Paeds Genetics (breif) Flashcards
Pathophysiology of Down Syndrome
Incidence increases proportionately to maternal age
- 3 copies of chromosome 21: Trisomy21
- Often caused by meiotic nondisjunction where chromosome 21 fails to separate in meiosis
Signs and Symptoms of Down Syndrome
- Hypotonia
- Brachycephalpy
- Short head and statue
- Prominet Epicanthic folds (eyelid)
- Palmar crease.
- duodenal atresia
- Congential Heart problems (see other card)
Long term complications of down syndrome
Average Life expecrancy is around 60y
- Recurrent otitis media; can have glue ear and conductive hearing loss
- Visual problems – myopia, strabismus and cataracts
- Subfertility: males are almost always infertile due to impaired spermatogenesis.
- Learning disability
- Alzheimer’s (40%)
- Leukemia in children
Cardiac Complications of Downsyndrome
- Multiple cardiac problems may be present
- Endocardial cushion defect (most common, 40%, also known as atrioventricular septal canal defects)
- Ventricular septal defect (c. 30%)
- Secundum atrial septal defect (c. 10%)
- Tetralogy of Fallot (c. 5%)
- Isolated patent ductus arteriosus (c. 5%)
Investigations Down Syndrome
- Confirmed by Senior paediatrician then genetic blood testing performed
- When risk > 1 in 150 the woman is offered aminocentesis or chronic villous sampling - karyotyping of fetal cells
Pathophysiology of Klinefelter syndrome
X linked
- Chromosomal abnormality where a male will have an extra X chromosome – gives them 47, XXY.
- Rarely those with Klinefelter syndrome can have even more X chromosomes i.e. 48, XXXY or 49, XXXXY. These are associated with more severe features.
Signs and Symptoms of Kilinefelter syndrome
Occur after puberty
- Infertility – most common presentation
- Taller height
- Wider hips
- Gynaecomastia
- Weaker muscles
- Hypogonadism with smaller testicles
- Reduced libido
- Shyness
- Subtle learning difficulties – particularly speech and language
Invsetigations and Management Klinfelter’s
- Hormone testing: blood or urine samples can reveal abnormal hormone levels
- Chromosomal analysis to confirm a diagnosis.
- Testosterone injections improve many symptoms
- Advanced IVF techniques have potential to allow fertility
Complications Klinfelter’s
Normal Life expectancy
- Breast cancer compared with other males but still less than females
- Osteoporosis
- Diabetes
- Anxiety and depression
Genetic Chromosomal disorder
Pathophysiology of Turner syndrome
in 1/2500 females
- Lack of X chromosome in girls: 45 XO
Early miscarriage in 95% cases.
Signs and Symptoms Turner Syndrome
Occurs in Girls
- Short Stature
- Lymphoedema of the hands and feet (neonates)
- Webbed neck/thick neck
- Widely spaced nipples
- High arching palate
- Ammenhorrea
- Infertility
- Raised Gonadotrophin
Complications: Coarction of Aorta, Recurrent Otitis media & UTSs, Hypothroidism, HTN, LD
Investigations and Management of Turner Syndrome.
- Ultrasound antenatalys can see oedema in hands and feet
- Chronix villus sampling
- Amniocentesis
- Growth Hormone for statures
- Oestrogen and Progesterone for sex features
Pathophysiology Marfan’s Syndrome
1 in 3000
- Autosomal Dominant Connective tissue disorder
- Defect in the FBN1 gene on chromosome 15 which creates fibrillin which is important component of connective tissue
Signs & Symptoms Marfan’s
- Tall stature
- Long neck and limbs
- High arching palate
- Arachnoactyly (longer fingers)
- Pectus excavatum
Complications of Marfan’s
Life expectancy 40-50y
- Greatest risk comes from dilation of aortic sinusess, leading to mitral valve prolapse and aortic aneurysms.
- Scoliosis of > 20 degrees
- Pneumothroax
Myopia
Investigations and Management of Marfan’s
Clinical diagnosis made.
* Arm span greater than height
* Can test for arachnodactyly; ask the patient to cross their thumb across palm and if the tip goes past the opposite edge this indicates arachnodactyly
Management
* B Blockers and ACEi to keep BP low and reduce risk to heart
Ghrent criteria also used (looks at heart)
Syndromic Form of Diabetes
Pathophysiology Prader Willi Syndrome
opposite to Angelman’s
- Absence of Paternal gene on Chromosome 15 (father)
Symptoms Prader Willi
- Constant insatiable hunger that leads to obesity
- Poor muscle tone as an infant – hypotonia
- Mild-moderate learning disability
- Hypogonadism
- Skin prone to bruising
- Mental health problems, particularly anxiety
- Dysmorphic features
- Narrow forehead , almond shaped eyes, thin upper lip, downturned mouth, strabismus (eyes don’t line up in direction)
NICE recommend GH for some symptoms
Pathophysiology Angelmans
opposite to Prader Willi
Absence of Maternal gene on Chromosome 15 (mother)
Signs & Symptoms Angelmans
are unusual fascination with water, happy demeanour and widely spaced teeth.
- Severe delay or absence of speech development
- Coordination and balance problems
- Inappropriate laughter
- Hand flapping
- Abnormal sleep problems
- Microcephaly
- Fair skin, light hair and blue eyes
- Wide mouth
Link to Epilepsy
There can be feeding difficulties with this condition. Hyperactivity/ADHD is also a problem in children with this condition. Scoliosis can also occur.
Pathophysiology Edward’s Syndrome
Second most common autosomal trisomy after trisomy 21.
Maternal age RF. More commonly affecting Females
- Trisomy of chromosome 18
Symptoms Edward’s
- Micrognathia (undersized jaw)
- Low-set ears
- Rocker bottom feet
- Overlapping of fingers
Associated with cardiac and renal malformations.
Patau Syndrome
- Trisomy 13
- Microcephalic, small eyes
- Cleft lip/palate
- Polydactyly
- Scalp lesions
Can be associated with structural defects of the brain and cardiac and renal abnormalities.
Pathophysiology Fragile X
Prevalence of learning difficulties in males due to fragile X syndrome is about 1 in 4000. Males are always affected but it can affect females as well – vary in how much they are affected.
- Caused by mutation in the fragile X mental retardation 1 (FMR1) gene on the X chromosome.
- X-linked condition but unclear if it is recessive or dominant.
Symptoms Fragile X
Clinical features include:
- Moderate-severe learning difficulty (IQ 20-80; mean 50)
- Macrocephaly
- Macro-orchidism – post pubertal
- Characteristic facies – long face, large everted ears, prominent mandible, broad forehead. This is most evidence in affected adults.
Pathophysiology Duchenne Muscular Dystrophy
- X-linked recessive inheritance disorder majority
- Deletion of the gene for dystrophin – this connects the cytoskeleton of a muscle fibre to the surrounding matrix through the cell membrane
Symptoms Duchenne Muscular Dystrophy
- Progressive proximal muscle weakness from 5 years
- Calf Pseudohypertrophy
- Gower’s sign: child uses arms to stand up from a squatted position
- 30% of patients have intellectual impairment
most children cannot walk by the age of 12 years
patients typically survive to around the age of 25-30 years
associated with dilated cardiomyopathy
Investigations and management Duchenne Muscular Dystrophy
- Raised creatinine kinase
- Genetic testing has now replaced muscle biopsy as the way to obtain a definitive diagnosis
- Management is supportive with Physio
Corticosteroids may help preserve mobility and prevent scoliosis; shown to slow progression of muscle weakness by as much as two years. Creatine supplementation can give a slight improvement in muscle strength.
Noonan Syndrome
Often seen as Male Turners
- Defect in a gene on chromosome 12
- As well as features similar to Turner’s syndrome (webbed neck, widely-spaced nipples, short stature, pectus carinatum and excavatum), a number of characteristic clinical signs may also be seen:
cardiac: pulmonary valve stenosis
ptosis
triangular-shaped face
low-set ears
coagulation problems: factor XI deficiency - Cryptorchidism
Diagnosed using Fish Studies
William Syndrome
Usually the result of random deletion around conception, rather than being inherited from an affected parent.
William’s syndrome is an inherited neurodevelopmental disorder caused by a microdeletion on chromosome 7.
* Elfin-like facies
* Characteristic like affect - very friendly and social
* Learning difficulties
* Short stature
* Transient neonatal hypercalcaemia
* Supravalvular aortic stenosis
