent function of the maternally imprinted UBE3A gene on chromosome 15q11.13.

Question 30

Angelmann Syndrome Presentation

Answer 30

A distinctive neurobehavioural condition with severe developmental delay
Profound speech impairement
An ataxic wide gait
Specific behavioural phenotype (excitable personality, hand-flapping and inappropriately happy affect
Seizures are common

Question 31

Fragile X syndrome

Incidence

Answer 31

1/5500 males

Question 32

Fragile X syndrome Description

Answer 32

Commonest cause of mental retardation

Question 33

Fragile X syndrome Caused by

Answer 33

A full expansion (>200 repeats) in the (CGG) triplet repeat in the FRAXA gene on chromosome Xq27.3

Question 34

Fragile X syndrome Boys with fragile X syndrome

Answer 34

Typically have global developmental delay often with gaze avoidance, sterotyped repetitive behaviours such as hand-flapping and resistance to change of routines

Question 35

Fragile X syndrome Up to 50% of girls with a full FRAXA expansion will have

Answer 35

Learning and behavioural difficulties that are similar to, but less severe than those seen in affected boys

Question 36

Fragile X syndrome Learning and behavioural difficulties that are similar to, but less severe than those seen in affected boys

Answer 36

Very complex and there will be genetic implications for relatives.
Referral to a clinical geneticist is recommended