Genetics & Metabolics Flashcards
Trisomy 13 genetics
- patau syndrome
- trisomy caused by maternal neurotic nondisjunction
- risk increases with maternal age
- can be suspected on prenatal screening
- confirmatory diagnosis with karyotype
Trisomy 13 features
- facial: sloping forehead, eye abnormalities (small eyes, close together eyes, iris colobomas), low set abnormal ears, small jaw
- cleft lip and palate
- cutis aplasia congenita (helps distinguish from T18)
- midline defects
- central apnea high risk
- heart: VSD, ASD, ToF
- renal problems - multi cystic, horshshoe
- often die within 2 weeks of birth (cardio respiratory) (10% survive beyond 1yr)
Trisomy 13 health surveillance
If they survive beyond neonatal period
- echo
- kidney ultrasound
- brain MR
- sleep study for central apnea
- monitor growth on T13 curve
- feeding assessments
- regular eye checks by optho
- development and intellectual delays common (most remain non verbal)
Rett Syndrome
X linked
Hand wringing
Autistic behaviour
Female
Should be investigated for differential genetic cause of ASD or severe ID in female
MECP2 molecular testing for dx
Sturge Weber
Mosaic somatic mutations
Port wine birthmark +/- brain involvement +/- glaucoma
Brain MR to diagnose
Optho consult for glaucoma
Overlap with Klippel-Trenaunay syndrome (mixed capillary/venous/lymphatic malformations involving bone and muscle in one limb)
Can have seizures, development problems, stroke-like episodes, headaches
Lesch Nyhan Syndrome
Classic: kidney stones, gout, self-injurious behaviour, GDD, dystonia
X-linked recessive (boys)
If gout, think purine metabolism disorder (decreased enzyme or overproduction)
Allopurinol for gout treatment
Diagnose with HPRT enzyme analysis, high serum uric acid, high urine uric:Cr
Cervical spine xrays in Down syndrome
onlyif symptoms:
Any child with neck pain, radicular pain, weakness, spasticity, changes in gait, hyper-reflexia, change in bowel/bladder or signs of myelopathy warrant plain cervical spine xrays in neutral position.
clinical manifestations of A1AT
Lung disease (ex bronchiectasis, emphysema) :(occurs with severe genotype)
PFT: reduced expiratory air flow, hyperinflation, low diffusion capacity
Liver disease (hepatoma, cirrhosis):
Prolonged neonatal jaundice
Cholestasis symptoms
Mildly elevated liver enzymes
Can develop portal hypertension
Skin & soft tissue:
Panniculitis (rare but classic, can occur with all genotypes)
Cellulitis like areas or tender red nodules on trunk or proximal extremities
Nodules tend to ulcerate spontaneously and discharge oily yellow fluid
Persistent cutaneous vasculitis
Cold urticaria
Acquired angioedema
PFT finding to suggest A1AT
Anyone with fixed airflow obstruction on spirometry should be screened for A1AT
Male with ambiguous genitalia, edema and proteinuria
Denys Drash syndrome
Cafe au lait macules and axillary freckling
Neurofibromatosis
Neurofibromatosis type 1
-Cafe au lait macules 6+ (most on trunk and extremities)
-Axillary or inguinal freckling
-Iris lisch nodules 2+ (identified on slit lamp - need optho assessment)
-Neurofibromas 2+
-Bone abnormalities (Osteopenia, Scoliosis, Long bone dysplasia)
-Optic gliomas (optho!!) - can extend to hypothalamus and cause precocious puberty
autosomal dominant
Wilm’s tumor + ambiguous genitalia
denys drash
abdo distension, hematuria, fevers, anorexia, pallor, weight loss
wilms tumor
Wilm’s, absent iris, undescended testes, GDD
WAGR syndrome
Wilms
Aniridia: absent colored region of eye
GU abnormalities: undescended testes, hypospadias, internal genital/urinary anomalies
Retardation
Frasier syndrome
congenital nephropathy, ambiguous genitalia in males, underdeveloped gonads that may lead to cancer. Early ESRD in childhood
ADHD, ataxia, intellectual dissability and adrenal insufficiency
x linked adrenoleukodystrophy
progressive weakness, intellectual impairment, hypertrophy of calves
ducehenne muscular dystrophy
x linked recessive
cerebellar ataxia, oculomotor apraxia, choreoathetosis, telangiectasia, immunodeficiency
ataxia telangectasia
autosomal recessive
symptom onset before age 5
E.coli sepsis related to metabolic condition
galactossemia
Wilms Tumor Genetic Syndromes
WT1 mutation
- denys drash
- fraser syndrome
- WAGR
Bottom line: WT1 mutation = Wilms Tumor, Kidney disease, abnormal genitals
Beckwith Wiedemann also has wilms tumor association
Dent disease
proteinuria & nephrolithiasis
X-linked
nephrolithiasis
low molecular weight proteinuria,
hypercalciuria
Fanconi Syndrome (proximal tubule defect- glycosuria, amino aciduria, phosphaturia)
Consanguinity common gene inheritance
think autosommal recessive
Smith Lemli Opitz Syndrome
Autosomal recessive (think consanguinity)
Mutation in 7-dehydroxycholesterol-delta7 reductase- the final step in cholesterol synthesis.
Have low cholesterol and buildup of cholesterol precursors and many congenital anomalies
Type 1 (classic): Prenatal and postnatal growth retardation, microcephaly, ptosis, anteverted nares, syndactyly of 2nd and 3rd toes, and severe cognitive impairment. 70% are males- genotypic makes have ambiguous genitalia or complete sex reversal with female genitalia. Associated with pyloric stenosis
Type 2: acrodysgenital syndrome- lethal within 1 yr, severe malformations, postaxial polydactyly, extremely abnormal external genitalia. Cleft Palate have been seen in Type II
Rx= dietary cholesterol (egg yolks lol) and HMGCoA reductase inhibitors to prevent precursor buildup
Turner syndrome heart
left sided heart problems
- bicuspid AV
- aorta things
Achondroplasia
Autosomal Dominant- FGFR3 mutation
The most common short-stature skeletal dysplasia marked by rhizomelia (disproportionate length of proximal limb), macrocephaly, midface hypoplasia, and normal cognition
Can get spinal stenosis and small foramen magnum
Growth hormone NOT effective
VACTERL investigations
CXR (butterfly vertebrae)
abdo US (kidney problems
no genetic testing
VACTERL Association
V- Vertebral anomalies- CXR (spine xray)- butterfly vertebrae
A- anal atresia/anorectal anomalies- examine
C- Cardiac
TE- TEF
R- enal- ultrasound
L- limb
Gilbert syndrome
A familial, nonhemolytic, unconjugated hyperbilirubinemia
Most common hereditary hyperbilirubinemia syndrome (5-10% white ppl)
Autosomal recessive
Defect in promoter region for UDPGT-1 (enzyme that makes bilirubin water soluble)- making it only partially effective
Unlike Crigler Nijjar (also defect in UDPGT)- it often presents after puberty and not associated with chronic liver disease.
Mild, fluctuating levels of bili. No treatment. Only really important in some chemotherapies because this enzyme breaks it down
What test for Beckwith Wiedemann
DNA Methylation test
Tests requiring DNA methylation test
Uniparental disomy syndromes
Beckwith Wiedemann
Prader Willi
Angelman
Loss of methylation on mom
Beckwith Wiedemann
big tongue
keep eating
organomeagly
Neonate with persistent hypoglycemia, seizure and absent septum pellucidum
Septo optic dysplasia
- midline brain defects (think absent corpus callosum or septum pellucidum)
- can get panhypopit (and pituitary hormone issues)
Septo-optic dysplasia
Also called “optic nerve dysplasia syndrome”
Classic “triad” or any combo of:
Optic nerve hypoplasia (nystagmus, visual impairment)
Pituitary gland hypoplasia (75%, most common is GH deficiency)
Midline brain defects (absent corpus collosum, corpus collosum dysgenesis)
can have seizures
Causes: genetic (unknown), cocaine in pregnancy, other environmental
Isolated polydactyly
pretty normal. can remove the digit
Typically autosomal dominant in inheritance
If isolated, especially with family history, no other workup
Treatment is ablation of digit (Suture ligation or surgical depending on how formed)
Ash leaf spots
hypopigmented lesions
can be seen with Wood’s lamp (blue light)
tuberous sclerosis
- tubors in brain
autosomal dominant with variable expressivity
McCune Albright
Triad of- precocious puberty (peripheral), polyostotic disease (fibrous dysplasia), abnormal pigmentation with irregular borders
Autonomous hyperfunctioning of 1 or more gland (pituitary, thyroid, and adrenal glands). GNAS mutation which stimulates cAMP and activates receptors including those for ACTH, TSH, FSH, LH). In short, get lots of endocrinopathies (hyperthyroid, cushings, etc)
neurocutaneous disorders
Neurofibromatosis 1/ 2
Fanconi Anemia
Russell Silver Syndrome (Cutis aplasia, cardiac stuff)
Noonan Syndrome
Bloom Syndrome
Tuberous Sclerosis (usually hyPOpigmented)
McCune Albright
Sturge Webber
Males only transmission
x linked recessive
Mccune Albright
bone problems (Polyostotic Fibrous Dysplasia)
large cafe au lait macules
endocrine problems - precocious puberty
hypoketotic hypoglycemia
fatty acid oxidation disorder (acidosis)
hyperinsulinism (no acidosis; insulin inhibits ketosis)
Anions minus cations
Na - (HCO3 + Cl) = AG
**Sometimes sources say (Na+K)- (HCO3+Cl)
Wide Anion Gap >12 (+/-2) = Acid Gain
Causes of wide anion gap metabolic acidosis = MUDPILES
A newborn baby is found to have choanal atresia.
CHARGE syndrome
(coloboma, heart defects, atresia choanae (also known as choanal atresia), growth retardation, genital abnormalities, and ear abnormalities)
CHARGE syndrome
- Coloboma
- Heart defects (commonly TOF)
- Atresia of the choanae
- Retardation of growth & development
- GU anomalies
- Ear anomalies (ear abnormalities, SNHL)
Other:
asymmetric facial nerve palsy, cleft lip/palate, EA/TEF
usually sporadic mutation
single gene testing - SHD 7
Trisomy 21 surveillance
Birth
- echo before 1 mo age
- TSH as newborn
- cbc within 1 week
Annual
Hearing screen
CBC
TSH
Optho q 2 years
Celiac only if symptomatic
cervical spine screen if symptomatic
sleep study by age 4
Carnitine-acylcarnitine translocase deficiency
Fatty acid oxidation disorder
- avoid prolonged fasting
Beckwith Wiedemann associated cancers
Associated health conditions:
Embryonal cancer (until at least age 8):
- Wilm’s tumour
- Hepatoblastoma
- Neuroblastoma
- Rhabdomyosarcoma
Screening:
AFP (for hepatoblastoma) & abdo US q3mo until 4yo
Then renal US including adrenal glands q3mo until 8yo (then less frequently)
Periodic CXR and urine HVA/VMA (for neuroblastoma) have been suggested but low yield so not in most screening protocols
DNA methylation testing (MS-MLPA)
Beckwith Wiedemann symptoms
Pits and creases (ears)
Macrosomia, macroglossia
Hypoglycemia (neonatal) - pancreatic beta cell hypertrophy
Facial nevus simplex and other vascular malformations
Asymmetric growth, hemihypertrophy
Characteristic facies: midface hypoplasia and infraorbital creases
Omphalocele, umbilical hernia
Premature and overgrown at birth
Organomegaly
Enlarged adrenal cortex
Cardiomegaly or structural cardiac anomalies
Renal abnormalities: nephromegaly, nephrocalcinosis, etc.
Advanced bone age
Prader Willi Symptoms
In Infancy:
Poor suck
Need tube feeding
Poor growth/FTT
Central hypotonia
Childhood: 4Hs and an O
Hypotonia
Hypogonadism
Hypomential/devel delay
Hyperphagia
Obesity (truncal)
Other physical features: almond shaped eyes, thin upper lip, small hands/feet
DNA methylation studies
growth hormone helps in Prader Willi
Digeorge syndrome testing
FISH for 22q11
or microarray
test PTH and calcium
immune workup (T and B cells, immunoglobulins, vaccine titers)
renal US for anomalies
Williams syndrome testing
FISH for 7q
think if HYPERcalcemia
CATCH 22
Digeorge:
CHD: VSD, TOF, interrupted aortic arch
Abdomal facies
thymic hypoplasia
cleft palate
hypocalcemia
22q11 deletion syndrome
Baby has tetrology of fallot - what genetic disorder do you test for
DiGeorge (22q11 deletion)
congenital central hypoventilation syndrome
primary central apnea, hypercarbia, and hypoxemia.
presents within first several weeks of life
associated with risk of Hirschsprung and neuroblastoma
they should have holter every 12 mo - risk of sinus pauses (may need pacemaker)
PHOX2B
Noonan Syndrome symptoms
hypertelorism, big forehead, webbed neck
MSK: pectus, wide nipples
CHD: right sided lesions (PS), cardiomyopathy
Cryptorchidism
Hypotonia
Failure to thrive
Abnormal bleeding and bruising
multi gene testing panel
similar to Turner’s but hypertrophic cardiomyopathy for heart lesion and has cryptorchidism
Smith Lemli Opitz
microcephalic
cleft palate
syndactylyl 2nd and 3rd toes
low cholesterol problem (think opposite of familial hypercholesterol)
Myotonic muscular dystrophy
Affects all muscles
- hypotonia at birth
- inverted v of upper lip
- shitty muscles everywhere - look thin, muscle wasted
- reflexes preserved (different from Duchenne late illness)
- CK not as high as other muscular dystrophies
Autosomal dominant
PCR testing
2year-old boy with hypoglycemia, triangular faces with 4 café au lait macules. Ht 3rd, wt 3rd, HC 50th.
Russel Silver
Russel Silver syndrome
Small for gestational age (asymmetric SGA)
FTT
Relative macrocephaly, triangular face, fifth finger clinodactyly
Feeding difficulties
Micrognathia with narrow chin
Hypoglycemia
Cafe au lait macules
Testing: DNA methylation studies
Russell Silver acute illness
measure ketones and blood sugar - risk of ketotic hypoglycemia when ill
Cafe au lait ddx
NF1
Legius syndrome (SPRED1): no neurofibromas or lisch nodules
NF2: vestibular schwannoma
Noonan: congenital cardiac defects, dysmorphisms
Constitutional mismatch repair genes mutations: GI cancers
Russell-Silver syndrome: Small for gestational age
McCune-Albright syndrome: endocrinopathies, fibrous dysplasias
Fanconi anemia: hematologic abnormalities, multiple congenital abn
2 year old boy 3 days of vomiting and diarrhea. Lethargic. Glucose low (2.4?). Ketones 2+. Most likely diagnosis?
hyperketotic hypoglycemia
Adrenocorticoleukodystrophy
think if:
- tanned (signs of addison disease)
- ADHD symptoms
- ataxic
LCFAD
x linked
affects the brain and adrenals (Addison like picture)
Dx:
- check long chain FA to confirm diagnosis
- brain MR after diagnosis
- cortisol w/u after diagnosis
ELFIN FACIES
Williams syndrome
supravalvular AS and coarctation
hypercalcemia
stelatte iris
Beckwith Wiedemann tumor association
Hepatoblastoma highest risk - check AFP every few months
Neonate with severe hypotonia and requiring gavage feeding. often puffy feet and hands
Prader Willi
Timing for achondroplasia neuroimaging sreening
by 1 month of age, MR brain
What test is warranted for kids with new developmental delay?
chromosomal microarray
3 week old . PH 7.1. High ammonia, high lactate. Etiology?
organic acidemia
(ex. methylmalonic acidemia)
If cafe au lait spots, refer to?
optho for optic glioma and Lisch nodules (need slit lamp to help with diagnosis
Turner syndrome features
XO
sporadic inheritance (can have mosaicism)
Classic things:
- webbed neck
- broad chest, wide spaced nipples
- low birth weight
- short stature
- wide carrying angle
- low hairline
Turner syndrome systemic conditions
- screen for celiac disease
- hypothyroid
- CHD: coarc and bicuspid AV valve
- renal malformations
- hearing loss from AOM
- ovarian failure - delayed puberty
- short stature (can improve with GH)
Diagnostic testing for galactossemia
elevated GALT level urine
Galactossemia inheritance
autossomal recessive
Galactossemia features
Jaundice, hepatomegaly, hepatic failure, ascites, splenomegaly
Feeding difficulties, vomiting, poor weight gain
Hypoglycemia
Seizures, lethargy, irritability
Aminoaciduria
Cataracts, vitreous hemorrhage
Increased risk for E coli sepsis
Pseudotumor cerebri can occur and cause a bulging fontanelle
Organic acidemia
- accumulation of toxic acid metabolites
- excrete the organic acids in urine (test the urine)
- appear in newborn period or infancy typically
- life threatening episode of AG Metabolic acidosis first presentation
- AG from ketosis
- frequently neutropenic or pancytopenic d/t bone marrow suppression
dx: urine organic acids
Highest risk during periods of catabolism (fasting)
Urea cycle defect
normally urea cycle helps convert nitrogen into urea to be excreted
- often presents similar to sepsis with lethargy –> coma
- hyperammonemia
- central hypoventilation leading to respiratory alkalosis due to the toxic metabolites
- high ammonia
- hormal glucose
- anion gap
- respiratory alkalosis
Klinefelters
XXY
can cause primary hypogonadism
ambiguous genitalia (varying degrees)
infertility later in life
often developmental delay
delayed puberty
tall stature
high FSH and LH
low testosterone
Karyotype dx
Marfan
connective tissue disorder
aortic anneurysm, disection, rupture is risk
AV valve prolapse
rhythm problems
eye problems - refer to optho
can get dislocation of the lens (ectopia lentis)
refer to optho and cardio if questioning
High ammonia with respiratory alkalosis
urea cycle defect
High ammonia with acidosis AG
aminoacidopathy or organic acidemia
Hypoketotic hypoglycemia
fatty acid oxidation disorder or hyperinsulinism
Hypoglycemia with high lactate
glycogen storage disorder
High lactate constantly
mitochondrial disorder
liver failure in newborn
galactossemia
gram negative sepsis in newborn (ex. ecoli)
galactossemia
Smith Lemli Opitz
slOw, dont grOw, weird tOes,
Central congenital hypoventilation syndrome
PHOX2B mutation
can’t sense hypercarbia
need PSG in first yr life
arrhythmia so need holter
urine screen and US for neuroblastoma
Hirschsprung
genetic conditions with cafe au lait macules
Neurofibromatosis 1
Neurofibromatosis 2
Fanconi Anemia
Russell Silver Syndrome
Noonan Syndrome
Bloom Syndrome
Tuberous Sclerosis
McCune Albright
syndromes with craniosynostosis
Crouzon Syndrome
Apert Syndrome
Pfeiffer Syndrome
Saethre Chotzen
Muenke Syndrome
3 syndromes requiring PSG before age 1
achondroplasia
congenital central hypoventilation syndrome
prader willi *not necessairly before 1
cocaine teratogen association
placental abruption
most common cardiac defect from perinatal alcohol use
septal defects - ASD/VSD
fetal hydantoin syndrome
microcephaly
cleft lip
hypoplastic nails
hypoplastic distal phalanges (short stubby tips of fingers)
maternal diabetes teratogen features
- sacral agenesis (caudal regression syndrome)
- small left colon syndrome
- hypertrophic cardiomyopthy
maternal PKU during pregnancy
if mom’s disease is well controlled, limited effects on baby
if maternal phenylalanine is high and uncontrolled, risk of:
- IUGR
- microcehaly
- heart defects
- ADHD
syndrome strongly associated with cutis aplasia
patau (Tri 13)
baby with IUGR, prominent occiput, overlapping fingers and rockerbottom feet
trisomy 18
Edwards
down syndrome heart disease
AVSD > VSD > ASD > ToF > PDA
girl with delayed puberty, short stature and followed by cardiology
Turner syndrome
Turner syndrome heart defects
left side - turn left!
bicuspid aortic valve
coarctation
long QTc
baby with hypocalcemia and recurrent infections and cleft palate
DiGeorge 22q11.2
C-cardiac (conotruncal)
A-abnormal facies
T-thymus hypoplasia
C-cleft lip
H-hypocalcemia
diGeorge heart disease
conotruncal
- ToF
- interrupted aortic arch
- truncus arteriosus
autosomal dominant diseases examples
Achondroplasia
Crouzon syndrome
CHARGE
Ehlers-Danlos
Familial adenomatosis Polyposis
Hereditary breast/ovarian cancer
Li-Fraumeni syndrome
Marfan syndrome
Neurofibromatosis 1
Neurofibromatosis 2
Noonan syndrome
Osteogenesis imperfecta
Treacher Collins syndrome
Tuberous sclerosis complex
Huntington disease
Denys-Drash syndrome
autosomal recessive diseases examples
Congenital adrenal hyperplasia
Cystic fibrosis
Phenylketonuria
Sickle cell disease
Tay-Sachs disease
Congenital myasthenia syndrome
Jeune asphyxiating thoracic dystrophy
Alpers-Huttenlocher syndrome
Leigh syndrome can be mitochondrial
x linked recessive examples
Duchenne muscular Dystrophy
Hemophilia A/B
Lesch-Nyhan syndrome
x linked dominant examples
Incontinentia pigmenti
Rett syndrome
Fragile X syndrome
mitochondrial inheritance examples
moms will pass mtDNA to all children; dad’s don’t pass on
hetoplasmy occurs when there is more than one population of mitochondria in the oocyte
- MELAS
- Leigh syndrome (also AR)
uniparental disomy examples
patient inherits two copies from one paren’t chromosome (instead of one) leading to identical chromosomal markers on both
- prader willi (maternal - inherit 2 from mom; where is papa?!)
- angelman (paternal - inherit 2 from dad; missing mom )
- beckwith wiedemann
- Russel silver (maternal - inherit from mom)
trinucleotide repeat exansion examples
DNA appears as repeat sequences of three bases. disease occurs when number of rpts exceeds a threshold
- fragile X
- Friedreich ataxia
- huntington
methotrexate teratogen exposure
craniosynostosis
craniofacial anomalies
underossified skull
limb defects
MTX FUX UP DA BONES IN DA BABY ESP DA SKULL
Angiotensin receptor blockers in late pregnancy teratogen effects
rena dysgenesis
skull ossification defects
oligohydramnios
tobacco teratogen effects
premature delivery
miscarriage
stillbirth
warfarin teratogen effects
nasal hypoplasia
stippled epiphysis
developmental delay
valproic acid teratogen effects
spina bifida / neural tube defects
craniofacial
hypospadias
isotretinoin (Accutane/vit A) teratogen effects
CNS defects
absent thymus
conotruncal defects
intellectual disability
miscarriage
baby with large occiput, rockerbottom feet and overlapping fingrs
trisomy 18
crouzon syndrome
craniosynostosis
big forehead
hypertelorism, proptosis
cleft lip/palate
NORMAL intelligence, normal extremities
CROUZON CRANIOSYNOSTOSIS FCKED UP CRANIUM but smart
AD inheritance
most common craniosynostosis syndrome (but occurs in 1/16 million)
Pfeiffer syndrome and Apert syndrome
Pfeiffer
- craniosynostosis
- hearing loss
- THUMB/BIG TOE problems (curved out) +/- syndactylyl
Apert
- craniosynostosis
- hearing loss
- PROMINENT SYNDACTYLY
is turner syndrome associated with advanced maternal age?
no
puberty in turner syndrome
delayed puberty
amenorrhea
breast development limited to breast buds, minimal pubic hair
infertile d/t streak ovaries with premature ovarian failure
significant growth retardation d/t estrogen insufficiency
list 3 genetic syndromes with short stature
Turner syndrome
Noonan syndrome
prader willi
Turner syndrome unique features
XO
shield chest, wide spaced nipples, webbed neck
heart: left sided lesions
short stature
delayed puberty/amenorrhea
increased with autoimmune disorders
normal intelligence
Noonan syndrome unique features
webbed neck, low set ears, down slanting palpebral features
heart: right sided lesions (pulm stenosos, hypertrophic CM)
cryptorchidism
coagulopathy
short stature
*Facial features: droopy noonan - droopy eyes (down slanting palpebral), droopy ears (low set and posterior rotation), droopy neck (webbed)
NOT DROOPY TESTICLES
AKA Doppy from Snow White
which of the following syndromes appear normal at birth?
Turner
Klinefelter
Noonan
DiGeorge
Klinefelter
often confused with Marfan d/t tall stature later in life
delayed puberty and infertility
Klinefelter features
XXY
normal appearing at birth
Tall stature
GU: tiny testes and penis, hypospadias
Delayed puberty and infertility (testosterone
replacement in adolescence if no puberty)
+/- development/learning disabilities
boy with big ears, big testicles and intellectual disability
fragile X
fragile X genetics
x linked dominant
FMR1 gene
PCR diagnosis
CGG repeats
- premutation 55-200 rpts
- full mutation 200+ rpts
fragile x features
mild to mod intellecutual disability (apparent by age 2)
face: long, narrow, big ears, big forehead
big testicles
fam hx of miscarriages in mom (female carriers can be symptomatic and often have premature ovarian failure)
NF 2 pearls
AD
Think
- schwanomas
- gliomas
- meningiomas
- neurofibromas
other: cataracts, hearing loss, tinnitus, cafe au lait
workup and investigations for NF1
NF1 molecular genetic testing
MRI brain (only if symptomatic)
annual optho
annual BP monitoring
monitor for scoliosis
routine tumor surveillance (incr risk of pheo, gliomas, juvenile myelomonocytic leukemia, breast ca)
investigations and wokrup for tuberous sclerosis
genetic testing TSC1 and TSC2
brain MR (rpt q3 yr)
EEG
Echo
optho
renal US
if sz, use vigabatrin
incontentia pigmenti
x linked dominant
weird rashes present at birth
classically blistering rash at infancy (mistaken for HSV) but follows lines of Blashko
rash changes over time –> hyperpigmented –> hypopigmented
at risk for seizures and retinal detachment
angelman syndrome
UPD (paternal inheritance; missing mom)
features
- microcephaly
- seizures
- sleep problems
- ataxia
- happy demeanor, innappropriate laughter, anger outbursts
- developmental delays, non verbal
do an EEG d/t increased risk seizures
lesch nyhan inheritance and prominent features
x linked recessive
hyperuricemia d/t abnormal purine metabolism
self injurious behaviour, gout, developmental delays
tx: allopurinol
Rett syndrome inheritance
MECP2
x linked dominant (the boys die)
Rett syndrome investigations
mollecular genetics for MECP2 to confirm
ECG for prolonged QTc
EEG for risk seizures
suprastar memory aid for which syndrome
Williams syndrome
stellate iris
Super personality “cocktail party”
supravalvular aortic stenosis
williams syndrome features
suprastar
- supravalvular AS
- super personality
- stellate iris
elfin facies
intellectual disability
hernias, rectal prolapse
endo: hypothyroid, hypercalcemia
williams syndrome investigations
chromosomal microarry for dx
serum/urine calcium (hypercalcemia)
thyroid function (hypothyroid)
echo (supravalvular AS)
renal bladder US
hearing screen
optho
timing of PSG for baby with achondroplasia
often before leaving hospital d/t risk of central apneas due to foramen magnum stenosis
may need head imaging as well to assess for degree of stenosis
growth hormone for achondroplasia
no role - ineffective
precautions for patients with achondroplasia
avoid contact sports, diving, gymnastics d/t risk of atlantoaxial instability
respiratory insufficiency d/t central apneas - routine management of sleep apnea
activity avoidance for marfan vs. ehlers danlos
Marfan
- weight lifting and contact sports
- wind instruments/scuba diving (ptx)
- pregnancy is high risk
Ehlers danlos
- activities with high strain on joints
- weight lifting IF aortic dilation
marfan syndrome eye finding
ectopia lentis
ectopia lentis ddx
Marfan (most common cause)
- usually bilateral and occurs most often in the superotemporal direction
Homocystinuria (second most common)
- usually bilateral and in 60% of cases occurs in the inferior or nasal direction
medications used in osteogenesis imperfecta
bisphosphonates
growth hormone
pierre robin features plus myopia and skeletal abnormalities
Stickler syndrome
who hates genetics the most?
Michelle (WRONG!)
John
syndromes associated with omphalocele
T21
beckwith Wiedemann
wilms tumor associated conditions
- Beckwith Wiedemann
- denys drash
- WAGR
- Frasier
beckwith wiedemann increased tumor risk
embryonal tumors
- Wilms (nephroblastoma)
- Neuroblastoma
- hepatoblastoma
*embryonal tumors think blastomas
alpers huttenlocher syndrome
triad: intractable epilepsy, psychomotor regression, liver disease
autosomal recessive, mitrochondrial
leigh syndrome
mitochondrial, autosomal recessive
classic findings
- lactic acidosis
- FTT
- hypotonia
- peripheral neuropathy
- hypertrophic cardiomyopathy
MELAS
mitochondrial encephalomyopathy, lactic acidosis and stroke like episodes
development is normal. symptoms begin in childhood with stroke like episodes
Arginine used for acute treatment of stroke like episodes
mitochondrial inheritance
CHARGE Syndrome
AD inheritence
C- coloboma
H- heart (conotruncal, arch)
A - atresia choanal
R- retardation of GROWTH
G- GI/GU (microphallus)
E- ear (helix malformation, deafness)
E - extremities (clubfoot, absent tibia, hand anomalies - finger like thumb, hockey stick palmar crease, square palm)
OTHER features
- TEF or esophageal atresia
- dysphagia
- facial palsys
- orofacial clefts
investigations for CHARGE syndrome
C - ophtho
H - echo
A - temporal bone CT
r
G - renal bladder US
E - audiology
how many features do you need for vacterl
at least 3 of the following
Vertebral
Anal atresia
Cardiac
TE fistula
Renal anomalies
Limb anomalies
rhizomelic long bone shortening
proportionally shorter proximal limb bones compared to distal long bones
seen in achondroplasia
eye problems in Marfans
ectopia lentis (up and out)
glaucoma
cataracts
homocystinuria
similar to marfans
marfanoid body habitus
ectopia lentis (down)
intellectual disability!!
thrombotic events!!
dx: measure serum homocysteine levels
hypertension in NF1
screen for renal artery stenosis and pheo
ectodermal dysplasia
can’t sweat – at risk of hyperthermia
conical teeth
hypotonia, gavage feeding and puffy hands and feet with cryptorchidism newborn
prader willi
key pearl for urea cycle defect
High ammonia
may be alkalotic or mildly acidotic
low urea!
key pearl for organic acidemia
profound metabolic acidosis (much more than urea cycle defect)
also have high ammonia
normal urea
Phenylketonuria
aminoacidopathy
autosommal recessive
incidious onset! no crisis
features: microcephaly, GDD, rash, mood
NMS is usual diagnosis
tx: breast milk or phenylalanine free formula
homocystinuria
looks like marfan’s but will have intellectual disability and can have recurrent thrombosis
ectopia lectis (down)
no metabolic crisis
life long methianine avoidance
maple syrup urine disease
autosomal recessive
presents with acute crisis
–> headache, lethargy, vomiting
neonate: hypertonic, coma
high ketones!
methylmalonic acidemia
organic acidemia
presents with metabolic acidosis and high ammonia and high urea
elevated urine organic acids
OTC deficiency
urea cycle defect
high ammonia!!! low/normal urea!!
x linked (but females can be affected)
liver transplant is curative
glycogen storage disease
metabolic acidosis but NO ammonia elevation
presents after a few months when infant starts stretching feeds
unable to store/use glycogen so goes hypoglycemic with fasting BUT able to make ketones (unlike FAOD) so therefore ketotic hypoglycemia
pompe disease
glycogen storage disorder type 2 (doesn’t really present like glycogen storage disease type 1 - no hypoglycemia, rarely any lab findings, mainly problems with glycogen storage deposition)
- cardiomegaly
hypotonia
hepatosplenomegaly
baby with hypotonia, respiratory insufficiency, cardiomegaly and ECG with short PR interval - what condition?
Prader Willi
Noonans
neonatal lupus
Pompe disease
pompe disease (Glycogen storage type 2)
condition that causes a false positive newborn screen for galactossemia
G6PD
fatty acid oxidation disorder presentation
crisis during times of fasting or poor intake
hypoketotic hypoglycemia –> lethargy, sz, coma
may have hepatitis
dx with acylcarnitine profile (increased) and carnitine profile (decreased)
acute tx: high dextrose infusion. No lipids!
avoid prolonged fasting
bone finding in congenital hypothyroidism
distal femoral epiphysis is often absent on xray
