SYNDROMES Flashcards
Explain the cytogenetics of Down Syndrome.
Risk factors?
Extra chromosome 21 may result from:
meiotic non-disjunction
translocation
mosaicism
94% are meiotic non-disjunction.
Pair of 21 chromosomes fails to separate so that one gamete has 2 chromosome 21s. If its fertilised, it results in trisomy 21.
Translocation (5%) is when the extra chromosome 21 is joined onto another chromosome (Robertsonian translocation). Usually 14, but also 15, 22, 21.
In mosaicism (1%), some cells are normal, some have trisomy 21. Usually from mitotic non-disjunction.
What are the obstetric risk factors for Down syndrome?
If previous baby with Down syndrome , risk of recurrence is 1 in 100.
If one parent has Down syndrome, the chance of the child having it is 50%
Incidence of meiotic non-disjunction is related to maternal age.
What are the clinical features of Down syndrome?
Facies Single palmar crease Pronounced "sandal" gap betweem the big and second toe. Incurved 5th finger. Hypotonic.
What are the diagnostic investigations for Down syndrome?
ANTENATAL
At 10-14 weeks - blood test and US (nuchal thickness)
Chorionic villus sampling can be done from 11-14 weeks.
Amniocentesis from 15 weeks. Both are diagnostic.
POSTNATAL
Blood test:
rapid FISH (fluorescent in situ hybridisation)
What are the associated problems in Down syndrome?
Risk of: Hypothyroidism Impairment of vision and hearing. Cataracts Increased risk of infection Leukaemia (1%) Developmental hip dysplasia Eczema Atlanto-axial instability.
Describe the cranio-facial appearance of someone with Down Syndrome.
Round face Flat nasal bridge Epicanthic folds Small mouth and protruding tongue Small ears Flat occiput
Associated anomalies in Down syndrome?
Congenital heart defects
Duodenal atresia
Hirschprung disease
What are the long-term problems in Down syndrome?
Clearly involves a multidisciplinary team
Delayed motor milestones.
Learning difficulties.
Increased susceptibility to infections.
Secretory otitis media and hearing impairment.
Visual impairment from cataracts, myopia.
Higher risk of leukaemia and solid tumours.
Risk of atlanto-axial instability.
Increased risk of hypothyroidism and coeliac disease.
Epilepsy
Alzheimer’s disease
Cytogenetics of Turner’s syndrome
Presence of only one X chromosome
Or
Deletion of the short arm of one of the X chromosome
What are the clinical features of Turner’s syndrome
Lymphoedema of hands and feet as neonate - may persist Short stature Widely spaced nipples Webbed neck High arched palate
Delayed puberty
Primary amenorrhea
Infertility
What are the associated problems with Turner’s syndrome
Heart problems
bicuspid aortic valve (15%)
coarctation of the aorta (5-10%)
Kidney problems and ureter malformations (horseshoe kidney, rotational anomalies, obstructions)
Hypoplastic ovaries - amenorrhoea and infertility
Osteoporosis and pathological fractures
Increased incidence of autoimmune disease (thyroiditis) and Crohn’s
Pigmented naevi
Investigations for Turner’s
Karyotyping is diagnostic Hypergonadotropic hypogonadism (low oestrogen and androgens but high FSH and LH)
Management options for Turner’s
Growth hormone replacement (SC injections)
Oestrogen replacement for development of secondary sexual characteristics at the time of puberty (infertility remains, however) - between 12-14 yrs
What is the role of genetic counselling?
Support
Education
Diagnosis - thorough examination, history, investigations
Helps understand situation, make decisions about risks of diseases - RISK estimation
Provide greater autonomy in reproductive decisions
List some common dysmorphic features associated with syndromes (incomplete)
malformation - spina bifida, cleft lip/palate
disruption - amniotic membrane rupture causing limb reduction defects
Small ear with overfolded helix
Fifth-finger clinodactyly (incurving of the fifth finger - Down’s)
Syndactyly (fusion) of the fingers or toes
Key dysmorphic features of fetal alcohol syndromes
Dysmorphism: Thin upper lip absent philtrum Down-slanting, short palpebral fissures Narrow, receding forehead Short nose Hypertelorism Epicanthal folds Receding chin Microcephaly
Neurodevelopmental problems associated with fetal alcohol syndrome
Holoprosencephaly (forebrain fails to divide into hemispheres)
Structural - microcephaly, cerebellar hypoplasia, agenesis of corpus callosum
Impaired fine motor skills
Neurosensory hearing loss
Poor eye hand coordination
Effects:
Hyperactivity
Intellectual disability (learning disabilities, memory and reasoning deficits, and impaired language development)
Problems in social interactions and school performance
What is fragile X syndrome and features
X linked dominant
Unstable Trinucleotide repeat disorder
Features in females vary, whereas fully expressed in males
Learning difficulties in fragile X
After trisomy 21, fragile X syndrome accounts for the most cases of intellectual disability due to a genetic cause
Delayed language development and autism
Dysmorphic features of fragile Xq
large low set ears, long thin face, high arched palate
macroorchidism
X-tra large → big ears, testes, face
IQ score range in Down syndrome
25-70
Managing the long-term problems in Down syndrome (MDT)
Refer for detailed cardiac assessment, hip US, audiology
Genetic counselling if the karyotype shows a translocation
Put in contact with a support organization (eg. Down Association)
Long-term MDT follow up lead by a paediatrician. Include physiotherapist for tone and posture
Test TFT annually
Refer for audiology and ophthalmic assessment 1-2 yearly
What is a sequence
a pattern of multiple abnormalities occurring after one initiating defect
Potter syndrome is an example of a sequence in which all abnormailiteis may be traced to one original malformation – renal agenesis
What is a syndrome
a particular set of multiple anomlaies occurs repeatedly in a consistent pattern and there is a known or thought to be common underlying casual mechanisms
often associated with moderate or severe cognitive impairment
may be due to:
chromosomal defects
single gene defect
exposure to teratogen
dysmorphism in noonan syndrome
Males and females. Similar phenotype to Turner.
Facies Mild learning difficulties Short webbed neck Pectus excavatum Short stature Congenital heart disease (pulmonary stenosis or ASD)
dysmorphism in william syndrome
Short stature Characteristic facies Transient neonatal hypercalcaemia Supraventricular aortic stenosis Mild to moderate learning difficulties
Dysmorphism in prader willi syndrome
Facies Hypotonia Neonatal feeding difficulties FTT in infancy Obesity in later childhood Hypogonadism Developmental delay Learning difficulties
Dysmorphism in Patau syndrome
Trisomy 13 Structural defect of brain Scalp defects Microphthalmia Cleft lip + palate Polydactyly Cardiac and renal malformations
Dysmorphism in Edwards syndrome
Trisomy 18
Low birthweight Prominent occiput Small mouth and chin Short sternum Flexed, overlapping fingers Cardiac and renal malformations
Mode of inheritance of Duchenne Muscular Dystrophy
X-linked recessive
1/3 are new mutations (deletion of short arm of X chromosome at xp21 site)
Codes for dystophin (absence leads to myofibre necrosis)
Affects all men and homozygous women
Main Clinical features of DMD
Developmental delay: late walking and speech delay
Early: boys have difficulty rising from the floor.
9 years: early loss of ambulation. Slower than peers
Mount stairs one-by-one. Run slowly
Cardiomyopathy
30% have non-progressive mild learning disability.
Average age of diagnosis: 5.5yrs
Additional signs in DMD
Waddling lordotic gait Calf pseudohypertrophy (replacement by fat and fibrous tissue) Weakness in limb girdles (Gower's sign)
Sparing of facial, extraocular and bulbar muscles
Language delay
Scoliosis
Screening tests for DMD
neonatal screening test: serum creatinine phosphokinase markedly elevated
Serum creatinine kinase also grossly elevated.
Genetic testing often enough for diagnosis.
Prognosis of DMD
Death from cardiorespiratory failure or infection by early 20s
management of DMD (preventative)
Genetic counselling (X-linked recessive)
Exercise for power and mobility (delay scoliosis)
Passive stretching and night splints to prevent ankle contracture
Lengthening of Achilles tendon? For ambulation
Attention to good sitting posture (scoliosis)
Parent self-groups for information and support
Ambulant children: corticosteroids to preserve mobility and prevent scoliosis (prednisolone 10 days each months)
Management of scoliosis in DMD
Truncal brace
Moulded seat
Surgical insertion of metal spine rod
Late life management of DMD
Respiratory aids (CPAP) for nocturnal hypoxia secondary to weak intercostal muscles.
Improves quality of life
Types of neurofibromatosis
Group of conditions where tumours grow on the nervous system. 3 types:
NF1 - chromosome 17. light brown spots of the skin, freckles in armpit and groin. Small bumps within nerves
NF2 - chromosome 22. Hearing loss, cataracts at young age, balance problems, flesh coloured skin flaps and muscle wasting
NF3 - Schwannomatosis
Genetics of neurofibromatosis
Autosomal dominant
Highly penetrant
1/3 new mutations
Tumours generally non-cancerous
Diagnostic criteria of NF1
2 or more of these criteria:
6 or more cafe-au-lait spots (>5mm before puberty, >15mm after)
> 1 neurofibroma (firm overgrowth of a nerve)
Axillary freckles
Optic glioma which may cause visual impairment
1 Lisch nodule (hamartoma of the iris)
Bony lesions from sphenoid dysplasia, which can cause eye protrusion.
1st degree relative with NF
Diagnosis of NF 2
Less common than NF1.
1 major and 2 minor criteria:
Major:
Unilateral vestibular Schwannoma & 1st degree relative with NF2
Bilateral vestibular Schwannoma
Minor: Meningioma Schwannoma Ependymoma Glioma Cataract
Genetics of tuberous sclerosis
Dominant
70% are new mutations in TSC1 and TSC2 genes.
They code for hamartin and tuberin respectively (tumour suppressor genes)
1 in 9000 live births
Diagnosis of tuberous sclerosis
Definite: 2 major features with 2 or more minor
Possible.. 1 major feature or 2 minor
Major features of Tuberous Sclerosis
Facial angiofibromas Ungul fibroma Hypomelanotic macules (>3) Shagreen patch Subependymal nodules SubE giant cell astrocytoma Retinal nodular haematoma Cardiac rhabdomyomata
(basically affects brain, skin, heart, kidney, eye, lung)
Minor features of Tuberous sclerosis
Pits in dental enamel Rectal polyps Bone cysts Non-renal haematoma Retinal achromatic patch Cerebral white matter migration tracts Gingival fibromas Confetti skin lesion Multiple renal cysts
Clinical features of NF1
Cutaneous features more evident after puberty
Spectrum of mild-to-severe
Neurofibromata in any peripheral nerve including cranial nerves (symptoms if they occur where the nerve passes through a bony foramen)
Visual or auditory impairment if 2nd or 8th cranial nerves are compressed
Menalencephaly with learning difficulties and epilepsy sometimes
Features of NF2
Bilateral acoustic neuromata are predominant feature
Deafness and sometimes a cerebellopontine angle syndrome with a facial (7th) nerve paresis and cerebellar ataxia
There can be an overlap between the features of NF1 and NF2. Both can be associated with endocronological disorders
Tuberous sclerosis features
Cutaneous:
depigmented “ash-leaf” shaped patches which fluoresce uner UV light
Shagreen patches (roughened patches of skin usually over lumbar spine)
Adenoma sebaceum in a butterfly distribution over the bridge of the nose and cheeks
Neurological:
Infantile spasms and developmental delay
Epilepsy (often focal)
Intellectual impairment
Severe learning difficulties and often autistic features when older
Long term health problems with NF
phaeochromocytoma Pulmonary HTN Renal artery stenosis with HTN Skeletal dysplasia Cognitive impairment
Long term health problems with tuberous sclerosis
Subungal fibromata (beneath the nails)
Ophthalmological haematomata
Cardiac rhabdomyomata (usually resolve in infancy)
Polycystic kidneys
Gliomatous change can occur in brain lesions
Symptomatic epilepsy
