Unstable repeat sequences
Specific nucleotide copies within a gene increases resulting in increased disease severity
Huntington’s, Fragile X
Uniparental disomy
Both members of a chromosome or gene pair are inherited from one parent
Genomic imprinting
A gene defect is expressed solely based on the sex of the parent passing on the defective gene
Malformation
Intrinsically abnormal process forms an abnormal tissue
Deformatin
Mechanical forces exerted on normal tissue resort in abnormal tissues
Disruption
Normal tissue becomes abnormal after being subjected to disruptive forces
Syndrome
Collection of seemingly unrelated abnormal features occur in a familiar pattern
AFP, unconjugated estriol, and B-hCG in Down’s
Decaeased AFP
Decreased estriol
Increased B-hCG
Marfan’s Syndrome
AD disorder due to defective fibrillin gene on Cr. 15
S/S: Tall stature w/ elongated fingers Decreased U/L ratio ***Upward lens subluxation ***Aortic root dilatation, MVP, aortic regurg.
Comps: HTN =» AORTIC DISSECTION
Prader-Willi Syndrome
Genomic imprinting caused by the absence of the paternally inherited gene on Cr. 15
S/S: Almond-shaped eyes Fish-like mouth downturned) FTT in first year of life ***Hyperphagia in childhood Hypotonia MR Hypogonadism
-Obesity can lead to obstructive sleep apnea (childhood) and cardiac disease (adults)
Happy puppet syndrome
Angelman Disease; caused by genomic imprinting and loss of maternally inherited gene on Cr. 15
S/S: Jerky arm movements Ataxia ***Inappropriate laughter ***Severe MR Small head, large mouth w/ widely spaced teath, blonde hair, blue eyes
Male version of Turner Syndrome
Noonan syndrome; **(AD) gene on Cr. 12
S/S: Short webbed neck Shield chest Short statue ***Right sided heart lesions
Most common cardiac issue w/ Noonan syndrome
Pulmonary stenosis
right sided heart lesion
CATCH-22
Cardiac anomaly
Abnormal facies
Thymic hypoplasia
Cleft palate
Hypocalcemia
22q11 chromosomal defect
-Describes a combination of DiGeorge Syndrome and Velocardial syndrome
DiGeorge Syndrome
Defect in the structures derived from the 3rd and 4th pharyngeal pouches
S/S:
Short palpebral fissures, small chin, low ears (craniofacial probs)
Aortic arch anomalies, TOF, VSDs (cardiac)
Thymus and parathyroid hypoplasia
Comps: Infnx, seizure
Velocardiofacial syndrome
Neurologic findings of neonatal hypotonia, learning disabilities
Cardiac findings of VSDs, right-sided arches
Facial findings of cleft palate, fish-shaped mouth, wide and prominent nose
Ehlers-Danlos Syndrome
Type V collagen defect
S/S: Hyperextensible joints Loose, fragile skin =>> Tissue-paper thin scars MVP, fragile blood vessels Constipation, rectal prolapse
Osteogenesis Imperfecta
Type I collagen synthesis prob
S/S: Blue sclerae Fragile bones (genu valgum, scoliosis, fractures) Gray teeth Easy bruising
Comps: ***Conductive hearing loss
VACTERL association
Vertebral defects Anal atreia Cardiac anomalies (VSDs) TE Renal and genital defects Limb defects (radial hypoplaia, syndactyly)
CHARGE association
Colobomas (absence of ocular tissue, usually the retina) Heart defects (TOF) Atresia of the nasal choanae Retardation of growth and cognition Genital anomalies Ear abnormalities (hearing loss)
Cocktail party personality
Williams Syndrome; (AD) deletion on chromosome 7
S/S:
Elfin facies (flat nasal bridge, short palpebral fissures)
MR and loquacious personality
Supravalvular aortic stenosis
Idiopathic hypercalcemia in infancy
CT abnormalities =» hoarse voice, hernias
Child with synophrys and short stature
Cornelia de Lange syndrome
S/S: FTT Single eyebrow (synophrys) Thin, downturned lip Infantile hypertonia MR Small hands and feet Autistic features
Small-triangular fafce, limb asymmetry, and Cafe-au-lait spots
Russel-Silver Syndrome
-Kids also have excessive sweating and short stature
Micrognathia, cleft lip/palate, large protruding tongue
Pierre-Robin Synrome
-have recurrent otitis media and upper airway obstruction often requiring tracheostomy
Cri du chat Syndrome
Partial deletion of chromosome 5; sporadic
S/S: Microcephaly Downslanting palpebral fissures Catlike cry MR Hypertelorism
Complications assoc. w/ Downs
Atlantoaxial cervical spine instability (20%)
ALL
Celiac disease
Early Alzheimer’s
Hypothyroidism
Cataracts, glaucoma
GI features of Down’s
Hirschsprung’s
Duodenal ATRESIA
Pyloric stenosis
Second most common trisomy syndrome
Trisomy 18 (Edward’s Syndrome)
- Defined by MR, hypertonia of the lower extremities, small facial features, rocker bottom feet, clenched hands
- 95% die within one year
Patau Syndrome
Holoprosencephaly, severe MR, seizures, cleft palate/lip
Syndrome to consider in any female w/ developmental delay
Turner Syndrome
MCC of male hypogonadism and infertility
Klinefelter’s Syndrome
-Variable intelligence, tall, gynecomastia, possible antisocial behavior
Rhizomelia
Proximal bone abnormalities
-Short humerus, femur
Mesomelia
Medial long bone abnormalities
Short ulna and tibia
Acromelia
Distal abnormalities
Small hands and feet
Abnormalities of the spine
Spondylodysplasia
MC skeletal dysplasia
Achondroplasia (AD), although most cases are actually sporadic
- Megalencephaly, ***foramen magnum stenosis, frontal bossing, midface hypoplasia
- Lumbar kyphosis in infancy; lordosis as adult
- Rhizomelic limb shortening, bowed legs
- Trident shaped hands
**Recurrent otitis media w/ conductive hearing loss
Severe complication w/ Achondroplasia
Foramen magnum stenosis =» hydrocephalus and spinal cord compression
- May present as head sweating and dilated facial veins
- Causes SUDDEN INFANT DEATH
POTTER Syndrome
Pulmonary hypoplasia Oligohydramnios Twisted face Twister Skin Extremity defects Renal agenesis (BILATERAL)
Amniotic band syndrome
Occurs as a result of rupture of the amniotic sac where small bands of amnion wrap around the fetus causing limb scarring and amputation
Most common teratogen
Alcohol
CFs: SGA at birth FTT Microcephaly Smooth philtrum MR VSD
Cigarette as a teratogen
Causes SGA, polycythemia
Cocaine as a teratogen
Causes IUGR, microcephaly, GU tract abnormalities
DES as a teratogen
Increased risk of cervical carcinoma, GU abnormalities
Isotretinoin as a teratogen
CNS malformations, microtia, cardiac defects, thymic hypoplasia
Phenytoin as a teratogen
MR
Cardiac defects
Nail and digit hypoplasia
PTU as a teratogen
Hypothyroidism, goiter
Thalidomide as a teratogen
Phocomelia (malformed, flapper like appendages)
Valproic acid as a teratogen
Narrow head, high forehead, midface hypoplasia, spina bifida, cardiac defects, convex nails
Warfarin as a teratogen
Hypoplastic nose, stippling of the epiphyses, hypoplastic nails
Most common congenital anomalies of the nervous system
Neural tube defects
IEMs can present similar to what serious condition?
Sepsis
Management of acidosis
Sodium bicarbonate
Management of hyperammonemia
Sodium benzoate and Sodium phenylacetate
-Increases NH3 excretion
Homocystinuria
AR deficiency of cystathionine synthase
CFs:
Marfanoid body habitus w/o arachnodactyly
**Downward lens subluxation
**Hypercoagulable state (stroke, DVT, MI)
Scoliosis
Cardiac left sided Regurgitations
Mild MR
***Dx: Increased URINE METHIONINE
Tx: Methionine-restricted diet, aspirin, folic acid and B6 supplementation
PKU
AR condition
CFs: Progressive MR ***MOUSY ODOR Decreased eye and hair pigmentation Eczema
Dx: Increased SERUM phenylalanine:tyrosine ratio
Tx: Phenyalanine restricted diet
-Good prognosis if started in first month of life
Maple Syrup Urine Disease
AR
CFs: Lethargy, hypotonia, coma Maple syrup odor to urine Hypoglycemia Severe acidosis
Dx: Increased urine branched-chain AAs
Tx: Dietary protein restriction
-If restricted in first 2 weeks of life, no neuro damage
Tyrosinemia Type I
AR
CFs: Episodic peripheral neuropathy Chronic liver disease ***ROTTEN CABBAGE ODOR Renal tubular dysfnxn
Dx: Succinylacetone in URINE
Tx: Dietary restriction of phenylalanine, tyrosine
***Liver transplant
***INCREASED RISK OF HEPATOCELLULAR CARCINOMA AND CIRRHOSIS
Transient tyrosinemia of the newborn
Occurs in premies w/ high protein diets
CFs: Poor feeding, lethargy
Dx: Elevated serum tyrosine and phenylalanine
Tx: Self-limiting, Vitamin C helps eliminate tyrosine
Cystinuria
AR disorder caused by defect in renal reabsorption of
Cystine
Ornithine
Lysine
Arginine
CFs: UTIs, abdominal/back pain, dysuria
Hartnup disease
AR disease caused by defect in the transport of neutral AAs
CFs: Photosensitive rash, intermittent ataxia, MR
-May be asymptomatc
Self-limited disease in newborns w/ respiratory distress, alkalosis, lethargy, and increased NH3 levels
Transient hyperammonemia of the newborn
- Aggresive tx. required to prevent neurologic sequelae
- Use Sodium benzoate and sodium phenylacetate
Most common urea cycle defect
Ornithine transcabamylase deficiency ****(XLR)
CFs:
Vomiting, lethargy
Dx: Elevated urine orotic acid
Decreased serum citrulline
Increased serum ornithine
Tx: Low protein diet + hyperammonemia management
Disorder to suspect in any infant w/ hepatomegaly and hypoglycemia
Galactosemia
AR deficiency of galactose-1-phosphate uridyltransferase
CFs: Begins after a newborn feeds on cow's milk Vomiting, diarrhea, FTT Hepatomegaly Catarcts w/ "Oil-droplet appearance" RTA
Dx: Positive clinitest (nonreducing sugars)
Tx: Galactose free diet
Complications w/ galactosemia
Newborns: Sepsis from E. coli
Females: Ovarian failure
MR if diagnosis is delayed
Hereditary fructose intolerance
Deficiency of fructose-1-phosphate aldolase B
CFs:
Begins after infant first feeds on fruit juice
FTT, vomiting, diarrhea, seiure
Tx: Avoid fructose, sucrose, sorbitol
Von-Gierke’s Disease
AR deficiency of glucose-6-phosphatase
CFs: H Hypoglycemia Hepatomegaly Metabolic acidosis Hypertriglyceridemia
Tx: Carb-free diet
**Increased risk for hepatocellular carcinoma
Disease to suspect in any infant w/ muscular weakness and cardiomegaly
Pompe’s Disease
Deficiency of a-glucosidase
CFs: In the first two weeks of life... Flaccid weakness Poor feeding Progressive cardiomegaly Hepatomegaly Acidosis
Most common fatty acid oxidation disorder
Medium-chain acyl-CoA dehydrogenase deficiency
Tx: High-carb, low-fat die
Kearns-Sayre syndrome
Opthalmoplegia
Retinal pigmentary degeneration
Hearing loss
Neurologic deterioration
MELAS
Mitochondrial Encephalopathy
Lactic Acidosis
Strokelike episodes
-Suspect mitochondrial disorders if a common disease has an atypical presentation or involves >3 organ systems
Infantile Tay-Sach’s Disease
AR deficiency of hexosaminidase A
CFs: Decreasing eye contact, hypotonia, motor weakness HYPERACUSIS Macrocephaly CHERRY-RED MACULA Severe developmental delay
Death by 4 yrs of age
Juvenile/Adult-onset Tay-Sach’s Disease
Begins after 2 years of age
CFs: Ataxia, dysarthria, choreoathetosis
*ABSENT cherry red macula
Most common gangliosidosis
Gaucher’s Disease; (AR) deficiency of glucocerebrosidase
CFs:
Hepatosplenomegaly
Thrombocytopneia
Erlenmeyer-shaped femur
Tx: Enzyme replacement
Niemann-Pick Disease
Sphingomyelinase deficiency
CFs: Progressive neurodegeneration Hepatosplenomegaly Ataxia, seizure Cherry-red macula
Death by 4 years of age
Metachromatic leukodystrophy
Arylsulfatase A deficiency
CFs:
Ataxia, seizure, progressive MR
Death by 10-20 years of age
Dystosis multiplex
Constellation of bony abnormalities:
Thickened cranium
J-shaped sella turcia
Beak-like vertebrae
Short-thickened clavicles
*****Presents w/ mucopolysaccharidoses alongside MR, organomegaly
Most severe mucopolysaccharidosis
Hurler Syndrome; (AR) deficiency of a-L-iduronidase
CFs: Begin after 1 year of age... Hepatosplenomegaly Kyphosis Coarsened facial features ***CORNEAL CLOUDING Stiff, contracted joints
Dx: Dermatan and heparan sulfate in urine
Decreased a-L-iduronidase activity in PMNs
Tx: BM transplant
XLR mucopolysaccharidosis
Hunter Syndrome
CFs:
Hepatosplenomegaly
Hearing loss
Dystosis multiplex
Dx: Increased dermatan and heparan sulfate in urine
Tx: None; death by 20
AR mucopolysaccharidosis characterized by severe mental and motor retardation
Sanfilippo syndrome
Mucopolysaccharidosis w/o MR but severe scoliosis compromising respiratory fnxn by 40 years of age
Morquio syndrome
Diagnosis of porphyrias
Increased serum and urine porphobilinogen
Wilson’s Disease
AR defect in copper excretion
CFs:
Kayser-Fleischer rings (copper deposited in DESCEMET’s MEMBRANE)
Dysarthria, tremors, ataxia, weirdness
Hepatic dysfnxn
Dx: Decreased ceruloplasmin
Increased serum and urine copper
Tx: Avoid copper containing food (nuts, liver, chocolate) and chelation w/ penicillamine
Menke’s Kinky Hair Disease
XLR disorder caused by abnormal copper transport
CFs: Myoclonic seizure Pale, kinky, and friable hair Optic nerve atrophy Sever MR
Dx: Low serum copper and ceruloplasmin