Chromosomal syndromes - trisomy 13/18/21, Noonan, Prader-Willi, Turner, Klinefelter Flashcards
Chromosomal syndromes (incl. trisomy 13 (Patau), 18 (Edwards), 21 (Down), Noonan, Prader-Willi, Turner, Klinefelter)
What is the cause of Down’s syndrome?
Trisomy 21 makes up 94% of cases (in 88% the extra copy is derived from the mother due to non-dysjunction)
Partial trisomy or mosaicism(2,4%) can also occur. Translocation (3.3%)can also cause Down’s whereby the long arm of chr 21 is moved to chr 14 or 22.
How common is Down’s syndrome?
Most common genetic disorder affecting 1 in 650-1000
What are the risk factors for Down’s syndrome?
- Family history
- Maternal age is the strongest risk factor
Statistics:
- 0.84 per 1,000 for ages 25-29.
- 1.48 per 1,000 for ages 30-34.
- 4.72 per 1,000 for ages 35-39.
- 15.22 per 1,000 for ages 40-44.
- 30.71 per 1,000 for 45 years and older.
What are the presenting features of Down’s syndrome?
General:
- hyperflexibility
- hypotonia
- transient myelodysplasia in newborn
Head and neck:
- bradycephaly
- oblique/upgoing palpebral fissures
- epicanthic folds
- Brushfield spots - iris speckles
- abnormal ears
- flat nasal bridge
- loose skin on nape of neck
Mouth:
- protruding tongue (small narrow palate)
- high arched palate
Hands:
- single palmar crease
- short little finger
- in-curved little finger
- short broad hands
Feet:
- gap between hallux and second toes
Congenital heart disease
Duodenal atresia
What gastorintestinal disoders are associated with Down’s syndrome?
- Oesophageal atresia or tracheo-oesophageal fistula.
- Duodenal atresia.
- Pyloric stenosis.
- Meckel’s diverticulum.
- Hirschsprung’s disease.
- Imperforate anus.
- GORD
Describe the neurological and psychiatric disorders found in Down’s syndrome.
- Learning difficulties - but range from severe to ‘low normal’ IQ
- Behavioural problems
- Seizures in 5-10%
*
What problems with immune function occur in Down’s syndrome?
12x greater risk of infection due to impaired cellular immunity (e.g. pneumonia)
Increased risk of AML and ALL
Polycythaemia regressing within 2 months may occur in newborns
What screening should be done for those with Down’s syndrome?
- Cardiac - 50% have congenital heart defects
- Feeding - marked hypotonia
- Vision and hearing - check red reflex for congenital cataracts, 90% have any type of hearing loss and are susceptible to otitis media, sinusitis and pharyngitis.
- Thyroid - hypothyroidism common
- Haematological - risk of transient myeloproliferative disorder, polycythaemia, leukaemoid reaction
What orthopaedic problems occur in Down’s syndrome?
- Atlanto-axial instability - few need treatment unless problems
- Hyperflexibility
- Scoliosis
- Hip dislocation
- Patellar subluxation/dislocation
- Foot deformities
Wha are the late complications of Down’s syndrome?
- subfertility: males are almost always infertile due to impaired spermatogenesis. Females are usually subfertile, and have an increased incidence of problems with pregnancy and labour
- learning difficulties
- short stature
- repeated respiratory infections (+hearing impairment from glue ear)
- acute lymphoblastic leukaemia
- hypothyroidism
- Alzheimer’s disease
- atlantoaxial instability
What is the prognosis with Down’s syndrome?
Survival dramatically increased in last few decades (due to CHD repair) from 10yr in 1970s to mid-50s now.
Leading cause of death are respiratory infections and cardiac causes. Dementia common after age 40yrs. Malignancy risk is low in all age groups apart from leukaemia.
What are the key features of Cri du Chat syndrome?
- (chromosome 5p deletion syndrome)
- Characteristic cry (hence the name) due to larynx and neurological problems
- Feeding difficulties and poor weight gain
- Learning difficulties
- Microcephaly and micrognathism
- Hypertelorism (large distance between eyes)
What are the key features of William’s syndrome?
- Short stature
- Learning difficulties
- Friendly, extrovert personality
- Transient neonatal hypercalcaemia
- Supravalvular aortic stenosis
What are the key features of Fragile X?
- Learning difficulties
- Macrocephaly
- Long face
- Large ears
- Macro-orchidism
What are the key features of Pierre-Robin syndrome? What is it similar to?
- *
- Micrognathia
- Posterior displacement of the tongue (may result in upper airway obstruction)
- Cleft palate
*this condition has many similarities with Treacher-Collins syndrome. One of the key differences is that Treacher-Collins syndrome is autosomal dominant so there is usually a family history of similar problems
A 14-year-old girl presents to her GP due to developmental concerns. She is the shortest girl in her class and has failed to start menstruating. On examination she has cubitus valgus and low-set ears.
What is the most likely diagnosis?
Turner’s syndrome
What kind of murmur are you most likely to hear in Turner’s syndrome?
Ejection systolic murmur - due to the bicuspid aortic valve causing AORTIC STENOSIS(ESM)
How common is Turner’s syndrome?
1 in 2,500 females
What is the genetic basis of Turner’s syndrome?
45,XO or 45,X
Single X or the deletion of the short arm of one of the X chromosome
What is the presentation of Turner’s syndrome?
- Short stature
- High-arched palate
- Webbed neck
- Shield chest, widely spaced nipples
- Short fourth metacarpal
- Multiple pigmented naevi
What are the medical features of Turner’s syndrome?
Cardiac:
- Bicuspid aortic valve (15%)
- Coarctation of the aorta (5-10%)
- Lymphoedema in neonates (especially feet)
Endocrine:
- hypothyroidism
- elevated gonadotrophin levels
- primary amenorrhoea
Renal:
- Horseshoe kidney
Neurological:
- Cystic hygroma (prenatally diagnosed)
Dermatological:
- Multiple pigmented naevi
What autoimmune diseases are patients with Turner’s syndrome at risk of?
- Autoimmune thyroiditis
- Crohn’s disease
What is the most common X linked cause of learning difficulties?
Fragile X syndrome
What is fragile X syndrome?
X linked
dominant
trinucleotide repeat disorder
Name 3 complications of fragile X syndrome.
- Large low set ears, long thin face, high arched palate
- Mitral valve prolapse
- Hypotonia
- Macroorchidism
- Pes planus (flat feet)
Mental:
- Autism
- Memory probelms
- Speech disorders
How do you diagnose fragile X syndrome?
- Antenatally by chorionic villus sampling/amniocentesis
- Analysing CGG repeats by restricton endonucleases and Southern blotting
Why do females with fragile X syndrome have normal to mild features?
They have one normal X chromosome
What is the karyotype XXY?
Klinefelter’s syndrome
What are the physical features of Klinefelter’s syndrome?
- taller than average
- gynaecomastia - increased incidence of breast cancer
- lack of secondary sexual characteristics
- small, firm testes
Other:
- elevated gonadotrophin levels but low testosterone
- infertile
How common is Prader-Willi?
Esimated 1:10,000 prevalence
1:1 male:female ratio
More common in Caucasians
Most common known genetic cause of life threatening obesity in humans
What are the key features of Prader-Willi syndrome?
- Hypotonia during infancy and failure to thrive - interest in food becomes apparent at 12-18 months (usually blue eyes and blond hair)
- Dysmorphic features
- Hypogonadism + infertility; hypothalamic dysfunction causing temperature instability, high pain threshold, hypersomnia, GH and thyroid deficiencies, central adrenal insufficiency.
- Hyperphagia and obesity
- Short stature
- Learning difficulties and behavioural problems in adolescence
What is the cause of Prader Willi syndrome? What does the phenotype depend on?
Absence of the Prader-Willi gene on the long arm of chromosome 15. This may be due to:
- microdeletion of paternal 15q11-13 (70% of cases, from father)
- maternal uniparental disomy of chromosome 15 (2 copies from mother)
Prader-Willi is an example of genetic imprinting and phenotype depends on whether the deletion occurs on a gene inherited from mother or father:
- If gene deleted from father –> Prader-Willi syndrome
- If gene deleted from mother –> Angelman syndrome
How do you diagnose Prader-Willi syndrome?
-
There is a criteria with minor and major points required for diagnosis:
- Birth to age 3yr - 5 points including 4 major criteria.
- Age 3yr to adult - 8 total points including 5 major criteria
- https://patient.info/doctor/prader-willi-syndrome-pro#ref-2
- DNA methylation analysis and FISH - diagnose PWS and differentiate from Angelman syndrome
- Screening for endocrinopathies - GH, hypogonadism, thyroid, adrenal, vitamin D and bone health, HbA1c checked annually.
- Psychological and educational testing also required
How do you manage PWS?
MDT approach - involving gastroenterologists/endocrinologists, psychologists, psychiatrist, dietician, OCT, SALT, orthopaedics and bariatric input.
- Intensive rehabilitation
- Nutritional management
- Treatment of complications, GH replacement if necessary
- Family support - to keep child away from food, exercise, enable transition into adulthood.
- Pharmacological therapies - octerotide reduces ghrelin secretion but does not affect behaviour or weight; fluoxetine and haloperidol sometimes effective; SSRIs have a stabilising effect reducing tantrums but none universally successful.
What are differential diagnoses for PWS?
- Obesity
- Fragile X syndrome
- Cryptorchidism
- Short stature
- Hyperphagic short stature syndrome
List some complications of PWS.
- Cardio-respiratory - sleep apnoea
- Endocrine - gonads, thyroid, pancreas (T2DM), hypothalamus, bone
- Neurological - scoliosis, kyphosis, squint, myopia
- Skin - cellulitis, oedema, infections due to skin picking
- Gastrointestinal - bloating, perforation due to overeating and gastroparesis
What is the prognosis of Prader-Willi syndrome?
Early death (average of 29.5 years) usually due to:
- Respiratory failure (31%)
- Cardiac (16%)
- Gastrointestinal (10%)
- Infection
- Obesity
- PE
- Choking
- Accidents
What are the key features of Noonan syndrome?
- ‘Male Turner’s’
- Broad and webbed neck
- Pectus excavatum
- Short stature
- Pulmonary stenosis (congenital heart disease)
- Increased bleeding tendency
- Dysmorphic features*
- Developmental delay
- Cryptorchidism
*
- many have very blue/green eyes and curly/wooly hair
- tall forehead
- downslanting parpebral features (also seen in fetal alcohol syndrome)
- low set ears
- low posterior hairline
- triangular shaped face
How common is Noonan syndrome? What is the cause?
~1 in 1000-2500
Caused by mutation in RAS/MAPK pathway (60% spontaneous) essential for cell cycle differentiation, growth and senescence. Most common mutations are PTPN11 (50%), KRAS etc. + have marked variable expressivity
Describe the karyotype in Noonan’s syndrome. What are the genetics?
Normal karyotype
Autosomal dominant condition thought to be caused by a defect in gene on chr12
What kind of bleeding disorders are present in NS?
Nearly 40% have easy bruising or bleeding sye to clotting factor deficiencies, low platelet count, platelet dysfunction - there is a factor XI deficiency
How do you diagnose Noonan’s syndrome?
Clinical features including 2 or more of the following - learning difficulties, cadiac defect (PS), chest deformity, short stature, crytorchidism, FH of any of above of NS.
Molecular genetic testing using NGS - can get a prenatal diagnosis if affected parent present
How do you manage Noonan’s syndrome?
Manage the complications and monitor for them using a multidisciplinary team approach (including paediatricians, endocrinologists, psychologists/psychaitrists, neurologists).
What are the complications of Noonan’s syndrome? What is the prognosis?
Complications -
- Cardiorespiratory - regular follow up for issues inlcuding PS
- Endocrine - growth failure, hypothyroidism, pubertal delay
- Renal and GU - undescended testes
- GI issues - recurrent vomiting or feeding difficulties
- Anaesthesia - at risk of malignant hyperthermia
Prognosis - depends on severity and most lead normal lives with normal cognition. Mortality higher in group with hypertrophic cardiomyopathy.
What are the key features of Patau syndrome?
Many fetuses never survive until term and are stillborn or spontaneously abort.
- (trisomy 13)
- Microcephalic, small eyes
- Cleft lip/palate
- Polydactyly
- Scalp lesions
- Rocker-bottom feet (also present in trisomy 18)
Other:
- congenital heart defects
- holoprosencephaly (brain not divided into two halves)
- brain and CNS - neural tube defects, learning disability (severe), central apnoea
- ear malformations and deafness
- capillary haemangioma
Can be difficult to differentiate from Edwards’s syndrome.
What are the genetics of Patau syndrome?
Trisomy 13 (extra chr 13) although chromosomal translocations and mosaic variations can occur
How common is Patau syndrome?
1 in 5,000-29,000
Third most common trisomy after 21 and 18.
What are the risk factors for development of trisomy 13?
Increasing risk with maternal age but not as markedly as with Down’s syndrome or Edwards’ syndrome.
How do you diagnose Patau syndrome?
Cytogenetic studies and chomosomal analysis - amniocentesis or chorionic villus sampling needed for definitive diagnosis
Ultrasound may show features of Patau syndrome during pregnancy
What is the management of Patau syndrome?
Supportive but life-sustaining measures are not always carried out (if liveborn)
Wishes of parents must be taken into account before surgical interventions
Parents should undergo chromosomal analysis as this can affect future pregnancies
What is the prognosis of Patau syndrome?
Life expectancy limited - median survival 2.5 day (50% live longer than a week and 5-10% longer than one year) but variable phenotype.
Profound learning disability and developmental delay in those that survive; common feeding difficulties and seizures.
What are the key features of Edward’s syndrome?
- (trisomy 18)
- Micrognathia (small jaw)
- Low-set ears
- Rocker bottom feet
- Overlapping of fingers
Diagnosis leads to TOP in 86% of cases. Other features:
- Small facial features - microphthalmia, microstomia
- Microcephaly
- Cleft-lip and palate
- Coloboma of iris
- Abnormal clenched hands
- Congenital heart defects - 90% have these (incl. ASD, VSD, PDA, CoA)
- Anencephaly, hydrocephaly, severe learning disability
What are the genetics of trisomy 18?
Phenotype can be full, mosaic or partial but FULL trisomy is the most common (i.e. every cell contains 3 full copies of chr18)
How common is trisomy 18?
Second most common autosomal trisomy after 21
Prevalnce between 1 in 3,600-10,000
Females more affected (may be because males are more likely lost to miscarriage or stillbirth)
What are the risk factors for Edwards’ syndrome?
Maternal age from 35-45 years is associated with increased risk
Small association with increased paternal age
How do you diagnose Edward’s syndrome?
Cytogenetic studies and chromosomal analysis - confirm diagnosis
What is the prognosis of Edwards’ syndrome?
Must be recognised that infants with Edwards’ have a high mortality (median survival time is 14 days) and 38% die during labour. Only 8% survive to 1yr.
Major causes of death are central apnoea, cardiac failure and respiratory insufficiency.
