Paeds - Genetics Flashcards
Dysmorphic features of Down’s syndrome
- HYPOTONIA
- Brachycephaly (SMALL HEAD; FLAT BACK)
- Short stature + Short neck
- Upward sloping palpebral fissures (on eyes)
- PROMINENT EPICANTHIC FOLDS
- Single palmar crease
When is gneteics usually tested
- Prenetal: MALFORMATIONS detected on scan
- Paediatric:
- Developmental delay
- Seizures
- Physical malformations -
CANCER:
- Early onset
- Extensive FHx
- Multiple cancers - Adult medicine: cardiomyopathies; kidney disease; neurology
- Postmortem: Sudden death
Types of genomic tests
- COMPARATIVE GENOMIC HYBRIDISATION
- chromosome deletion/duplication
- particularly for intelectual disbility/physical malformations
- KARYOTYPING (translocation)
- GENE PANEL/sequencing (for single gene change)
- NGS panel
- Exome; Genome
Types of genetic variations
- Single Nucleotide Variant (SNV):
- Missense (one amino acid for another)
- Loss of function (STOP, Frameshift)
- Splice site
- Short Trinucleotide Repeat (STR)
Down’s syndrome complications
- Congenital heart defects
- Failure to thrive
- Physical abnormalities
- Recurrent Otitis Media + DEAFNESS from Eustachian tube abnormalities
- VISUAL - myopia, cataracts
- Atlantoaxial instability - Learning difficulties
- Hypothyroidism
- LEUKAEMIA
- Alzheimers
- INFERTILITY, Stillbirths + miscarriages
Down’s pathophys
Non-disjunction in ovaries
- more likely in older mothers but oft due to translocation
Robertsonian translocation
One of the chromosome 21s is translocated to chromosome 14 in parent
So baby gets one normal chromosome 21 from mum; one from dad and an extra 21 attached to one of their other chromosomes - overall has 3 21s = Down’s
Test parent’s if baby has translocation
Turner’s Syndrome + Px
(45, X)
- Prenatal: increased nuchal translucency (look at neck on scan)
- Neonatal: Lymphoedema (SWOLLEN)
- Cardiac: Aortic coarctation
- Fertility: dysplastic ovaries (risk of malignancy)
Klinefelter’s
47, XXY
Delayed puberty -> oft tall and slim as a result
Results in AZOOSPERMIA - oft found when investigating male INFERTILITY
Reason why some females get x-linked conditions
lyonisation (one x chromosome is inactivated)
Modes of genetic inheritance
- Autosomal dominant
- Autosomal recessive
- X-linked
- MITOCHONDRIAL disorders (exclusively from mitochondria from cytoplasm of ova - contain circular chromosome)
Heteroplasmy
More than one variant of mitochondrial dna exists within the same cell
- so can get a mix of normal and abnormal mitochondria esp if cell in question is an ovum
Gonadal mosaicism
Condition where the precusor cells to the ova and spermatazoa are a mixture of TWO or MORE GENETICALLY DIFFERENT CELL LINES
- kids can then get mutated gene from one parent
Expressivity
Some conditions can present with phenotypes of differing severities even if autosomal dominant
Penetrance
The % of individuals carrying a genetic varient who manifest the disease
Can be age related
Antenatal Screening for Down’s
- COMBINED TEST (11-14 wks)
- USS = NUCHAL THICKENING >6mm (the measurement checked is ‘nuchal translucency’)
- Maternal BLOODS:
- Beta- Human Chorionic Gonadotrophin (high levels = higher risk)
- Pregnancy Associated Plasma Protein-A (low levels = higher risk)
- USS = NUCHAL THICKENING >6mm (the measurement checked is ‘nuchal translucency’)
- TRIPLE TEST (14-20 wks)
- 3 maternal bloods:
- Beta-HCG
- Alpha Feto Protein (low = hihger risk)
- Serum OESTRIOL (should be high in preg - lower = risky) - Quadruple test (14-20 wks)
- 4 maternal bloods:
- All of above + INHIBIN-A (higher = riskier)
When is antenatal testing offered for Down’s + what are the methods
Offered if screening risk score > 1 in 150
- Chorionic Villus Sampling (<15 wks)
- USS guided placenta biopsy - Amniocentesis (only if enough fluid)
- USS guided amniotic fluid asp w/ needle
Fetal cells from sample are kareotyped
Can also consider - Non-Invasive Prenatal Testing:
- Maternal Blood test; some of the circulating DNA fragments will be from fetus
- not definitive
Management of Down’s
MDT management
- Physio/occupational
- SALT
- Dietician
- SOCIAL SERVICES
- Additional educational support
- Charity association
- Paeds + GP + Health visitors
- Cardiology (heart defects)
- ENT if ear problems
- Audiologist for hearing aids
- Optician for glasses
What are routinely followed-up in children with Down’s
- 2 yearly THYROID CHECKS
- ECHO for heart defects
- Regular AUDIOMETRY
- Regular EYE CHECK
Prognosis for Down’s
Average life expectancy is 60 years but varies depending on complications
Features of Turner’s
- SHORT
- WEBBED NECK
- Broad chest with WIDELY SPACED NIPPLES
- HIgh arching palete
- Downward sloping eyes + Ptosis
- Cubitus Valgus (vlgus shape at elbow extension)
- FERTILITY PROBLEMS
- Underdeveloped ovaries
- Late/incomplete puberty
- Infertility
Conditions/complications associated with Turner’s
- COARCTATION of AORTA
- Recurrent Otitis Media
- Recurrent UTI
- Hypothyroid
- Hypertension
- DIABETES, Obesity
- OSTEOPOROSIS
Learning disabilities
Management of Turner’s
- Growth hormone therapy (for height)
- OESTROGEN / PROGESTERONE REPLACEMENT
- FERTILITY TREATMENT
Tx of complications e.g. treating uti, otitis media, surg for coarctation
Monitor for associated conditions + Tx
Oft life expectancy similar to general populace
Kleinfelter presentation
Initially looks normal - tends to present at puberty or incidental finding on fertility treatment
- Taller during puberty
- WIDER HIPS
- GYNAECOMASTIA
- Weaker muscles
- Small testicles, reduced libido + Infertility
Subtle learning difficulties, esp SALT related
Klinefelter Mx
- TESTOSTERONE injections for Sx improvement
- Advanced IVF for fertility problems
- Cosmetic surgery (breast reduction)
MDT:
- SALT
- Physio + occupational
- Educational support for any learning disabilities
Complications of Kleinfelter
- Infertility
- Slightly increased breast cancer risk
- Increased risk of:
- OSTEOPOROSIS
- Diabetes
- Anxiety + Depression
However, life expectancy similar to general populace; affected by complications/associated
Fragile X syndrome
(Fragile X metal retardation 1) FMR1 gene mutation on X chromosome
- normally codes for Fragile X Mental retardation protein which has role in cognitive development
X-linked but females can be variably affected (males always affected)
Can be through inheritance or de novo mutation
Fragile X Px
- INTELECTUAL DISABILITY
- Long narrow face; BIG ears
- Large testicles post-puberty
- HYPERMOBILITY OF JOINTS (esp in hands)
Associated with ADHD, Autism + SEIZURES
Fragile X management + prognosis
Assistive management
Life expectancy similar to general populace
Prader-Willi Pathophys
Loss of functional genes on PROXIMAL ARM of chromosome 15 in PATERNAL copy
or because they inherit 2 copies of the chromosomal region from rhe mum and none from the dad
Only the maternal allele is expressed
Prader-Willi Px
- CONSTANT INSATIABLE HUNGER (-> obesity)
- HYPOTONIA in infants (resulting in poor initial feeding)
- Hypogonadism
- Mild-mod LEARNING disability / Developmental delay
- Mental health - esp Anxiety
- Softer, fairer skin -> Bruises easily
- SHORT
Dysmorphic features:
- Almond eyes
- Strabismus (SQUINT)
- Thin upper lip + Downturned mouth
- Narrow forehead
Prader-Willi Management
- Restrict access to food (with dietician advice)
- Usually requires fewer calories than average individual as they tend to be less active due to poorer muscle tone/strenght
- educate all care related individuals in child’s life
- Usually requires fewer calories than average individual as they tend to be less active due to poorer muscle tone/strenght
- Physio + exercise to improve muscle tone
- Educational support
- Behavioural Mx of hyperphagia + developmental delay
GROWTH HORMONE can be used to improve muscle devlopment + body composition
Prader WIlli Dx
Clinical px + confirmed with genetic testing
Genetic imprinting
Term describing a mechanism where genes are expressed in a parent-of-origin manner
e.g. Prader-Willi vs Angelman
- In Prader-Willi only maternal allele is presented
- In Angelman only paternal allele is presented
Angelman syndrome pathophys
Caused by LOSS OF FUNCTION of one copy of the UBE3A gene inherited from the MOTHER
Can be due to chromosome 15 proximal arm; specific mutation in gene; or 2 copies from dad and none from mum
Angelman Px
- Developmental delay + learning disability
- Delayed/absent speech development
- Ataxia
- FASCINATION WITH WATER
- HAPPY DEMEANOUR
- Inappropriate laughter
- Hand flapping
- Abnormal sleep patterna
- Dysmorphic features
- Microcephaly
- Fair skin + hair; Blue eyes
- Wide mouth with WIDELY SPACED TEETH
Angelman’s Mx
- Parental education
- Social services + support
- Educational support
- Physio / Occupational
- Psych/CAMHS
Treat associated e.g. anti-epilepsy meds
Edward’s syndrome
Trisomy 18 - most babies die in the perpartum period
Can be complete (trisomy 18 in every cell); Mosaic (trisomy 18 in only some cells): Partial (only part of an extra chromosome 18 in their cells)
Mosaical babies typically live till at least 1 y/o and can live till adulthood
NOT HEREDITARY; more common at older age
Screening of Edwards’
Done at same time as Down’s + Patau’s in the combined test at 10-14 wks gestation
- Check Nuchal translucency + b-HCG
- USS at 20 wks if first one inconclusive
Edwards’ classic presentation
- Small mouth, jaw, neck
- Prominant occiput
- Sheild chest / short + prominant sternum
- Wide set nipples
- Dysplastic/malformed ears
- Clenched hands with overlapping fingers
- Rocker-bottom feet
Edwards’ Dx
Chorionic villus sampling or amniocentesis - antinatal
If not Dx before birth - Newborn bloods
Common complications of Edwards
- Congenital heart defects
- Impaired lung function
- Immunocompromise
- Difficulty feeding
- Impaired mobility/motor ability as they get older
Patau’s syndrome
Trisomy 13
- oft miscarry or die perinatally
- low birth weight
Risk increases with maternal age
Typically not hereditary - more commonly hereditary if it is Patau’s sue to translocation
- Can get genetic testing for this reason to plan for future preg
- Also offered to family members
Common complications of Patau’s
- Restricted growth in utero -> low birth weight
- Heart defects
- Holoprosencephaly (brain doesn’t split into 2 halves)
- CLEFT LIP + PALATE
- Microphtalmia (SMALL EYES)
- Anopthalmia (Absence of eye(s)) - MICRCEPHALY
- Ear malformations + deafness
- Rocker-bottom feet
Less common:
- Omphalocele (intestines outside body)
- Kidney cysts
- Polydactyly
Muscular dystrophy types
Duchenne and Becker
Duchenne is OUT-OF-FRAME Dystrophin deletion
- virtually none of the protein is expressed
- More severe at earlier age
Becker muscular dystrophy: IN-FRAME Dystrophin deletion
- Protein expressed at lower levels or dysfunctional
- Can retain mobility into adulthood
Muscular dystrophy epidem
Duchenne is most common form
Typically affects males as it is X-LINKED RECESSIVE
What causes muscular dystrophy
Mutations (deletions) in the DYSTROPHIN GENE
Dystophin is required for MUSCLE CONTRACTION + STABILITY
Muscular dystrophy presentation
DUchenne:
- Presents in early childhood
- GOWER’S SIGN
- Difficult to pick the child up (too floppy)
- Usually wheelchair-bound before puberty
- Tend to die from resp failure in early 20s
(calves may be hypertrophic - broken down muscle is replaced with fat)
Becker:
- Later childhood muscle wasting + weakness
- Wheelchair bound by teens
- Survive well into adulthood (at least 30s usually)
PROXIMAL MUSCLES prominantly affected
DDx for muscle weakness
- X-linked recessive muscular dystrophy
- Limb-Girdle Musc Dystrophy
- (AUTOSOMAL INHERITANCE + later onset than Duchenne/Becker) - Spinal Muscular Dystrophy
- (caused by ANTERIOR HORN CELL DEGENERATION not dystrophin loss) - Myopathies (NON-PROGRESSIVE)
Muscular dystrophy Ix
- CK in blood - HIGH if muscle dystrophy
- Gold = GENETIC test
Can do muscle biopsy (also GOLD) but as it is more invasive, genetic testing is prefered
Muscular dystrophy Mx
Supportive treatment
- GLUCOCORTICOIDS - slows muscle breakdown
- Physio/occupational
- Tx heart/breathing problems
Genetic counselling for families (HEREDITARY CONDITION)
Main complications of muscular dystrophy
- Loss of mobility
- RESPIRATORY COMPLICATIONS due to muscle weakness
- nocturnal hypoventilation
- poor cough - can’t clear airways well - DILATED CARDIOMYOPATHY
Noonan syndrome
Number of genetic causes
Usually AUTOSOMAL DOMINANT
Noonan Px
Varies depending on underlying cause but commonly:
- SHORT
- Broad forehead
- Downward sloping eyes + Ptosis
- Hypertelorism (wide space between eyes)
- Prominent nasolabial folds
- Low set ears
- WEBBED NECK
- Widely spaced nipples
Associated complications of Noonan’s
- HEART DEFECTS - particularly PS + LVH; ASD
- CRYPTORCHIDISM (-> infertility in males)
- LEARNING DISABILITY
- BLEEDING DISORDERS
- Lymphoedema
- Leukaemia + Neuroblastoma risk
William syndrome
Deletion of genetic material on ONE copy of chromosome 7
- typically random - not hereditary
William syndrome Px
- WIDE MOUTH + WIDELY SPACED TEETH
- STARBURST EYES
- Happy, sociable personality
- Mild learning disabilty
- Broad forehead
- Flattened nasal bridge + long philtrum
- Small chin
Associated complications of William syndrome
- SUPRAVALVULAR AORTIC STENOSIS (need ECHOs)
- HYPERCALCAEMIA (low calcium diet)
- Hypertension (BP monitoring)
- ADHD
