Genetics & Cong heart defects Flashcards
Autosomal dominant & recessive conditions
AD:
Achondroplasia
Acute intermittent porphyria
Adult polycystic disease
Antithrombin III deficiency
Ehlers-Danlos syndrome
Familial adenomatous polyposis
Hereditary haemorrhagic telangiectasia
Hereditary spherocytosis
Hereditary non-polyposis colorectal carcinoma
Huntington’s disease
Hyperlipidaemia type II
Hypokalaemic periodic paralysis
Malignant hyperthermia
Marfan’s syndromes
Myotonic dystrophy
Neurofibromatosis
Noonan syndrome
Osteogenesis imperfecta
Peutz-Jeghers syndrome
Retinoblastoma
Romano-Ward syndrome
tuberous sclerosis
Von Hippel-Lindau syndrome
Von Willebrand’s disease*
Autosomal recessive:
Albinism
Ataxic telangiectasia
Congenital adrenal hyperplasia
Cystic fibrosis
Cystinuria
Familial Mediterranean Fever
Fanconi anaemia
Friedreich’s ataxia
Gilbert’s syndrome*
Glycogen storage disease
Haemochromatosis
Homocystinuria
Lipid storage disease: Tay-Sach’s, Gaucher, Niemann-Pick
Mucopolysaccharidoses: Hurler’s
PKU
Sickle cell anaemia
Thalassaemias
Wilson’s disease
General Infor
***Autosomal recessive
ARM - Autosomal Recessive are Metabolic defects
ADS - Autosominal dominant are Structural defects
Most of the autosomal recessive conditions are inborn errors of metabolism. There are some exceptions to this rule. However, on general basis if you are faced with a question about inheritance and the disease related to is an enzyme deficiency or a metabolic defect, the mode of inheritance is usually recessive.
If the condition causes structural defects within the body, the mode of inheritance is usually dominant.
Autosominal dominant conditions only require one affected gene, on one of the chromosomes to be present.
A recessive condition requires both of the two genes to be present in the genotype.
Common autosomal recessive diseases include:
Sickle cell disease
Cystic fibrosis
Tay-Sachs
Phenylketonuria (PKU)
Mucopolysaccharidoses
Glycogen storage diseases
Mitochondrial diseases include mitochondrial myopathy, diabetes, deafness, Leigh syndrome. These diseases are due to an inherited mitochondrial dysfunction. Mitchondondrial DNA is only maternally inherited.
_______
Autosomal recessive conditions are ‘metabolic’ - exceptions: inherited ataxias
Autosomal dominant conditions are ‘structural’ - exceptions: Gilbert’s, hyperlipidaemia type II
Autosomal recessive conditions are often thought to be ‘metabolic’ as opposed to autosomal dominant conditions being ‘structural’, notable exceptions:
some ‘metabolic’ conditions such as Hunter’s and G6PD are X-linked recessive whilst others such as hyperlipidaemia type II and hypokalaemic periodic paralysis are autosomal dominant
some ‘structural’ conditions such as ataxia telangiectasia and Friedreich’s ataxia are autosomal recessiv
X linked recessive diseases affect a gene carried on the X chromosome so in females a pathogenic variant must be inherited from each parent and females may be unaffected carriers. In males who only have a single maternal X chromosome there is no carrier status, they will either be affected or not. A female carrier will always pass the affected gene onto her sons. An affected male will have unaffected sons, but have carrier daughters.
Common X linked recessive diseases include red-green colour blindness, Duchenne’s and Becker’s muscular dystrophy, haemophilia A/B.
X linked dominant conditions only require one affected X chromosome to produce pathology and conditions include, Rett syndrome, Alport syndrome, and X linked hypophosphataemia.
Mitochondrial diseases include mitochondrial myopathy, diabetes, deafness, Leigh syndrome. These diseases are due to an inherited mitochondrial dysfunction. Mitchondondrial DNA is only maternally inherited.
no male-to-male transmission in
X-linked recessive conditions
TOF vs TGA
Tetralogy of Fallot (TOF) is the most common cause of cyanotic congenital heart disease typically presenting at around 1-2 months.
Transposition of the great arteries is another important cause of cyanotic congenital heart disease but more commonly presents within the first 24 hours of life.
TOF includes
TOF: The four characteristic features are:
ventricular septal defect (VSD)
right ventricular hypertrophy
right ventricular outflow tract obstruction, pulmonary stenosis
overriding aorta
Gastroschisis and exomphalos
Whereas gastroschisis tends to be a stand alone bowel condition, exomphalos is associated with cardiac and kidney diseases
Gastroschisis and exomphalos are both examples of congenital visceral malformations.
Gastroschisis
Gastroschisis describes a congenital defect in the anterior abdominal wall just lateral to the umbilical cord.
Management
vaginal delivery may be attempted
newborns should go to theatre as soon as possible after delivery, e.g. within 4 hours
Exomphalos (omphalocoele)
In exomphalos (also known as an omphalocoele) the abdominal contents protrude through the anterior abdominal wall but are covered in an amniotic sac formed by amniotic membrane and peritoneum.
Associations
Beckwith-Wiedemann syndrome
Down’s syndrome
cardiac and kidney malformations
Management
caesarean section is indicated to reduce the risk of sac rupture
a staged repair may be undertaken as primary closure may be difficult due to lack of space/high intra-abdominal pressure
if this occurs the sacs is allowed to granulate and epithelialise over the coming weeks/months
this forms a ‘shell’
as the infant grows a point will be reached when the sac contents can fit within the abdominal cavity. At this point the shell will be removed and the abdomen closed
Childhood syndromes
Patau syndrome (trisomy 13)
Microcephalic, small eyes
Cleft lip/palate
Polydactyly
Scalp lesions
Edward’s syndrome (trisomy 18)
Micrognathia
Low-set ears
Rocker bottom feet
Overlapping of fingers
Fragile X
Learning difficulties
Macrocephaly
Long face
Large ears
Macro-orchidism
Noonan syndrome
Webbed neck
Pectus excavatum
Short stature
Pulmonary stenosis
Pierre-Robin syndrome*
Micrognathia
Posterior displacement of the tongue (may result in upper airway obstruction)
Cleft palate
Prader-Willi syndrome
Hypotonia
Hypogonadism
Obesity
William’s syndrome
Short stature
Learning difficulties
Friendly, extrovert personality
Transient neonatal hypercalcaemia
Supravalvular aortic stenosis
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
Raised FSH/LH in primary amenorrhoea - consider
primary amenorrhoea (given that she has never had a menstrual period before), in addition to underdevelopment of secondary sexual characteristics.
gonadal dysgenesis (e.g. Turner’s syndrome)
Down’s syndrome complications
Down’s syndrome: features
Clinical features
face: upslanting palpebral fissures, epicanthic folds, Brushfield spots in iris, protruding tongue, small low-set ears, round/flat face
flat occiput
single palmar crease, pronounced ‘sandal gap’ between big and first toe
hypotonia
congenital heart defects (40-50%, see below)
duodenal atresia
Hirschsprung’s disease
Cardiac complications
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%)
Later complications
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
______
The correct answer is C. Hearing loss
Over 90% of adults with Down’s syndrome have significant ENT symptoms including hearing loss. Of the other options given:
> 60% of those who reach the age of 60 will develop Alzheimer’s or an Alzheimer’s-type picture
60-80% of people with Down’s syndrome will have eye disease including early age cataracts
5-10% will have seizures
7-9% will have scoliosis
1st & 2nd degree relatives
The correct answers are D. Female first cousin and G. Grand-aunt
A female first cousin and a grand aunt are third degree relatives.
First degree relatives are a person’s mother, father, daughter, son, sister, and brother. Second degree relatives are a person’s grandparents, grandchildren, aunt, uncle, niece, nephew, half-sister, and half-brother.
Autosomal dominant
The correct answer is A. Autosomal dominant
Autosominal dominant conditions only require one affected gene, on one of the chromosomes to be present. A recessive condition requires both of the two genes to be present in the genotype.
Common autosomal dominant diseases include:
Neurofibromatosis types 1 and 2
Familial hypercholesterolemia (most prevelant)
Adult polycystic kidney disease
Hereditary spherocytosis
Marfan’s syndrome
Huntingdon’s
Von Willebrand’s disease
Hereditary non-polyposis colorectal cancer (HNPCC)
Folic acid & Prevention of neural tube defects (NTD) during pregnancy:
Consequences of folic acid deficiency:
-macrocytic, megaloblastic anaemia
-neural tube defects
Prevention of neural tube defects (NTD) during pregnancy:
-all women 400mcg of folic acid until the 12th week of pregnancy
-women at higher risk of conceiving a child with a NTD 5mg of folic acid from before conception until the 12th week of pregnancy
-considered higher risk:
–either partner has NTD,
–they have had a previous pregnancy affected by a NTD,
–they have a family history of a NTD
–the woman is taking antiepileptic drugs or has coeliac disease, diabetes, or thalassaemia trait.
–the woman is obese (defined as a body mass index [BMI] of 30 kg/m2 or more).
Brushfield spots are small grey or brown spots seen on the periphery of the iris. They are associated with
Down syndrome
mother notes ‘white speckles on his eyes’. Eye examination is unremarkable with a bilateral red reflex
Clinical features
face: upslanting palpebral fissures, epicanthic folds, Brushfield spots in iris, protruding tongue, small low-set ears, round/flat face
flat occiput
single palmar crease, pronounced ‘sandal gap’ between big and first toe
hypotonia
congenital heart defects (40-50%, see below)
duodenal atresia
Hirschsprung’s disease
Cardiac complications
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%)
Later complications
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
Autism
Families with one autistic child have a
-10% risk of recurrence in next child
-20-25% risk of another neurodevelopmental disorder.
If a family has two autistic children then the risk for any new child is 36%.
