paediatric inherited conditions

Question 1

What is the typical inheritance pattern of autosomal recessive diseases?

examples of autsomal recessive diseases?

Answer 1

• for an autosomal recessive disease to be inherited both parents need to be carriers
• of those children has a 1/4 or 25% chance of being affected
• examples are cystic fibrosis and sickle cell disease

Question 2

What is the most common inherited condition in the UK?

Answer 2

cystic fibrosis

Question 3

What is the inheritance pattern of autosomal dominant diseases?

Answer 3

With autosomal dominant; one parent is a carrier and one is unaffected

Potential children, half will be unaffected, half will be affect and have the condition

Only one faulty copy required to have the disease –> 50% affected, 50% unaffected

Examples: AD PCKD, huntingtons

Question 4

What is the inheritance pattern of recessive X linked disease when the father has the condition?

Examples of x linked recessive disease?

Answer 4

• X linked recessive disease:
  
  • father has the condition (carrying affected X chromosome)
  • mother does not have the condition –> two working x chromosomes
  • sons –> all will be unaffected; sons inherit unaffected X chromosome from mother
  • daughters –> all daughters will be carriers, inheriting one affected X chromosome from the father
  • examples = beckers and duchenne’s muscular dystrophy

Question 5

What is the inheritance pattern of X linked recessive disease when the mother is a carrier of the disease?

Answer 5

• mother is a carrier with one affected X chromosome, and one healthy x chromosome
• father is unaffected
• potential inheritance pattern:
  
  • sons –> can inherit the unaffected X chromosome from mum and Y chromosome from dad OR can inherit the affected X chromosome from mum and unaffected Y chromosome (has the disease).
  • daughters –> can inherit unaffected X chromosome from mum and another unaffected from dad, or affected X chromosome from mum and unaffected X chromosome from dad (carrier).
  • 1/2 sons affected
  • 1/2 sons unaffected
  • 50:50 daughters carriers/ unaffected

Question 6

What is the inheritance patterns of mitochondrial disease?

Answer 6

• can only be inherited from mothers due to mitochondria contributing to the embryo only coming from the ovum.
• often complex diseases
• often rare

Question 7

What type of chromosomal abnormalities can occur?

Answer 7

1. Numerical –> trisomy (down’s syndrome Chromosome 21) or monosomy
2. Structural –> duplication, deletion, translocation (unbalanced).

Question 8

How common is down syndrome?

how is it detected ?

what are the typical features?

Answer 8

Trisomy 21 / down syndrome occurs in every 1/1000 births

detected by very sensitive antenatal screening

characteristic facial features

important internal features

later life complications

Question 9

Gowers sign is linked with a particular genetic condition –> how is this condition inherited?

Answer 9

Gower’s sign = weakness of proximal muscles, particularly those of lower limb

patient has to use hands and arms to “walk up” their own body from squatting due to lack of thigh/ hip muscle strength.

Often seen in DMD (duchenne muscular dystrophy), DMD is X linked recessive disease

Question 10

What are the characteristic facial and external features if down’s syndrome (trisomy 21) ?

Answer 10

• Hypotonia
• upward slanting palpebral fissures
• brachycephaly –> flat occiput
• clinodactyly (curving finger) with short 5th finger
• protruding tongue
• flat nasal bridge
• epicanthal folds
• brushfield spots (spots on iris)
• ear abnormalities –> small low set ears, stenotic meatus
• single palmar crease
• loose nuccal skin (Skin at back of neck)
• short fingers
• sandal gap

Question 11

What are the important internal features of down syndrome?

Answer 11

• AVSD (atrioventricular septal defect) , VSD (ventricular septal defect) , ASD (atrial septal defect).
• hirschsprung’s disease (abscence of ganglions within the bowel leading to lack of peristalsis)
• duodenal atresia
• low IQ (Mean of 50)
• ENT issues
• hypothyroidism
• atlanto-axial instability
• Cataracts
• TAM (transient abnormal myelopoesis) –> AML (acute myeloid leukaemia).
• later in life –> early onset alzheimer’s (median age life expectancy 68 yrs)

Question 12

What is Edward’s syndrome?

How common is it?

Answer 12

Edwards syndrome (trisomy 18) is a severe genetic disease.

Occurs in 1 in 3000-8000

not usually comptible with life (rarely gets to term, often spotaneous abortion).

50% of patients die by 1 week of life

90% of patients die by one year of life

Question 13

What are the features of Edward’s syndrome?

Answer 13

• Clenched hand with overlap of 2nd and 5th fingers over the 3rd and 4th
• rocker bottom feet (prominent calcaneus and convex rounded bottom of foot).
• micrognathia (undersized jaw), prominent occiput, micro-opthalmia
• low set ears
• VSD and ASD
• generalised muscle spasticity
• renal anomalies
• mental retardation

Question 14

What is patau’s syndrome?

Answer 14

Patau syndrome is the least common and most severe of the viable autosomal trisomies

caused by trisomy 13

Question 15

How does patau’s syndrome normally present?

consistent features?

other features?

when is it generally recognised?

Answer 15

Many of the clinical features widely vary; however, severe mental deficiency is a consistent feature in children born with Patau syndrome.

Others:

• Holoprosencephaly - where prosencephalon (forebrain) fails to develop into two hemispheres
• Microcephaly
• neural tube defects
• midline facial features - single orbit or single nostril
• facial clefting - cleft lip and cleft palate
• polydactyly
• flexion of the fingers
• rocker-bottom feet
• heart defects

Patau syndrome is generally recognized at birth by the presence of structural birth defects and poor neurologic performance.

Question 16

List the features of patau’s syndrome?

Answer 16

• holoprosencephaly
• polydactyl
• seizures
• deafness
• microcephaly
• midline cleft lip/ palate
• abnormal ears
• sloping forehead
• cutis aplasia - areas of skin that have not formed properly
• omphalocele - abdominal organs fail to return to abdominal cavity in development
• cardiac and renal anomalies

Question 17

What are the two important sex chromosome conditions?

Answer 17

45, XO = Turner’s syndrome

47, XXY = Klinefelter’s syndrome

Question 18

What is the cause of turner’s syndrome?

Answer 18

Tuner’s sydrome: 45 XO

About half of individuals with Turner syndrome have monosomy X, which means each cell in the individual’s body has only one copy of the X chromosome

can also occur if one of the sex chromosomes is partially missing or rearranged rather than completely absent.

Some women with Turner syndrome have a chromosomal change in only some of their cells, which is known as mosaicism. Women with Turner syndrome caused by X chromosome mosaicism

Question 19

How does turner’s syndrome normally present?

Answer 19

• Most commonly presents with short stature evident around age 5
• early loss of ovarian function (premature ovarian failure or ovarian hypofunctino)
• ovaries often develop but oocytes die prematurely and most ovarian tissue degenerates before birth
• many girls do not undergo puberty without hormone therapy, most are infertile
• Features:
  
  • low birth weight + length
  • short stature
  • low posterior hairline
  • webbed neck
  • puffy hands + feet (due to lymphoedema)
  • shield chest + wide spaced nipples
  • cubitus valgus –> elbows inward with forearms deviated outwards
  • short 4th metacarpal
  • high palate
  • low set ears

Question 20

What are the internal issues of turners syndrome?

Answer 20

• some women with turner syndrome have a chromosomal change in only some of their cells which = mosaicism
• mosaic turner syndrome caused by a random event during cell division in early fetal development
• often affects endocrine organs –> gonadal dysgenesis, sexual infantilism ( lack of sexual development after puberty or delayed puberty) and hypothyroidism
• cardiovascular issues –> coarctation of the aorta (detected by palpating femoral pulses); hypoplastic left heart, bicuspid aortic valve, essential hypertension
• renal –> horshoe kidney, Pelvicoureteric junction obstruction, double collecting systems

Question 21

What is Klinefelter’s syndrome?

how common is it?

when does it present?

Answer 21

Extra sex chromosome, occuring only in males –> XY plus extra X (XXY)

1 in 600 male births

usually presents in adolescence

Question 22

How does klinefelter’s present?

Answer 22

muscle weakness

increased height

poor coordination

reduced body hair

gynaecomastia

reduced libido

primary hypogonadism –> low testosterone, high FSH

microorchidism (abnormally small testes), infertility

Question 23

What is williams syndrome?

what is it characterised by?

caused by?

Answer 23

Williams syndrome is a developemental disorder that affects many parts of the body

characterised by mild to moderate intellectual disability, outgoing/ engaging personality, distincitive facial features and cardiovascular problems

Caused by deletion of regions 26-28 on chromosome 7.

7 q (long arm of chromosome 7) 11. 23 ( region 11, locus 23)

Question 24

what are the characteristic facial features of william’s syndrome?

Answer 24

Characteristic elfin facies:

short nose broad nasal tip

small widely spaced teeth

small chin

wide mouth

puffy eyes

full cheeks full lips

can appear more gaunt as adult

Question 25

What are the features of williams syndrome?

Answer 25

• supravalvular aortic stenosis
• hypercalcaemia
• diabetes
• hypothyroidism
• visuspatial and numerical difficulties
• spoken language + music abilities
• cocktail party chatter/ personality –> over friendliness, lack of fear with stranger, strong pro-social compulsion, excessive talkativeness, verbal fluency with extensive + expressive speech rich in vocabulary
• elastin region
• IQ differences

Question 26

What is the cause of prader willi syndrome?

how common is it?

Answer 26

prader will syndrome is caused by deletion of paternal 15 q 11- q 13

people normally inherit one copy of this chromosome from each parent, and only the paternal genes remain on due to genomic imprinting on the maternal copy. Therefore deletion of critical genes that are normally expressed on chromosome 15 and non expression in maternal chromosome 15 leads to prader willi.

occurs in 1 in 15000- 20000

Question 27

What are the characteristic facies of prader willi syndrome?

Answer 27

narrow temples

thin upper lip

elongated face

large nose

there is distinctive evolution of the condition and impaired hypothalamic function

early features:

• hypotonia
• failure to thrive
• poorly developed genitals
• developmental delay –> walking at 24 months enhanced VP skills
• hyperphagia
• tantrums –> psychosis

Later features:

• central obesity (IHD, T2DM, OSA)
• Short stature
• hypogonadism –> incomplete, delayed or abnormal pubertal developement
• men are thought to be infertile
• intellectual disability