138

Chromosomal/trisomy
 Newborn w/ flat face, epicanthal folds, Brushfield spots on iris, single palmar crease: Down
syndrome
 Et: Trisomy 21
 Pathophys:
1. Maternal nondisjunction (MCC)
2. Robertsonian translocation = 1 part of one chromosome goes to another -->
teeny-tiny chromosome + big boy chromosome
 Dx: elevated bHCG + inhibin, low AFP + estriol, karyotyping
 Sx (mostly from neural crest issues):
1. Endocardial cushion defects w septa + valves --> atria and ventricles not
separated properly
2. Duodenal atresia --| recanalization
 Vs. jejunal atresia d/t vascular insult in utero
3. Hirschsprung disease --| Auerbach/Meissner plexi
 Sx: meconium ileus
4. C/b ALL, Alzheimers (amyloid-precursor protein on chr21)
 RF: advanced maternal age = less eggs to fertilize, higher likelihood of fertilizing
nondisjunction egg
 Second most common trisomy: Edwards Syndrome
 Et: Trisomy eighteen
 RF: advanced maternal age
 Sx: prominent occiput, micrognathia, overlapping digits, rocker-bottom feet, death by
age1-2
 Least common trisomy: Patau syndrome
 Et: Trisomy 13
 RF: advanced maternal age
 Sx: microcephaly, micropthalmia, holoprosencephaly, multiple digits, cleft lip/palate,
rocker-bottom feet, death <1Y
 Cat-like cry: cri-du-chat syndrome
 Et: chr5 defect
 Sx: microcephaly, high-pitched cat-like cry
 6mo losing motor milestones, fasciculations: spinomuscular atrophy
 Et: chr5 @ SMR1 gene
 Pathophys: destruction of anterior horn cells in spinal cord
 White reflex/leukocoria: retinoblastoma
 Et: chr15 Rb tumor suppressor deletion
 C/b osteosarcoma
 Visual problems (no iris), flank mass, posterior urethral valves, ID: WAGR
 Sx: Wilms tumor + aniridia + genitourinary + mental retardation
 Et: chr11 gene deletion
 Beckwith-Wiedemann Syndrome
 Sx: Wilms tumor, macroglossia, hemihypertrophy, hepatoblastoma
1. Seizures at birth d/t hypoglycemia <-- overgrowth of pancreatic islet beta cells
(insulin)
  25M infertility, 6', breast tissue, micropenis: Klinefelter syndrome
 Et: 47XXY
 Pathophys: gonads do not work --> no inhibition @ pituitary --> elevated FSH/LH
(hypergonadotropic hypogonadism)
 Sx: no sperm, female distribution of hair
 Female w short stature, short posterior hairline: Turner Syndrome
 Et: 45XO
 Pathophys: second X chromosome is necessary for forming ovaries! Therefore they have
streak ovaries --> no estrogen --> defect in secondary sexual characteristics
 Sx:
1. cubitus valgus (elbow turned inward)
2. short stature,
3. low posterior hairline
4. congenital lymphedema (cystic hygromas, webbed neck)
5. primary amenorrhea
6. coarctation of the aorta
 Delayed radial-femoral pulse
 d/t stenosis past the subclavian
7. Bicuspid aortic valve --> early onset aortic stenosis
 *MCC of aortic stenosis <70Y! (afterwards: senile calcification)
8. Horseshoe kidney
9. Later in life, abdominal mass: streak ovary --> gonadoblastoma
10. hypergonadotropic hypogonadism
 Vs: athlete that works out a ton --> shut down HPG axis -->
hypogonadotropic hypogonadism
 Vs. Hypothyroidism --> elevated TSH --> prolactin --| GnRH, FSH, LH
 Vs. Kallmann syndrome --| GnRH cells
 Genomic imprinting disorders or uniparental disomy
 Obesity, hypotonia, deletion of paternal chr15: Prader-Willi
 Inappropriate laughter, deletion of maternal chr15: Angelman
 
Autosomal recessive: enzyme defects, earlier sx, need 2 bad copies of allele
 5th percentile weight, 10th percentile weight, recurrent infections: cystic fibrosis
 Et: chr7 deltaF508 @ CFTR channel
 Pathophys: Cl does not leave the cell --> attracts extracellular sodium --> water follows
--> thick secretions of exocrine, sweat glands
 Sx:
 Pancreas: fat malabsorption ADEK (night blindness, secondary hyperpara,
cerebellar ataxia, acanthocytosis, bleeding),
 Recurrent sinus infections d/t impaired mucus clearance
 Inflammatory response --> "cystic" dilation of airways = bronchiectasis + fibrotic
damage
 Pneumonia 1) Staph aureus 2) Pseudomonas
 Burkholderia cepacia --> TERRIBLE pulm infection --> sudden death 2/2
pneumonia
 Plugging of seminiferous tubules, agenesis of vas deferens --> infertility
 Meconium ileus
  Secondary primary biliary cholangitis d/t thick secretions of bile canaliculi
 Tx: Ivacaftor
 Dx: sweat chloride test, conductance of nasal epithelium, low serum trypsinogen
(pancreas), DNA testing
 Child w/ musty odor, ID: phenylketonuria
 Et: deficiency of phenylalanine hydroxylase
 BH4 cofactor; mutation in tetrahydropterine reductase could cause similar sx
 Pathophys: buildup of phenylalanine
 Sx
 Toxicity @ neurons
 Musty odor (phenyl = benzene ring = aromatic compound)
 Albinism d/t deficiency of tyrosine (--> melanin)
 Tx: no phenylalanine in diet, avoid aspartame (artificial sweeteners)
 Dx: newborn screen
 Ppx: mom has PKU --> needs to be placed on careful diet during pregnancy;
phenylalanine can cross placenta --> sx in baby
 25Y, osteoarthritis, black joints on synovial analysis, discoloration of ears/nose:
alkaptonuria/ochronosis
 Et: deficiency of homogentisic acid oxidase
 Sx: "cartilage fetish"
 Albinism
 Et: deficiency in tyrosinase
 tyrosine --tyrosinase--> melanin
 Sx: oculocutaneous albinism
 C/b basal cell/squamous cell carcinoma (melanin helps absorb some of the bad UV)
 Cherry-red spot on macula, loss of motor milestones, no HSM: Tay-Sachs disease
 Lysosome = "waste basket of the cell"
 Et: deficiency of hexosaminidase A --> buildup of GM2 ganglioside (@CNS)
 Sx: hyperreflexia, ID, cherry-red (ganglion cells in retina enlarge, engorge/compress
blood vessels), death <2Y
 RF: Ashkenazi-Jewish heritage
 Niemann-Pick Disease
 Et: deficiency of sphingomyelinase --> buildup of sphingomyelin in macrophages (@
reticuloendothelial system = liver, spleen, bone marrow + @CNS)
 Sx: cherry-red spot on macula, hyperreflexia, ID, hepatosplenomegaly (c/b
thrombocytopenia)
 Pancytopenia, macrophages on bone marrow biopsy w/ crumpled paper appearance: Gaucher
disease
 Et: deficiency of glucocerebrosidase @ macrophages in reticuloendothelial system
 Sx: ineffective erythropoiesis, joint problems ^^^
 Corneal clouding, coarse facial features: Hurler syndrome
 Et: mutation in alpha-L-iduronidase --> buildup of heparin + dermatan sulfate
 Sx:
 Vs. Hunter syndrome (X-linked recessive): mutation in alpha-iduronate sulfatase
 Pathophys: buildup of heparin + dermatan sulfate
 Sx: no corneal clouding or coarse facial features
 Von Gierke disease (Type 1 GSD)
  Et: deficiency of glucose-6-phosphatase (glycogen-->glucose) --> buildup of G6P in liver
 --> hepatic cells expand, explode!
 Sx: hypoglycemia between meals d/t lack of gluconeogenesis
 Pompe disease (Type 2 GSD)
 Et: deficiency of alpha-1,4-glucosidase/acid maltase
 Sx: heart failure
 Cori disease (Type 3 GSD)
 Et: deficiency of debranching enzyme/alpha-1,6-glucosidase (@muscle, liver)
 Sx: hepatosplenomegaly, muscle sx
 McArdle's disease (Type 5 GSD)
 Et: deficiency of glycogen (myo)phosphorylase @muscle
 Sx: muscle cramping w/ exercise
 I-cell disease: --| phosphotransferase --> cannot put mannose-phosphate on things, so things
are improperly transported
 FA oxidation disorders
 Medium chain, long chain FA: metabolized @ mitochondria
 MCAD/LCAD --| beta-oxidation --> impaired FA oxidation --> elevated
acylcarnitine
 Vs. carnitine deficiency: low acylcarnitine
 Very long chains: metabolized @ peroxisome
 Adrenoleukodystrophy: demyelination, cerebellar ataxia, death <2Y
 Hemophilia C --| Factor 11
 African missionary with oxidizing drug --> hemolytic anemia: G6PD
 Sx: heinz bodies, bite cells
 Dx: G6PD assay weeks after episode
 
X-linked recessive (sx @ boys)
 Immunodeficiencies!
 Recurrent infections, hypopigmented skin (eczema), low platelets: Wiskott Aldrich
syndrome
 Chronic Granulomatous Disease
 Et: deficiency in NADPH oxidase
 Sx: recurrent infections w Staph aureus (abscesses)
 Dx: tetrazolium, dihydrorhodamine test
 Tx: interferon-gamma
 Vs.
 Interferon alpha --| HepC
 Interferon beta --| MS
 Kiddo w/ gout, chews off fingers/toes: Lesch-Nyhan syndrome
 Et: deficiency of HGPRT (purine salvage pathway)
 Sx: hyperuricemia --> toxicity @ neurons, self-mutilation
 Bruton's agammaglobulinemia
 Et: mutation in Bruton's tyrosine kinase (B-cells)
 Sx: small tonsils, bacterial infections
 Tx: IVIG
 Hemophilia A --| Factor 8
  Sx: elevated PTT
 Dx: correct w mixing studies (but sometime create Ab-factor8)
 Hemophilia B --| Factor 9
 Sx: elevated PTT
 Dx: correct w mixing studies (but sometime create Ab-factor9)
 Meinke's disease/kinky hair disease
 Et: ATP7A mutation (copper metabolism)
 Vs. ATP7B Wilson's disease (copper @ basal ganglia, liver dz, psych, Kayser, c/I
copper IUD, tx penicillamine/trientine)
 *penicillamine/trientine = chelators; ae: zinc deficiency (also chelated)
 Sx: death <2Y
 
Autosomal dominant: structural protein or receptor defect, later sx
 If two copies of bad dominant allele: death in utero i.e. lethal form of osteogenesis imperfecta
 19Y, father died from MI @30Y, severe chest pain, STEMI, xanthelasma/xanthomas: familial
hypercholesterolemia
 Et: mutation in LDL receptor --> will not clear cholesterol
 Type 1: No LDL receptor
 Type 2: LDL receptors do not reach surface of the cell (--| exocytosis pathway)
 Type 3: LDL has trouble binding to LDL receptor; MCC
 Type 4: LDL binds to LDL receptor but not endocytosed
 Type 5: --| recycling LDL receptor
 Sx: accelerated atherosclerotic dz
 Tx: statin, PCSK9 inhibitors (-cumab)
 6'5", hyperextensible joints, displacement of lens, tearing chest pain radiating to back: Marfan's
syndrome
 Et: mutation on chr15 fibrillin gene/FBN1 (maintains integrity of elastic fibers)
 Sx:
 Mitral valve prolapse/myxomatous degeneration
 Impaired elasticity of arteries (@intima) --> dilation without collapse -->
aneurysm --> ascending aortic dissection (highest pressure vs. abdominal aorta) -->
pull leaflets apart --> aortic regurgitation
 Circle of willis aneurysm --> subarachnoid hemorrhage
 Lens subluxation/ectopia lentis: up and out
Marfan's syndrome Homocystinuria

Aut dom Aut rec

Fibrillin mutation Cystathionine beta-synthase deficiency

Lens up and out Lens down and out

Normal intelligence ID

  *B6/B9/B12 elevate homocysteine*

 Problems w/ wound healing, hyperextensible joints: Ehlers-Danlos syndrome
 Et: mutation in Type 3 collagen
  Sx: aortic dissection, thoracic aortic aneurysm, wound dehiscence, rupture of
colon (thicker fecal material d/t water absorption --> wall of colon w type3 collagen
struggles)
 Kiddo w blue sclera, fractures, short: osteogenesis imperfecta
 Et: defect in Type 1 collagen (COL1)
 Kiddo w hematuria, hearing problems, cataracts: Alport syndrome
 Et: defect in Type 4 collagen COL4A5 (@eye, ear, kidney)
 *X-linked dominant
 Vs. Goodpasture syndrome: Ab-Type4collagen
 Kiddo w short stature, dwarf, problems w long bone growth: achondroplasia
 Et: mutation in fibroblast-growth-factor3
 Café au lait spots, growths on body: NF1
 Et: chr17 @ neurofibromin = tumor suppressor of p21 (RAS cascade)
 Sx: neurofibromas, meningiomas, pheochromo, Lisch nodules (hamartomas @ iris)
 NF2
 Et: chr22 @ merlin = tumor suppressor that tells cells when they're too close (contact
inhibition)
 Sx: bilateral acoustic neuromas
 Posterior fossa mass, hematocrit 60%: VHL
 Et: chr3 @ VHL gene = ubiquitination of proteins that cause growth/proliferation
 Sx: hemangioblastoma (esp @cerebellum, inhibited downregulation of HIF1
vascularization), EPO production, cysts @ liver/pancreas, bilateral renal cell carcinoma
 Multiple polyps in colon: FAP
 Ppx: colonoscopies <20Y
 + medulloblastoma = Turcot syndrome
 + soft tissue osteoma = Gardner syndrome
 Hgb 8, paternal relatives have blood disorders: hereditary spherocytosis
 Et: mutation in ankyrin, spectrin, band3.2
 Tx: splenectomy
 F with heavy menstrual bleeding: Von Willebrand Disease
 Et: deficiency of VWF
 Dx: normal plt, elevated PTT
 
Trinucleotide repeat
 Autosomal dominant
 Myotonic dystrophy
 Et: CTG @ DMPK1
 Sx: trouble releasing grip, early balding
 Huntington's
 Et: CAG @ chr4
 w/ anticipation!
 Sx: choreiform movements, dementia, inappropriate behavior
 DDx choreiform movements:
 Huntington's
 Sydenham chorea 2/2 rheumatic fever
 Lesion @ subthalamic nucleus = contralateral hemiballismus
  PANDAS = pediatric autoimmune neuropsych disorder 2/2 GAS
 Vs. myoclonus
 Neuroblastoma (flank mass, posterior mediastinum,
calcified, crosses midline): "opsoclonus-myoclonus syndrome"
 Crutzfeld-Jakob disease: elevated 14-3-3, prion
 Serotonin syndrome
 Tx: haloperidol, tetrabenazine
 X-linked dominant (only 2 = Fragile X + Alport!)
 Big ears, testicles, long face, ADHD/autism: Fragile X syndrome
 Et: CGG repeat
 Autosomal recessive
 Friedrich ataxia
 Et: GAA repeat
 
Mitochondrial disorders: from mom!
 Leber optic neuropathy
 MELAS = mitochondrial dz "ragged red fibers" --> encephalopathy, lactic acidosis, stroke
 
Multifactorial inheritance
 Neural tube defects
 Congenital heart disease
 T2DM