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>
<p>Lithium prenatal exposure is associated with what cardiac defect?</p>
<p>Ebsteins</p>
<p>What gestational age is highest risk for warfarin (Coumadin) exposure?</p>
<p>T1• Risk of CNS defects after T1 possibly secondary to micorhemorrhages</p>
<p>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</p>
<p>Warfarin</p>
<p>List some signs and symptoms of congenital warfarin exposure?</p>
<p>– Hypoplasia of the nasal bridge – Laryngomalacia– Pectus carinatum– Congenital heart defects– Ventriculomegaly– Agensis of the corpus callosum– Stippled epiphyses– Telebrachydactyly– IUGR</p>
<p>What gestational risk is the highest exposure for ACEi and ARBS</p>
<p>all of them</p>
<p>What is the main effect of congenital ACE and ARB Exposure?</p>
<p>Renal development in the fetus</p>
<p>What are some features of congenital methotrexate or aminopterin exposure?</p>
<p>• Fetal aminopterin syndrome – 20-30% risk of malformation• Consequences:– Spontaneous abortion– Craniofacial anomalies – Skeletal anomalies– Limb reduction– IUGR– Stillbirth/neonatal death</p>
<p>What teratogenic exposure could this be?– IUGR– Micropthamia– Cleft palate– GU anomalies – Limb reduction</p>
<p>Alkylating agents...chemocyclophosphamide</p>
<p>What teratogenic exposure could this be?Fetal effects:– Bilateral limb deficiency-phocomelia – Anotia (no ears)– Microtia– Cardiac defects– GI defects– Facial hemangioma</p>
<p>Thalidomide</p>
<p>Pre existing diabetes can cause what kind of fetal abnormalities?</p>
<p>– Poor control increases risk of anomalies – 20-25% if HbA1c>10– Macrosomia– Skeletal defects - ONTD– Cardiac – 8% if HbA1c>8.5%– Sacral agenesis</p>
<p>What is the most common pattern for Trisomy 21?</p>
<p>Free trisomy 21 seen in 95% of cases</p>
<p>Does a free T21 need a parental karyotype?</p>
<p>Norecurrence risk <1% until over the age of 40</p>
<p>What percent of T21 are due to an unbalanced translocation?</p>
<p>3-4%</p>
<p>Does an unbalanced translocation leading to T21 need a parental karyotype?</p>
<p>YESRecurrence risk is 15% if mother the carrier and less if it is from the dad</p>
<p>Trisomy 18 features</p>
<p>Prenatal onset growth retardation• Cardiac anomalies• Overlapping fingersshort sternumALL SMALL</p>
<p>Trisomy 13 features</p>
<p>Post-axial polydactylyCutis aplasiaMidline cleftOne of most common causes of holoprosencephalySlightly hypoteloric eyesslightly upsplanting palpebral fissuresLots of midline defects</p>
<p>What condition is this?Low set hair lineredundant nuchal skinhorseshoe kidneylymphedemaCoarc and Bicuspid Aortic Valve</p>
<p>Turner45 XO</p>
<p>What condition is this:Short StaturePectus abnormalitiesHypertrophic cardiomyopathyArrythmias</p>
<p>Noonanthe male turnerDIFFERENT CARDIAC ABNORMALITIES</p>
<p>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)</p>
<p>Prader Willi</p>
<p>List some features of how PWS presents in the newborn period</p>
<p>1. Severe central hypotonia (Hyporeflexia, weak cry, lethargy)2. Feeding difficulties (Poor suck, FTT)3. Hypogonadism (Cryptorchidism, small testes and scrotum)</p>
<p>List some chronic features of PWS</p>
<p>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</p>
<p>What is the genetic mechanism of prayer willi?</p>
<p>PATERNAL DELETION of 15q13 (65-75%)Maternal UPD (20-30%)May also rarely be paternal imprinting defects</p>
<p>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</p>
<p>Angelman Syndrome</p>
<p>What are some features of Angelman Syndrome</p>
<p>– 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</p>
<p>What is the genetic mechanism of angel man syndrome?</p>
<p>MATERNAL DELETION of 15q13 (65-75%)Paternal UPD (3-7%)May also rarely be maternal imprinting defectsUBE3A mutation on maternal chromosome</p>
<p>How to test for PWS and Angelman Syndrome?</p>
<p>Methylation specific testmay also choose microarray and FISH</p>
22q11 deletion syndrome symptoms
CATCH 22 Cleft palate Abnormal facies Thymus Aplasia Cardiac Abnormalities (ToF, Great vessels interrupted aortic arch, right sided aortic arch, VSD) Hypocalcemia (from hypo PTH) 22q11 deletion
Developmental delay/autism/velopharyngeal insufficiency
Immune dysfunction
Teen with psychosis or other psychiatric presentation
<p>How to test for 22q11 deletion?</p>
<p>FISH or MLPA – rules in or out the diagnosisChromosomal microarray – will also pick up other copy number variants</p>
<p>VACTERL abnormalities are what?</p>
<p>Vertebral abnormalities (THINK HEMIVERTEBRAE)Anal AtresiaCardiovascular abnormalities (ASD/VSD)TEFRenal abnormalitiesLimb defects (absent radius)</p>
<p>Alagille Syndrome inheritance</p>
<p>Autosomal Dominant</p>
<p>Symptoms of Alagille Syndrome</p>
<p>- 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</p>
<p>Beckwith Weidemann Syndrome Symptoms</p>
<p>OMGOmphaloceleMacroglossiaGigantism (hemihypertrophy)Ear pitting, anterior ear creases, Hepatoblastoma (monitor with AFP)</p>
<p>What monitoring should children with BWS get?</p>
<p>AFP and USmonitor for hepatoblastoma</p>
<p>Russell Silver Syndrome features</p>
<p>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</p>
<p>What is the inheritance of achondroplasia?</p>
<p>Autosomal Dominantbut 80% have a de novo mutation</p>
<p>Gene associated with achondroplasia</p>
<p>FGFR3 mutation</p>
<p>What is the suspected diagnosis?- Prenatal: shortened long bones (usually <5th percentile) are noted on third trimester ultrasonography.- “collar hoop” sign- Poorly ossified metaphysis</p>
<p>Achondroplasia</p>
<p>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</p>
<p>Achondroplasia</p>
<p>If there is ay suspicion of achondroplasia in a neonate, what is the next step?</p>
<p>Skeletal survey</p>
<p>What are some skeletal survey findings indicating achondroplasia?</p>
<p>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</p>
<p>Surveillance of children with achondroplasia</p>
<p>- 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)</p>
<p></p>
<p>- require a thorough neurologic examination and neuroimaging with head CT or MRI</p>
<p>- Polysomnography is likewise indicated because of the risk of obstructive sleep apnea.</p>
<p>- Frequent monitoring of head circumference is important during the first 2 years after birth because hydrocephalus can develop.</p>
<p>- They sweat more than the general population</p>
<p>- Thoracolumbar kyphosis is seen in 90% to 95%</p>
<p>- Infants need support to sit until they have the truncal muscle strength to maintain themselves, and soft strollers should be avoided.</p>
<p>- External rotation of the hips, a normal feature in infants with achondroplasia, should self-correct within 6 months of weightbearing</p>
<p>- A general orthopedic evaluation should be considered when the child is 5 years old.</p>
<p>-Standardized developmental milestones and condition-specific growth curves are available for children with achondroplasia.</p>
<p>- Yearly hearing tests are recommended to check for conductive hearing loss.</p>
<p>- Occupational therapy from an early age can help affected children use adaptive aids for both the home and school settings.</p>
<p>- Foot support</p>
<p>- Because of cervical spinal stenosis, collision sports and gymnastics are usually discouraged</p>
<p>- Females with achondroplasia are at increased risk for uterine fibroids, so oral contraception, which can worsen fibroids, should be avoided for long-term use.</p>
<p>- Consultation with a gynecologist or an adolescent medicine provider well versed in contraceptive methods can be helpful.</p>
<p>Common presentations of TS</p>
<p>Seizures in 85%• Cognitive/behavioral problems• Brain tumours – 5-15%</p>
Types of Brain Tumours in TS?
subependymal nodules (SENs) – 90%
• cortical tubers – 70%
• SEGAs (5-15%)
Types of seizures in TS?
Focal to generalized, infantile spasms (vigabatrin) – Start in first months or years of life; often become intractible
Other signs and symptoms of TS
Eyes – retinal hamartomas
• Heart (~50%) - rhabdomyomas, arrhythmias
• Kidneys - angiomyolipomas, cysts, renal cell carcinomas
• Lungs (40% of women) - lymphangioleiomyomatosis [LAM]
• Skin (100%) - hypomelanotic macules, facial angiofibromas, shagreen patches, fibrous facial plaques, ungual fibromas
Inheritance of TS?
Autosomal dominant
Although most are sporadic mutations
Rett Syndrome Signs and Symptoms
Seizures (up to 90%) •Non-epileptic “vacant spells” •Autistic features, hand stereotypies •Gait ataxia and apraxia •Tremors and hyperkinetic movement disorder •Dystonia and spasticity
What is the inheritance of Rett Syndrome?
X linked
Males so affected they likely don’t survive
Stages of Rett syndrome
Stage 1 – The Early-Onset Stagnation Period (6-18 m of age)
Stage 2 - The Rapid Developmental Regression Period (1-4 years)
Stage 3 – Pseudo-Stationary Period
Stage 4 - Late Motor Deterioration
Diagnosis of Rett Syndrome
Clinical Diagnosis
Genetic testing of Rest Syndrome
MECP2mutation testing – for confirmation (95%)
Clinical Features of Fragile X Syndrome
Classical:male with moderate intellectual disability or a female with mild intellectual disability
macrocephaly
-characteristic facies
-joint laxity, flatfeet, MVP
post pubertal macroorchidism
Often: co-morbid ASD, ADHD, anxiety disorders
Seizures (10-15%) – complex partial most common
Genetic test for Fragile X
DNA testing for number of CGG repeats in the promoter region of the FMR1 gene
What does a premutation of Fragile X look like in males and females?
PREMUTATION allele carrier females:–Premature ovarian failure (20%)
–Chance to have (more) children with FXS
–Chance to develop FXTAS
PREMUTATION allele carrier males:
– Chance to develop FXTAS (onset ~60)
– All female offspring will be premutation carriers
One investigation to diagnose NF1
> EYE EXAM!
>2/7 CRITERIA ARE EYE FINDINGS
Genetic Cause of NF 1?
Heterozygous loss-of-function mutations ofNF1gene
Genetic testing available but not required for diagnosis
What are the signs and symptoms of Williams Syndrome?
Heart and blood vessel problems (supravalvular aortic stenosis) Hypercalcemia Low birth-weight / slow weight gain. Feeding difficulty (generally limited to the early years) Irritability (colicduring infancy) Dental abnormalities. Kidney abnormalities. Hernias.
Genetic Testing for Williams Syndrome
Micro-array analysisor thefluorescent in situ hybridization(FISH)
Since 98-99% of individuals with Williams syndrome lack half of the 7q11.23 region of chromosome #7, where the elastin gene is located, the presence of only one copy of the gene is a strong sign of the syndrome.
Inheritance of Smith- Lemil- Opitz Syndrome
AR
Signs and symptoms of Smith lemil Opitz syndrome
prenatal onset growth retardations feeding problem intellectual delay webbing between 2/3 toes postaxial polydacyly short nose upturned nares hypospadias low serum cholesterol RECESSIVE
Inheritance of Marfan Syndrome
Autosomal Dominant
MFS is caused by a mutation inFBN1, one of the genes that makesfibrillin, which results in abnormal connective tissue.
Gene Affected in Marfan Syndrome
MFS is caused by a mutation inFBN1, one of the genes that makesfibrillin, which results in abnormal connective tissue.
What criteria do you use to diagnose Marfans
Ghent Criteria
In the presence of a family history of MFS (as defined above):
Ectopia lentis Systemic score* ≥ 7 Aortic root Z-score ≥ 2 Points for systemic score: Wrist AND thumb sign = 3 (wrist OR thumb sign = 1) Pectus carinatum deformity = 2 (pectus excavatum or chest asymmetry = 1) Hindfoot deformity = 2 (plain pes planus = 1) Dural ectasia = 2 Protrusio acetabuli = 2 pneumothorax = 2 Reduced upper segment/lower segment ratio AND increased arm/height AND no severe scoliosis = 1 Scoliosis or thoracolumbar kyphosis = 1 Reduced elbow extension = 1 Facial features (3/5) = 1 (dolichocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia) Skin striae (stretch marks) = 1 Myopia > 3 diopters = 1 Mitral valve prolapse = 1
Main difference between Marfans and Homocystinuria
marfans: cardiac!!! AD
homocystinuria: LEARNING issues. thromboembolism
Ectopia Lentis (inferior homo cystinuria, superior marfans)
What is this? and what is the next investigation?
Resp Alkalosis, little/no anion gap?
Urea Cycle Defect
Ammonia
What is this? and what is the next investigation
Metabolic Acidosis, big anion gap
Organic Acidemia
Urine Organic Acids
What is this and what is the next step?
Hyperchloremic Acidosis, little/no gap
Fatty Acid Oxidation Defect
Acylcarnitine
Hypoglycemia by itself?
Hyperinsulinism
Hypoglycemia with hepatomegaly?
GSD and Fructose 1,6 BPD
Hypoglycemia with acidosis or ketosis
Organic Acidurias
Hypoglycemia with no ketosis
FAOIs
Enzyme Affected in PKU?
phenylalanine hydroxylase
Inheritance of PKU?
Autosomal Recessive
Signs and Symptoms of PKU? If untreated
Intellectual disability Seizures Behavioral problems Mental disorders Musty smell and lighter skin. Spasticity Hyperreflexia Tremors Microcephaly Prominent maxilla enamel hypoplasia and growth retardation. Tx A baby born to a mother who has poorly treated PKU may have heart problems, a small head, and low birth weight.
Treatment of PKU?
Diet low in foods that contain phenylalanine and special supplements.
Babies should use a special formula with a small amount of breast milk.
The medication sapropterin dihydrochloride may be useful in some.
Diagnosis of PKU?
Mostly on newborn screen now!!
Screening for PKU is done with bacterial inhibition assay (Guthrie test), immunoassays using fluorometric or photometric detection, or amino acid measurement using tandem mass spectrometry (MS/MS).
Measurements done using MS/MS determine the concentration of Phe and the ratio of Phe to tyrosine, the ratio will be elevated in PKU.
Inheritance of Tyrosinemia
Autosomal Recessive
Seen in French Canadians
Enzyme affected in different types of Tyrosinemia
Signs and Symptoms of Tyrosinemia
Severe disease of the liver, kidney and peripheral
nerves
Organ damage results from accumulation of metabolites of tyrosine degradation.
If untreated presents at 2-6 mos.
Usually presents with an acute hepatic crisis (jaundice,
fever, vomiting, high enzymes, low glucose).
Diagnosis of Tyrosinemia
Diagnosis is based on high levels of succinylacetone in serum.
Treatment of Tyrosinemia
A diet low in tyrosine and phenylalanine slows progression but Tx is NTBC which inhibits tyrosine
degradation (risk of HCCC).
Other Tx is liver transplant.
What is Transient tyrosinemia of the newborn
Seen in premature infants receiving high protein diets.
Most are asymptomatic and id’d on NBS but some have lethargy, poor feeding etc.
Usually resolves by 1mo, can be corrected by lowering dietary protein.
Homocystinuria Diagnosis
Increased methionine and homocystine are diagnostic.
Accumulation of homocysteine in the serum and an increased excretion of homocysteine in the urine.
Homocystinuria Signs and Symptoms
Infants present with nonspecific symptoms including developmental delay.
Dx made by 3yo when subluxation of the ocular lens (ectopia lentis).
Also have skeletal abnormalities and thromboembolic complications.
Treatment of Homocystinuria
high doses of vitamin B6 (also known as pyridoxine). Low-sulfur diet (especially monitoring methionine), and most will need treatment with trimethylglycine.
A normal dose of folic acid supplement and occasionally adding cysteine to the diet
Inheritance of homocystinuria
AR
MSUD Signs and Symptoms
Infants develop nonspecific symptoms in the first week of life.
On exam have hypertonicity and opisthotonos (spasm of neck and back- arching).
Correction of BG does not improve symptoms.
Urine, sweat and cerumen smell like maple syrup.
Inheritance of MSUD?
AR
More common in mennonites
Pathophysiology of MSUD
Deficiency in the branched-chain alpha-keto acid dehydrogenase complex (BCKAD), leading to a buildup of the branched-chain amino acids (leucine, isoleucine, and valine)
Diagnosis of MSUD
Affected individuals are now often identified with characteristic elevations on plasma amino acids which do not have the characteristic odor.
Treatment of MSUD
Hydration + removal of branched chain AAs with hemodialysis (renal clearance not good enough on its own).
Long term Tx is diet low in branched chain AAs.
Propionic Acidemia Signs and Symptoms
Clinical findings are nonspecific and can be severe within the first few days of life.
If survive the first attack similar episodes may occur with infections, high protein meal etc.
Produces mod to severe MR.
Diagnosis of Propionic Acidemia
Metabolic acidosis, high AG, ketosis, low plts/neutrophils and low BG.
Mod to severe high ammonia is common (pathogenesis not well understood).
Serum and urine propionic acid and MMA levels are high.
Treatment of Propionic Acidemia
Tx involves hydration, nutrition, low protein diet, carnitine and dialysis if severe.
Causes of Hyperammonemia
Hyperammonemia: urea cycle defects, some organic academia and FAOIs.
FAOIs generally cause hypoglycemia while UCDs do not, organic acid disorders can be distinguished by the presence of acidosis.
Urea Cycle Defects Presentation and Ix
The affected infant is normal at birth but becomes symptomatic within a few days of protein feeding. Presents with lethargy, poor feeding, tachypnea which can progress to coma.
Seizures are common.
May find hepatomegaly on exam, as well as neuro findings.
Hyperammonemia can trigger increased ICP.
Labwork is nonspecific except for high ammonia. BUN is usually normal or low, pH is normal or mildly increased. There may be mild increases in ALT and AST.
What is the most common urea cycle defect?
Ornithine Transcarbamylase Deficiency
Inheritance of OTC?
X linked
Signs and Symptoms of OTC
Classic presentation, a male infant appears well initially, but by the second day of life becomes irritable, lethargic, and stops feeding.
Infants may have poorly-controlled body temperature and respiratory rates, and may experience seizures.
Without urgent intervention, a metabolic encephalopathy develops; this can progress to coma and death within the first week of life.
High levels of ammonia cause preferential damage to the brain.
Diagnosis of OTC
Ammonia
Plasma and urine amino acid analysis
Urine organic acid analysis (to identify the presence or absence of orotic acid)
Plasma acylcarnitines
Decreased citrulline and arginine and increased orotic acid.
This biochemical phenotype (increased ammonia, low citrulline and increased orotic acid) is classic for OTC deficiency
Confirm diagnosis by Molecular genetics testing (Caveat Emptor). Enzymology
What is the most common FAOD?
MCAD: the most common fatty acid oxidation disorder.
What is the inheritance of MCAD?
Autosomal recessive
Most pts have northwestern European ancestry.
Presentation/ Signs and Symptoms of MCAD
Pts usually present between 3mos-5yo with episodes of acute illness triggered by prolonged fasting (12-16h).
Symptoms include vomiting, lethargy, seizures and coma.
The liver may be enlarged from fat deposition.
Older children are at higher risk as begin to fast through the night.
MCAD Investigations/Diagnosis
Low BG Low ketones No acidosis bc no ketones. Liver function may be abnormal. Secondary carnitine deficiency is seen.
Treatment of MCAD
Should be treated with D10 fluids and chronic therapy avoids fasting.
Up to 25% of pts die during first attack bc unrecognized, up to 35% of pts will never have an episode.
VLCAD Presentation
VLCAD: the second most common disorder of fatty acid oxidation.
Pts are usually more severely affected than those with MCAD, presenting earlier in infancy and having more chronic problems with muscle weakness and rhabdo. Cardiomyopathy may present during acute attacks.
Primary Carnitine Deficiency S/Sx
The most common presentation is progressive cardiomyopathy with or without skeletal muscle weakness beginning 1-4yo.
Plasma carnitine levels are low, tx is with oral carnitine.
Peroxismal Disorders Presentation
Symptoms include: Severe psychomotor retardation Weakness and hypotonia Dysmorphic features Seizures Retinopathy Glaucoma hearing deficits Enlarged liver and impaired liver function
Peroxismal Disorders Inheritance
All of which are AR traits except X linked adrenoleukodystrophy (X-ALD).
Diagnosis of Peroxismal Disorders
Lab findings include increased VLCFA (not increased in all disorders) and a panel of rare tests.
X linked adrenoleukodystrophy presentation
Accumulation of saturated VLCFA
Progressive dysfunction fo the adrenal cortex and central and peripheral nervous system white matter.
There is the cerebral form (hyperactivity, impaired auditory discrimination, spatial orientation, seizures; impaired response to ACTH stim often noted after dx),
Adolescent form (similar to childhood except slower progression)
Adrenomyeloneuropathy (adolescence, progressive paresis caused by long tract degeneration of the SC) and Addison only phenotype.
X-ALD Diagnosis
Dx is based on high VLFCA and characteristic white matter changes on CT or MRI.
X-ALD Treatment
Tx includes steroids for AI, BMT if rapidly progressive neuro disability and Lorenzo’s oil.
Family members should be screened.
Who should be screened for cholesterol disorders?
Cholesterol screening: according to AAP guidelines (2008):
1) Children whose parents or GP had documented CAD before 55yo.
2) Children whose parents have been found to have high blood concentrations of cholesterol (>240 mg/dL)
3) Children whose family hx is unattainable, particularly if other RFs (HTN, obesity, DM)
Treatment of Hyperlipidemia in Children:
Tx hyperlipidemia: no restriction of fat recommended for kids <2yo while brains developing.
1) AHA step I diet: calories consumed from fat should not exceed 30% of total calories, saturated fat should not exceed 10%, total cholesterol should be less than 300mg/dL per day, intake of trans fatty acids should be <1% of total calories.
2) For LDL persistently >130 step II diet should be started (restricts saturated fats to <7-8% and cholesterol to <200/day) with f/u q3-6 mos.
3) If low HDL counsel on weight management, tobacco avoidance and daily physical activity.
4) Children should accumulate at least 60 mins of age appropriate PE most days of the week and extended periods of daytime inactivity and/or screen time (>2h) are discouraged.
5) Drug therapy should be considered in children at least 8yo who have not achieved therapeutic goals (LDL>190, LDL>160 + RFs ie obesity, HTN, fam hx, LDL>130 + DM) despite an adequate period of dietary restriction.
a) HMG CoA reductase inhibitor: block intrahepatic biosynthesis of cholesterol which stimulates the production of more LDL receptors. Consistently reduce LDL by up to 50% and may decrease TGs and increase HDL. SEs include liver dysfunction and rarely rhabdo.
b) Nicotinic acid: used for increased TGs. Can lead to mild increase in liver enzymes, hyperglycemia etc.
c) Ezetimibe: reduces LDL by blocking sterol absorption in enterocytes.
Familial hypercholesterolemia inheritance?
AD disorder
Pathophysiology of Familial hypercholesterolemia
Mutations in the LDL receptor which leads to high LDL and premature CV disease.
If homozygous get very bad disease and often die in early adulthood.
Abetalipoproteinemia inheritance
Rare AR
Presentation of abetalipoproteinemia
Mutations in the gene encoding microsomal TG transfer proteins necessary for the transfer of lipids to chylomicrons.
Leads to fat malabsorption, diarrhea and FTT. Vit E deficiency results in spinocerebellar degeneration. Malabsorption of fat soluble vitamins occurs.
Inheritance of Tay Sachs
AR
Signs and Symptoms of Tay Sachs
Destruction of nerve cells in the brain and spinal cord.
Becomes apparent around three to six months of age, with the baby losing the ability to turn over, sit, or crawl.
Abnormally strong response to sudden noises or other stimuli, known as the “startle response”.
This is then followed by seizures, hearing loss, and inability to move, with death usually occurring by the age of four.
What type of disorder is Tay Sachs?
Lysosomal Storage Disorder
Most common Lysosomal Storage Disorder?
Gaucher disease
Most common in Ashkenazi Jews
What is Gaucher Disease?
Multisystemic lipidosis with:
- Heme abnormalities (pancytopenia)
- Organomegaly (Painless hepatomegaly and splenomegaly)
- Skeletal involvement (Severe pain associated with joints and bones)
Neurological symptoms occur only in some types of Gaucher’s (see below):
Type I: impaired olfaction and cognition
Type II: serious convulsions, hypertonia, intellectual disability, and apnea
Type III: myoclonus, convulsions, dementia, and ocular muscle apraxia
Osteoporosis: 75% of patients develop visible bony abnormalities due to the accumulated glucosylceramide. A deformity of the distal femur in the shape of an Erlenmeyer flask is commonly described.
Yellowish-brown skin pigmentation
Niemann Pick S/Sx
Fatal disorder of infancy characterized by FTT, HSM and rapidly progressive neurodegenerative course leading to death by 2-3yo.
There are types A (typical), B and C.
No specific Tx.
Krabbe Disease S/Sx
AR fatal disorder of infancy.
Results from white matter accumulation of built up substrate, affects peripheral and central myelin.
Results in neurodegeneration, seizures, blindness.
No Tx.
Glycogen Storage Diseases
Enzyme deficiencies affecting either glycogen synthesis, glycogen breakdown or glycolysis, typically in muscles and/or liver cells.
Typically causes an accumulation of glycogen in the tissues.
The glycogen found in these disorders is abnormal in quantity or quality or both.
Three Tests in UCD
ONLY DO 3 TESTS ACUTELY!! Plasma amino acids
Urine Organic Acids
Plasma Acylcarnitines
Treatment of UCD/OTC
Stop protein
Stop Catabolism – IV glucose
Replace Arginine!
Provide alternate waste nitrogen pathway
ie IV NaBenzoate/NaPhenylacetate Dialysis – hemodialysis
NAGS deficiency – Carglumic acid (Carbaglu)
Chronic Treatment of UCD
Low protein diet, with adequate calories, trace nutrients
Supplementation with UC intermediates ie Arginine or Citrulline
Medications: N2 scavengers
Transplantation liver
Horizon scanning: hepatocyte infusions, gene therapy
What enzyme is missing in Galactosemia?
(Galactokinase and galactose-1-phosphate uridyltransferase)
What is the problem in Galactosemia?
Can’t break down galactose to glucose and lactose
Signs and Symptoms of Galactosemia
Hepatomegaly (an enlarged liver) Cirrhosis Kidney failure Cataracts Vomiting Seizure Hypoglycemia Ovarian failure. Without treatment, mortality in infants with galactosemia is about 75%.
Long term Consequences of Galactosemia
Long term complication of galactosemia includes:
Speech deficits Ataxia Dysmetria Diminished bone density Premature ovarian failure Cataract
22q11 Facies
Abnormal / dysmorphic features: Hypertelorism Low set notched ears Short philtrum Mandibular hypoplasia
What is CHARGE Syndrome
Coloboma Heart defect (TOF, PDA, ASD, VSD) Chonanal atresia Growth / development retardation Genital hypolasia Ear abnormalities
Inheritance of 22q11
Genetics:
- Usually sporadic born to normal parents
- Dominant inheritance from affected parent
-Parental FISH analysis for micro deletion for 22q11.1 indicated before genetic counselling is provided
22q11 Surveillance
Recommendations:
- Cardiology evaluation: echo
- Endocrine evaluation: calcium, hypoparathyroid studies
- Renal ultrasound
- Developmental evaluation
- Early referral for speech therapy
- Monitor for hearing loss
- Immunology evaluation
- Absolute leukocyte count normal, reduced or absent
- Immunoglobulins usually normal but IgA may be low and IgE high
- Mitogen response normal, reduced or absent
- CXR for thymus
- Genetics for 22q11 deletion
Thymus transplant
BMT if complete DiGeorge
NO live viral vaccines until assessed
Need CMV negative, irradiated blood products
Irradiated blood removes leukocytes which prevents GVHD
Angelman Syndrome Features
Severe learning difficulties Ataxia Seizure disorder Subtle dysmorphic facial features (a wide, smiling mouth, prominent chin, and deep set eyes) Happy, sociable disposition.
Characteristic behavioural phenotype with jerky movements, frequent and sometimes inappropriate laughter
Love of water
Sleep disorder.
Incidence of Fragile X
Affected estimated 1 in 1000 males and 1 in 2000 – 6000 females
-2 – 6% of males subjects and 2 – 4% of females subjects with unexplained MR will carry the full fragile X mutation
Genetic Testing for Fragile X
PCR/Southern blot: number of trinucleotide CGG repeats in FMR1 gene
Inheritance of Noonan
AD
Differences Between Noonan and Turner Syndrome
In contrast to Turner syndrome, Noonan syndrome:
- AD (Turner syndrome is a chromosome disorder)
- Affects both sexes (Turner syndrome only females)
- Different pattern of CHD which are usually right sided lesions such as pulmonary stenosis (Turner syndrome usually coarctation)
- Mental deficiency (Turner syndrome normal intelligence)
- Normal menstrual cycle (Turner syndrome has amenorrhea from ovarian dysgenesis)
Health Surveillance for PWS
Health Supervision Issues:
- Weight and height tracking
- Feeding issues
- Annual vision and hearing
- Annual scoliosis screening
- Decreased salivation and cavities
- Sleep apnea related symptoms
- Thyroid and other end screening
Chronic Health Issues PWS
Nutrition:
- Infants require support of feeding
- Caloric needs may be reduced
Feeding tubes
-Poor feeding is usually a transient problem
Endocrine
- generalized hypothalamic insufficiency is characteristic of PWS, including GH, thyroid and possibility adrenal insufficiency
- Cortisol levels when well
- Consider stress dosing
Behavioural food controls
Hypogonadism
- both males and females
- Males have undescended testis
- May consider hCG
Inheritance of Williams Syndrome
- Usually sporadic, born to normal parents.
- Autosomal dominant inheritance from affected parent
- Clinical diagnosis is confirmed with FISH analysis for micro deletion chromosome 7q11.23, locus of elastin gene
Characteristics of Williams Syndrome
- Congenital heart defects in 50-75% (supravalvular aortic stenosis, VSD, ASD, PAS)
- 15% hypercalcemia of infancy that gradually resolves over time.
- Facial features: open mouth with prominent lips, long philtrum, epicentral folds, blue eyes common with stellate iris pattern, upper lateral periobrital fullness of subcutaenous tissue
- Short stature, occasional scoliosis
- Renal malformations in 15%
- GI: celiac disease, GERD, constipation
- Increased prevalence of diabetes mellitus in adolescents
- Joint hyper mobility during childhood; development of joint conjectures and tight heel cords during adolescence and young adulthood
Developmental outcomes:
- Average full scale IQ 56 with range 41 to 80
- “Loquacious” personality: every is my friend with consequent risk for unrealistic trusting of strangers, deeply empathetic, excellent reading of others feelings and facial expresion 12% with anxiety disorder
Wilson’s disease Inheritance
Autosomal recessive: defective transport of copper from liver into apoceruoloplasmin and into the biliary system
-Excess copper accumulation in liver
-Diagnosis: ATP7B gene DNA sequence analysis. Most patients carry two different mutations (compound heterozygotes).
Wilson’s disease S/Sx
Associated Medical Findings:
- Lifelong neurologic impairment
- Drooling
- Tremors
- Fulminant hepatic failure
- Cirrohsis, portal hypertension
- Hemolytic crises
- Cerebral and brain stem atrophy
- White matter changes on brain MRI
- Kayser-Fleischer rings
- Low serum ceruloplasmin
Treatment of Wilson’s Disease
Recommendations:
- Early diagnosis and treatment can prevent progression
- Partner with pedsGI
- Copper chelation therapy
- pencilliamine or triethylene tetramine dihydrochloride +oral zinc
- Copper avoidance
- Shellfish, nuts, liver, chocolate
Trisomy 21 Health Surveillance Birth to 1 month
• Feeding problems
• Strabismus, cataracts, and nystagmus at birth or
by 6 months
• Congenital hearing loss with objective testing,
such as brainstem auditory evoked response or
otoacoustic emission at birth or by 3 month
• Perform cardiac evaluation
• Duodenal atresia
• Constipation with increased risk of Hirschsprung
disease
• Leukemia— Obtain complete blood count.
• Congenital hypothyroidism (1% risk)
• Respiratory tract infections
Trisomy 21 Surveillance 1 month to 1 year
• Review the infant’s growth and development
• Review availability of Down syndrome support groups
• Assess the emotional status of parents and in- tra family relationships.
• Review the early intervention services relative to the strengths and needs of the infant and family
• Review the family’s understanding of the risk of
recurrence of Down syndrome and the availability of prenatal diagnosis.
Trisomy 21 Surveillance 1-5 years
• Child’s audio- gram every 6 months up to 3 years or up to when a pure tone audiogram is obtained. Refer the child to an otolaryngologist or audiologist if necessary
- Perform thyroid screening tests annually (3%–5% risk of hypothyroidism).
• If appropriate, discuss skin problems
• Discuss symptoms related to obstructive sleep apnea, . Refer to a specialist as indicated
Trisomy 21 Surveillance 5 years-adolescent
Examination
• Perform physical examination including CBC and thyroid function tests.
• Obtain annual audiologic evaluation.
• Obtain annual ophthalmologic evaluation.
• Discuss skin care.
Anticipatory Guidance
• Discuss issues related to transition into adulthood.
• Discuss appropriateness of school placement with emphasis on adequate vocational training within
the school curriculum.
• Talk about the recurrence risk of Down syndrome
with the patient and her family if she were to become pregnant.
• Discuss sexuality and socialization. Discuss the need for and degree of supervision and/or the need for contraception. Make recommendations for routine gynecologic care.
• Discuss group homes and independent living op- portunities, workshop settings, and other community-supported employment.
• Discuss intrafamily relationships, financial planning, and guardianship.
• Facilitate transfer to adult medical care.
