Genetics Flashcards
Deep creases in palm and sole + developmental delay + mild dysmorphic features (deep set eyes and an everted lower lip) what mutation?
Mosiac trisomy 8
Features of tetrasomy 12p?
AKA Pallister-Killian Syndrome
Normal blood karyotype.
Coarse facial features and bitemopral sparsity of hair
Severe developmental delay
Karyotype of Klinefelter syndrome
47XXY
Patient with Klinefelter syndrome are at increased risk of what diseases
Pulmonary disease
Varicose veins
Breast cancer, leukaemia and mediastinal germ cell tumors
McCune-Albright syndrome is associated with learning difficulty T/F
F
Note: it is assoc with cafe-au-lait macules, precocious puberty and polyostotic fibrous dysplasia
Features of Cowden syndrome?
Autosomal dominant
Macrocephaly
Variable developmental delay
Increased risk of breast, thryoid and endometrium tumors and skin lesions (including papillomas and facial trichilemmomas)
Mutation associated with cowden syndrome
PTEN gene (AD inheritance)
NSD1 gene or 5q35 deletion, what genetic disoder?
Soto syndomre
Soto syndrome is associated with what abnormalities?
Macrocephaly + large feet and hands + prominent forehead, down slanting palpebral fissues, prominent jaw and high and narrow palate
Seizures
Mild ventricular dilatation
Note: facial features - prominent forehead, down slanting palpebral fissures, prominent jaw and high, narrow palate
Soto syndrome is mostly due to de novo gene mutations T/F
True
GPC 3 gene mutation, what syndrome?
Simpson-Golab - Behmel syndome
Simpson-Golab-Behmel syndrome is X-linked recessive T/F
True
Note: carrier females can have subtle facial manifestations including a large mouth, pointed chin or coccygeal appendage
What is the most common form of inherited congenital deafness?
Pendred’s syndrome
Note: AR inheritence; presents with simple goitre and mild hypothyroidism; deafness is sensorineural
Clinical features of glutaric aciduria type 1
Choreiform and dystonic movements Normal eye exam Macrocephaly Developmental delay Often presents after a minor illness as the body is working at a higher rate of metabolism which unmasks the deficiency
Canavan’s disease eye findings
Optic atrophy
Alexander disease is associated with hypotonia T/F
F - it is assoc with stiff limbs
Note: rare demyelinating leukodystrophy, presents around 2 yrs old with progressive macrocephaly, seizures, stiff limbs and ataxia
Eye findings in mucopolysaccharidosis?
Corneal clouding (except Hunter syndrome)
Eye findings in GM2 gangliosidosis?
Cherry red spot
Tay–Sachs and Sandhoff disease
What may be seen on a CT brain of a patient with glutaric aciduria type 1?
Subdural effusion
Note: subdural effusion is also a common complication of streptococcal meningitis
Are carnitine levels high or low in carnitine transporter defect?
Very low - as carnitine is not taken up by the cells and hence it is lost in the urine.
Hence diagnosis is confirmed by high fractional excretion of carnitine
Note: also associated with cardiomegaly; carnitine is essential for long chain FA oxidation and FA are the preferred fuel source for the heart
In antenatal screening T21 is a cause of elevated alpha fetoprotein T/F
F - T21 is a cause of REDUCED AFP
Causes of elevated AFP - liver necrosis, anencephaly, spina bifida, sacrococcygeal teratoma
How does arginase deficiency commonly present?
Lab abnormality?
Spastic diplegia and subsequently seizures, ataxia and dystonia
Increased arginine and ammonia
Male with short stature, webbed neck, hypertelorism, downslanting palpebral issues has what syndrome
Noonan syndrome (“male Turner syndrome”)
Other features: skeletal defects, cryptorchidism, bleeding diathesis, card abnormality
What is the most common cardiac abnormality with Noonan syndrome?
Pulmonary stenosis and hypertrophic cardiomyopathy
What is the cardiac abnormality in Turner syndrome
Coarctation of aorta and bicuspid aortic valve
Cardiac abnormality in Alagille syndome
Peripheral pulmonary artery stenosis (up to 90%)
Tetrology of fallot
Cardiac abnormality in William syndrome
Supravalve aortic stenosis
Overly friendly
What is the most common form of inherted mental retardation affecting boys?
Fragile X syndrome
Female carries of Fragile X syndrome are usually of normal intelligence but may have what?
Premature menopause
What is the gene involved in fragile X
FMR1 gene on x chr; caused by expansion triplet repeats
Mutation in HERG is assoc with what cardiac abnormality
Long QT syndrome
Deletion of 22q11.2 is common in may congenital cardiac diseases including DiGeorge syndrome. What other ones
Tet of Fallot
Common arterial trunk
Familial VSD
Cystinosis causes what acid base abnormality?
Hyperchloraemic acidosis
Also rickets
It is AR
Inheritance of fabry’s disease and broad category of pathology
X linked recessive
Lysosomal storage
Fabry’s disease what cardiac pathology
Mitral valve prolapse
Clinical features of Fabry disease
Neuro: neuropathic pain; decreased ability to sweat; cloudiness of eye, hearing loss
Card: MVP
Derm: dark red spots on the skin called angiokeratomas
Characteristic lab abnormality in MCADD
Hypoketotic hypoglycaemia
Note: this is a fatty acid oxidation defect –> not able to make ketones; mgmt avoid prolonged fasting and glucose supplementation during illness
Other presentations: lethargy, seizure, coma, acute hepatic failure
MECP2 mutation, what disease?
Rett Syndrome
SNRPN mutation, what disease?
Prader Willi
UBE3A mutation, what disease?
Angelman Syndrome
In a pt with pendred syndrome what would you expect to see on imaging of middle/internal ear?
Bilateral dilation of vestibular aquaducts
Inheritance of Marfan’s syndrome
Autosomal dominant
Helpful way to distinguish AD vs X linked AD in pedigree chart?
A male with the disease - all daughters will be affected but no males will be
Examples of x linked dominant: Rhett syndrome (although sporadic 99%), Alport syndrome, fragile X, X linked hypophosphataemia, incontinentia pigmenti
Incidence of PKU
1 in 10,000 live births
Abnormality on chr11p15 is assoc with what syndrome?
Beckwith Wiedemann syndrome
Beckwith Wiedemann is assoc with risk of what malignancy?
Wilms tumor
Hepatoblastoma
Note: surveillance
AFP every 2-3 weeks until 4 yrs old + abdo USS every 3 months until age of 8
What is Williams syndrome also known as?
Idiopathic infantile hypercalcaemia
Note: mutation on chr 7
What is the aetiology of Smith-Lemli-Opitz syndrome
Inability to break down cholesterol due to def in cholesterol reductase. This lead to a low cholesterol level, tx is with a high cholesterol diet
Maternal uniparental disomy of chr 15 what syndrome?
Prader Wili
Paternal uniparental disomy of chr 15 what syndrome?
Angelman’s syndrome
Both copys inherited from father
HLA A3 is associated with what disease?
Haemochromotosis
HLA Cw6 is associated with what disease?
Psoriasis
HLA B5 is associated with what disease?
Bechet’s syndrome, polycystic kidney disease, ulcerative colitis
HLA DR2 is associated with what disease?
MS and goodpastures syndrome
HLA DR3 is associated with what disease?
Addison’s disease, Sjogren disease , Graves disease, diabetes mellitus
HLA DR4 is associated with what disease?
Rheumatoid arthritis and diabetes mellitus
Phenylketonuria leads to low phenylalanine serum T/F
F
Due to a def of phenylalanine hydroxylase, hence unable to convert phenylalanine to tyrosine
Patients with phenylketonuria have fair skin T/F
T “dilute pigmentation” due to inadequate melanisation
Other features - low IQ, poor head growth, seizures and eczema-like rash.
MSK abnormalities with Alagille syndrome
Most common: butterfly vertebrae
Less common: Radio-ulnar synostosis and short phalanges
Note: also cholestasis, congenital heart disease (commonly pulmonary valve), anterior segment abnormalities (mainly posterior embryotoxon)
Presentation of ornithine aminotransferase deficiency?
Worsening myopia and night vision
Affects the retina and the choroid
Most males foetuses with incontinentia pigmenti will result in miscarriage. T/F
T
NLG3 is associated with what?
Non syndromic autism
Triple X syndrome is associated with problems of gonadal determination and sexual differentiation T/F
False - this is due to lyonisation/inactivation of the extra X. Hence phenotypically normal.
Note: features are delays in language, gross motor and auditory processing; learning difficulty, EEG abnormalities. Can have premature ovarian failure but normal fertility is usually present
In a pt with Down syndrome and other family members with DS such as first cousins what is the likely cause?
Unbalanced Robertsonian Translocation
Note: this is known as translocation down syndrome, as opposed to T21. A balanced translocation will not result in down syndrome
What is the inheritance of Hunter syndrome?
X linked recessive
Note: most other mucopolysaccharidoses are autosomal recessive
What is the inheritance of hereditary spherocytosis
Autosomal dominant
What is the inheritance of Vit D resistant rickets?
X linked dominant
Galastosaemia can lead to precocious puberty T/F
F - it can lead to delayed puberty in females due to ovaries not producing enough oestrogen
There is an increasing incidence of Turners syndrome in with increasing maternal age T/F
F
Anosmia, early onset retinitis pigmentosa (night blindness), chronic axatia, variable neuropathy, deafness and pruritus what disease?
Refsum’s disease (a peroxisomal disorder)
What does VACTERL stand for?
Vertebral Anorectal Cardiac Tracheo-esophageal Renal/radial Limb
Characteristic “aged” appearance with deep set eyes and significant ocular manifestations (cataracts, optic atrophy and pigmentary retinopathy) what syndrome?
Cockayne syndrome
Note: also have significant post natal growth failure and progressive neuro dysfunction.
Triangular face with blue sclera, small body but normal head circumference, 5th finger clinodactyly and cafe au lait spots and increased sweating. What syndrome
Russell silver syndrome
Features of Holt Oram syndrome?
Upper limb abnormalities and congenital heart disease (mainly ASD and VSD)
Main Ddx TAR syndrome but no cardiac issues in TAR
What are the 3 cardinal features of Bloom syndrome?
Photosensitivity
Telangiectatic erythema of face
Stunted growth
Note: can also have recurrent infections and predisposition to malignancy and dysmorphic features
What is the pathology of Bloom syndrome?
AR inheritance and caused by a DNA repair defect
DDx of hypoketotic hypoglycaemia
- Hyperinsulinism
- Fat oxidation defects such as MCADD
- Liver failure (site of fat oxidation)
- Some mitochondrial disorders
Autosomal recessive disorder that arises from a mutation of a lysosomal trafficking regulator protein, which leads to a decrease in phagocytosis. What disease?
Chediak Higashi syndrome
Axatia, seizures, muscle weakness, recurrent infections and albinism what disease?
Chediak Higashi syndrome
Note: also have ocular symptoms, secondary to oculocutaneous albinism include nystagmus, photophobia and increased red reflex
Self mutilation what genetic disorder?
Lesch Nyhan
What is the most specific diagnostic test for galactosaemia?
Reduced or absent GALT enzyme (galactose-1-phosphate uridyltransferase)
The presence of succinylacetone in urine is pathognomonic of what?
Classical/type 1 tyrosinaemia
Note: leads to progressive liver failure, neuro disease and renal tubular acidosis
When does hereditary fructose intolerance typically present? What is it caused by?
Does not present until infant starts weaning onto foods from breastmilk/formula
Cause: deficiency of aldolase B
Note: formula used to be sweetened and so it used to present earlier. Leads to a build up of fructose 1 phosphate
Clinical and exam features of hereditary fructose intolerance?
Infants will vomit and prove difficult to wean
Hepatomegaly and deteriorating liver function/failure , marked acidosis and hypoglycaemia
What is the inheritance of Rhett syndrome?
Sporadic in 99% of cases
Although it is on the X Chr and fxns in a dominant manner –> it can be maternally inherited in the few cases where familial cases have occurred. It is lethal in males so fathers cannot be carriers
Mutations in the gene FGFR3 what disease?
Achondroplasia
Note: 2 specific mutations found to cause over 98% of this disease
Features of Zellweger syndrome in an infant?
Hypotonia, apnea, seizures and craniofacial abnormalities
Anosmia, obesity and hypothalamic hypogonadism what pathology and inheritance?
Kallmann syndrome (X linked recessive)
What is the mainstay of treatment of Kallmann syndrome?
HCG or testosterone
What is the typical inheritance of William syndrome?
Typically sporadic
LCHAD (long chain hydroxy acyl-CoA dehydrogenase) deficiency is associated with what eye abnormality?
Pigmentary retinopathy
What is the inheritance of SMA?
Autosomal recessive
Mutation in KCNQ1 is associated with that syndrome?
Long QT syndrome
The mutation in Williams syndrome is on what Chr?
Chr 7 (del)
Typical features of Niemann Pick disease?
Ataxia and developmental regression
Hepatomegaly
Cherry red spots on fundoscopy
How does biotinidase deficiency typically present in infancy?
Progressive neuro symptoms esp hearing and vision
Rash with or with out hair loss
What is Lesch-Nyhan commonly misdiagnosed as?
Cerebral palsy - due to hypotonia and developmental delay which later evolves in spasticity and a choreiform movement disorder. Later the aggression towards themselves and others provided a clue to diagnosis
Deficiency of hypoxanthine guanine phosphoribosyltransferase what disease? What lab abnormality?
Lesch-Nyhan
Elevated uric acid but sometimes it is at the upper limit of normal as it is being excreted in the urine
What does VACTERL association stand for?
Vertebral anomalies Anal atresia Cardiac defects Tracheo- oesophageal fistula and/or Esophageal atresia Renal anomalies Limb (radial) anomalies
Rocker bottom feet, what pathology and other clinical features?
T18/Edward syndrome - cardiac defects ASD, VSD or PDA; multiple large choroid plexus cysts, overlapping digits
Features of CHARGE syndrome
Coloboma Heart defects Atresia choanae (also known as choanal atresia) Growth retardation/ genital abnormalities Ear abnormalities
NB absent and/or hypo plastic semi-circular canals on internal ear imaging in 95% - appearance of the external ear is often characteristic too with a rather triangular concha
What is the inheritance of Tay Sachs
Autosomal recessive
Hereditary haemochromatosis is on what chromosome?
Chr 6 (HFE gene)
Difference in inheritance of mtDNA point mutations vs mtDNA large segment duplications or deletions?
mtDNA point mutations - inherited from mother, only female can pass it on but males or females can be effected
mtDNA large segment - tend to be sporadic mutations
Edward syndrome which trisomy?
18
Patau syndrome which trisomy?
13
Cutis aplasia is a feature of Edward or Patau syndrome?
Patau (13)
Typical facial features of Simpson Golabi Behmel syndrome
Macrocephaly coarse facial features and down slanting palpebral fissues in males
Female carriers can have more subtle features
Vertical supranuclear gaze palsy is a typical finding in what genetic disease? What other ophthalmic finding may be present?
Niemann Pick disease type C
Cherry red spot
It can manifest as uncertainty walking down stairs.
If a parent has isochromosome 21 what is the risk of the child having trisomy 21?
100%
Elevated urinary glycosaminoglycans in what pathology
Mucopolysaccharidoses
Lab to investigate for Refsum’s disease?
Plasma phytanic acid
Note: it is a fatty acid oxidation disorder
Laurence Moon Biedl syndrome is associated with failure to thrive T/F
F - it is associated with obesity
Laurence Moon Biedl syndrome is associated with obesity T/F
T
A patient with obesity, hypothalamus abnormalities (central DI and hypogonadism) and night blindness/retinitis pigmentosa
Laurence Moon Biedl syndrome
Note: can also have polydactyl
Typical features of Beckwith Wiedemann
Macrosomia and macroglossia, asymmetric limb growth , abdominal wall defects and increased malignancy risk ( Wilms > Hepatoblastoma)
Typical facies of Lysch Nyhan?
None, these patients are not dysmorphic
What are 2 features on history that can help differentiate Noonan syndrome from Turner?
Noonan : hx of poor feeding as infant and bleeding tendency
Investigation to diagnose fanconi’s anaemia?
Chromosome breakage studies
A non dysmorphic neonate with normal acid base balance who was very active in utero develops neonatal encephalopathy with myclonic jerks and hiccups. Diagnosis?
Non ketotic hyperglycinaemia
Note: diagnosis is made by elevated glycine in plasma or CSF. Myoclonic jerks may not be prominent but EEG will show a burst suppression appearance. The increased fetal movements are seizure
A child with pulmonary stenosis, dysmorphic features and areas of skin thickening with hyperkeratosis. What pathology?
Cardio facio cutaneous syndrome
What type of immune deficiency is Kostmann syndrome?
A severe congenital neutropenia
Mutation in fibrillin 1 gene what pathology?
Marfan’s
What is the management of Jeune syndrome?
Usually require intubation and ventilation at birth until they grow or have insertion of cartilage in their sternum.
AKA asphyxiating thoracic dystrophy
Features of Jeune syndrome
AKA asphyxiating thoracic dystrophy
Lung hypoplasia, poor cartilage development, renal abnormalities such as cystic kidneys
1st line genetic testing for patient with global developmental delay with no obvious aetiology for history or exam?
CMA
Lab abnormalities in Leigh syndrome
Elevated lactate, pyruvate and alanine
Ambigious genitalia, nephropathy and bilateral Wilms tumors what syndrome?
Drash syndrome
