deck 1 baby nelson

Question 1

What is the most common type of congenital malformations?

Answer 1

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%)

Question 2

How much of the human genome (DNA) codes for proteins?

Answer 2

<25 of the genome
human genetic material has 3.1 billion bases
the rest of the DNA is called junk DNA

Question 3

Types of mutations - most common?

Answer 3

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)

Question 4

What is penetrance?

Answer 4

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)

Question 5

What is variable expressivity?

Answer 5

same gene can show a wide range of manifestations of the clinical disease

Question 6

A child with achondroplasia is born to two parents without achondroplasia, how is that possible for an autosomal dominant condition?

Answer 6

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

Question 7

What are 3 diseases that are associated with mutation in fibroblast growth factor receptor 3 (FGFR 3) mutation

Answer 7

achondroplasia
thanatophoric dysplasia
Crouzon syndrome
nonsyndromic craniosnostosis

Question 8

What are the features of achondroplasia

Answer 8

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

Question 9

How to diagnose achondroplasia?

Answer 9

characteristic X ray findings
molecular testing - if difficult to diagnose or if want prenatal diagnosis
Prenatal diagnosis: molecular testing from amnio or CVS

Question 10

Name some common autosomal dominant diseases (table 47-1 in Baby Nelson)

Answer 10

achondroplasia
thanatophoric dysplasia
Crouzon syndrome
Nonsyndromic craniosynostosis
NF1
NF2
Huntington
Myotonic Dystrophy 
Marfan syndrome
Hereditary angioneurtoci edema (C-1 esterase inhibitor)

Question 11

What are 5 rules of autosomal dominant inheritance

Answer 11

1. trait in every generation
2. each chip of an affected parent has a one in two chance of being affected
3. males and females are equally affected
4. male to male transmission occurs
5. traits generally involve mutations in genes that code for regulatory or structural proteins (collagen)

Question 12

Neurofibromatosis type 1 - name the features/diagnostic criteria

Answer 12

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

Question 13

NF-2 -

Answer 13

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

Question 14

Marfan syndrome - findings

Answer 14

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

Question 15

How is Tay-Sachs Disease inherited?

Answer 15

Autosomal recessive inheritance

Question 16

What are some examples of X linked conditions where some heterozygous carrier females can show some manifestations

Answer 16

colour-blindness
Duchenne MD
hemophilia
**some skewed X chromosome inactivation

Question 17

What are rules of autosomal recessive inheritance

Answer 17

1. trait in siblings, not in their parents or their offspring
2. 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)
3. normal sibling has a 2/3 chance of being a carrier (heterozygote)
4. mens and females are likely to be affected equally
5. rare traits likely to be associated with consanguinity
6. 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

Question 18

Provide some examples of AR diseases

Answer 18

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

Question 19

X linked recessive inheritance rules

Answer 19

• *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

Question 20

examples of autosomal recessive inheritance

Answer 20

muscular dystrophy (Duchenne)
hemophilia A

Question 21

Name some examples of X linked recessive diseases

Answer 21

1. fragile X - females may have some expression
2. Duchenne muscular dystrophy
3. hemophilia A - factor VII deficiency
4. Colour blindness
5. Adrenoleukodystrophy - long chain fatty acid coA
6. G6PD - but again females can have some expressivity

Question 22

What are some examples of X linked dominant inheritance

Answer 22

1. X linked vitamin D resistance rickets - hypo phosphatemic rickets - kidney can’t reabsorb phosphate
2. Incontinentia pigmentia - affected sons die in utero, females, variable involvement
3. 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

Question 23

What are some examples of multifactorial disorders?

Answer 23

aka polygenic inheritance - multifactorial - genetic and environmental
cleft lip and palate, spina bifida
adult disorders: asthma, atherosclerosis, diabetes, cancer

Question 24

true or false - pyloric stensois has a inherited component

Answer 24

true - it does

Question 25

a parent has a child with a myelomeningocele, what is the chance of having a second affected child

Answer 25

20-40x more likely

Question 26

What is MELAS

Answer 26

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

Question 27

How does mitochondrial inheritance work?

Answer 27

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

Question 28

What is uniparentl disomy

Answer 28

nomal karyotype | inherit two copes of one parent's chromosome, no copy from the other parent

Question 29

What is the genetic basis of Prader-Willi and Angelman syndrome

Answer 29

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

Question 30

What are the features of Prader-Willi

Answer 30

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

Question 31

What are features of Angelman syndrome

Answer 31

``` moderate to severe MR absence of speech ataxic movement of the arms and legs craniofacial appearance seizure disorder - inappropriate laughter ```

Question 32

Features of fragile X syndrome

Answer 32

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

Question 33

What is the chance of first cousins producing a child with a autosomal recessive disorder

Answer 33

1/64

Question 34

Genetic disorders associated with high AFP

Answer 34

neural tube defects omphalocele gastroscheisis

Question 35

Genetic disorders associated with low AFP

Answer 35

fetal aneuploidy ie T21, T18, T13 (detects 50%)

Question 36

What four proteins are part to eh quad screen

Answer 36

``` AFP estriol inhibin A HCG (detects 80%) done in the second trimester ```

Question 37

first trimester screen

Answer 37

nuchal translucency | PAPP-a and beta HCG - detection rate is almost 90%

Question 38

What are some types of samples that you can send for chromosome analysis

Answer 38

bone marrow fibroblasts amniotic fluid or chorionic villi

Question 39

most common findings in Down syndrome (i.e. dysmorphisms and symptoms involved

Answer 39

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

Question 40

Systems in Down syndrome

Answer 40

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 -

Question 41

What is the recurrence risk for parents that have a child with trisomy 21 ?

Answer 41

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%

Question 42

Clinical features of trisomy 18

Answer 42

``` 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 ```

Question 43

Clinical features of trisomy 13

Answer 43

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

Question 44

most common genetic cause of infertility and hypogonadism in men

Answer 44

``` 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 ```

Question 45

Turner syndrome

Answer 45

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

Question 46

what is the genetics in Turner

Answer 46

monosomy X - NOT associated with advanced maternal age - from loss of one of the two chromosomes after conception

Question 47

features of cri du chat syndrome

Answer 47

``` 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 ```

Question 48

Williams syndrome features

Answer 48

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

Question 49

What is WAGR syndrome?

Answer 49

Wilms tumor - in 50% of patients with these other problems Aniridia Genitourinary anomalies - crytoorchidism, hypospadias MR short stature microcephaly

Question 50

Other names for digeorge!

Answer 50

``` all refer to deletion of chromosome 22q11.2 velocardiofacial syndrome conotruncal anomaly face syndrome Shprintzen syndrome DiGeorge syndrome ```

Question 51

inheritance of 22q11

Answer 51

can be autosomal dominant , most are denovo mutations

Question 52

Features of DiGeorge

Answer 52

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

Question 53

What are the abnormalities in Pierre-Robin sequence

Answer 53

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

Question 54

What is an example of an association?

Answer 54

``` VACTERL Vertebral anomalies Anal atresia Cardiac defects Tracheoesophageal fistula REnal anomalies limb anomalies ``` no single unifying cause

Question 55

findings associated with polyhydramnios

Answer 55

intestinal obstruction | CNS anomaly that leads to poor swallowing

Question 56

findings associated with oligohydramnios

Answer 56

chronic amniotic fluid leak | urinary tract abnormality that results in a failure to produce urine

Question 57

differential for large baby

Answer 57

most common GDM Beckwith-Wiedemann

Question 58

infant can't pronate or supinate the elbow, what are some causes

Answer 58

fetal alcohol syndrome | X chromosome aneuploidy syndromes

Question 59

syndromes associated with oligodactyly

Answer 59

fanconi syndrome - anemia, leukopenia, thrombocytopenia and associated heart, renal and limb anomalies - radial aplasia an thumb malformation or aplasia

Question 60

Syndactyly syndromes

Answer 60

many, including Smith Lemli-Opitz | which is a disorder of cholesterol metabolism

Question 61

when are you more worried about hypospadias?

Answer 61

isolated can be common | if it is happening with other abnormalities - especially crytorchidism, strong possibility of a syndrome