Genetics Flashcards
What is the most comom major congenital malformation in the US
neural tube defects
Where are most port wine stains nevus flammeus), located?
85% are unilateral and msot are present on the head and neck
What are the major criteria for the diagnosis of CHARGE to be considered?
coloboma, atresia of the choanea, cranial nerve dysfunction, and characteristic ear anomalies (hypoplastic lobule, prominent antihelix, triangular cocncha)
What is the most common autosomal trisomy found in live newborns?
T21
What tests need to be done on an infant with T21 before being discharged from the hospital?
CBC.to assess for leukomaoif reaction or transient myeloproliferative disorder; thyroid function tests to eval for hypothyroid, hearing screen, red reflex to assess for cataract formation; GI contrast studies in infants with bilious emesis to rule out duodenal atresia
Give example of microdeletion syndromes
DiGeorge, PWS
Give example of missense mutation
Sickle cell anemia (new nucleotide changes the codon and the amino acid profile is changed; in SS, replacement of A by T at the 17th necleotide of the gene for the beta hemoglobin chain change the codon GAG (glutamic acid) to GTG (valine)
Give example of nonsense mutation
CF; new nucleotide changed the codon to a stop codon which stops the translation of messenger RNA; the earlier this happens the more dysfunctional the protein
This is a type of translocation where the the long arms of 2 different chromosomes fuse at the centromere and the very small short arms are lost; only involves chromosomes 13,14,15,21, and 22
Robertsonian translocation; normal phenotype; most common type is between chromosome 21 and 14 which is responsible for 3-5% of T21
What is the most common single gene disorder in the Caucasian population?
Cystic fibrosis
List examples of single gene disorders that are autosomal recessive
Cystic fibrosis, majority of inborn errors of metabolism; alpha and beta thalassemia, sickle cell disease, 21 hydroxylase defiency, congenital muscular dystrophy
Lis the 9 syndromes that result from imprinting
PWS, Angelman, Beckwith-Weideman, Russell-Silver, maternal hypomyelination syndromes, maternal and paternal uniparental disomy of chromosome 14, pseudohypoparathyroidism type 1b, transietn neonatal diabetes
What are two examples if single gene disorders with autosomal dominant inheritanace?
spherocytosis, Waarderburg syndrome (these disorders are commonly recognzed as disorders with this inheritance)
What are some examples of single gene disorders with x-linked recessive inheritance ?
glucose-6-phosphate dehydrogenase deficiency, Wiskott-Aldrich syndrome, hemophilia A and B (these are commonly recognized disorders with this type of inheritance)
Female infant born at 36 weeks for fetal intolerance to labor and maternal exhaustion. IOL for IUGR. Decreased fetal movement during pregnancy. On exam, infatn holds the BUE and BLE in flexion. Complete extension of the elbows, hips, and knees is impossible. Normal DTR. Infant has a weak cry and cannot lift his head with horizonal suspension. Post-natally, you notice mother with few facial expressions, drooping eyelids, and difficulty releasing your hand after a handshake. What is the pathogenesis for arthrogryposis in the neonate?
congenital myotonic dystrophy secondary to a trinucleotide expansion (CTG repeat) resulting in altered RNA binding proteins; this disease has autosomal dominant inheritance
What are some disorders a/w advanced paternal age?
achondroplasia, Apert syndrome, Marfan syndrome, Treacher Collins syndrome, osteogenesis imperfecta, Waardenburg syndrome
One or more fingers is permanently bent (Camptodactyly); thick lips, deep set eyes, prominent cupped ears,
trisomy 8; most that survive are mosaic since comlete trisomy 8 is lethal
cleft lif and palate, midline abnormalities, cutis aplasia, narrow convext fingernails, holoprosencephaly, seizures with hypsarrhythmia, persistent of fetal hemoglobin; triple screen not helpful
trisomy 13, extra chromosome from maternal origin, 95% of trisomy 13 conceptons lead to spontaneous abortions;
females> males; VSD, PDA, clenched hands, overlapping of 2nd finger over 3rd or 5th finger over 4th; rocker bottom feet, small mouth / micrognathia (may be a/w Peirre Robin), short sternum; triple screen with low beta-hCG, low estriol, low AFP,
trisomy 18; > 95% with complete trisomy 18, with extra copy of maternal origin in ~90%
1 in 800 live births; 5th finger with hypoplastic middle phalynx, 5th finger clinodactyly, hyperflexicle joints, upslanting palpebral fissures, flat facies, Brushfield spots (speckled iris), epicanthal folds, infertility in both males and females, hypotonia
T21; 94% with complete trisomy, ~3-5% with Robertsonian translocation, 2% mosaicism; increased risk in older females due to increased risk of non-dusjunction with age
What are some increased risks in patients ith T21
increased risk of immunolgic dysfunction, leukemia (15-20x compared to general pop), Alzheimer’s
hyertelorism, downward slant of palpebral fissures, severe mental deficiency, cat-like cry, 2/2 abnormal laryngeal development, FTT microcephaly, hypotonia, VSD, PDA, TOF
Cru di chat; partial deleiton of the short arm of 5th chromosome (deleted portion is of paternal origin in 80% of de novo events) majority are de novo
thumb hypoplasia, colobomas, increased risk of retinoblastoma, microcephaly, high nasal bridge, 5th finger clinodatyly
deletion 13q
puppet- like gait, blonde hair color, decreased iris pigment, wide spaced teeth, large mouth, seizures
Angelman sydrome; 70% result fro 15q11-13 deletion, <5% uniparental disomy, 20-30% occur because of point mutations or other abnormality of maternal 15 q 11-13 region; deleted piece is always of maternal origin
most common chrosomsal deletion in humans
Digeorge; occur in 1 in 4000; autosomal dominant with variable expession
secondary to defect in 4th brachial arch and derivatives of 3rd and 4th pharyngeal pouches; aortic arch abnormalities; hypoplastic to aplastic thymus, hypocalcemia, deficient celluar immunity, developmental delay, cleft palate
DiGeorge,, majority with 22q11.2 deletion
small hands and feet, undescended testes, FTT initially but then obesity, breech presentation at delivery, almond shaped palpbral fissures
PWS, ~70% with deletion of 15 q 11-13, ~25% result from maternal uniparental disomy, ~5% result from methylation at several loci within 15 q 11-13; deleted piece is always of paternal origin
broad thumbs, downward slanting palpebral fissures, prominent and/or beaked nose, hypoplastic maxilla, broad toes, hirsuitism, 25% with cardiac anomalies (PDA, VSD, ASD); due to deletion of 16p13.3 which encodes for cAMP-regulated enhancer-binding protein (CREB)
Rubenstein-Taybi syndrome; majority are sporadic
Wilms tumor, aniridia, GU abnormalities, moderate to severe mental deficiency, congenital cataracts,
WAGR syndrome, due to 11p13 deletion, usually de novo
supravalvular aortic stenosis> peripheral pulmonic stenosis, hypoplastic nails, prominent lips, hoarse voice, stellate iris pattern, mental deficiency
Williams syndrome, 11q13 deletion leading to deletuon of elastin gene, majority sporadic
diandric triploidy (69, XYY) is a/w with what 3rd trimester US finding?
placentomegaly with the placenta resembling a a hydadidiform mole; fetuses have mild growth restriction and noro-microcephaly
Digynic triploidy (69 XXY( is associated with what findings prenatally
small placenta, severe growth restriction, relative macrocephaly
trident hands (Separation between middle and ring fingers), short limbs, depressed nasal bridge, megalocephaly, caudal narrowing of the spinal cord, normal intelligence; autosomal dominant, 80-90% result from new mutations, increased risk with paternal age
achondroplasia; secondary to a mutation in the transmembrane domain of the FGF receptor 3 gene (at 4p16.3 locus)
hypertelorism, midfacial hypoplasia, broad distal phalanx of thumb and big toe, syndactyly, irregular craniosynostosis; autosomal dominant, majority sporadic,
Apert Syndrome= acrocephalosyndactyly, due to mutation in the the FGF receptor 2 gene
maxillary hypoplasia, shallow orbits, premature craniosynostosis (especially coronal, lambdoid, sagittal sutures), mental deficiency less common, autosomal dominant with variable expression
Crouzon syndrome (craniofacial dyostsis, due to diferent mutation I the FGF2 receptor gene than Apert’s syndrme
polyhyramnios, large tongue, linear earlobe fissures, macrosomia, organ hypoplasia, fetal adrenocortical cytomegaly, intra-abdominal malignancies (Wilms tumor and hepatoblastoma), hypoglycemia
Beckwith-Wiedemann syndrome; autosomal dominant with variable expression and incomplete penetrance with gene located at 11p15.5
ASD (most common, but can have VSD or Coractation), upper limb defects; absent, hypoplastic or abnormally shaped shaped thumbs, narrow shoulders, decrease rangeo of motion of upper extremities
Holt-Oram, Autosomal dominant with varible expression, some cases a/w 12q2 locus
dilated aorta, arachnodactyly, hyperextensibility, scoliosis, lens subluxation (usually upward),
Marfan syndrome, autosomal dominant with varianle expression
ASD (most common, but can have VSD or Coractation), upper limb defects; absent, hypoplastic or abnormally shaped shaped thumbs, narrow shoulders, decrease rangeo of motion of upper extremities
Neonatal Marfan’s syndrome, results from diferent mutation in fibrillin gene from Marfan’s syndrome that presents later in life
What is the treatment for Marfan’s?
beta blocker to prevent aortic dilatation
dysplastic pulmonary valve, webbed neck, cryptorchidishm, short stature abnormalities in the coagulation pathway,
Noonan syndrome, autosomal dominant with wide varianble expression, abnormalities mapped to the 12q22 region
defect in type 1 collagen (COLA1 gene), blue sclera, increased risk of fractures (8% noted at birth, 25% noted in first year of life), easy bruisability, deafnes, postnatal growth deficiency, abnormal dentition, wormian bones in cranial sutures
osteogenesis imperfecta (type 1); autosomal dominant
blue sclera, increased risk of fractures, short and broad long bones, patients are usually still born or die early in infancy 2/2 resp failure,
osteogenesis imperfecta (type 2); defect in type 1 collagen (COLA1 gene), autosomal dominant
blue sclera in infancy that normalizes as an adult, increased risk of fractures (usually present at birth), IUGR, macrocephaly, abnorml dentition, deafness, kyphoscoliosis, short stature
osteogenesis imperfecta type 3; defect in type 1 collagen (COLA1 gene), autosomal dominant
normal sclera, increased risk of bone deformities, may have abnormal dentition
osteogenesis imperfecta type 4; defect in type 1 collagen (COLA1 gene), autosomal dominant
aka hereditary arthro-opthalmopathy, flat facies, myopia, spondyloepiphyseal dysplasia (flat vertebrae with anterior wedging, poorly developed distl tibial epiphyses, flat femoral epiphyses, mitral valve prolapse, can be a/w Pierre Robin sequence
Stickler syndromel autosomal dominant , 2/2 mutation in the COL2A gene (type 2 collagen gene), located at 12q13.1-q13.2 locus
large cranium, short limbs, low nasal bridge, flat vertebral bodies, curved long bones
type 1, thanatophoric dysplasia, more common, autosomal dominant, 2/2 new mutation in the tyrosine kinase domain of FGF receptor 3 gene (at 4p16.3 locus)
large cranium, short limbs, low nasal bridge, flat vertebral bodies, straight femoral bones, taller vertbebral bodies, cloverlea skull
type 2 thanatophoric dysplasia autosomal dominant, 2/2 new mutation in the tyrosine kinase domain of FGF receptor 3 gene (at 4p16.3 locus)
lower eyelid coloboma downslanting palpebral fissures, mandibular hypoplasia, malformed ears, malar hypoplasia, dysmorphic ears, aka mandibulr facial dysostosis, 40% with conductive hearing loss, 40% with visual loss, normal intelligence
Treacher Collins, 60% due to new mutations, autosomal dominant, 2/2 mutation in the TCOF 1 gene that leads to 1st and 2nd brachial arch maldevelopment
white forlock, partial albinoism, deafness (more severe ins type 2 form),
Waardenburg syndrome, autosomal dominant (Type 1 due to mutation in the PAX 3 gene); 4 different types,
polydactyly, lateral displacemnet of inner canthus, brachycephaly; 50% with cardiac anomalies (VSD, PDA, ASD, PS, TOF, TGA)
Carpenter syndrome, auto recessive
short distal extremities, polydactyly (fingers more than toes), nail hypoplasia, narrow thorax, 50% with cardiac anomalies (single atrium, ASD)
Ellis- van Creveld syndrome ; autosomal recessive, aka chrondoectodermal dysplasia
hyperpigmentation (increases with age, esp involving groin, axilla, trunk), radial hypoplasia, thumb hypoplasia, short stature, pancytopenia (presents at ~7 years but may occur during infancy)
Fanconi pancytopenia syndrome, auto recessive, increased number of chromosomal breaks in lymphocytes and amniotic fluid cells
What is the prognosis of patients with Fanconi pancytopenia
~35% mortality 2/2 hematologic anomaiies, increased risk of AML
encephalocoele, microphthalmia, cleft palate, micrognathia, ear anomalies, polydactyly, cystic dysplastic kidneys
Meckel-Gruber syndrome, auto recessive, locus mapped to 17q21-q24
encepalocoele, facial disruptions cleft lip/palate, amputations of digits or limbs
amniotic band syndrome
encephalocoele, hypertelorism, widely set nostrils, anterior cranium bifidum occultum
frontonasal dysplasia
eye abnormalities (microphthalmia, cataracts), CNS anomalies (ventriculomegaly, midline abnormalities, lissencephaly)
Walker-Warburg syndrome
2-3 toe syndactyly (95%), anteverted nostrils, genital anomalies (70%) because of failure of masculinization of male genitalia ( like hypogenitalia, hypospadius, crytorchidism), IUGR, breech
Smith-Lemli- Opitz syndrome, auto recessive, defect in cholesterol synthesis leading to low cholesterol levels and elevted 7-dehydrocholesterol
thrombocytopenia precipitated by viral illnesss (esp GI illness), absent bilatearl radii (100%); thumbs present, ulnar abnormalities, abbnormal humerus in some, cardiac anomalies (30%) like TOF or ASD
TAR syndrome; auto recessive, ~40% mortality a/w hemorrhage in early infancy
long facies, prominent forehead, large ears, large testes post-puberty, mental deficieny, autism, hypertextensible fingers/joints, mild connective tissue dysplasia
Fragile X syndrome, x-linked dominant with 80% penetrance in males and 30% penetrance in females, loss of function mutation, due to expansion of premutation (with increased number of CGG repeats) leading to full mutation (with extremely high number of CGG repeats)
twisted fractured lightly pigmented hair, progressive cerebral deterioration (typically presents at 1-2 months of age with hypertonia, irritability, seizures, feeding difficulties), increased risk of fractures
Menkes disease, x-linked recessive, gene located at Xq13, secondary to abnormality of copper transport leading to copper deficiency
47, XXY, 1 in 500-1000 male births, equally derived from maternal or paternal erors, if maternally derived, increased risk with advancing materal age
Klinefelter’s syndrome
hypogonadism, hypogenitalia, infertility, behavioral difficultyl disporprotionately long arms and legs, 5th finger clinodactyly,
Klinefelter’s syndrome
cystic hygroma, webbed posterior neck , gonadal dysgenesis, congenital lymphedema, short stature, broad chest with wide spaced nipples, increased risk of gonadoblastoma
Turner’s syndrome, 1 in 2000-5000 live born females, 50% 45X, 30-40% mosaics (45 X, /46XX more common than 45X/46XY) the chromosome that is deleted is paternal and thus no increased risk with advanced maternal age
Cardiac (> 33%) including TAPVR, persistent L subclavian, down-slanting palpebral fissures, anal atresia with rectovestibular fistula, coloboma of the iris
Cat eye syndrome; extra part of 22 usually in quadruplicate or triplicat at 22q11 region (vs DiGeorge that is deletion of 22q11)
expressionaless facies, micrognathia, 6th and 7th nerve palsy (usually bilateral); may also have 3,4,5,9,10,12 cranial nerve involement; talipes equinovarus (1/3)
Mobius syndrome
4 types of abnormal development: 1 destruction of central brain nuclei, 2 hypoplasia or absence of central brain nuclei, 3 peripherla nerve involvement, 4 myopathy; a/w limb reduction defects, Poland sequence and Klippel Feil anomaly
Mobius syndrome; majority sporadic
micrognathia, glossoptosis (normally sized tongue in small oral cavity), cleft palate (U-shaped); secondary to mandibular hypoplasia prior to 9 weeks; may be isolated or a/w genetic disorders (T18, Stickler syndrome, Teracher- Collins, FAS);
Pierre Robin sequence
Coloboma, heart disease ( TOF, DORV, VSD, ASD, PDA, R sided aortic arch), choanal atresia, retarded growth, genital hypoplasia, ear anomalies or deafness; may also have mental deficiency (94%)
CHARGE association, may also have anal atreisa, DiGeorge sequence, hypocalcemia; unknown etiology
Cardia anomalies (VSD>TOF), micromelia (small hands and feet), 5th fiinger clindodactyly, 2-3 toe syndactyly, synophrys, thin down turned upper lip, long and curly eye lashes, intiial hypertonicity, microbrachcephaly, hirsutism, low posterior hairline, cutis marmorata
Cornelia de Lange syndrome; unknown etiology, majority sporadic
What causes Goldenhar syndrome (aka oculo-auriculo-vertebral spectrum or facio-auriculo-vertebral specturm?
unknown etiology, usuually sporadic, 1 in 3000- 5000; due to 1st and 2nd brachial arch abnormalities
malar, maxillary or mandibular hypoplasia, lateral extension of the corner of the mouth, malformed ears, ear tags/pits,. Tongue abnormalities, deafness, mental defiency, hemivertebrae or hypoplasia or vertebrae (cervial most common), cardiac (VSD>PDA>TPF> coractation
Goldenhar syndrome
short neck, low posterior hairline, limited movement of the head (may lead to webbed neck, torticollis, +/- facial aymmetry), deafness (conductive or neural) abnormal cervical vertebrae (typically fused); can be a/w Sprengel deformity (failure of scapula to descen to normal location leadting to elevation and medial rotation of inferior portion of the scapula
Klippel-Feil- unknown etiology, majority sporadic
asymmetric limb hypertrophy, vascular lesions
Klippel-Trenaunay Wber syndrome
syndactyly of hand, unilateral hypoplasia or absence of pectoralis muslce; possibly due to proximal subclavian arterial disruption in utero leading to poorly developed distal lumb and pectoral region on that side
Poland Sequence; unknown etiology, majorrity sporadic; male?female (3:1); 75% right sided
small triamgular facies, short stature, congenital asymmetry of the skeleton, small curved 5th finger, café au lait spots, late closure of anterior fontanelle
Russell-Silver syndrome; majority sporadic, some with maternal uniparental disomy (possibiliuty of imprinting)
vertebral anomalies, anal atresia, cardiac (VSD> TOF, coarctation), TEF, renal anomaly (35% with single umbilical artery), limb dysplasia
VACTERL association, unknown etiology, increased risk in IDM
What is needed to make the diagnosois of VACTERL
3 of any of the features, of those who meet the criteria, 1/2 will have isolated VACTERL association and the other 1/2 will have another genetic anomly
What is in the differential diagnosis for masses in the supraclavicular/paratracheal area of the neck
thyroid mass, parathyroid mass, esophageal diverticulum, lipoma, dermoid cyst, lymnphadenitis, cystic hygroma
define malformation
abnormal tissue formation eg renal agenesis, micrognathia, cleft palate
What is the inheritance pattern for most single gene mutations?
Autsomomal dominant
What is the inheritance pattern for enzyme or protein deficiencies?
autorecessive
What are the two dieases with x-linked dominant inheritance?
incontinentia pigmenti and Fragile X
define deformation
a/w altered mechanical forces (extrinsic or intrinsic) on normal tissue eg. Arthrogryposis resulting from in utero constraints
define disruption
breakdown of normal tissue; destructive; eg amniotic bands, porencephaly, limb reduction secondary to vascular anomalies
define dysplasia
abnormal organization of cellular formation into tissue; deregulation. Eg hemangioma, ectodermal dysplasia
define syndrome
a pattern of many malformations 2/2 one etiology
define sequence
a primary defect with secondary effects eg Pierre Robin sequence 2/2 primary mandibular maldevelopment with secondary findings of micrognathia, cleft palate, and glossoptosis
What is the inheritance pattern for most inborn errors of metabolism?
AR: exceptions are Hunters and OTC deficiency and x-linked adrenal leukodystrophy
define maternal imprinting
silence the maternally derived gene
define paternal imprinting
silence the paternally derived gene
infant with lethargy and vomiting. Labs show low ketones and hypoglycemia. Name the class of this metabolic disorder
fatty acid oxidation disorder
metabolic acidosis with LARGE anion gap, elevated ketones and hyperammonemia. P/w neonatal lethargy, vomiting, coma. Name the metabolic error
organic acidemia (protein, defect in amino acid breakdown leads to accumulation of organic acid bypass) like MSUD
no acidosis or hyperammonemia; elevations in specific amino acids
aminoacidopathy
hyperammonemia without acidosis; neonatal lethergy, vomting, coma, death; primary respiratory alkalosis
urea cycle disorders; defect in making urea (BUN), from ammonia that results from amino acid breakdown
ammonoia above what level is an emergency need for dialysis
300 micromol/L: think of urea cycle disorders and organic acidemia
mousy or musty urine odor
PKU
What are the effects of elevated maternal phenylalanin on the fetus?
microcephaly, IUGR, intellectual disability and congenital heart defects
labs show elevated Phenylalanine and low-normal tyrosine
PKU
elevated Phenylalanine and elevated tyrosine ( up to 2000 micromol/L- name the Dx
transient tyrosisnemia (late fetal maturation of 4-hydroxyphenylpyruvate dioxygenase ; therefore preterm infants are at risk for this; one of the most common AA disorders; Tx protein restriction, and Vit C. Resolves in 4-6 weeks
Labs showing elevated tyrosine, elevated urinary levels of succinylacetone, normal phenylalanine levels. P/w liver failure, Fanconi syndrome due renal tubular dysfunction. Dx?
tyrosinemia type 1; defiency in fumarylacetoacetate hydrolase. At risk for liver carcinoma
What is the treatment for tyrosinemia type 1?
Nitisinone (formerly NTBC); prevents the breakdown of phenlpyruvate therefore decreaing toxic compounds distal in the pathway such as fumarylacetoacetate. Decreases risk for hepatocellar carcinoma
This disease is a/w agenesis of the corpus callosum and presents by 48 hours of life with lethargy profound CNS deterioration with alternating hypertonia and hypotonia, respiratory depression and hiccups
non-ketotic hyperglycinemia; elevated glycine in CSF compared to plasma (> 0.08); note: glycine is an excitatory neurotransmitter that accumulates in body fluids
infant with severe lethargy/coma; labs show anion gap metabolic acidosis and elevated ammonia, neutropenia, thrombocytopenia, hyperglycinemia. Other labs show elevated propionyl carnitine and methylcitrate. Name the Dx
propionic acidemia: defect in propionyl-CoA carboxylase; Tx diet and carnitine
infant with severe lethargy/coma; labs show anion gap metabolic acidosis and elevated ammonia, neutropenia, thrombocytopenia, hyperglycinemia. Acyl carnitine profile showed elevated C3 carnitines, urine organic acids show elevated methylmalonic acid and plasma amino acids show elevated glycine. Homocysteine is normal
Methylmalonic acidemia
Defiency in what vitamin can cause a false positive for methylmalonic acidemia.
B12
labs show elevated ammonia (>700), increased glutamine and alanine, decreased citrulline and arginine, very elevated orotic acid in the urine. Name the defect
OTD deficiency, X-linked recessive
labs show elevated ammonia, very high citrulline, high orotic aciduria, decreased arginine. Brittle hair on exam
argininosuccinic acid synthetase def; note orotic acid high but not as high as OTC def
orotic aciduria, some increased citrulline, decreased arginine, if severe, leads to hyperammonemia. Brittle hair on exam
argininsuccic lyase def
spastic diplegia, orotic aciduria and elevated arginine
arginase deficiency: may only see spastic diplegia
normal or low orotic acid only on labs. Dx?
N-acetylglutamate synthetase deficiency
What’s the treatment for OTC deficiency?
ammonia scavenging drugs like phenylbutyrate and glycerol phenylbutyrate; arginine
This disorder presents soon after feeding started with poor feeding, vomiting, typically within the first 2-3 days of life, lethargy, jaundice, hepatomegaly, liver failure, renal tubular dysfunction (fanconi syndrome –>hyperchloremic metabolic acidosis, glycosuria, amino aciduria). Cataracts at birth, increased risk for E. coli sepsis. Also can have hypoglycemia.
galactosemia
what are females with galactosemia at increased risk for ?
premature ovarian failure
How do you diagnose galactosemia?
presence of reducing substances in urine
symptoms of vomiting, lethergy and seizures, hypoglycemia begin soon after beginning cows milk or whern diet contains fruits and vegetables;
hereditary fructose intolerance: absence of fructose 1 phosphate aldolase in the liver
due to a defect in alpha iduronidase, presents a 1 year. Has dysostosis multiplex, cloudy cornea but normal retina, HSM, short stature, course facia features and kyphosis, hirsuitism with stiff joints
MPS-1 Hurler; also have hydrocephalus and cardiac valve disease
x-linked recessive inheritance, due to iduronidase 2 sulfatase, dysostosis multiplex, clear cornea buth with retinitis papilledema, HSM, slow loss of CNS function, presents a 1-2 years, course facial features
MPS-2 Hunter’s, note only MPS with retinal abnormality
macular cherry red spots is pathognomonic for what?
lipid storage diseases affecting the brain
clinically have hepatomegaly, hypoglycemia with periods of fasting, lactic acidemia, hyperuricemia, hyperlipidemia and hypertrigluceridemia
glycogen storage disease= glucose 6 phosphatase
dilated cardiomyopathy, FTT, macroglossia, hypotonia; elevated CPK. name the diagnosis
Pompe disease = alpha- 1,4 glucosidase def (lysosomal storage disease)
This group of disorders presents in early infancy with acute life threatening episodes of hypoketotic, hypoglycemiia induced by fasting or febrile illnesss. CPK and uric acid often elevated.
fatty acid oxidation disorder
What is the most common fatty acid oxidation disorder?
MCAD Def = defect in medium chnain Acyl CoA dehydrogenase
high forehead, flat orbital ridges, wide open fontanelle, epicanthal folds, flat nasal bridge, FTT, seizures, cataracts, glaucoma, polycystic kidney disease,. Labs shows elevated very long chain fatty acids, and increase urine pipecolic acid’
Zellweger syndrome; aka cerebro-heptao-renal syndrome
What is the most common type of congenital abnormality of the upper extremity?
syndactyly
erythematous and vesicular papules in the flexor surfaces of the limbs and trunk in a female infant. It then developes in to a verrucous eruption and then into areas of pigment. Dx? What is seen on the Tzanck smear?
incontinentia pigmenti ; eosinophils
what is the most common tumor of infancy?
hemangioma
term infant at 6 hours of age p/w profound metabolic acidosis, elevated pyruvate and lactate, hyperammonenima, ketonuria. What is the diagnosis and Tx?
pyruvate carboxylase deficiency, Tx is biotin
hypertelorism, downward slant of palpebral fissures, mental deficency, cat-like cry, microcephaly, hypotonia. Name the syndrome
Cri du chat- deletion 5p syndrome. Note deleted part of the 5p is of paternal origin
Name the syndrome: high forehead broad or beaked nose (Greek warrior helmet), hypertelorism, low-set simple ear with preauricular dimple, microcephaly, cranial asymmetry,
Wolf- Hirschhorn syndrome = 4p deletion (origin of deleted piece is usually paternal)
What are functional deficits in children with Wolf-Hirschhorn syndrome?
hypotonia, seizures, FTT, intellectual disability ( mod-severe), May also have CHD
What is the most common chromosomal deletion on humans?
DiGeorge, aka Shpritzen; auto dom with variable expression
What kind of tumors are infants with Beckwith-Weideman syndrome at risk for developing?
increased risk for developing embryonal tumors, particularly Wilms tumor and hepatoblastoma, although neuroblastoma is observed rarely
Mom is acute fatter liver of pregnancy (AAFLP). What should the infant be monitored for after delivery?
hypoglycemia; there is an association between mothers with AFLP and fetuses affected by LCHAD (long chain 3 hydroxyacyl-CoA dehydrogenase deficiency); these mother’s are obligate carriers of the condition
What are the fatty acid oxidation disorders in the fetus that can cause maternal HELLP or acute fatty liver disease of pregnancy?
LCHAD, MCHAD, carnitine palmitoyltransferase 1 (CPT-1) deficiency, and trifunctional protein deficiency
What is the best screening test for fatty acid oxidation disorders?
plasma acylcarnitine profile; these conditions present with non-ketotic or hypoketotic hypoglycemia; you can do urine organic acids but the acylcarnitine profile is first line
3 month old infant presents with seizures, poor growth, and hepatomegaly. Labs show mild metabolic acidosis and elevated uric acid and lactic acid. Whats the diagnosis and long term treatment?
glycogen storage disease, type 1 is most common. Manage with corn starch
What is the dietary management of LCHAD?
low fat diet and MCT oil
In a patient with hyperammonemia, what imaging study should be obtained immediately?
head US since hyperammonemia causes cerebral edema
What are the most common causes of hyperammonemia?
urea cycle disorders and organic acidemias; you distinguish the two with a blood gas; urea cycle disorders have a respiratory alkalosis and organic acidemias (and fatty acid oxidation disorders) cause a metabolic acidosis
Child with Short stature with macrocephaly that develops over time; coarse facial features, and enlarge liver on exam. Whats the most likely diagnosis? Whats the best screening test?
lysosomal storage disorder; screen for this with urine mucopolysaccharide
CF and most IEM inheritance
autosomal recessive
spherocytosis and Waardenburg sydrome inheritance
autosomal dominant
G6PD, Wiskott-Aldrich, Hemophilia A and B inheritance
x-linked recessive
A person with a genotype for a disease may not exhibit the phenotype but can transmit the disease to the offspring (all or none phenomenon)- What is this called and what is an example of this?
reduced penetrance; retinoblastoma
what is the most common genetic cause of short stature?
Achondroplasia
