Genetics Flashcards
Dravet syndrome
See neuro
West syndrome
See neuro
Rett syndrome
MEPC2
Prader Willi and Angelman
- Deletion of the region 15q11-q13 is associated with Prader-Willi and Angelman syndromes.
- This can present with poor feeding, generalised hypotonia but with otherwise normal neurological exam.
- Prader willi–> facial features such as a narrow forehead, almond-shaped eyes, and a triangular mouth; short stature; and small hands and feet. Some people with Prader-Willi syndrome have unusually fair skin and light-colored hair
- -> ID usually mild. Usually need GH. Risk of obesity
–> PATERNAL copy is deleted, OR has two maternal copies, OR Paternal copy is silenced
-Angel man –> happy puppet, microcephaly, hand flapping, Severe ID, bouts of laughter, love water, poor sleep
- -> lareg mouth, large chin
- -> MATERNAL copy is deleted OR has two paternal copies OR maternal copy is silenced OR deletion of UBE3A
Williams syndrome
- Williams syndrome is caused by a deletion in chromosome 7q11.23
- can detect on microarray
- Aortic stenosis
- Joint laxity
- Hypercalcemia
Periorbital fullness, a flat nasal bridge and a broad nasal tip, a long relatively smooth philtrum with a wide mouth. The vermilion of lower lip is thick. Full cheeks and an ‘elfin’ face, which is often seen in young children with Williams syndrome.
alagille syndrome (aka arteriohepatic dysplasia)
AD
Mutation on chromosome 20p
JAG1 (90%) or NOTCH2
Variable expressivity (may have mild dysmorphism, mild cholestasis)
- Bile duct paucity of INTRAhepatic ducts
- Absence or marked reduction in the number of interlobular bile ducts in the portal triad (may initially not have these findings and instead look histologically like biliary atresia
- Chronic liver disease
- Conjugated hyperbilirubinaemia with cholestasis
- Increase lipoprotein X (++ xanthoma) and raised cholestrol
- Vit E deficiency MUST rx
- “butterfly” verterbrae
- abnormal radius/ulna
- abnormality of embryotoxin of eye
- Cardiac defects (pulmonary valve, artery and branches) –> peripheral pulmonary valve stenois
- renal failure
- Increase risk of vascular anomalies (aneurysm) especially of circle of willis
FACIES: Frontal bossing Prominent jaw with sharply pointed chin Deep set eyes Bulbous tip of nose
Goldenhar syndrome
Aka oculoauriculovertebral syndrome
incomplete development of ear, nose, soft palate, lip and mandible
anomalous development of first and second branchial arch
other features
teratoma
strabismus
preauricular skin tags
Autosomal dominant
Beckwith wiederman
Imprinting disorder 11p15 IGF2 gene Loss of maternal = paternal OVEREXPRESSION = growth promoting
Diagnosis is based on either three major features or two major plus three or more minor features.
Major:
- Pre and/or postnatal overgrowth (>90th centile),
- Macroglossia
- Abdominal wall defects.
Minor features:
-Characteristic ear signs (ear lobe creases, posterior helical pits),
-Facial naevus flammeus
-Hypoglycaemia
-Organomegaly
-Hemihypertrophy (25% of cases).
- increased risk of embryonal tumours (those with hemihypertrophy are at greatest risk)
esp wilms, hepatoblastoma, neuroblastoma, rhabdomyosarcoma
-abdo USS every 3/12 until 8 years old
- big risk of neonatal hypoglycemia due to hyperplasia of islet cells –> increased insulin secretion –> needs MORE dextrose
- associated with IVF conception
- Infants are more likely to be delivered prematurely, 35% before 35 weeks. Exomphalos occurs in 50% of cases. Hypoglycaemia, which is usually mild and transient, occurs in 50% due to hyperinsulinism. Deaths that occur are usually related to prematurity or congenital cardiac defects (<10%)
- During childhood, dysmorphic features become less apparent, although macroglossia can cause feeding problems, speech problems and occasionally obstructive apnoea.
- Overgrowth is most marked in the first few years and is associated with advanced bone age. It tends to slow down in late childhood, and most adults are <97th centile.
Turner
XO
- 1/5000 live irths
- not associated with maternal age
- In 75% X lost is paternal
features: Small for age Delayed puberty webbed neck protruding ears Wide spaced nipples lymphoedema of hands and feet Short
Cardiac lesions (40%)
- usually bicuspid aortic valve
- aortic stenosis
- mitral valve prolapse
Gonadal dysgenesis
- primary amenorrhoea
- lack of secondary sex characteristics
-mental retardation in 6%
Renal issues:
Structural renal abnormalities in 60%
Treacher Collins
-autosomal dominant
- midface hypoplasia, micrognathia, ear dysplasia, deafness) amongst others. Microphthalmia.
- ADD
Friedriech ataxia
ADD
Noonans
- Noonan syndrome is usually caused by a SINGLE NUCLEOTIDE mutation in one of 14 genes including in PTNP11 (50% cases)
- Similar presentation at times to Turner’s
- CANNOT be detected on microarray
- Cardiac lesions:
- pulmonary stenosis
ADD
Charcot marie tooth
ADD
SMA
ADD
Mcune Abright
- syndrome of endocrine dysfunction associated with patchy cutaneous pigmentation and fibrous dysplasia of the skeletal system
- missense mutation in the gene encoding the α-subunit of GS
- large irregular cafe au lait called ‘coast of maine spot)
- Cutaneous pigmentation typically is most extensive on the side showing the most severe bone involvement
- precocious puberty; and numerous hyperfunctional endocrinopathies.
- The full syndrome with gonadotropin independent precocious puberty occurs only in girls
- Autonomous hyper function of many glands, caused by the missense mutation
- Polyostotic fibrous dysplasia of bone, leading to pathologic fractures. Can involve any bone but most commonly affects the long bones, ribs, and skull
- Fibrous dysplasia ranges from small asymptomatic areas detectable only by bone scan to markedly disfiguring lesions that can result in frequent pathologic fractures and impingement on vital nerves.
NF1 and NF2
ADD
Spinocerebellar ataxia
ADD
Ataxia telangectasia
ADD
can get bleeds in brain
VACTERL
Association
Usually sporadic
V- vertebral defects
A- anal atresia (and other GU defects)
C- cardiac defects (40-80%)
TE- tracheo-oesophageal fistula (40-80%)
R- Renal anomalies (50-80%) -include horseshoe, duplex, abnormal shape
L- Limb anomalies (40-50%) - including radial anomalies and hypoplastic/missing thumbs
CHARGE syndrome
CDH7 gene mutation on chromosome 8 (among other gene mutations)
C-coloboma
H- heart defects
A- atresia of chonae
R- retardation of growth and development
G- Genitourinary defects (hypospadias etc)
E- ear anomalies (bowl shaped and concaved eare = lop ears) and deafness
15-20% have Tracheo-oesophageal fistula
Russell Silver syndrome
Imprinting disorder –> methylation studies
11p15
IGF2 gene
Loss of Paternal = Maternal OVEREXPRESSION
= growth restricting
-UPD7 gene defect in 10%, the rest is loss of paternal –> SNP study
- IUGR, macrocephaly (pseudohydrocephaly), assymetry, clinodactyl of pinky finger (= much smaller)
- Often speech delay but normal IQ
- short when older
- risk of neonatal fasting hypoglycemia
Smith lemli opitz syndrome (SLOS)
- 7-dehydrocholesterol reductase deficiency
- Inborn error of cholesterol synthesis
- AR
- incidence 1/20 000–1/70 000. SLOS is more common in individuals of European heritage. Carrier frequencies of specific mutations vary widely depending on ethnic background, and for Caucasians, they are in the 1–2% range
- Born with multiple congenital abnormalities including : ◾Microcephaly ◾Ptosis ◾Micrognathia ◾Epicanthal folds ◾Capillary haemangioma of the nose ◾Syndactyly of the second and third toes ◾Low-set and posteriorly rotated ears ◾High-arched, narrow, hard palate ◾Cleft lip/pale ◾Agenesis or hypoplasia of the corpus callosum ◾Cerebellar hypoplasia ◾Increased ventricle size ◾Decreased frontal lobe size ◾Polydactyl of hands or feet ◾Short, proximally placed thumb ◾Other finger malformations ◾Syndactyly of second and third toes ◾Ambiguous or female-like male genitalia ◾Congenital heart defects ◾Renal, pulmonary, liver and eye abnormalities
-syndactyly of second and third toes is MOST common physical finding
- Can range from mild disease to lethal
- In older children with mild disease may present with other malformations, growth failure, intellectual disability, behavioural problems or autistic characteristics –> if any of these should test for SLOS
- Testing –> serum levels of 7-dehydrocholesterol reductase which will be ELEVATED (as reductase cannot convert to cholesterol
Rx: Cholestrol supplements
GLUT1 deficiency
ADD
Connexin 26
add
SNHL if homozygous
