Genetics Flashcards
Name some autosomal dominant diseases.
- Noonan syndrome
- Neurofibromatosis type I
- Tuberous sclerosis
- Huntington’s disease
- Myotonic dystrophy
- Marfan syndrome
- Ehlers-Danlos syndrome
- Achondroplasia
- Osteogenesis imperfecta
- Autosomal dominant polycystic kidney disease
- von Willebrand disease
- Hereditary spherocytosis
- Familial hypercholesterolemia
Name some autosomal recessive diseases.
- Congenital adrenal hyperplasia
- Cystic fibrosis
- Sickle cell anemia
- Thalassemia
- Friedreich’s ataxia
- Ataxia telangiectasia
- Werdnig-Hoffmann disease (Type I)
- Phenylketonuria
- Glycogen storage diseases
- Galactosemia
- Mucopolysaccharidoses
- Tay-Sachs disease
Name some X-linked recessive diseases.
- G6PD deficiency
- Hemophilia A and B
- Wiskott-Aldrich Syndrome
- Duchenne muscular dystrophy
- Lesch-Nyhan syndrome (Fragile X syndrome)
What is the most common genetic cause of severe learning difficulties?
Down syndrome (47, T21)
What is the most common autosomal chromosomal abnormality?
Down syndrome (47, T21)
What is the incidence of Down syndrome?
1 in 650-800 - Increases with maternal age
>> 1 in 1500 in age 20
>> 1 in 20 in age 45
What are the features of Down syndrome on inspection?
Head
- Microcephaly
- Brachycephaly
Eyes
- Upslanting palpebral fissures
- Inner epicanthal folds
- Speckled iris with Brushfield spots
- Strabismus
- Nystagmus
Ears
- Low-set and small ears
Face
- Protruding tongue
- Low and flat nasal bridge
- Small nose
Hands
- Transverse palmar (Simian) crease
- Clinodactyly
- Absent middle phalanx of the 5th finger
Toes
- Wide “sandal” gap between the big and second toe
Skeletal
- Short stature
- Excess nuchal skin (increased nuchal translucency)
What medical conditions are associated with Down Syndrome?
Eyes
- Refractive errors
- Acquired cataracts
- Strabismus
- Nystagmus
Ears
- Recurrent acute otitis media due to horizontal Eustachian tube
- Hearing loss
Skeletal
- Short stature
- Joint hyperflexibility
>> Hip dysplasia
>> Atlantoaxial instability
>> Vertebral anomalies
Cardiac
- Atrioventricular septal defect (50%)
Gastrointestinal
- Duodenal atresia
- Tracheoesophageal fistula
- Hirschsprung’s disease
Genitourinary
- Cryptorchidism
- Infertility
Neurological
- Intellectual impairment
- Developmental delay
- Hypotonia at birth
- Alzheimer’s disease onset at 40 years
Hematological
- Polycythemia
- 1% lifetime risk of leukemia
Others
- Hypothyroidism
What are the possible causes of the extra chromosome in Down syndrome (T21)?
Meiotic non-disjunction (94%)
- An error at meiosis
- Related to maternal age
Translocation (5%)
- Robertsonian translocation: when the extra chromosome 21 is jointed onto another chromosome (e.g. chr 14, 15, 22 or 21) – usually chromosome 14
- Down syndrome with a set of 46 chromosomes but with three copies of chromosome 21 material
Mosaicism (1%)
- Some cells are normal, and some have T21
- After formation of a chromosomally normal zygote by non-disjunction at mitosis
- Can arise by later mitotic nondisjunction in a T21 conception
What is the management for Down syndrome?
LONG-TERM!
- Support for the child and parent
- Genetic counseling
- Recommended chromosomal analysis: confirm dx
- Hearing test: hearing losses
- Ophthalmology assessment: cataracts, refractive errors
- Atlanto-occipital X-ray at 2 years: atlantoaxial instability
- Echocardiogram: ASVD
- CBC: polycythemia, increased risk of leukemia
- Annual thyroid test: hypothyroidism
What is the most common sex chromosome disorder?
Turner syndrome (45XO)
What is the most common outcome of ALL CASES of Turner syndrome?
Early miscarriage
What is the relationship between maternal age and Down syndrome?
Significant increased risk in advanced maternal age Mother 20 years: 1 in 1500 Mother 45 years: 1 in 20
What is the relationship between maternal age and Turner syndrome?
Incidence does NOT increase with maternal age. The risk of recurrence is VERY LOW.
What are the clinical features of Turner syndrome?
- Lower posterior headline
- Short webbed neck
- Cystic hygroma in newborn with polyhydramnios
- Broad chest with widely spaced nipples
- Lung hypoplasia
- Coarctation of the aorta with biscuspid aortic valve
- Renal abnormalities
- Increased risk of hypertension
- Lymphedema of the hands and/or feet
- Wide carrying angle
- Streak gonads with infertility
What is the prognosis of Turner Syndrome?
Normal life expectancy if no complications
What is the management for Turner syndrome?
- GH therapy for short stature
- Estrogen replacement for development of secondary characteristics at the time of puberty
- Echocardiogram/ECG for cardiac malformations
>> Coarcation of the aorta
>> Bicuspid aortic valve
How common is Turner syndrome?
1 in 4000 live female births
How common is Klinefelter syndrome?
1 in 1000 live male births
What are the clinical features of Klinefelter syndrome?
- Tall and slim
- Long bones with unfused epiphyseal plates
- Developmental delay/Intellectual subnormality
- Eunuchoidism
- Feminizing features: gynecomastia
- Sterility: azoospermia, hypogonadism
What are the complications of Klinefelter syndrome?
Increased risk of germ cell tumours and breast cancer
What is the management of Klinefelter syndrome?
Testosterone in adolescence
What is the relationship between maternal age and Klinefelter syndrome?
Increased risk with advanced maternal age
>> Recurrence risk very low
What is the mode of inheritance of Noonan syndrome?
Autosomal dominant
How common in Noonan syndrome?
1 in 2000 female and male live births
What are the clinical features of Noonan syndrome?
“Male Turner Syndrome” - although can occur in both females and males
>> Short stature
>> Webbed neck
>> Triangular facies
>> Hypertelorism (orbital)
>> Low set ears
>> Epicanthal folds
>> Ptosis
>> Moderate intellectual disability
>> Delayed puberty
- Pectus excavatum
- Right-sided congenital heart disease: Pulmonary stenosis
What is the management for Noonan syndrome?
- ECHO/ECG for cardiac abnormalities (PS)
- Testosterone for affected males
What is the mode of inheritance for Fragile X syndrome?
X-linked with genetic anticipation and mixed penetrance
(Recessive VS. dominant debatable)
>> CGG trinucleotide repeat on X-chromosome non-coding region
What are the clinical features of Fragile X syndrome?
6Ms!
M: Mutation in FMR1 gene on X-chromosome
M: Mental retardation
M: Macrotia (large everted ears)
M: Macrognathia
M: Macro-orchidism
M: Mitral valve prolapse
+ Long and thin face
+ Hyperextensibility
+ High arched palate
What are the complications of Fragile X Syndrome?
- Mitral valve prolapse
- Seizures
- Scoliosis
- Premature ovarian failure in females
- Tremor/ataxia in males later in life
What is the most common heritable cause of intellectual disability in boys?
Fragile X syndrome
How common is Fragile X syndrome?
1 in 3600 males 1 in 6000 females
How is Fragile X syndrome diagnosed?
Molecular testing of FMR1 gene
What is the genetic cause of Prader-Willi Syndrome?
Deletion of paternal chromosome 15q11 or two maternal chromosomes 15q11
What are the presenting features of Prader-Willi Syndrome?
H3O
- Hypotonia and weakness
- Hypogonadism
- Hyperphagia
- Obesity
+ Short stature
+ Almond-shaped eyes
+ Small hands and feet with tapering of fingers
+ Hypopigmentation
+ Type II DM
What is the genetic cause of Angelman syndrome?
Maternally derived deletion of typically maternally expressed genes - paternal copy silenced epigenetically
What are the presenting features of Angelman syndrome?
- Severe mental retardation with ataxia
- Uncontrollable laughter
- Hypotonia
- Seizures
- Tremor
- Midface hypoplasia
- Fair hair
“Blonde laughing bimbo - high!”
What is the most common genetic diagnosis?
Down syndrome
What is the second most common genetic diagnosis?
DiGeorge syndrome
What is the genetic cause of DiGeorge syndrome?
Microdeletion of chromosome region 22q11
What are the presenting features of DiGeorge syndrome?
CATCH 22
C: Cardiac abnormalities - truncus, TOF
A: Abnormal facies - micrognathia, low-set ears
T: Thymic aplasia
C: Cleft palate/Cognitive impairment
H: Hypoparathyroidism, hypocalcemia
22: 22q11 microdeletions
How common is Prader-Willi syndrome?
1 in 15000
What is the genetic cause of Williams syndrome?
Sporadic mutation
What are the clinical features of Williams syndrome?
- Short stature
- Characteristic facies
- Transient neonatal hypercalcemia
- Congenital heart disease: supravalvular aortic stenosis
- Mild-moderate learning difficulties
What are two common causes of lens subluxation?
- Marfan syndrome
- Homocystinuria
What are the types of inborn errors of metabolism?
Carbohydrate
- Galatosemia
- Glycogen storage diseases
Proteins
- Phenylketonuria
- Tyrosemia
- Homocystinuria
- Organic acid disorders
- Urea cycle disorders
Lipids
- Fatty acid oxidation defects
Organelle disorders
- Congenital disorders of glycosylation
- Mucopolysaccharidoses
What is the underlying pathophysiology of galactosemia?
Galactose-1-phosphate uridyltransferase deficiency
>> Autosomal recessive
>> Inability to process lactose or galactose
What are the presenting features of galactosemia?
- Vomiting
- Jaundice
- Failure to thrive
- Liver and renal failure
- Cataracts
- Developmental delay
(+ Hypoglycemia)
>> Usually onset when lactose-containing milk feeds such as breast or infant formula are introduced
What is the management of galactosemia?
Elimination of galactose and lactose from the diet
>> Soy-based diet
What are some examples of glycogen storage diseases?
Muscle-predominant
- Type II: Pompe’s disease – death by cardiomegaly/CHF
- Type V: McArdle’s disease
Liver-predominant (hepatomegaly/hypoglycemia)
- Type I: von Gierke’s disease
- Type III: Cori’s disease (milder form of type I)
Type II and III can affect both liver and muscle.
What are some long-term complications of von Gierke’s disease (type I glycogen storage disease)?
- Hyperlipidemia
- Hyperuricemia
- Hepatic adenomas
- Cardiovascular disease
What are the types of metabolic diseases associated with hyperammonemia?
- Organic acid disorders
- Urea cycle disorders
- Aminoaciduria
What are some examples of lipid storage disorders?
- Tay-Sachs disease
- Gaucher disease
- Niemann-Pick disease
What is the mode of inheritance of Tay-Sachs disease?
Autosomal recessive
What are the clinical features of Tay-Sachs disease?
- Developmental regression in late infancy
- Severe hypotonia
- Enlarging head
- CHERRY RED SPOT ON MACULA
- Death by 2-5 years
What are the clinical features of Gaucher disease?
- Chronic childhood form
- Splenomegaly
- Bone marrow suppression
- Bone involvement
- Normal IQ - Acute infantile form
- Splenomegaly
- Neurological degeneration with seizures
What are the clinical features of Niemann-Pick disease?
Onset at 3-4 months of age
- Feeding difficulties and FTT
- Hepatosplenomegaly
- Developmental delay
- Hypotonia
- Hearing and visual deterioration
- Cherry red spot in macula in 50% (ddx: Tay-Sachs disease)
- Death by four years
What are mucopolysaccharidoses?
Progressive multi-system disorders of lysosomal storage affecting:
- Neurological
- Ocular
- Cardiac
- Skeletal
Characterized by certain enzyme defects and URINE EXCRETION OF GAGs (glycosaminoglycans), the major storage substances
What are the clinical features of mucopolysaccharidoses?
Developmental delay following a period of essentially normal growth and development: UP TO 6-12 MONTHS OF AGE
Other neurological
- Carpal tunnel syndrome
- Conductive hearing loss
Ocular
- Corneal clouding
- Retinal degeneration
- Glaucoma
Cardiac
- Valvular lesions
- Heart failure
Abdomen
- Hepatomegaly
- Splenomegaly
- Umbilical and inguinal hernias
Skeletal
- Thickened skull
- Broad ribs
- Claw hand
- Thoracic kyphosis
- Lumbar lordosis
Skin
- Thickened skin
- Coarse facies
What are some types of mucopolysaccharidoses?
MPS I: Hurler
MPS II: Hunter
MPS III: Sanfilippo
MPS IV: Morquio
MPS IV: Maroteaux-Lamy
What are some examples of mineral storage disorders?
- Wilson’s disease (copper)
- Hemosiderosis (iron)
