Genetics and Metabolism Flashcards
Septo-Optic Dysplasia
- Hypoplastic optic nerve (nystagmus, vision issues)
- Pituitary deficiencies (micropenis, direct hyperbili)
- Absence of septum pellucidum
- HESX1 gene mutation
Tuberous Sclerosis signs/symptoms
- Skin: hypomelanotic macules, facial angiofibromas, shagreen patches, fibrous cephalic plaques, ungual fibromas
- CNS: brain lesions (subependymal nodules, cortical dysplasias, subependymal giant cell astrocytoma), seizures, developmental delay, ASD, ADHD
- Nephro: benign angiomyolipomas, renal cysts, malignant angiomyolipoma, and renal cell carcinoma
- Cardiac rhabdomyomas
- Pulm: lymphangioleiomyomatosis, multifocal micronodular pneumocyte hyperplasia
- Eye: retinal hamartomas
Tuberous Sclerosis Treatments
- Topical mechanistic target of rapamycin inhibitor (like sirolimus or rapamycin) can improve lesions
- Oral mechanistic target of rapamycin inhibitors (sirolimus, everolimus) are often used in the treatment of TSC-related complications
Tuberous Sclerosis Genetics
- Mutations in TSC1, which encodes hamartin, or TSC2, which encodes tuberin.
- Autosomal dominant but 2/3 have de novo mutation
- Abnormal cellular proliferation that involves activation of rapamycin pathway
Glycogen storage disease type 1 genetics
- Autosomal recessive deficiency of glucose-6-phosphatase catalytic activity (GSDIa) or by a defect in glucose-6-phosphate translocase (GSDIb)
Glycogen storage disease type 1 signs/symptoms
- Exam findings: hepatomegaly, renomegaly, doll like facies, big abdomen, short stature, thin extremities
- Lab findings: hypoglycemia and lactic acidosis (with fasting), elevated lipids and triglycerides, hyperuricemia
- Symptoms: poor growth, pubertal delays, gout, CKD, pulmonary hypertension, osteoporosis, hepatic adenomas, pancreatitis, polycystic ovaries, seizures, elevated triglycerides
Bone disease (lytic lesions on xray), hepatosplenomegaly, cytopenias, pulmonary disease, neurologic involvement
- Autosomal recessive lysosomal storage disorder
- Gaucher disease
Pompe disease genetics
- Autosomal recessive - glycogen and lysosomal storage disorder
- Deficiency in lysosomal breakdown of glycogen
Infant normal at birth that becomes floppy at 1 month of age, failure to thrive, cardiomegaly (HCM), hepatomegaly
Pompe disease (glyogen storage disease type II)
- Other sx: macroglossia, death due to respiratory failure, hypotonia but muscles hard on exam
- Labs: elevated CK and urinary oligosaccharides, reduced acid a-glucosidase activity, elevated LFTs
- Tx: enzyme replacement therapy and high protein/low carb diet
Hurler syndrome
- Autosomal recessive lysosomal storage disorder (mucopolysaccharidosis type 1)
- Presents before age 2
- Coarsening facial features, umbilical/inguinal hernias, upper respiratory infections, skeletal involvement, hearing loss, hepatosplenomegaly, valvuar cardiac disease, progressive intellectual disability, corneal clouding
- Labs: reduced alpha-L-iduronidase activity in WBCs
Most common cause of inherited intellectual disability
- Fragile X –> have significant receptive and expressive language problems as well as autistic behaviors and hyperactivity
- Fragile X is also the most common single gene cause of autism spectrum
Fragile X syndrome exam findings
Long face, prominent jaw, portruding ears, high arched palate, strabismus, hyperflexible joints, macro-orchidism
Fragile X genetics
- Trinucleotide repeat of > 200 CGG repeats in the FMR1 gene
- Seen in 1 in 4000 males and 1 in 8000 females
- Think of this when running in the family of males
- Need DNA testing (FMR 1 gene) to diagnose, can’t do on a microarray
Prader Willi syndrome genetics
- Microdeletion on paternal chromosome 15
- Occurs in 1:10,000-30,000
- Need a methylation test to detect this
Intellectual disability, hypotonic infant with failure to thrive, obesity/hyperphagia later on
Almond shaped eyes, thin upper lip and downturned mouth, hypogonadism, short stature, small hands/feet
Prader Willi syndrome
PKU metabolics
Lack of phenylalanine hydroxylase leads to accumulation of phenylalanine
PKU treatment
- Low protein and low phenylalanine formula
- Tyrosine is an essential amino acid so need to have adequate intake
- Can be over-treated (lethargy, rash, diarrhea –> low phenylalanine levels)
- If not treated can lead to irreversible intellectual disability
Marfan syndrome genetics
- Mutation in fibrillin-1 gene (chromosome 15)
- Autosomal dominant
Stickler syndrome
- Pierre Robin sequence (cleft palate, glossoptosis, micrognathia) and severe myopia or other ocular abnormalities
- Also commonly have skeletal abnormalities (arthritis) or sensorineural hearing loss.
First line genetic testing for global developmental delay and intellectual disability
Fragile X and chromosomal microarray
In utero testing and timing
- Chronic villus sampling can be done at 12 weeks
- Amniocentesis can be done at 16 weeks
X-linked recessive facts
- Males are affected (think uncles), females are carriers
- NO male to male transmission
- If any affected females in the family then it’s not X-linked recessive
- Often due to an enzyme deficiency
X-linked recessive transmission
- If mom is carrier: 50% risk of male being affected, 50% risk of female being carrier, 25% risk of any child being carrier or having disease and 50% risk of any child being normal
- If dad is affected: 100% chance of female being carrier, 0% chance of male being affected, 50% chance of child being carrier/50% being normal
X-linked dominant transmission
- If dad is affected then 100% of daughters will be affected and 0% of sons will be affected
- If mom has gene on two of her X chromosomes then 50% of her kids will have it and 50% wont
- There are no carriers of a dominant trait
What inheritance pattern is the only type that can be passed from father to son
Autosomal dominant
Genetic anticipation
Altered gene is passed down from generation to generation but can begin earlier in life and signs/symptoms become more severe, often due to an increased length of the unstable region in the gene
In an autosomal recessive condition, what portion of unaffected offspring are carriers
2/3
Mitochondrial inheritance
- Only moms can pass this on but both males and females can be affected
- Often many deaths in the family
Karyotype
Looks for defects in number, large rearrangements, and inversions
FISH
- You have to know what you’re looking for to do this test
- Single chromsome locus resolution
Chromosomal Microarray
- Order for children with abnormal phenotype or development and unsure what is going on
- Does NOT detect point mutations, tiny deletions/duplications, balanced chromsomal rearrangements
Methylation test
- Methylation pattern to see which of the parental copies of the gene got deleted
Short stature, broad webbed neck, bicuspid aortic valve, coarcation of the aorta, lymphedema of hands/feet at birth
Turner Syndrome
Turner syndrome clinical symptoms
Most common: Short stature, broad webbed neck, bicuspid aortic valve, coarcation of the aorta, lymphedema of hands/feet at birth
Others: short 4th/5th metacarpal bones, broad chest with widely spaced nipples, horseshoe kidney, streak ovaries (primary ovarian failure), increased risk of autoimmune conditions like diabetes/IBD/hypothyroidism
Cognition: Normal IQ but can have delayed speech or learning disabilities
Tx: can use growth hormone for short stature
Turner Syndrome genetics
- Full or partial X chromosome deletion (45 XO)
- Only in females
- Most common chromosomal defect found in spontaneous abortions
- Need a karyotype –> can get a FISH if mosaic
Pectus excavatum, webbed neck, low set ears, pulmonic stenosis
Noonan syndrome
Noonan syndrome full features
- Eyes: hypertelorism, downslanting, epicanthal folds, droopy lipids
- Head/neck: coarse hair, inverted triangular facies, deeply grooved philtrum, short/webbed neck
- Ears: low set, posteriorly rotated, fleshy helices, high frequency hearing loss
- Short stature
- Pectus carinatum/excavatum
- Cardiac: pulmonary valve stenosis is MC, hypertrophic cardiomyopathy
- Joint laxity
- Cryptorchidism
- Coagulation defects
- Developmental delay
Noonan syndrome genetics
- Male:female ratio is 1:1
- Karyotype is NORMAL
- Autosomal dominant inheritance
Ectopia lentis, skeletal abnormalities, aortic dissection/dilation, lumbosacral dural ectasia, asymmetric pectus carinatum
Marfan Syndrome
Marfan Syndrome clinical signs
- Skeletal: tall, high arched palate, dental crowding, hypertensible joints, scoliosis, long extremities, pectus excavatum/carinatum
- Long thing face
- Cardiac: aortic root dilation/dissection, MVP (but not a major criteria) –> need close cards follow-up
- Spontaneous pneumothorax/apical blebs
- Ectopia lentis (upward/anterior displacement of lens of the eye) –> need serial slit lamp exams
Marfan type body but lens displaced downwards/posterior and have developmental delay
Homocystinuria
Genetic condition that increases with advanced maternal age
Trisomies
Down syndrome genetics
- Translocation: need chromsomal studies of the parents, 10-15% if translocation in mother, 2% if translocation in father
- Nondisjunction: risk for recurrence is the same as the general population (1%) but must factor in maternal age related risk
- REMEMBER: age group that GIVES BIRTH TO MORE INFANTS WITH DOWNS is still women in their 20s (overall having more babies) but HIGHEST RISK is women in their 40s
Down syndrome clinical features
- Most common is hypotonia (80%)
DOWN SYNDROME - Dysplasia of middle phalanx of the 5th finger
- Ouch! Cardiac disease (AV canal or endocardial cushion defects - NW axis on EKG)
- Wide gap between 1st and 2nd toe
- Neck has excess skin
- Spots (brushfield spots in the eye)
- Y - protruding tongue
- Nice transverse palmar crease
- Duodenal atresia (“double bubble”, associated with hirschsprung disease too)
- Really extensible joints
- Oncology/leukemia (ALL)
- Moro reflex is incomplete
- Ears are small and anomalous (low set)
- Face: downslanting palpebral fissures
- Atlantoaxial instability
Trisomy 18 clinical features
- Skeletal: Clenched fist, rocker bottom feet, overlapping fingers, hypoplastic nails
- Face: prominent occiput, microcephaly, microophthalmia, low set malformed ears
- Seizures
- Horseshoe kidneys
- Cardiac abnormalities
- Developmental delay
Trisomy 13 clinical feautres
BAD LUCK
- Brain (holoprosencephaly, microcephaly, punched out scalp lesions)
- Airs (Low set ears)
- Digits (Polydactyly)
- Leukocytes
- Uterus (bicornate uterus and hypoplastic ovaries)
- Cleft lip and palate
- Kidneys (cystic)
- ** CUTIS APLASIA *** is essentially pathognomonic
Tall and infertile teen with small testes and normal intelligence
- Kleinfelter syndrome
- 47 XXY is most common (80%) but the others are mosaic or variable
- 30% have social issues or behavior problems, some have speech delays
- Can also have gynecomastia, increased risk of breast cancer and mediastinal tumors
- Tx: testosterone supplementation
Angelman syndrome genetics
- Missing maternal portion of chromsome 15
- Need methylation test to diagnose
- Often diagnosed between ages 3-7
Profound speech impairment, intellectual disability, ataxia, frequent laughter, happy, microcephaly, seizures, feeding problems
Angelman syndrome
Beckwith Wiedemann Syndrome genetics
- An overgrowth syndrome due to alteration in chromosome 11
- Need a methylation test to diagnose (imprinting disorder)
- Hypoglycemia is due to islet cell hyperplasia
Hypospadias, omphalocele, macroglossia, macrosomia, hypoglycemia, hemihypertrophy, renal anomalies
- Beckwith Wiedemann syndrome
- At risk for: rhabdomyosarcoma, Wilm’s (nephroblastoma), or neuroblastoma
Beckwith Wiedemann Syndrome monitoring
Need AFP every 3 months until age 4 and abdominal ultrasound every 3 months until age 8
Differences between 3 types of Gaucher disease
- Type 1: no neurologic involvement
- Type 2: neuro involvement early before age 2, rapidly progressive, die by age 4 –> due to decreased beta glucosidase activity
- Type 3: neuro involvement but later onset and not as aggressive
Gaucher disease diagnosis and treatment
- Glucocerebrosidase enzyme activity
- Enzyme replacement therapy and then symptomatic management
Elfin facies, wide spaced teeth, upturned nose, mild intellectual disability, always happy
Williams syndrome
- Also commonly have poor feeding and growth in infancy
What electrolyte abnormality and cardiac defect are associated with Williams syndrome
- Hypercalcemia
- Supravalvular aortic stenosis (can also have pulmonary stenosis)
Genetics of DiGeorge syndrome
- Autosomal dominant
- 22q11 microdeletion
- Diagnose with a microarray
Clinical symptoms of DiGeorge
CATCH 22
- Conotruncal defects (Tet)
- Abnormal facies
- Thymic aplacia and immunodeficiency (due to poor development of pharyngeal pouches)
- Cleft palate
- Hypoparathyroidism (can present with neonatal tetany d/t hypocalcemia)
- Can treat with thymic transplantation
Charge syndrome clinical symptoms
CHARGE
- Coloboma/cognitive deficits
- Heart defects
- Atresia/stenosis (choanal)
- Retarded growth and development
- GU abnormalities (genital hypoplasia)
- Ear anomalies (hearing loss)
CHARGE syndrome genetics
- Autosomal dominant
- CHD7 gene
Broad thumb and cryptorchidism
Rubinstein Taybi Syndrome
Girl around age 2 that has lost developmental milestones (regression) with autistic behaviors and wringing hands
Rett Syndrome
Rett syndrome clinical features
- Loss of developmental milestones around 18 months of age
- Head growth decelerates around 4 months of age
- Wringing hands
VACTERL symptoms
Need 3 for diagnosis:
- Vertebral defects/tethered cord
- Anal atresia
- Cardiac defects
- TE fistula
- Renal abnormalities
- Limb abnormalities
- Often presents with single umbilical artery and growth deficiency is common but INTELLIGENCE IS NORMAL
Age needed to recognize to correct craniosynostosis
- Deformation caused by premature fusion of one or more of the sutures
- 5 months of age
- Treatment is most successful when done prior to period of greatest head growth
- Complications if not treated: hydrocephalus, increased ICP
Positional plagiocephaly
- NORMAL HEAD CT (sutures are normal)
- Will improve over time on its own
Unilateral lambdoid synostosis head shape
Trapezoidal (contralateral frontal bossing)
Sagittal synostosis head shape
Dolichocephaly/scaphocephaly (long skinny egg shaped head)
Bilateral coronal synostosis head shape
Brachycephaly (short wide head)
Metopic synostosis head shape
Trigonocephaly (triangle head)
Small chin, cleft palate, micrognathia, glossoptosis (tongue sticks out)
Pierre Robin sequence
Pierre Robin sequence clinical features
- Small chin, cleft palate, micrognathia, glossoptosis –> upper airway obstruction
- Syndactyly, clinodactyly, hip/knee anomalies, kyphosis/scoliosis
- 50% have language delay, seizures, or developmental delay
Pugilistic facies, hypoplastic lungs, limb malformations (club feet), renal agenesis
- Potter syndrome (oligohydramnios sequence)
- Cause is renal agenesis
- Can also have glove like excess skin on hands and fetal membranes covered by yellowish nodules
- Die of pulmonary complications
Triangle face, growth retardation, poor appetite in early years, fifth finger incurving
Russell Silver syndrome
Prune Belly syndrome cause
Lack of abdominal muscle development
- Bladder outlet obstruction –> oligohydramnios –> pulmonary hypoplasia
- Also have undescended testes
Conductive hearing loss, small jaw, ear anomalies, lower eyelid abnormalities, cleft palate, coloboma of lower eyelid, normal intellectual ability
Treacher Collins
Large heads, very short extremities, short limbed dwarfism
Achondroplasia
- Autosomal dominant, 80% are de novo mutations
- Frontal bossing, relative macrocephaly, genu varum (bowlegs)
- Lumbar lordosis, nerve root compression, sleep apnea
Poor feeding, hypoglycemia, lethargy, vomiting, tachypnea, irritability, seizures, coma, apnea
General symptoms of inborn errors of metabolism
- Septic kid that is afebrile
- Trigger like feeding
Metabolism errors with metabolic acidosis and elevated ammonia
- Propionic acidemia
- Methylmalonic acidemia
- Fatty acid oxidation defects
Metabolism errors with metabolic acidosis and normal ammonia
- MSUD
- Some organic acidemias
Metabolism errors with normal pH and elevated ammonia
- Urea cycle defect
- Transient hyperammonemia
Metabolism errors with normal pH and normal ammonia
- Aminoacidopathy
- Galactosemia
- Non-ketotic hyperglycinemia
- “Drunk like” infant 1-2 days after introduction of protein
- Organic acidemias: methylmalonic acidemia, propionic acidemia, isovaleric acidemia (odor of sweaty feet)
- Labs: high anion gap, ketonuria, elevated serum ammonia level, acidemia
- Can have bone marrow suppression so may have low platelets and low WBC
Organic acdemias symptoms
- Decrased appetite, falling down, delayed milestones, no dysmorphic features
- Fast onset (not slow like a brain tumor would be)
Treatment of organic acidemias
- Hydration, appropriate diet
- Need to measure urine organic acid levels
Inheritence of fatty acid oxidation defects
Autosomal recessive
Hypoglycemia in first 2 years of life during illness or stress (decreased oral intake), hepatomegaly, seizures, cardiomyopathy
Fatty acid oxidation defects
- MCAD, LCAD, VLCAD, glutaric aciduria
- Kiddo is fine between episodes
Fatty acid oxidation defect labs
- Absence of reducing substances and ketones in the urine (NON KETOTIC!)
- Metabolic acidosis, hypoketotic hypoglycemia
- Normal serum amino acids
- Elevated ammonia and LFTs
- Definitive diagnosis is plasma acylcarnitine profile (newborn screen)
Fatty acid oxidation defect treatment
- D10 IVF and oral L-carnitine
- Avoid fasting
Infant with poor feeding and failure to thrive after introduction of lactose
Galactosemia (problem with lactose)
- All states screen for galactosemia but infants can present with symptoms before NBS is back
Galactosemia symptoms
Abdominal distension, hepatomegaly, hypoglycemia, lethargy, hypotonia
- REDUCING SUBSTANCES IN THE URINE
Galactosemia treatment
- Soy formula, remove all lactose
Galactosemia complications
- Cataracts (reversible with diet change)
- Intellectual disability
- Liver and renal disease (reversible)
- Prolonged jaundice (direct hyperbilirubinemia)
- Ovarian failure (not reversible - prenatal insult)
- GRAM NEGATIVE SEPSIS!! (if infant with this infection need to screen for galactosemia)
Galactosemia deficiency
- Galactose-1-phosphate uridyltransferase (GALT)
- Definitive diagnosis is made by measuring GALT in RBCs
Most important lab to determine etiology of hypoglycemia in an infant
Urine ketones and reducing substances
Presentation of hyperinsulinism
- Afebrile infant, hypoglycemic seizures, resolves with injection of glucagon
- Height, weight, head circumference are all above 95th percentile
Hypoglycemia, distended abdomen, doll like or cherubic face
Present when infant starts sleeping through the night
Glycogen storage disease type 1 (Von Gierke disease)
- Have lactic acidosis, hyperuricemia, hypertriglyceridemia
Glycogen storage disease type 1 (Von Gierke disease) treatment
- Frequent meals/snacks
- Continuous tube feeds – HAVE TO CONTAIN GLUCOSE
- Cornstarch after age 2 (releases glucose slowly)
Infant with hyperammonemia but no acidosis or ketosis
Urea cycle defects
- Unable to break down nitrogen properly –> accumulation of ammonia
- Symptom free period followed by encephalopathy within 48-72 hours after birth hypotonia and coma
- Can have respiratory alkalosis with lactic acidosis
- Normal anion gap, normal glucose
Urea cycle defect types
- OTC (ornithine transcarbamylase) deficiency –> X linked, high urine orotic acid
- Carbamoyl phosphate synthetase 1 (CPS1) deficiency would have low/undetectable urine orotic acid and is autosomal recessive
Urea cycle defect treatments
- Dialysis, hemofiltration
- IV arginine hydrochloride
- Protein restriction
- Increase IV glucose
3-6 months of age: motor dysfunction, behavioral disturbances (self injurious), cognitive impairment, hyperuricemia
Lesch Nyhan syndrome
- Uric acid metabolism disorder
- Screen with urate:creatinine in urine
- Confirm with hypoxanthine-guanine phosphoribosyltransferase enzyme activity
- X-linked recessive
Maple syrup urine disease symptoms
- Maple smelling urine
- Tachypnea, shallow breathing, lethargy, irritability, hypertonicity, ketonuria
- Onset in 1st week of life
Maple syrup urine disease lab
- Elevated VIAL amino acids in plasma levels
- Valine, Isoleucine, Alloisoleucine, Leucine
- These will be elevated by the end of the first day of life
Homocystinuria labs
- Error in methionine metabolism
- Elevated blood homocystine and methionine levels
- Elevated urine homocystine levels
Homocystinuria symptoms
- Marfans body type but POSTERIOR LENS DISPLACEMENT
- Cognitive deficits
- Unpleasant odor
- Light colored skin, hair, and eyes
- Thromboembolism –> early death
- Tx: diet low in methionine and protein as well as betaine, folate, and vitamin B12 supplementation
Non-ketotic hyperglycinemia
After being fed protein containing formula for the first time
- Lethargic, comatose –> spastic CP if they survive
PKU in pregnant woman risks
- Risk for miscarraige, SGA, microcephaly, cardiac defects, intellectual disability
Asymptomatic for a few months (blond hair and blue eyes) –> severe vomiting, irritability, eczema, musty odor of the urine
PKU
False positive PKU newborn screen
- PKU screening is only valid after a protein feeding so needs to be done at 48-72 hours
- PKU screening checks for elevated phenylalanine levels: delayed enzyme maturation, hyperphenylalaninemia, biopterin deficiency
Hunter syndrome
- MPS type II, X-linked recessive
- Coarse facial features, organomegaly, joint contractures, skin appears pebbly over upper back, progressive deafness, short
- NO CORNEAL CLOUDING (as compared to Hurler syndrome)
- Labs: reduced iduronate sulfatase enzyme activity in WBCs
Normal development through 9 months –> lethargy, hypotonia, exaggerated startle reflex, cherry red spot on the retina, macrocephaly
Tay Sachs disease
- Autosomal recessive
- Deficiency of hexosaminidase A enzyme (lysosomal enzyme)
- Blindness and seizures, death by age 5
- Increased in Ashkenazi Jews
Cherry red spot, CNS deterioration, hepatosplenomegaly
Niemann-Pick disease
Osteogenesis imperfecta
- Fractures with minimal or no trauma
- Often have short stature
- Blue sclera
- Progressive hearing loss
- Most are autosomal dominant
Fusion of at least 2 cervical vertebrae (short neck, low hairline, limited ROM)
Klippel Feil Syndrome
- At risk for spinal stenosis, facial asymmetry, cervical dystonia, scoliosis
Infant with failure to thrive, alopecia, scaling dermatitis
Biotinidase Deficiency
- Can also have vomiting, dehydration, seizures, hypotonia, ataxia, hearing loss, metabolic acidosis
Glycogen storage disease type 1 (Von Gierke disease) complications
- Neutropenia
- Increased bleeding
- Short stature
- Gout
- Osteoporosis
- Nephropathy
- Pancreatitis
- Polycystic ovaries
- Pulmonary hypertension
Autosomal dominant - hearing loss, lobster claw hands, midface abnormalities
Apert’s syndrome
Facial - hypertelorism, proptosis, saddle nose, high arched palate, low set ears
Autosomal dominant - atresia and stenosis of ear canal, conductive hearing loss, small maxilla, short upper lip, hypertelorism
Crouzon’s syndrome
Vertebral fusion or absence of cervical vertebra, facial asymmetry, ear abnormalities/hearing loss, eye abnormalities
Goldenhar syndrome
Smith Lemli Opitz Syndrome
- Autosomal recessive disorder of cholesterol metabolism
- Will have low total cholesterol but high 7-dehydrocholesterol
- Also have abnormal facial features
