Genetics Please let this work Flashcards
What is this:Resp alkalosis, normal electrolytes, anion gap
Urea Cycle Defect
What is this: Ectopia Lentis myopia Osteoporosis skeletal dysplasia long fingers high palate Developmental delay Psychiatric issues Thrombosis
Homocystinuria
Treatment of Homocystinuria
Pyridoxine Protein restriction
Betaine
ASA,
Heparine
Urea Cycle Defect: Ammonia: high, low or normal?
HIGH!!!
Where does most of the urea cycle take place?
Hepatocytes
What precipitates hyperammonemia?
Increased catabolism Febrile Illness Dehydration Increased Protein Intake Slow accumulation of ammonia during the initial days of life
Most common Urea Cycle Defect
Ornithine Transcarbamylase (OTC) Deficiency
OTC inheritance
X linked
Side Effects of High Ammonia
AMS Lethargy Vomiting Cerebral Edema Coma Death
Treatment of High Ammonia (emergent)
Discontinue all protein intake
Initiated D10W for promote anabolism
Insulin to help control glucose and also promote anabolism
Broad Spectrum Antibiotics for possible sepsis
Treat like cerebral edema
Nitrogen scavengers
Nitrogen Scavengers (for high ammonia)
Sodium Benzoate
Sodium Phenylacetate
When is it safe to add protein back to diet with a UCD?
When ammonia is less than 100 umol/L
When to start dialysis in UCD?
Ammonia > 500No drop in ammonia despite 4 hours of medical management
Hemodialysis not peritoneal
List a few conditions ashkenazi jews should be screened for?
Tay-Sachs disease(1/30) Canavan disease(1/37-1/57) Familial dysautonomia (1/32)
Inheritance of Cystic Fibrosis?
Autosomal Recessive
Which Canadian Population is most at risk fo CF?
French Canadians
Who should get screening for fragile X?
- Woman with personal or family history of Fragile X orFragile X mental retardation
– Unexplained intellectual disability or developmental delay
– Autism
– Ovarian insufficiency with elevated FHS at age <40years of unknown etiology
– Woman with family history of male relatives with DD, autism or isolated cerebellar ataxia and tremor
What type of prevention is this? To stop inherited and non-inherited disordersfrom arising in the first place by identifying and avoiding causative factors
Primary Prevention
Give some Examples of Primary Prevention
- Preventing rhesus hemolytic disease of the newborn by pre and postnatal injection of anti-D immunoglobulin
- Immunization of young girls against rubella Preventing toxoplasmosis and CMV
- Folic acid supplementation to prevent neural tube defects
- Screening couples for autosomal recessive conditions- Hemoglobinopathies and thalassemia screening among couples of Asian, Black and Mediterranean descent- Ashkenazi Jewish Screen
- Screening couples with a family history of autism/mental retardation, premature menopause and tremor/ataxia for Fragile X syndrome
What type of prevention is this? Procedures that detect and treat pre-clinical pathological changes
Secondary Prevention
Give some examples of secondary prevention
- Screening for Down syndrome and other aneuploidies- Screening for Open Neural Tube Defects- Screening for structural fetal abnormalities
Who should be screened for aneuploidies?
All pregnant women in Canada, regardless of age, should be offered, through an informed counseling process, the option of a prenatal screening test for the most common fetal aneuploidies
At what age does risk of T21 exceed that of the general population?
40
Non invasive prenatal screening
nuchal translucency serum screening
18-22 week ultrasound
NIPT
Confirmatory Invasive testing
Amniocentesis
CVS
Fetal Blood Sample
All women should be offered what type of screening?
– A fetal u/s between 11-14 wga
– A level II ultrasound between 18-22 wga
Differential for nuchal translucency >6.5mm (cystic hygroma)
Turners
Noonans
Aneuploidies
What prenatal screen is this positive for? Increased NT Decreased PAPP-A Increased BHCG Decreased AFP Increased HCG
Trisomy 21
What prenatal screen is this positive for? Increased NT Decreased NT Decreased PAPP-A Decreased BHCG Decreased AFP Decreased HCG
Trisomy 18
What prenatal screen is this positive for?
Increased AFP
Neural Tube Defect
What does NIPT look at?
NIPT measures circulating cell free fetal DNA (ccffDNA) present in maternal blood & reports increases in fetal DNA for chromosomes 13, 18 and 21, X,Y
When can a NIPT be performed?
As early as 9 weeks
What does a prenatal US look at
It is a non-invasive test which can assess • Fetal proportions • Sex • Position • Growth • Placenta • Amniotic fluid • Fetal abnormalities
List 5 soft markers on US that are associated with aneuploidies.
Thickened Nuchal Fold (NOT THE SAME AS NUCHAL TRANSLUCENCY) Echogenic Intracardiac Focus Echogenic Bowel Choroid Plexus Cyst Mild Ventriculomegaly
What is the measurement of thickened nuchal fold?
6mm at 18-24 weeks
Differential for Echogenic Bowel
Cystic fibrosis Congenital infection Malformations of the bowel Intra-amniotic bleeding IUGR Aneuploidies
Choroid Plexus Cyst: What aneuploidy?
Trisomy 18 *but not if in isolation
Mild Ventriculomegaly is from what?
Can arise from agenesis of the corpus callosum, vascular abnormalities, cerebral maldevelopment and obstruction
If Mild ventriculomegaly what should your next steps be?
Approach: Look for other soft markers/abnormalities Maternal TORCH screen Karyotype MRI
Single Umbilical Artery is associated with what?
Renal and cardiac abnormalities, low birth weight
Mild Pyelectasis is associated with what?
Hydronephrosis
Which is the only soft marker that if there in isolation should be investigated further?
Increased Nuchal Fold
Increased Nuchal fold is associated with what?
Aneuploidies
Congenital Heart Disease
Work up for Isolated Nuchal Fold
Fetal karyotyping
When can CVS be done?
10-14 weeks
Risk of miscarriage with CVS?
1%
When can Amniocentesis be performed?
15 weeks onward
What is the risk of fetal loss with amniocentesis?
0.5%
Sequence definition
A pattern of multiple defects resulting from a single primary malformation/event.
Like Pierre robin…everything happens because of the small jaw
Association Definition
Non-random collection of anomalies seen together more often than chance (VACTERL)
Cutis Aplasia is commonly associated with what genetic syndrome?
Trisomy 13
Causes of Hemifacial Microsomia
– Goldenharsyndrome
– Sporadic
- Treacher Collins
Causes of Hemihypertrophy
- BWS– Proteus
– NF
– Sturge-Weber
– Lymphangioma
Causes of facial asymmetry that are not hemifacial microsomes or hemihypertrophy
CHARGEsyndrome – Russell-Silversyndrome – Moebiussyndrome – Saethre-Chotzensyndrome – 22q11.2deletion
Syndromes with coarse facial Features
Storage disorders (MPS, hurler, Hunter)
CFC (Craniofacial cutaneous syndrome)
Costello syndrome
Williams syndrome
Palpebral fissures in FAS are short or long?
Short
Microretrognathia + glossoptosis +U shaped cleft palate causes
- mechanical deformation of jaw in utero
- Stickler syndrome
- 22q11.2 deletion syndrome
- Marshall syndrome
What are the first tier tests for ASD, global developmental delay, and multiple congenital anomalies?
Chromosomal Microarray Analysis
What is a nonsense mutation?
No protein or truncated protein produced
What is a missense mutation?
Protein has new amino acid at site of mutation
What is a silent mutation?
Neutral - or other effects (e.g. splicing) ?
What is a frameshift mutation?
Deletion or insertion, usually introduces a premature termination
Which conditions have a methylation variation?
PW
Angelman
BWM
Russell Silver
Which condition has a triplet expansion?
Fragile X
Conditions caused by recurrent or common point mutations
Achondroplasia
Sickle cell anemia
Cystic fibrosis
Congenital Anomaly definition
Structural or functional anomalies that occur during intrauterine fetal life and can be identified prenatally, at birth or later in life
What are the most common severe congenital anomalies
Neural tube defects
Cardiac malformations
Trisomy 21
Definition of an association
Two or more anomalies not pathogenically related andoccur together more frequently then expected by chance
Definition of a teratogen
Environmental factor that can produce a permanent abnormality in structure or function, restriction of growth, or death of the embryo or fetus
What early congenital infection is this? • Congenital deafness • Abn teeth and bones • Hydrocephalus • Mental deficiency
Syphilis
What Late congenital infection is this?
• Destructive lesions of palate and nasalseptum
• Dental abnormalities – Hutchinson teeth
• Facial defects – frontal bossing, saddle nose, poorly developed maxilla
Syphilis
<p>Which congenital infections can you acquired via raw/poorly cooked meat or close contact with infected domestic animals or contaminated soil</p>
<p>Toxoplasmosis</p>
<p>What gestation is the transmission risk of toxoplasmosis the highest?</p>
<p>Third!• T1:10-20%• T2:30%• T3:60%• Overall:20-50%</p>
<p>Name some features of congenital toxoplasmosis infection</p>
<p>Destructive brain changesIntracranialcalcificationsMicrocephalyMicrophthalmiaHydrocephalyChorioretinitis</p>
<p>What gestation is the transmission risk of rubella the highest?</p>
<p>Highest risk <10 wga• Hematogenous spread 5-7 days after maternal inoculation• Overall risk ~20%</p>
<p>What congenital infection is this?Features:– IUGR– Cataracts– Cardiacdefects– Deafness– Petechiaeandpurpura(blueberrymuffin lesions)</p>
<p>Rubella</p>
<p>What gestation is the transmission of CMV the highest?</p>
<p>Transmission risk increases with gestational age, however, severity decreases</p>
<p>What congenital infection is this?Features:– Microcephaly– Ventriculomegaly– Large cisterna magna– Cerebral calcifications– Hyperechogenic fetal bowel– IUGR– Fetal hydrops– Placental enlargement– Mental retardation– Sensorineural hearing loss– Ocular - chorioretinitis– Hepatosplenomegaly– Hepatic calcifications– Thrombocytopenia</p>
<p>CMV</p>
<p>What congenital infection is this?Rash based illness, “slapped cheek"– Severe anemia– Hydrops – Cardiomyopathy</p>
<p>Parvo B19</p>
<p>What gestation age is the highest risk for Parvo B19 infection</p>
<p>Fetal death: 2.5-9%• Increased in < 20 wga</p>
<p>What gestation is the highest risk for varicella?</p>
<p>– 20% if it occurs during key period of development– Rare when after 20 weeks</p>
<p>List some features of congenital varicella infection</p>
<p>Features– Neurological abnormalities:• Microcephaly, mental retardation, hydrocephalus, seizures, Horner’s syndrome– Ocular abnormalities: • Cataracts• Chorioretinitis• Microphthalmos • Nystagmus– Skin scarring in a dermatomal pattern– Hypoplasia of the hands and feet– Muscle atrophy– GI abnormalities: reflux, stenotic bowel– IUGR</p>
<p>What is the highest risk period for HSV transmission?</p>
<p>Intrauterine transmission rare– Majority is perinatal although may occur postnatally</p>
<p>What is this congenital infection?Placental infarcts– Opthalmalogic– CNS• Hydranencephaly, microcephaly• Spasticity – IUGR– Skin lesions</p>
<p>HSV</p>
<p>What is this congenital infection?Current features:– MicrocephalyBrain abnormalities– Ocular abnormalities– Hydrops fetalis – IUGR– Fetal death– Hearing loss</p>
<p>Zika</p>
<p>In utero cigarette exposure can lead to what fetal abnormalities?</p>
<p>- IUGR/LBW– Conotruncal and atrioventricular septal heart defects– Vasoconstrction– Chronic fetal hypoxia</p>
<p>What in utero exposure could cause these abnormalities?– IUGR– Cerebral infarcts– Microcephaly– Bowel atresia– Cardiac/limb/facial/GU tract abnormalities– Abruption</p>
<p>Cocaine</p>
<p>What is the safe limit of EtOH use in pregnancy</p>
<p>NONE</p>
<p>What prenatal exposure is this describing?Facial features:• Short palpebral fissures• Smooth/flattened philtrum• Thin upper lip• Micrognathia• Railroad track ears</p>
<p>FASD</p>
<p>List the facial features seen in FASD</p>
<p>Facial features:• Short palpebral fissures• Smooth/flattened philtrum• Thin upper lip• Micrognathia• Railroad track ears</p>
<p>What exposure in utero could this be?</p>
<p>• Clinodactyly• “Hockey Stick” configuration of upper palmar crease</p>
<p>What prenatal exposure could this be:– Growth deficiency– Skeletal defects– Renal anomalies– Ocular and auditory abnormalities– Cardiac defects– CNS damage• Neurological signs/brain structure• Lower IQ, poor communication, memory, executive function, abstract reasoning</p>
<p>FASD</p>
<p>Which Anticonvulsants are teratogenic?</p>
<p>– Trimethadione – Phenytoin– Valproic Acid– Carbamazepine</p>
<p>Which anticonvulsants are safe during pregnancy</p>
<p>– Lamotrigine– Levatiracetem– Phenobarbital</p>
<p>What is the syndrome called if there is fetal exposure to phenytoin?</p>
<p>Hydantoin Syndrome</p>
<p>What is Hydantoin Syndrome?</p>
<p>In utero phenytoin exposure:craniofacial anomalies (Ridged frontal suture, Depressed nasal bridge)fingernail hypoplasiaDistal phalangesgrowth deficiencydev delaycardiac effectsfacial clefts</p>
<p>What is associated with carbamazepine in utero exposure?</p>
<p>Hydantoin syndromespina bifida(open NTD)</p>
<p>What is one recommendation for all pregnant women on anti convulsants?</p>
<p>Should be on folic acid</p>
<p>What are some features of congenital exposure to phenobarbital?</p>
<p>Clefts, cardiac, urinary tract abnormalities</p>
<p>What gestation is the highest risk for accurate exposure?</p>
<p>T1: 5-25% risk</p>
<p>What is the risk of topical accutane/isoretinoin exposure during pregnancy?</p>
<p>none</p>
<p>List some effects of teratogenic exposure of accutane?</p>
<p>Fetal effects:– Microtia/Micropthalmia – Craniofacial– Cleftliporpalate– Micrognathia– Cardiac– ONTD– Stippledboneepiphyses – IUGR– Mentalretardation</p>
