deck 1 baby nelson Flashcards
What is the most common type of congenital malformations?
multifactorial inherited conditions - 20%
other types are single gene mutations (6%) of children, chromosomal disorders (7.5%), unusual pattern of inheritance (2-3%), exposure to teratogens (6%)
How much of the human genome (DNA) codes for proteins?
<25 of the genome
human genetic material has 3.1 billion bases
the rest of the DNA is called junk DNA
Types of mutations - most common?
point mutation is the most common - change in a single DNA base
Types of point mutation:
1. changes a codon and the amino acid - missense mutation
2. Nonsense mutation - changes the codon to a stop codon, transcription stops prematurely
(frameshift is the other type of mutation, causes a shift and leads to premature stop codon)
What is penetrance?
complete penetrance - everyone who carries a mutation for an AD disorder shows signs of that disorders
incomplete penetrance - some people who are obligate carriers of a mutation known to cause an AD may not show clinical signs of the disorder (and others might show symptoms)
What is variable expressivity?
same gene can show a wide range of manifestations of the clinical disease
A child with achondroplasia is born to two parents without achondroplasia, how is that possible for an autosomal dominant condition?
spontaneous mutation
approximately 80% of patients with achondroplasia have a spontaneous mutation in the FGFR3 gene
can be associated with advanced paternal age >35 years
What are 3 diseases that are associated with mutation in fibroblast growth factor receptor 3 (FGFR 3) mutation
achondroplasia
thanatophoric dysplasia
Crouzon syndrome
nonsyndromic craniosnostosis
What are the features of achondroplasia
cause: defect in carilage-derived bone, most common skeletal dysplasia in humans
short stature, macrocephaly, flat mid face with a prominent forehead
rhizomelic shortening of the limbs (i.e. disproportional shortening of the proximal limb)
infancy: hydrocephalus and central apnea from narrowing of the foramen magnum, and compression of the brainstem may happen and present as life-threatening in infancy
Childhood: bowing of the legs - unequal growth of tibia and fibula , dental malocclusion, OSA< hearing loss
Adults: compression of nerve roots and sciatica
**normal life spans and normal intelligence
How to diagnose achondroplasia?
characteristic X ray findings
molecular testing - if difficult to diagnose or if want prenatal diagnosis
Prenatal diagnosis: molecular testing from amnio or CVS
Name some common autosomal dominant diseases (table 47-1 in Baby Nelson)
achondroplasia thanatophoric dysplasia Crouzon syndrome Nonsyndromic craniosynostosis NF1 NF2 Huntington Myotonic Dystrophy Marfan syndrome Hereditary angioneurtoci edema (C-1 esterase inhibitor)
What are 5 rules of autosomal dominant inheritance
- trait in every generation
- each chip of an affected parent has a one in two chance of being affected
- males and females are equally affected
- male to male transmission occurs
- traits generally involve mutations in genes that code for regulatory or structural proteins (collagen)
Neurofibromatosis type 1 - name the features/diagnostic criteria
quite common 1/3500
Cafe au lait spots >5 that are 0.5 mm in prepuberty or >1.5 mm in puberty
Axillary Freckling
Neurofibromas (plexiform)
F
Optic Glioma
Osseous changes (ie sphenoid dysplasia)
Lisch Nodules
Complications of NF-1: learning disability, scoliosis, seizures, cerebral vasculature abnormalities
can also get optic nerve gliomas, astrocytomas of brain and spinal cord, malignant peripheral nerve tumours
Life expectance - reduced by 10-15 years
malignancy most common cause of death
AD but spontaneous mutations in 30-50% of cases
NF-2 -
much less common than NF-1
tumor suppressor bgene - so results in neurologic eye and skin lesions, multiple intracranial and spinal tumours - i.e. bilateral acoustic schwannomas, schwannomas of other cranial and spinal nerves, meningioma and glioma
cataracts
skin plaque like lesions, sC nodules and cutaneous schwannomas
Marfan syndrome - findings
Skeletal findings: tal, thin body habits, Spider like fingers and toes , Sternal abnormalities - excavatum/carinatum, scoliosis, pes planus, joint laxity
Eye findings: high myopia (can lead to retinal degeneration), ectopia lentos
Cardiac findings: progressive dilation of the aortic root, aortic insufficiency followed by aortic dissection is a common complication
How is Tay-Sachs Disease inherited?
Autosomal recessive inheritance
What are some examples of X linked conditions where some heterozygous carrier females can show some manifestations
colour-blindness
Duchenne MD
hemophilia
**some skewed X chromosome inactivation
What are rules of autosomal recessive inheritance
- trait in siblings, not in their parents or their offspring
- on average 25% of the siblings of the pro band are affected (at the time of conception, each sibling has a 25% chance of being affected)
- normal sibling has a 2/3 chance of being a carrier (heterozygote)
- mens and females are likely to be affected equally
- rare traits likely to be associated with consanguinity
- traits involve mutations in genes that code for enzymes (i.e. phenylalanine hydroxylase-deficient in PKU) are associated with serious illness and shortened life span
Provide some examples of AR diseases
CAH
PKU (lots of different mutations) - women with high phenylalanine during pregnancy, babies have brain damage
CF
Friederich Ataxia (does NOT show anticipation)
Gaucer disease -
Sickle cell disease
X linked recessive inheritance rules
- *most X linked diseases are recessive - so males are more likely to be affected
1. incidence higher in males than in females
2. trait from carrier females (who may show mild expression of the gene) to half of their sons (more severely affected)
3. each son of a carrier female has a one in two chance of being affected
4. Transmitted from affected males (trait) to all of their daughters, it is NEVER transmitted father to son
5. the trait may skip generations - can be passed through multiple carrier females
examples of autosomal recessive inheritance
muscular dystrophy (Duchenne) hemophilia A
Name some examples of X linked recessive diseases
- fragile X - females may have some expression
- Duchenne muscular dystrophy
- hemophilia A - factor VII deficiency
- Colour blindness
- Adrenoleukodystrophy - long chain fatty acid coA
- G6PD - but again females can have some expressivity
What are some examples of X linked dominant inheritance
- X linked vitamin D resistance rickets - hypo phosphatemic rickets - kidney can’t reabsorb phosphate
- Incontinentia pigmentia - affected sons die in utero, females, variable involvement
- Rett syndrome - mutations in MECP2 gene, normal at birth, later develop microcephaly and developmental regression
50% have seizures
hand washing posture - by 2 years of age
lethal in males
What are some examples of multifactorial disorders?
aka polygenic inheritance - multifactorial - genetic and environmental
cleft lip and palate, spina bifida
adult disorders: asthma, atherosclerosis, diabetes, cancer
true or false - pyloric stensois has a inherited component
true - it does
a parent has a child with a myelomeningocele, what is the chance of having a second affected child
20-40x more likely
What is MELAS
mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes
normal in early childhood - episodic vomiting, seizures and recurrent cerebral insults (resemble strokes )
can have a range of symptoms in first degree relatives - progressive external opthalmoplegia, hearing loss, cardiomyopathy, diabetes mellitus
all offspring of a woman who carries a mutation would be affected but because of heteroplasmy variation on the severity depending on the percentage of mitochondria with the mutation
How does mitochondrial inheritance work?
supplied by the ooctye - the woman passes it to all her kids
heteroplasmy is when there are different populations of mitochondria in the oocyte
so can have a variation of manifestations of mutated mitochondria - i.e. in in certain tissues - brain, muscle liver
What is uniparentl disomy
nomal karyotype
inherit two copes of one parent’s chromosome, no copy from the other parent
What is the genetic basis of Prader-Willi and Angelman syndrome
impringting - only have expression on the maternal chromosome 15 (i.e. deletion in the paternal one) then get Praderwilli (think since mama’s is working, he is hypogonadic) vs if only express the paternal one (i.e. deletion of the maternal one) then get Angelman
imprinting - when there are changes on one of the chromosomes - i.e. methylation
What are the features of Prader-Willi
hypotonia of prenatal onset
postnatal growth delay
characteristic appearance - almond shaped eyes and small hands and feet, developmental disability; hypogondadotropic hypogonadism and obesity after infancy
What are features of Angelman syndrome
moderate to severe MR absence of speech ataxic movement of the arms and legs craniofacial appearance seizure disorder - inappropriate laughter
Features of fragile X syndrome
most common cause of inherited intellectual disability
large head
prominent forehead, jaw and ears
macro-orchidism with testicular volume twice normal in adulthood
mild connective tissue disorder - joint laxity
patulous eustacian tubes
mitral valve prolapse
neurobehavioural profile - intellectual disability
autism spectrum disorders
is related to expansion of trinucleotide repeats
What is the chance of first cousins producing a child with a autosomal recessive disorder
1/64
Genetic disorders associated with high AFP
neural tube defects
omphalocele
gastroscheisis
Genetic disorders associated with low AFP
fetal aneuploidy
ie T21, T18, T13
(detects 50%)
What four proteins are part to eh quad screen
AFP estriol inhibin A HCG (detects 80%) done in the second trimester
first trimester screen
nuchal translucency
PAPP-a and beta HCG - detection rate is almost 90%
What are some types of samples that you can send for chromosome analysis
bone marrow
fibroblasts
amniotic fluid or chorionic villi
most common findings in Down syndrome (i.e. dysmorphisms and symptoms involved
facial appearance: brachycephaly, flattened occiput, hypoplstic midface, flattened nasal bridge, upslanting palpebral fissures, epicanthal folds and large protruding tongue, apparent at birth
shot broad hands - single transverse palmar crease, wide gap between 1st and second toes
Systems in Down syndrome
Cardiac - 50% - AVSD, VSD, valvular disease
GI - 10% - most common duodenal atresia, annular pancreas, imperforate anus
Endocrine - congenital hypothyroidism - 4-18% ; acquired hypo more common
Heme:
- Polycythemia at birth: Hct >70%
- leukemoid reaction - ressembles congenitl leukemia - resolves on its own over the first month of life
- increased risk of leukaemia - 10-20x increase in risk - AML in 3 year old smiler to other kids - ALL most predominant type
Increased chance of infection
Eyes - more likely to have cataracts - 10% have atlantoaxial instability - increased distance between first and second cervical vertebrae -
What is the recurrence risk for parents that have a child with trisomy 21 ?
empiric recurrence risk - 1% (added to age-specific risk)
robertsonian translocation - need to analyze the parents - 65% are de novo, 35% parents have a balanced translocaton; if mother has the translocation then risk is 10-15%, if father then 2-5%
Clinical features of trisomy 18
many are aborted, usually lethal SGA hyperteonia prominent occiput micrognathia low set and malformed ears short sternum rocker bottom feet hypoplastic nail clenching of fists congenital heart disease (PVSD, PDA, ASD) can get premature birth, polyhydramnios, inguinal or abdominal hernias **only 5% live >1 year
Clinical features of trisomy 13
scalp defects - ie cutis aplasia, microphthalmia, corneal abnormalities, cleft lip and palate, microcephaly, holoprosencephaly, capillary hemangioma, deafness
congenital heart disease (VSD, PDA< ASD) - in 80%, missing ribs
Extremities - overlapping fingers, polydactyly, hypoplastic nails/hyperconvex nails
General - renal abnormalities, severe developmental delays
hypospadias and cryptorchidism are common in boys, girls have hypoplasia of the labia minor
**only 5% live > 6 months
most common genetic cause of infertility and hypogonadism in men
klinefelter syndrome - have an extra X chromosome diagnosis - boy is 15-16 year old - has progressive development of pubic and axillary hair, testes remain infantile in volume tall long limbs can have gynecomastia testosterone deficiency can develop osteoporosis later need testosterone supplementation need IVF for babies
Turner syndrome
normal intelligence and life expectancy
low set, mildly malformed ears, triangular face, flattened nasal bridge, epicentral folds
webbing of the neck - with or without cystic hygroma
shield-like chest with widened nipples, puffy hands and feet
Cardia - coarctation most common, then bicuspid valve later in life
renal - horseshoe kidney
shot stature - cardinal feature
acquired hypothyroidism - 5x more frequently in women with TS than in the general population
streak gonads - amenorrhea, 10% can have normal periods, most will need estrogen replacement
infertility - not corrected by estrogen
what is the genetics in Turner
monosomy X - NOT associated with advanced maternal age - from loss of one of the two chromosomes after conception
features of cri du chat syndrome
catlike cry-tracheal hypoplasia low birth weight/FTT hypotonia developmental disability microcephaly craniofacial dysmorphism clefts of the lip and palate , congenital heart disease and other malformation may be seen
Williams syndrome features
Cardiac - 80% - supravalvular aortic valve and pulmonic valve stenosis and Periphearl pulmonic stenosis - most common
Growth - normal BW - growth delay and short stature
Facial appearance - median flare of the eyebrows, fullness of the perioral and periorbital region blue irides with a stellate pattern of pigment and depressed nasal bridge with ante version of the nares
Moderate intellectual disability (average IQ in the 50-60 range), developmental testing reveals strength in personal social skills and deficiencies in cognitive areas
Hypercalcemia in neonates
“cocktail personality” (although 10% have autism)
musical ability - 20% with perfect pitch
What is WAGR syndrome?
Wilms tumor - in 50% of patients with these other problems
Aniridia
Genitourinary anomalies - crytoorchidism, hypospadias
MR
short stature
microcephaly
Other names for digeorge!
all refer to deletion of chromosome 22q11.2 velocardiofacial syndrome conotruncal anomaly face syndrome Shprintzen syndrome DiGeorge syndrome
inheritance of 22q11
can be autosomal dominant , most are denovo mutations
Features of DiGeorge
Cleft palate
Abnormal facies - prominent nose and broad nasal root
Thymic aplasia - 70%
Cardiac defects - truncus, VSD, TOF, right sided aortic arch
Hypocalcemia/hypoparathyroidism
22
remember michelle’s sister
What are the abnormalities in Pierre-Robin sequence
micrognathia
U-shaped cleft palate
obstructive apnea
**sequence of events starting from the failure of the mandible to grow in early gestation
may children with Pierre Robin syndrome have Stickler syndrome - mutations in collagen genes , also have ocular and MSK abnormalities
What is an example of an association?
VACTERL Vertebral anomalies Anal atresia Cardiac defects Tracheoesophageal fistula REnal anomalies limb anomalies
no single unifying cause
findings associated with polyhydramnios
intestinal obstruction
CNS anomaly that leads to poor swallowing
findings associated with oligohydramnios
chronic amniotic fluid leak
urinary tract abnormality that results in a failure to produce urine
differential for large baby
most common
GDM
Beckwith-Wiedemann
infant can’t pronate or supinate the elbow, what are some causes
fetal alcohol syndrome
X chromosome aneuploidy syndromes
syndromes associated with oligodactyly
fanconi syndrome - anemia, leukopenia, thrombocytopenia and associated heart, renal and limb anomalies - radial aplasia an thumb malformation or aplasia
Syndactyly syndromes
many, including Smith Lemli-Opitz
which is a disorder of cholesterol metabolism
when are you more worried about hypospadias?
isolated can be common
if it is happening with other abnormalities - especially crytorchidism, strong possibility of a syndrome
