Chapter 10: Diseaes of Infancy and Childhood
Congenital Anommalies (448-463)
1. What is a deformation? Maternal factors likely to cause deformations? Fetal factors?
a. Compression, localized or generalized
b. Small uterus, leiomyoma
c. Oligohydramnios, multiple fetuses; causing clubbed feet and other issues, see #2
2. What is a good example of a sequence related to amniotic fluid?
a. Potter/oligohdramnios sequence: flattened facies and positional deformities due to leakage of amniotic fluid, maternal hypertension, or renal agenesis
3. What are the most common causes of congenital anomalies (malformations)? Do genetic aberrations tend to be familial? What’s an exception?
a. Unkown (40-60%)
b. Multifactorial (20-25%)
c. Genetic (10-15%)
d. Most genetic aberrations arise during gametogenesis, with the exception of Robertsonian translocation in a parent (causes some cases of Down syndrome)
4. What mutation causes achondroplastic dwarfism?
a. Fibroblast growth factor receptor 3 (FGFR3)
5. When is the risk of rubella infection greatest? What are the signs of congenital rubella syndrome? [micro crossover]
a. Shortly before conception to 16th week, greatest before 8th week
b. Cataracts, heart defects, deafness, and mental retardation
6. When is CMV most dangerous? What are the signs?
a. Second trimester
b. Less frequent, CNS is most prominent: mental retardation, microcephaly, deafness; and hepatosplenomegally
7. What are the features of diabetic embryopathy?
a. Macrosomia, cardiac anomalies, ARDS, neural tube defects, and CNS malformations
8. How does valproic acid disrupt development? What are the features of retinoic acid embryopathy?
a. Interferes with homeobox (HOX) proteins: patterning of limbs, vertebrae, and face
b. CNS defects, cleft lip and palate
i. Due to de-regulation of TGF-β pathway
9. What are the cutoffs for pre-term and post-term?
a. Before 37 weeks = pre-term; after 42 weeks = post-term
b. Birth weight is cut off at 10th and 90th percentiles
10. What is the principal sign of an ascending transcervical infection? [test Q]
a. Pus in the amniotic fluid
11. What are the histologic correlates of intrauterine infection? What microbes are most likely to cause preterm labor (6)? What are some of the hazards of prematurity?
a. Chorioamnionitis and funisitis (inflammation of the umbilical cord)
b. Ureaplasma urealyticum, Mycoplasma hominis,Gardnerella vaginalis, Trichomonas vaginalis, Neisseria gonorrhoeae, and Chlamydia trachomatis
[micro crossover: these are mostly causes of PID, though chlamydia and gonorrhea are most important]
c. Hyaline membrane disease (respiratory distress), necrotizing enterocolitis, sepsis, intraventricular hemorrhage
12. What are the signs of fetal growth restriction (FGR)? What is a genetic cause of placental fetal growth restriction besides chromosomal disorders and fetal mutations?
a. Asymmetric growth retardation with relative sparing of the brain
b. Genetic mosaicism confined to the placenta
i. Due to late mutations within the dividing trophoblast or extraembryonic progenitor cells
13. What is the most common factor causing infants to be SGA in the United States? What are some causes of this?
a. Decreased placental blood flow
b. Preeclampsia, smoking, chronic hypertension, narcotics, alcohol, dilantin
14. What conditions are associated with neonatal respiratory distress syndrome (3)? What structural factor compounds this syndrome?
a. Diabetic mothers: high insulin counteracts the positive effect of glucocorticoids
b. Cesarean section: labor normally induces production of surfactant
c. Male gender
d. Stiff atelectic lungs gang up with soft thoracic walls to cause trouble
15. What are the two negative results of oxygen therapy in infants? What conditions are infants more susceptible to once they recover from RDS (3)?
a. Retrolental fibroplasia (retinopathy of prematurity)
i. Due to hypoxia-induced VEGF increases once ventilation is stopped
b. Bronchopulmonary dysplasia
i. Due to VEGF decreases during ventillation
c. PDA, intraventricular hemorrhage, and necrotizing enterocolitis
16. How do you diagnose an infant with bloody stool, pneumatosis intestinalis, abdominal distension, and circulatory collapse? What causative factor is associated?
a. necrotizing enterocolitis
b. enteral feeding=> infection, worsened by increased platelet activating factor (PAF)?
17. What is the most likely result of parvovirus P19 infection? What are the signs of TORCH infections? What microbe causes perinatal early-onset sepsis? What 2 are known to cause sepsis one week after birth or more? Do they cause any other problems?
a. Usually normal pregnancy, although it can cause nonimmune hydrops
b. Encephalitis, chorioretinitis, hepatosplenomegaly, pneumonitis, myocarditis, vesicular/hemorrhagic skin lesions
c. Group B streptococcus (e.g. S. agalactiae); acquired just before or at birth
i. can also cause late term complications & stillbirth
d. Listeria and Candidia follow a latent period after perinatal infection
i. Listeria (often food borne) can also cause stillbirth with microabcesses
18. Which antigen causes immune hydrops? What factors predict a better outcome? Why are dangerous reactions somewhat rare? Finally, why do edema and anasarca occur?
a. The D antigen of the Rh system
b. ABO incompatibility (cells are coated and removed before an Rh reaction develops), small volume of transplacental bleeds, first exposure to the antigen (first pregnancy)
c. Most maternal blood antigen antibodies are IgM and don’t cross the placenta, neonates express antigens poorly, and other cell types absorb antibody
d. Hypoxia damages the heart and liver when hemolysis is severe
19. What are the three major causes of nonimmune hydrops? What is a disease that causes cystic hygroma?
a. Cardiovascular defects, chromosomal anomalies, fetal anemia
b. Turner syndrome
Inborn Errors of Metab (chap 10: 463-471)
20. Which two modes of inheritance are most common for inborn errors of metabolism?
a. Autosomal recessive or x-linked
21. What is most common potentially lethal genetic disease of ppl of Caucasian decent?
a. Cystic Fibrosis
22. What is the difference b/t classic phenylketonuria and benign hyperphenylalaninemia?
a. Classic PKU has no phenylalanine hydroxylase activity and leads to accumulation of phenylalanine (above 600 microM in serum);
b. Benign hyperphenylalaninemia has some enzyme activity so will have elevated serum levels (b/t normal 120 to 600 microM) but not the neurologic damage
23. The biochemical abnormality in PKU is an inability to covert ____to ______.
a. Phenylalanine to tyrosine
24. What enzyme is deficient in classic PKU? What can be deficient in PKU variants? Why is it important to recognize varients?
a. Classic- phenylalanine hydroxylase (98% cases); can also have defect in recycling of tetrahydrobiopterin (BH4) (2% cases) via dihydropteridine reductase
b. Important b/c ppl with variant forms the neurologic defects are not corrected by adjusting phenylalanine levels alone
25. Why do ppl w/ PKU have an odor?
a. They have a musty/mousy odor b/c phenylalanine is shunted into minor pathways generating phenylpyruvic acid, phenylactic acid, and phenylacetic acid that are excreted in sweat (also urine)
26. When is severe mental retardation in PKU evident? Other symptoms?
a. 6 months; seizures, inability to walk & talk, decreased pigmentation hair/skin
27. What is maternal PKU?
a. Women w/ PKU that stop monitoring diet have a 75-90% chance of having mentally retarded child b/c elevated phenylalanine and metabolites are teratogens
28. What are 2 enzymes that can be mutated in galactosemia? Which more common? Severe?
a. Galactose-1-phosphate uridyl transferase ( more common and more severe) and galactokinase (rare and less severe w/ no neurologic manifestations)
29. What tissues are most affected by accumulating galatose-1-phosphate? How diagnosed? What infection is likely?
a. Liver (hepatomegally, jaundice), eyes (cataracts w/in few wks birth), and brain (nerve cell loss, gliosis, and edema; mental retardation)
b. Diagnosed by evidence of reducing sugar other than glucose in urine, but more specifically w/ identification of deficient transferase in RBC or WBC
c. Removal of galactose from diet curative for first 2 years is curative, mostly
d. E. coli, for reasons unknown
30. What is Cystic fibrosis a disorder of? What are most common clinical features?
a. Ion transport that affects exocrine glands and epithelial linings of respiratory, GI, and reproductive tracts
b. Chronic lung disease (recurrent infection), pancreatic insufficiency, malnutrition, steatorrhea, hepatic cirrhosis, intestinal obstruction, and male infertility
31. What is the primary defect in cystic fibrosis? How is this receptor activated?
a. Abnormal function of epithelial chloride channel protein encoded by cystic fibrosis transmembrane receptor (CFTR) gene; activated by cAMP
32. What other channel is inhibited by CFTR activation in normal ppl? What happens in C.F.?
a. ENaC
b. increased activity b/c loss of that inhibition leads to more Na+ uptake across apical membranes; not in sweat glands (inhib of ENaC caused by mutation)
33. What causes the pathogenesis of respiratory and intestines in C.F.?
a. Lowered secretions of Cl- causes lowered secretion of Na+ and H2O into exocrine secretions lowering the water content of surface fluids of mucosal cells
b. Pathogenisis stems from isotonic but low-volume surface fluid
34. What other ion is transported via CFTR receptors?
a. Those mutations with abnormal HCO3- conductance acidify secretions and almost always cause pancreatic insufficiency
35. What are the 6 classes of mutations in cystic fibrosis? Which are considered ‘severe”? Which is most common? How can different levels of severity occur?
a. I defective protein synthesis (severe)
b. II defective protein folding, processing, trafficking (severe, most common ΔF508)
c. III defective regulation (severe)
d. IV decreased conductance (milder)
e. V reduced abundance (milder)
f. VI altered regulation of separate ion channel (depends)
g. C.F. is autosomal recessive so need two allelesà severe alleles gives classic presentation; presence of at least 1 mild allele= milder presentation (mainly true for pancreatic disease)
36. Polymorphic variants in what 2 other genes affect severity of pulmonary disease in C.F.?
a. Mannose binding lectin 2 (MLB2) and transforming growth factor β1 (TGFβ1)
[think: 1, no Team Games of Footβall or 2, Major League Baseball for kids with cystic fibrosis]
37. What is meconium ileus and what about cystic fibrosis causes it?
a. Small-bowel obstruction caused by thick mucus plugs
38. What pancreatic abnormalities and liver abnormalities are found in C.F.?
a. Mucus plugs in pancreas can cause atrophy of exocrine pancreas and leads to impaired fat absorption w/ avitaminosis;squamous metaplasia in pancreas possible
b. Bile canaliculi are plugged by mucus in liver and can lead to portal inflammation, hepatic steatosis, then focal biliary cirrhosis, and even diffuse hepatic nodularity (rarer)
39. Changes involved in salivary glands? Lungs?
a. Salivary ducts dilated w/ mucus; squamous metaplasia; gland atrophy/fibrosis
b. LUNGS – most serious complications of disease; obstruction of air passages (distention of bronchioles) w/ mucus; superimposed infections causing chronic bronchitis and bronchiectasis
40. 3 most common organisms to cause lung infection in C.F.? Which is especially found in chronic inflammation and produces alginate (protective capsule)?
a. Pseudomonas aeruginosa, Staphlococcus aureus, and Haemophilus influenzae
b. Pseudomonas aerginosa, alginate-producing form
41. What reproductive defects are often found in C.F. suferers?
a. Azoospermia and infertility (95% ppl); often congenital absence of vas deferens
42. What type of pancreatic insufficiency occurs? Outward manifestations of this?
a. Exocrine pancreas insufficiency (endocrine normally okay); large malodorous stools, poor weight gain, abdominal distension, generalized edema (low protein), vitamin A, D, or K deficiency
43. What are the 3 most common causes of death in C.F.? What is significance of recurrent sinunasal polyps?
a. Persistent lung infections, obstructive pulmonary disease, and cor pulmonale (right sided heart failure with dilated right ventricle)
b. 25% of ppl w/ these polyps have C.F. so child w/ them should be tested for C.F.
44. What is the 4th most common cause of death in C.F. (after pulmonary and transplant-related)?
a. Liver disease
45. What is diagnosis usually based on (4)? What is gold standard? 3 things that have improved the life expectancy in C.F.?
a. Sweat test (persistently elevated electrolytes in sweat), family history, clinical findings, and/or + newborn screening test
b. Sequencing of the CFTR gene is gold standard; may be done if suggestive clinical findings and/or positive family history
c. Bilateral lung transplants, more potent antimicrobials, pancreatic enzyme replacement
SIDS and Neoplasms
46. Between what ages is SIDS the most common cause of death in the United States? What is the most common morphologic finding at autopsy? What are some other findings (3+)? What are some risk factors for SIDS (4)?
a. from 1 month to 1 year
b. multiple petechiae on the thymus, pleura, and epicardium
c. congested lungs with vascular engorgement and sometimes pulmonary edema; astrogliosis in the CNS; hypoplasia of the arcuate nucleus
d. maternal smoking, young maternal age, frequent birthings, prone or side sleeping, and sleeping on soft surfaces
47. What’s our best guess as to why SIDS occurs? What are the big two current buzzwords?
a. Delayed development of arousal and cardiorespiratory control
b. Abnormalities in the serotonin signaling, and maybe laryngeal chemoreceptors
48. What is the most common tumor of infancy? What two mutations can be associated?
a. Hemangioma
i. Frequently enlarge and regress
b. Can represent a facet of von Hippel-Lindau syndrome or cerebral cavernous malformation gene mutations
49. What chromosomal translocation is associated with fibrous tumors in young people?
a. t(12;15)
50. What is the most common teratoma of childhood? Who gets them?
a. Sacrococcygeal teratoma (most are mature, benign teratomas)
b. Girls are 4X more likely to get them
51. What are many childhood tumors referred to as? Name some tumors in this family:
a. Small round blue cell tumors
b. Neuroblastoma, Wilms tumor, lymphoma, rhabdomyosarcoma, Ewing sarcoma, and retinoblastoma
52. What features do neuroblastic tumors share?
a. Spontaneous or therapy-induced differentiation of primitive neuroblasts into mature elements, spontaneous regression, and wide range of behavior/prognosis
53. What is the most common location for a neuroblastoma to originate? What are the usual histologic findings? What are signs of increasing differentiation? What do you call the more differentiated flavours of the tumor (2 levels)?
a. Adrenal medulla; otherwise, aong the sympathetic chain
b. Homer-Wright pseudorosettes and neuropil
c. ganglioneuroblastoma = a few large cells with more abundant cytoplasm, which are ganglion cells
d. ganglioneuroma = more mature ganglion cells with fewer residual neuroblasts
i. Usually accompanied by Schwann cells
54. How would you stage a localized tumor with incomplete gross resection, with no invasion of local lymph nodes?
a. Stage 2a
55. What defines stage 2b? Stage 4S?
a. Localized tumor with invasion of ipsilateral lymph nodes
b. Localized primary tumor with dissemination limited to skin, liver, and/or bone marrow only (if other stuff is inolved, then you have a plain stage 4)
i. Only appears in infants under 1 year of age
56. What are favorable prognostic factors for neuroblastoma (4)?
a. Stages 1, 2A, 2b, or 4S
b. Age under 18 months
c. In children under 2, hyperdiploidy or near-triploidy is a good sign
d. TRKA expression present
57. What substance do most neuroblastomas produce? Amplification of what gene has the most negative impact on diagnosis?
a. Catecholamines (like a happy meal-sized pheochromocytoma!)
i. Expect vanillylmandelic acid and homovanillic acid in the urine