genetics Flashcards
describe sturge weber syndrome
- port wine stain across face (angioma of trigeminal nerve)
- seizures
- hemiparesis (opposite to port wine stain)
- learning difficulties
presentation of metochromatic leukodystrophy
- developmental delay
- seizures
- muscle wasting
- deafness/ blindness
diagnosis of metochromatic leukodystrophy
urinary sulfatide positive
presentation of kearn sayre syndrome
- cerebellar ataxia
- proximal muscle weaakness
- growth hormone deficiency
- ptosis, ophthalmoplegia
- heart block
presentation of refsum disease
- ichythyosis
- hepatosplenomegaly
- retinitis pigmentosa
- cerebellar ataxia
- pes cavus
risk factors for spina bifida
- low maternal folic acid
- use of anti epileptics in pregnancy (sodium valproate)
- congenital conditions - arnold chiari, trisomy 13, 18
describe meningocele
cystic swelling containing dura and arachnoid mater protrudes through veretebral arch defect
describe myelomeningocele
cystic swelling containing spinal neural tissue protrudes through vetebral arch defect
mutation in Noonan syndrome
PTPNII gene on chromosome 12
inheritance of noonan syndrome
autosomal dominant
facial/ body features of noonan syndrome
FACIAL - triangular face, short webbed neck, low set ears, micrognathia
SKELETAL - short stature, wide spaced nipples
associations with noonan syndrome
- learning disability
- cardiac - pulmonary stensois *, hypertrophic cardiomyopathy, ASD, VSD
- VWD, thrombocytopenia
- pubertal delay
- ptosis, strabismus
diagnosis of noonan syndrome
molecular genetic testing
inheritance of tuberous sclerosis
autosomal dominant
mutation in tuberous sclerosis
TSC1 gene on chromosome 9 (encodes hamartin) - 10-30%
TSC2 gene on chromosome 16 (encodes tuberin) ***
skin features of tuberous sclerosis
- shagreen patches
- ash leaf macules
- adenoma sebaceum
- hypomelanotic macules
features of tuberous sclerosis
- infantile spasms, seizures
- learning difficultues, ADHD, Autism
- cardiac rhabomyomas
- subependeymal giant cell astrocytomas
- retinal hamartomas
- dentail fibromas
- polycystic renal disease
management of tuberous sclerosis
- vigabatrin - for infantile spasms
- mTOR inhibitors e.g. secrolimus
inheritance of neurofibromatosis type 1
autosomal dominant
mutation in neurofibromatosis
mutation on chromosome 17
NF1 encodes for neurofibrin (tumour suppressor protein)
criteria for diagnosis of neurofibromatosis
NEED >2 to be present :
- axillary or inguinal freckling
- > 6 cafe au lait
- > 2 lisch nodukes
- family history fo NF1
- > 2 neurofibromas
- optic glioma
- bone lesion
+ seizures, learning disbailities, scoliosis, phaecytochroma
inheritance of marfans disease
autosomal dominant
features of marfans disease
- tall stature, kyphoscoliosis , wide arm span
- cardiac - aortic root dissection, aortic dissection, mitral regurgitation
- upward and outward lens dislocation , myopia
- increased risk of pneumothorax
inheritance of familial hypercholesterolaemia
autosomal dominant
signficantly elevated LDL cholesterol
inheritance and mutation in cystic fibrosis
autosomal recessive
defective CFTR gene on chromosome 7 - most common F508 delta mutation (class 2)
neonatal presentation of cystic fibrosis
- meconium ileus
- jaundice
- failure to thrive
- guthrie heel prick test
- pseudo-bartter syndrome
- Vit E or K deficiency
cystic fibrosis features in children
- recurrent respiratory infections
- failure to thrive
- steattorhoea, pancreatitis
- nasal polyps
- rectal prolapse
- CF related diabetes
- boys infertile
causes of resp infections in cystic fibrosis
- start with staph aureus (causes pneumatoceles) + h.influenza
- pseudomonas 80% by adolescents
- burkholderia - life threatening sepsis
diagnosis of cystic fibrosis
- guthrie heel prick test - raised immunoreactive trypsin (if +ve, have CFTR mutation analysis)
- sweat test ** - gold standard, >60mmol/l Cl
- molecular genetic testing for CFTR mutation
management of cystic fibrosis
- twice daily physiotherpay
- hypertonic saline nebulisers BD
- prophylactic oral abx
- dornase alfa
- creon
- ursodeoxycolic acid
- CFTR modulators ***
treatment of burkholderia
ceftriaxone + aminoglycoside
treatment of pseudomonas in CF
3/52 oral ciprofloxacin + 3/52 nebulised colomycin
inheritance and cause of tay sachs disease
autosomal recessive
mutation in hEXA gene on chromosome 15 (deficiency of HEXA enzyme and causes neurodegeneration)
common in ashkenazi jews
presentation of tay sachs disease
- presents around 3-6 months old with seizures (myoclonic jerks), exaggerated startle.
- at 6-10 months, developmental regression and hypotonia
- cherry red spot
- death by 5 y/o with respiratory failure
diagnosis of tay sachs
enzyme activity of HEXA-A
inheritance and cause of wilsons disease
autosomal recessive
mutation in ATP7B on chromosome 13 - leads to copper accumulation and deposition
presentation of wilsons disease
- personality/ mood change, psychotic
- acute liver failure, jaundice -> cirrhosis
- kayser fleischer rings , sunflower cataracts
- tremor, ataxia, difficulty talking
- cardiomyopathy
diagnosis of wilsons disease
- liver biospy and genetic analysis **
- low serum caeruloplasmin
management of wilsons disease
- avoid high copper foods
- penicillamine
- liver transplant
inheritance of trisomy 21
- meiotic non disjunction **
- robertsonian transolocation
- mosaicism- milder phenotype, (46 XY/ 47 XY+21), low recurrence
facial features of trisomy 21
- epicanthic folds
- brushfield iris spots
- upslanting palpebral fissures
- low set small ears
- flat nasal bridge
- protruding tongue
features of trisomy 21
- small stature, wide sandal gap, single palmar crease
- learning disbailities
- cardiac - AVSD **, VSD
- increased risk of AML, ALL, alzheimers disease
- duodenal atresia, hirshsprungs disease, coeliac, imperforate anus
- hypothyroidism
- cataracts
antenatal testing for trisomy 21
10-14 weeks: beta HCG and PAPP
14-20 weeks: Beta HCG, alpha feto protein, inhibin A, oestriol
if risk 1 in 150 -> CVS at 13 weeks or amniocentesis at 15 weeks
diagnosis of trisomy 21
- QF PCR for chromosome 21 - rapid test
- chromosomal analysis (fISH)
features of trisomy 13 (patau)
- cleft palate
- microcephaly
- caput aplasia
- small eyes
- polydactyly
features of trisomy 18 (edwards)
- prominent occiput, low set ears, cleft palate
- overlapping fingers, clenched fists
- ASD, VSD, PDA
- rocker bottom feet
cause of klinefelters disease
47 XXY - caused by non disjunction**
features of klinefelters
- tall stature, gynaecomastia, truncal obesity
- learning difficulties
- infertility , small testes
- mitral valve prolapse
- increased risk of hypothyroid, diabetes, SLE, rheumatoids, hodgkins lymphoma
diagnosis of klinefelters
chromosomal analysis
inheritance of fragile X
X linked dominant
cause of fragile X
FMR1 gene on X chromosome causes repeat expansion of CGG trinucleotide repeat (>230 repeats = disorder)
features of fragile X
- facial - large jaw, long ears, high forehead, high arched palate, dental overcrowding
- learning disabilities, ADHD, Autism, anxiety
- mitral valve prolapse
- hyper extensible joints, joint laxity, scoliosis
diagnosis of fragile X
FRM1 gene testing
inheritance of duchenne muscular dystrophy
X linked recessive
cause of duchenne muscular dystrophy
mutation in dystrophin gene
presentation of duchennes muscular dystrophy
- delayed motor milestones - ‘waddle’ gait
- present around 3 y/o
- gower sign
- hypertrophy of calf muscles
- macroglossia
- eventual dilated cardiomyopathy
presentation of beckers muscular dystrophy
partially functional dystrophin gene
present around 12-13 y/o
hypertrophy of calf muscles
diagnosis of duchenne muscular dystrophy
initial test - serum CK
definitive diagnosis - genetic testing **
inheritance of kallman syndrome
X linked recessive - deficiency in GnRH
presentation of kallmann syndrome
- hypogonadism, absent puberty
- obesity
- anosmia
- infertility
cause of prader willi syndrome
IMPRINTING
70% deletion of paternal chromosome 15q11-q13
presentation of prader willi
- facial - almond shaped eyes, narrow forehead, small hands and feet
- neonatal hypotonia
- initial slow feeding, obesity
- aggressive, temper tantrums, learning difficulties
- obstructive sleep apnoea
- hypogonadism
- short stature
diagnosis of prader willi
FISH
cause of angelman syndrome
imprinting
loss of of function of materanl UBE3A gene on chromosome 15
presentation of angelman syndrome
- seizures
- severe learning disability, delayed milestones
- happy personality
- hand wringing
- microcephaly
diagnosis of angelman syndrome
DNA methylation testing
presentation of Rett syndrome
present at 2/3 y/o…
- developmental regression
- repetitive hand movements, hand wringing
- speech regression
- seizures
- laughing inappropriately
- seizures, hypotonia, dystonia
presentation of crouzon syndrome
- microcephaly - craniosyntosis
- ocular proptosis
- maxillary hyperplasia
- conductive hearing loss
presentation of menkes disease
- hypotonia
- myoclonic seizures
- chubby rose cheeks
- friable hair
- optic atrophy
presentation of ataxia telangiectasia
- ataxia, nystagmus
- telangiectasia
- recurrent infections
diagnosis of ataxia telangiectasisa
- increased alpha fetoprotein
- reduced IgA, IgG, IgE
- fragile chromosomes
presentation of smith-lemli-opitz
face - microcephaly, low seat ears, cleft lip, micrognathia
CNS - learning difficulties, autism
other- ambiguous genitalia, polydactyly
presentation of apert syndrome
- craniosyntosis
- syndactyly
- dysmorphic features - missing teeth, cleft palate
- short stature
presentation of fabry disease
- neuropathic pain - in hot weather or exercise
- corneal opacities
- present with stroke/ heart attack
- renal insufficiency
cause of williams syndrome
microdeletion on chromosome 7
presentation of williams syndrome
FACIAL - wide mouth, prominent upper lip, stellate pattern in iris, small teeth, broad forehead
cardiac - supravalvular aortic stenosis, pulmonary stenosis
hypercalcaemia as neonate
social personality, likes mucisc, learning disabilities
diagnosis of williams syndrome
- FISH
- chromosomal microarray analysis
presentation of turners syndrome
- widely spaced nipples, short webbed neck
- short stature, scoliosis
- cardiac - coarctation of aorta, bicuspid aortic valve, HTN
- ovarian dysgenesis, amenorrhoea, delayed puberty
- horseshoe kidneys, renal aplasia
diagnosis of turners syndrome
karyotype
cause of diGeorge syndrome
22q11 microdeletion on chromosome 22
presentation of DiGeorge syndrome
C- cardiac abnormalitues
tetralogy of fallot, truncus arteriosis, interrupted aortic arch
A - abnormal facies
short philtrum, small mouth, broad nasal bridge
T - thymus absence
increased risk of infections
C- cleft palate
H - hypocalcaemia
hypoparathyroidism
presentation of alagille syndrome
- dysmorphic - broad forehead, wide set eyes, triangular chin
- jaundice
- cardiac - pulmonary stenosis
- butterfly vertebra
- posterior embryotoxon
presentation of reye syndrome
- days after viral illness
- acute encephalopathy - vomiting and confusion
- liver dysfunction
features of potter syndrome
- antenatal oligohydramnios
- pulmonary hypoplasia -> resp distress
- dysmorphic - micrognathia, peaked nose
- contractures, clubbed feet
- renal - b/l renal agenesis, AR PKD
features of bardet biedl syndrome
- obesity
- retinal degeneration
- renal abnormalities
- syndactyly/ polydactyly
- learning difficulties
