Genetics (paeds) Flashcards
FAMILIARISE YOURSELF WITH PHOTOGRAPHS OF:
Downs, Edwards, patau Williams Turners Fragile X Kleinfelters Duchenne and Becker Pradra-willi Angelmans
What’s a rule of thumb for knowing whether a disorder is autosomal dominant or recessive?
AR = are all ‘metabolic’ e.g. CF, apart from inherited ataxias e.g. Friedreich’s ataxia
AD = all ‘structural’ e.g. HD, apart from Gilbert’s, hyperlipidaemia type 2 (though both can be recessive)
What are all the physical features of common genetic conditions?
Downs (trisomy 21) Slanting palpebral fissures Flat occiput Epicampal folds flat zygomatic arches upward/outward slanting eyes small mouth with protruding tongue small head/ears short neck
Wide short hands/fingers, single palmar groove; deep groove between 1st/2nd toes
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
What antenatal genetics tests can be done?
11-14wk scan - if consented to screen for Down’s/Edward’s/Patau’s, can comment on nuchal translucency - if likely changes - maternal blood test - if high risk (1/2-1/150 chance) then CVS (wk 11-14) or amniocentesis (wk 15) offered and karyotyping of foetal cells is done
20wks scan - more abnormalities detectable e.g. cardiac abnormalities, spina bifa, exomphalos etc - microarray testing may be offered to find other genetic conditions
What are some chromosomal genetic conditions?
Can be an increase in number = polyploidy; decrease in number = aneuploidy
Translocations - balanced (may be phenotypcially normal as have correct number of chromosomes) or unbalanced (5% of Down’s have a robertsonian translocation between Ch21-14 - need to test parents here as may have balanced translocations)
Lots of changes are not survivable - cause for lots of miscarriages
What are the three survivable trisomy’s?
Down’s - T21
Edward’s - T18
Patau’s - T13
What are the features of Down syndrome?
775 babies/year/UK
Hypotonia + low birth weight/length
Face - flat zygomatic arches, upward/outward slanting eyes, small mouth with protruding tongue, small head/ears, short neck
Wide short hands/fingers, single palmar groove; deep groove between 1st/2nd toes
Global developmental delay
Short attention span/impulsivity/slow learning/variable communication
What other conditions are associated with Down’s?
AVSD + other cardiac malformations
Coeliac, hirschprung’s, hypothyroidism, Alzheimer’s
What are the features of Edward’s?
Mosaic and partial forms = less severe (only some cells are T18) - 7/10 will survive for at least 1yr and possibly into adulthood
Low birth weight, small head/jaw/mouth, long overlapping fingers with underdeveloped thumbs, low set ears, smooth feet, cleft lip/palate, exomphalos
Breathing/feeding/immunity problems, heart/kidney/bone problems
What are the features of Patau’s?
Most die within 1st year; if mosaic or partial then may survive >1yr
Low birth weight, cleft lip/palate, small or absent eyes, microcephaly, ear and scalp malformation, polydactyly
What are the key feature of autosomal dominant inheritance?
Each child has a 50% risk rate of inheriting mutation
No ‘skipped’ generations
M:F equally affected (unless sex limited)
M-M transmission possible
Possible variable penetrance (being expressed in the first place) + variable expression (the degree to which it is expressed when it is penetrant)
Possible gonadal mosaicism (some gametes changes, some dont)
2x unaffected patents - could be de novo mutation; if they have more than one affected child - could be gonadal moasic
What are some examples of AD conditions?
Adult PKD Familial hypercholesterolaemia MArfan syndrome Huntington disease Familial breast and ovarian cancers
What are the key features of autosomal recessive inheritance?
Two germline mutations (one from each parent) to inherit the disease - heterozygous carriers
1/4 recurrent risk for siblings
2/3 carrier risk for unaffected siblings
Unless Hx of consanguinity then often only one generation affected
What are some examples of AR conditions?
CF - carrier prevalence = 1/25 therefore affected = 1/2500; most picked up on heel prick
Haemochromatosis
Phenylketonuria (PKU)
What are the features of X-linked inheritance?
Genes on X chromosome
M>F affected
F = carriers - 50% sons affected + 50% daughters are carriers
All daughters of affected males are obligate carriers
None of the offspring of affected males have the disorder
Possible de novo mutation + gonadal mosaics
What are some examples of X-linked recessive inheritance?
Duchenne + Becker Muscular dystrophy (although X-linked, female carriers are still affected, just to a lesser degree); Becker = in-frame deletion so less severe, no premature stop codons unlike Duchenne’s
Haemophilia (A = 1/5,000-10,000, factor VIII; B = 1/40,000, factor IX)
Fragile X
What is Turner’s syndrome?
45 X0 - part or complete absence of X chromosome in women
Physical features: short, webbed neck, low set ears, low hairline, cubitus valgus (forearm angled away from body a greater degree than normal), swollen hands and feet as newborn
Reproductive features: amenorrhoea, no breast development, infertility
Cardiac: bicuspid aortic valve, coarctation (most common), aortic valve stenosis
Other: horseshoe kidney, ADHD, hypothyroidism, DMT1
What is Fragile X syndrome?
X-linked dominant inheritance
1/2000 males (80% undiagnosed), 1/6000 carriers; females dont always have clinical features but may have some LD
Trinucleotide expansion in FMR1 gene - fails to produce enough fragile X mental retardation protein which is required for the development of normal connections between neurons
Physical features: large protruding ears, long face, high arched palate, hyper-extensible joints, flat feet, hypotonia
Psych/neuro: spectrum from severe LD-normal IQ, related to number of repeats; memory problems; strong associations with ASD (15-60%) and ADHD; increased seizure risk seizures
What is Klinefeler syndrome?
47, XXY
Symptoms are subtle but may present with hypotonia and weakness as infants; taller with less muscle coordination with age
Puberty - less testosterone produced = less muscular, less facial and body hair, broader hips, breast tissue, smaller testicles weaker bones, lower energy
Often infertile
What is multifactorial inheritance and an example?
Genes + environment = condition
Probably lots of diseases are multifactorial in this way
e.g. neural tube defects - increased risk if affected parents and siblings but not very large (2-10% relative risk) + environmental factors e.g. low maternal folic acid or maternal DM = increased risk
What is genomic imprinting?
Mostly, both copies of genes are expressed, in some they are maternally or paternally expressed = imprinting
What is Prader-Wili syndrome?
Deletion of a region on Ch15q from the paternal inherited chromosome, or due to maternal uniparental disomy (child inherits both of mums Ch15’s, not one of each)
Presentation: neonatal hypotonia, poor feeding; moderate mental retardation, hyperphagia + obesity, small genitals
What is Angelman’s syndrome?
Deletion of a region on Ch15q from the maternal inherited chromosome, or due to paternal uniparental disomy (child inherits both of dad’s Ch15’s, not one of each)
Presentation: ‘happy pupet’ = unprovoked laughing and clapping, microcephaly, mental retardation, seizures, ataxia, broad gait
What are the features of mitochondrial inheritance?
All Mt come from mother
All off spring of an affected or carrier female at risk of being affected
All daughters of an affected or carrier female are at risk of being a carrier
Affected males cannot pass to children
Example: MELAS (mitochondrial encephalopathy, Lactic acidosis, stroke-like episodes)
What is the process of predictive genetic testing?
Not generally done in children as not autonomous
Should be done over several visits in a 3-stage protocol = interview about motivations then blood test then a discussion of results
May want to test in known familial adenomous polyposis (FAP) as polyps that eventually turn cancerous are known to start developing young and children may need prophylactic surgery
What is Williams syndrome?
Cocktail party personality
Dysmorphic features - ‘Elvin’ appearance
Mostly Caucasian with blue eyes
