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
Which congenital infections can you acquired via raw/poorly cooked meat or close contact with infected domestic animals or contaminated soil
Toxoplasmosis
What gestation is the transmission risk of toxoplasmosis the highest?
Third!• T1:10-20%• T2:30%• T3:60%• Overall:20-50%
Name some features of congenital toxoplasmosis infection
Destructive brain changesIntracranialcalcificationsMicrocephalyMicrophthalmiaHydrocephalyChorioretinitis
What gestation is the transmission risk of rubella the highest?
Highest risk <10 wga• Hematogenous spread 5-7 days after maternal inoculation• Overall risk ~20%
What congenital infection is this?Features:– IUGR– Cataracts– Cardiacdefects– Deafness– Petechiaeandpurpura(blueberrymuffin lesions)
Rubella
What gestation is the transmission of CMV the highest?
Transmission risk increases with gestational age, however, severity decreases
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
CMV
What congenital infection is this?Rash based illness, “slapped cheek"– Severe anemia– Hydrops – Cardiomyopathy
Parvo B19
What gestation age is the highest risk for Parvo B19 infection
Fetal death: 2.5-9%• Increased in < 20 wga
What gestation is the highest risk for varicella?
– 20% if it occurs during key period of development– Rare when after 20 weeks
List some features of congenital varicella infection
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
What is the highest risk period for HSV transmission?
Intrauterine transmission rare– Majority is perinatal although may occur postnatally
What is this congenital infection?Placental infarcts– Opthalmalogic– CNS• Hydranencephaly, microcephaly• Spasticity – IUGR– Skin lesions
HSV
What is this congenital infection?Current features:– MicrocephalyBrain abnormalities– Ocular abnormalities– Hydrops fetalis – IUGR– Fetal death– Hearing loss
Zika
In utero cigarette exposure can lead to what fetal abnormalities?
- IUGR/LBW– Conotruncal and atrioventricular septal heart defects– Vasoconstrction– Chronic fetal hypoxia
What in utero exposure could cause these abnormalities?– IUGR– Cerebral infarcts– Microcephaly– Bowel atresia– Cardiac/limb/facial/GU tract abnormalities– Abruption
Cocaine
What is the safe limit of EtOH use in pregnancy
NONE
What prenatal exposure is this describing?Facial features:• Short palpebral fissures• Smooth/flattened philtrum• Thin upper lip• Micrognathia• Railroad track ears
FASD
List the facial features seen in FASD
Facial features:• Short palpebral fissures• Smooth/flattened philtrum• Thin upper lip• Micrognathia• Railroad track ears
What exposure in utero could this be?
• Clinodactyly• “Hockey Stick” configuration of upper palmar crease
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
FASD
Which Anticonvulsants are teratogenic?
– Trimethadione – Phenytoin– Valproic Acid– Carbamazepine
Which anticonvulsants are safe during pregnancy
– Lamotrigine– Levatiracetem– Phenobarbital
What is the syndrome called if there is fetal exposure to phenytoin?
Hydantoin Syndrome
What is Hydantoin Syndrome?
In utero phenytoin exposure:craniofacial anomalies (Ridged frontal suture, Depressed nasal bridge)fingernail hypoplasiaDistal phalangesgrowth deficiencydev delaycardiac effectsfacial clefts
What is associated with carbamazepine in utero exposure?
Hydantoin syndromespina bifida(open NTD)
What is one recommendation for all pregnant women on anti convulsants?
Should be on folic acid
What are some features of congenital exposure to phenobarbital?
Clefts, cardiac, urinary tract abnormalities
What gestation is the highest risk for accurate exposure?
T1: 5-25% risk
What is the risk of topical accutane/isoretinoin exposure during pregnancy?
none
List some effects of teratogenic exposure of accutane?
Fetal effects:– Microtia/Micropthalmia – Craniofacial– Cleftliporpalate– Micrognathia– Cardiac– ONTD– Stippledboneepiphyses – IUGR– Mentalretardation
Lithium prenatal exposure is associated with what cardiac defect?
Ebsteins
What gestational age is highest risk for warfarin (Coumadin) exposure?
T1• Risk of CNS defects after T1 possibly secondary to micorhemorrhages
What In utero exposure is this?– Hypoplasia of the nasal bridge – Laryngomalacia– Pectus carinatum– Congenital heart defects– Ventriculomegaly– Agensis of the corpus callosum – Stippled epiphyses– Telebrachydactyly– IUGR
Warfarin
List some signs and symptoms of congenital warfarin exposure?
– Hypoplasia of the nasal bridge – Laryngomalacia– Pectus carinatum– Congenital heart defects– Ventriculomegaly– Agensis of the corpus callosum– Stippled epiphyses– Telebrachydactyly– IUGR
What gestational risk is the highest exposure for ACEi and ARBS
all of them
What is the main effect of congenital ACE and ARB Exposure?
Renal development in the fetus
What are some features of congenital methotrexate or aminopterin exposure?
• Fetal aminopterin syndrome – 20-30% risk of malformation• Consequences:– Spontaneous abortion– Craniofacial anomalies – Skeletal anomalies– Limb reduction– IUGR– Stillbirth/neonatal death
What teratogenic exposure could this be?– IUGR– Micropthamia– Cleft palate– GU anomalies – Limb reduction
Alkylating agents...chemocyclophosphamide
What teratogenic exposure could this be?Fetal effects:– Bilateral limb deficiency-phocomelia – Anotia (no ears)– Microtia– Cardiac defects– GI defects– Facial hemangioma
Thalidomide
Pre existing diabetes can cause what kind of fetal abnormalities?
– Poor control increases risk of anomalies – 20-25% if HbA1c>10– Macrosomia– Skeletal defects - ONTD– Cardiac – 8% if HbA1c>8.5%– Sacral agenesis
What is the most common pattern for Trisomy 21?
Free trisomy 21 seen in 95% of cases
Does a free T21 need a parental karyotype?
Norecurrence risk <1% until over the age of 40
What percent of T21 are due to an unbalanced translocation?
3-4%
Does an unbalanced translocation leading to T21 need a parental karyotype?
YESRecurrence risk is 15% if mother the carrier and less if it is from the dad
Trisomy 18 features
Prenatal onset growth retardation• Cardiac anomalies• Overlapping fingersshort sternumALL SMALL
Trisomy 13 features
Post-axial polydactylyCutis aplasiaMidline cleftOne of most common causes of holoprosencephalySlightly hypoteloric eyesslightly upsplanting palpebral fissuresLots of midline defects
What condition is this?Low set hair lineredundant nuchal skinhorseshoe kidneylymphedemaCoarc and Bicuspid Aortic Valve
Turner45 XO
What condition is this:Short StaturePectus abnormalitiesHypertrophic cardiomyopathyArrythmias
Noonanthe male turnerDIFFERENT CARDIAC ABNORMALITIES
What condition presents like this is the neonatal period?1. Severe central hypotonia (Hyporeflexia, weak cry, lethargy)2. Feeding difficulties (Poor suck, FTT)3. Hypogonadism (Cryptorchidism, small testes and scrotum)
Prader Willi
List some features of how PWS presents in the newborn period
1. Severe central hypotonia (Hyporeflexia, weak cry, lethargy)2. Feeding difficulties (Poor suck, FTT)3. Hypogonadism (Cryptorchidism, small testes and scrotum)
List some chronic features of PWS
Global developmental delay:– Hypotonia improves with age– Early milestones on average reached at double the expected age• Intellect:– Mild ID (mean IQ: 60s to 70s)• Behaviour:– Often challenging due to hyperphagia, compulsivity, resistance to change, OCD tendencies
What is the genetic mechanism of prayer willi?
PATERNAL DELETION of 15q13 (65-75%)Maternal UPD (20-30%)May also rarely be paternal imprinting defects
What is this genetic condition?– Developmental delay notable around 6 months of age– Severe speech impairment– Gait ataxia and/or tremulousness of the limbs– Behaviour: happy demeanor, frequent laughing, smiling, hypermotoric and excitability– Microcephaly– Seizures
Angelman Syndrome
What are some features of Angelman Syndrome
– Developmental delay notable around 6 months of age– Severe speech impairment– Gait ataxia and/or tremulousness of the limbs– Behaviour: happy demeanor, frequent laughing, smiling, hypermotoric and excitability– Microcephaly– Seizures
What is the genetic mechanism of angel man syndrome?
MATERNAL DELETION of 15q13 (65-75%)Paternal UPD (3-7%)May also rarely be maternal imprinting defectsUBE3A mutation on maternal chromosome
How to test for PWS and Angelman Syndrome?
Methylation specific testmay also choose microarray and FISH
How to test for 22q11 deletion?
FISH or MLPA – rules in or out the diagnosisChromosomal microarray – will also pick up other copy number variants
VACTERL abnormalities are what?
Vertebral abnormalities (THINK HEMIVERTEBRAE)Anal AtresiaCardiovascular abnormalities (ASD/VSD)TEFRenal abnormalitiesLimb defects (absent radius)
Alagille Syndrome inheritance
Autosomal Dominant
Symptoms of Alagille Syndrome
- cholestasis with bile duct paucity on liver biopsy– congenital cardiac defects (with particularinvolvement of the pulmonary arteries)– posterior embryotoxon in the eye– characteristic facial features– butterfly vertebraeDistinctive face with jaundice
Beckwith Weidemann Syndrome Symptoms
OMGOmphaloceleMacroglossiaGigantism (hemihypertrophy)Ear pitting, anterior ear creases, Hepatoblastoma (monitor with AFP)
What monitoring should children with BWS get?
AFP and USmonitor for hepatoblastoma
Russell Silver Syndrome features
Prenatal onset growth deficiency• Preserved head circumference• Fifth finger clinodactyly and typical facial features• Early feeding issues• Limb-length asymmetry/hemiHYPOtrophy• Multiple genetic aetiologies and specialized/targeted molecular testing available
What is the inheritance of achondroplasia?
Autosomal Dominantbut 80% have a de novo mutation
Gene associated with achondroplasia
FGFR3 mutation
What is the suspected diagnosis?- Prenatal: shortened long bones (usually <5th percentile) are noted on third trimester ultrasonography.- “collar hoop” sign- Poorly ossified metaphysis
Achondroplasia
What is this condition presenting in a neonate?Proximal shortening of the upper and lower extremitiesExtra skin creases at the knees and elbowsShort fingers with a trident configuration of the hand Macrocephaly with frontal bossingDepressed nasal bridge
Achondroplasia
If there is ay suspicion of achondroplasia in a neonate, what is the next step?
Skeletal survey
What are some skeletal survey findings indicating achondroplasia?
radiographic abnormalities include:- metaphyseal changes- rhizomelic (proximal bone) shortening- relatively large cranial vault with a small base of the skull- small squared iliac wings- anteroposterior rib narrowing- posterior vertebral scalloping
Surveillance of children with achondroplasia
- infant should not be put in a swing or a bouncer (base of the skull is smaller than normal, arterial compression at the level of the foramen magnum can also occur)
- require a thorough neurologic examination and neuroimaging with head CT or MRI
- Polysomnography is likewise indicated because of the risk of obstructive sleep apnea.
- Frequent monitoring of head circumference is important during the first 2 years after birth because hydrocephalus can develop.
- They sweat more than the general population
- Thoracolumbar kyphosis is seen in 90% to 95%
- Infants need support to sit until they have the truncal muscle strength to maintain themselves, and soft strollers should be avoided.
- External rotation of the hips, a normal feature in infants with achondroplasia, should self-correct within 6 months of weightbearing
- A general orthopedic evaluation should be considered when the child is 5 years old.
-Standardized developmental milestones and condition-specific growth curves are available for children with achondroplasia.
- Yearly hearing tests are recommended to check for conductive hearing loss.
- Occupational therapy from an early age can help affected children use adaptive aids for both the home and school settings.
- Foot support
- Because of cervical spinal stenosis, collision sports and gymnastics are usually discouraged
- Females with achondroplasia are at increased risk for uterine fibroids, so oral contraception, which can worsen fibroids, should be avoided for long-term use.
- Consultation with a gynecologist or an adolescent medicine provider well versed in contraceptive methods can be helpful.
Common presentations of TS
Seizures in 85%• Cognitive/behavioral problems• Brain tumours – 5-15%
