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What is the mode of inheritance of Marfan's syndrome?

What is Marfan's syndrome? What are the clinical features?

Autosomal dominant

Disorder of connective tissue associated with tall stature, long thin digits, hyperextensible joints, a high arched palate, dislocation of the lenses and severe myopia


What are the later risks associated with Marfan syndrome?

Cardiovascular - aortic aneurysms which may dissect or rupture


What are the clinical features of Trisomy 21 (3)?

What are the associated problems (7)?

1. Facial appearance - round face, flat nasal bridge etc
2. Hypotonia
3. Flat occiput, single palmar crease, incurved fifth finger, wide 'sandal' gap between big and 2nd toes

Associated problems:
1. Congenital heart defects
2. Duodenal atresia
3. Delayed motor milestones
4. Learning difficulties
5. Increased susceptibility to infections
6. Hearing impairment from secretory otitis media
7. Obstructive sleep apnoea


What are the cytogenetics of Down syndrome and their obstetric risk factors?

Trisomy 21 - extra chromosome 21 from meiotic nondisjunction, translocation or mosaicism

Incidence of trisomy 21 due to nondisjunction is related to maternal age


What are the diagnostic investigations for down syndrome?
1. Antenatally (3)
2. Post-natally (2)

1. Biochemical screening tests
2. Nuchal thickening on USS

When increased risk is identified:
-amniocentesis to check fetal karyotype

3. Noninvasive prenatal testing is now possible in which cell-free fetal DNA is analysed from maternal blood

1. real time PCR
2. rapid FISH techniques


What are the long-term problems associated with Down syndrome (7)?

1. Congenital heart defects
2. Duodenal atresia
3. Delayed motor milestones
4. Learning difficulties
5. Increased susceptibility to infections
6. Hearing impairment from secretory otitis media
7. Obstructive sleep apnoea


What is the cytogenetics of Turner syndrome?

45,X in most cases

Can be: deletion of the short arm of one X chromosome, or another structural defect of one of the X chromosomes


What are the clinical features of Turner syndrome (4)?

What are its associated features (4)?

1. Short stature
2. Neck webbing or thick neck
3. Wide carrying angle
4. Lymphoedema of hands and feet in neonate, which may persist

Associated features:
1. Delayed puberty
2. Congenital heart defects
3. Ovarian dysgenesis resulting in infertility
4. Hypothyroidism


How is Turner syndrome diagnosed?
1. Antenatally
2. Post-natally

1. USS - fetal oedema of the neck, hands or feet or a cystic hygroma may be found

If suspicion - confirmed by chorionic villous sampling or amniocentesis

Postnatally or at puberty:
1. Karyotyping with blood sample


What are the long-term problems of Turner syndrome?
How are they managed (2)?

1. Short stature - Growth hormone therapy
2. Delayed puberty and infertility - Oestrogen replacement for development of 2o sexual characteristics at time of puberty (but infertility persists)


What does genetic counselling aim to do (5)?

1. Listen to concerns of patient and family
2. Establishing the correct diagnosis
3. Risk estimation
4. Communication - information presented in an understandable way
5. Discuss options for management and prevention


What are the dysmorphic features of the following syndromes?
1. Down syndrome (3)
2. Turner syndrome (1)
3. Fragile X syndrome (4)

1. Down syndrome
-Round face and flat nasal bridge, short neck
2. Turner syndrome
-Neck webbing
3. Long face, large everted ears, prominent mandible, broad forehead


What are the key features of fetal alcohol syndrome (4)?

1. Growth restriction
2. Characteristic face - saddle-shaped nose, maxillary hypoplasia, absent philtrum, short thin upper lip
3. Developmental delay
4. Cardiac defects


What are the cytogenetics of fragile X syndrome and what are its clinical features (4)?

A break in the distal part of the long arm of the X chromosome

1. Learning difficulties
2. Macrocephaly
3. Characteristic facies -long face, large everted ears, prominent mandible, broad forehead
4. Macroorchism postpubertally


What are the presenting features of Rett's?
Stage 1-4

Stage 1: Normal development for first 6 months, then development stagnates
-delay with speech
-difficulty feeding

Stage 2: Regression of development
-loss of the ability to use the hands purposefully
-social withdrawal
-difficulty eating, chewing or swallowing

Stage 3: Plateau (from around age of 2-10)
-improvement in social ability and behaviour
-may have more seizures
-arrythmias may develop

Stage 4: deterioration in movement which can go on for months-years
-development of a spinal curve
-muscle weakness and spasticity
-losing the ability to walk


What is duchenne muscular dystrophy?

What is its mode of inheritence?

An inherited disorder with progressive muscle degeneration
X-linked recessive disorder


What are the clinical features of muscular dystrophy (5)?

Children present with:
1. Waddling gait and/or language delay.
2.Have to mount stairs one by one and run slowly compared with their peers
3. Gowers sign (turning prone to rise)
4. Pseudohypertrophy of calves where muscle is replaced by fat and fibrous tissue
5. Learning difficulties

There is progressive muscle atrophy and weakness so they cannot walk by 10-14 years

Life-expectancy is reduced to late twenties from respiratory failure or associated cardiomyopathy


What are early diagnostic signs/symptoms of muscular dystrophy (4)?

What are the initial screening tests?

1. Waddling gait and/or language delay
2. Mounting stairs one be one
3.Gowers sign
4. Pseudohypertrophy of calves

Elevated creatine kinase


What is the management of muscular dystrophy from diagnosis (5)?

1. Physiotherapy - prevent contractures
2. Tendoachilles lengthening and scoliosis surgery if necessary
3. Overnight continuous positive airway pressure (CPAP) or non-invasive positive pressure ventilation for nocturnal hypoxia
4. Corticosteroids to preserve mobility and prevent scoliosis
5. Periodic review


What is neurofibromatosis? What are the different types?

What is its mode of inheritence?

Neurofibromatosis (NF) is a group of two conditions in which tumours grow in the nervous system: NF1 and NF2 (schwannomas, meningiomas and ependymomas)

Autosomal dominant


What is the diagnostic criteria for NF1?

2 or more of the following criteria:

1. 6 or more café-au-lait spots greater than 5mm in size before puberty or greater than 15mm after puberty
2. more than 1 neurofibroma
3. axillary freckling
4. Optic glioma which can cause visual impairment
5. one Lisch nodule (harmartoma of the iris)
6. bony lesions from sphenoid dysplasia which can cause eye protrusion
7. a first-degree relative with NF-1


What are the clinical features of NF2?

1. Bilateral acoustic neuromata are the predominant feature.
2. Deafness
3. Cerebellopontine angle syndrome sometimes with facial nerve paresis and cerebellar ataxia


What are the associated long term health problems with NF1 and 2 (4)?

1. Endocrinological disorders - the MEN syndromes
2. Phaeochromocytoma
3. Pulmonary hypertension
4. Renal artery stenosis with hypertension


What is tuberous sclerosis complex (TSC)?

What is its mode of inheritance?

Tuberous sclerosis complex (TSC) is a rare multisystem genetic disease that causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs, and skin.

Autosomal dominant


What are the clinical features of TSC?
Cutaneous (3)
Neurological (3)

Cutaneous lesions:
1. roughened patches of skin
2. depigmented shaped patches
3. angiofibromata over bridge of nose and cheeks

Neurological features:
1. infantile spasms and developmental delay
2. epilepsy
3. intellectual disability often with autism


What are the clinical features of achondroplasia (4)? What is its inheritance?

Autosomal dominant

1. Short stature (marked shortening of limbs)
2. Large head
3. Frontal bossing
4. Depression of the nasal bridge


What are the long term problems of achondroplasia (2)?

1. Lumbar lordosis
2 Hydrocephalus


What is phenylketonuria?

An inborn error of metabolism that results in decreased metabolism of the amino acid phenylalanine. Untreated PKU can lead to intellectual disability, seizures, behavioral problems, and mental disorders.


How is phenylketonuria diagnosed?

Newborn screening:

bacterial inhibition assay (Guthrie test), immunoassays using fluorometric or photometric detection, or amino acid measurement using tandem mass spectrometry (MS/MS).
Measurements done using MS/MS determine the concentration of Phe and the ratio of Phe to tyrosine, the ratio will be elevated in PKU


How is phenylketonuria managed?

Treatment is with a diet low in foods that contain phenylalanine and supplements - Supplementary "protein substitute" formulas are typically prescribed for people PKU (starting in infancy) to provide the amino acids and other necessary nutrients that would otherwise be lacking in a low-phenylalanine diet