chapter 7 (genetic and pediatric diseases)

Question 1

Define the following:

• hereditary
• familial
• congenital

Answer 1

• hereditary: are derived from one’s parents are transmitted in the gametes through the generations and therefore are familial
• congenital: present at birth

some congenital diseases are not genetic (congenital syphilis) on the other hand not all genetic disease are congenital: huntington disease which begins in the 3rd or 4th decade of life.

Question 2

Define mutation?

Answer 2

permanent changes in the DNA:
Somatic cells are not transmitted to the progeny (but can cause cancer)
germ cell mutations are transmitted to the progency (offspring)

Question 3

Name the 3 types of genetic mutations?

Answer 3

• point mutations (sickle cell anemia) can change coding to a stop codon = NONsense mutation.
• Frameshift mutations: occurs when the insertion or deletion of one or 2 base pairs alters the reading frame of the DNA
• Trinuleotide repeat mutations: 3 nucleotides are amplified, all affected regions share G and C. Fragile X-cyndrome causes the normal 29 CGG repeats into 200-4000 repeats preventing the FMR1 from being normally expressed, resulting in mental retardation.

Question 4

Alterations in protein-coding genes?

Answer 4

alterations in DNA sequence coding genes also can undergo structural variations such as copy number changes: Amplifications or deletions or translocations.
This results in aberrant gain or loss of protein function.

Question 5

what are some of the major categories of genetic disorders?

Answer 5

• Mendelian disorders resulting from mutations in single genes
• Complex disorders involving multiple genes as well as environmental influences (hypertension, diabetes, allregy)
• Diseases arising from chromosomal abnormalities (changes in the number or structure of chromosomes
• Other: inherited via triplet repeat mutations, mitochondrial DNA, epigenetic phenomenon called genomic imprinting.

Question 6

Mendelian disorders?

Answer 6

caused by a single-gene defect; can be: Autosomal dominant, autosomal recessive, or X-linked.

• a single gene can have many phenotypes: marfan syndrome: can have affects on the connective tissue and skeleton, eyes and cardiovascular system.
• on the other hand several mutations can cause retinitis pigmentosa (abnormal retinal pigmentation causing visual impairment.
• phenotypic manifestations of mutations affecting a known single gene are influenced by other loci, which are called modifier genes. cystic fibrosis can have modifiers that can affect the severity or extent of the disease.

Question 7

AUTOSOMAL Dominant inheritance? features?

Answer 7

• atleast on parent in an index case is affected.
• some patients do not have affected parents (the disorder if from a new mutation involving either the egg or the sperm.
• reduced penetrance and variable expressivity: inherited mutated gene by phenotypically normal (reduced penetrance). a trait that is mutated may be expressed differently in some people (variable expressivity)
• Autosomal dominant: 50% loss in normal gene. Enzymes are usually not affected because since autosomal dominant disorders do not code enzymes. These disorders usually affect receptors or structural proteins.

Question 8

Describe how mutations to genes encoding a multimeric protein are affected?

Answer 8

-If one subunit is affected it can affect the normal assembly of a structure such a the triple helix of collagen. This is called dominant negative.

Question 9

Describe the factors of inheritance for autosomal recessive inheritance.

Answer 9

1. trait does not usually affect the parents but siblings may
2. siblings have a 1/4 chance of getting the disease
3. mutant gene occurs in low frequency in the population.

enzymes may be affected and the patient may make equal amount of both mutated and normal enzymes function.

Question 10

describe the patterns of inheritance in X-linked disorders?

Answer 10

• heteroxygous female carriers transmit them only to sons who of course are hemizygous for the X chromosome.
• heteroxygous females rarely see expression of pheotype
• all affected male does not transmit the disorder to sons but all daughters are carriers. sons of heteroxygous women have 1/2 chance of getting disease.

Question 11

Diseases caused by mutations in genes condign structural proteins. (2).

Answer 11

-Marfan syndrome: autosomal dominant disorder of connective tissues, manifested principally by changes in skeleton, eyes and cardiovascular system. do to inherited defect in an extracellular glycoprotein called Fibrillin-1, FBN1 mutation. I has been linked to TGF-beta overexpression, which negatively affects vascular smooth muscle development and integrity of extracellular matrix.
CLINICAL features: tall stature, long fingers, bilateral subluxation of lens, mitral valve prolapse, aortic aneurysm and aortic dissection. Prevention of cardiovascular disease involved the use of drugs that lower blood pressure and inhibit TGF-beta signaling.
-Ehlers-Danlos syndrome: characterized by defects in collagen synthesis or structure. since there are multiple collagen types the disorder has both autosomal dominant and recessive patterns. hypermobile joints and stretchy skin. Skin is easily damaged. structural failure of organs: can lead to colon rupture and large arteries being damaged.

Question 12

mutations in genes encoding receptor protein or channels?

Answer 12

-Familial hypercholesterolemia: LDL receptor loss which is involved in metabolism of cholesterol. the normal feedback that keeps the cholesterol metabolism in check is lost.

Question 13

what is the normal cholesterol metabolism?

Answer 13

Chylomicrons - tissues -chylomicron reminant (to liver) - some enters the bile and the other enters the metabolic pathways - VLDL (to muscle and adipose tissue) - IDL - IDL can be taken up b the liver through LDL receptors and can be recycled to create VLDL.

Question 14

what happens to patients with impaired LDL receptors?

Answer 14

impair the intracellular transport and catabolism of LDL resulting in accumulation of LDL cholesterol in the plasma. The impaired IDL transport into the liver causes IDL to be converted to LDL. The high serum cholesterol casues: cholesterol uptake by monocyte-macrophages and vascular walls causing: xanthomas (yellow patch on the skin) and premature atherosclerosis.

Autosomal dominant: heteroxygotes have a 2x to 3x elevation of plasma cholesterol levels. Homozygoetes may have an excess of fivefold elevation.

heterozygoes have elevated cholesterol from birth but show no symptoms until they are older as cholesterol accumulates in the tissue forming xanthomas.

Question 15

what are the 5 classes of LDL receptor gene mutations?

Answer 15

1. loss of receptor synthesis
2. receptor synthesized but its transport to the ER and golgi is impaired
3. receptors are transported to cell surface but cannot bind LDL
4. receptors fail to internalize
5. receptors that bind LDL and internalized byt are trapped in endosomes because dissociation of receptor and bound LDL doe not occur.

PCSK9: posttranslational regulation of plasma LDL levels have been elucidated as anzyme referred to as PCSK9 that causes LDLR degradation.

Question 16

Describe cystic fibrosis?

Answer 16

epithelial ion transport affecting fluid secretion in exocrine glands and the epithelial lining of the respiratory GI and reproductive tracts.
the abnormal mucous secretion block airways and pancreatic ducts; leading to pulmonary infections and pancreatic insufficiency.
high level of sodium chloride in the sweat is a consistent and characteristic biochemical abnormality in CF.

its caused by reduced production or abnormal function of an epithelial chloride channel protein encoded by the CF transmembrane conductance regulator (CFTR) gene. This renders epithelial membranes relatively impermeable to chloride ions. there is a lack of chloride ions reabsorption causing salty sweat. In the respiratory and GI there is a reduction of Cl secretion causing Na+ absorption via active ENaCs causing PASSIVE water uptake and decreased mucous on cells.

Question 17

what is the most common coding abnormality in cystic fibrosis?

Answer 17

deltetion of 3 nucelotides coding for phentalanine at amino acid position 508 (F508).

Question 18

what bacteria commonly cause lung abscesses?

Answer 18

• staphylococcus aureus,
• haemophilus influenzae
• pseudomonas aeruginosa

Question 19

in CF pancreas-indufficiency causes what?

Answer 19

CFTR mutation to both alleles causes exocrine pancreatic insufficiency.
Patients who have one severe and one mild CFTR mutation or 2 mild CFTR mutations retain sufficient pancreatic exocrine function that enzymes supplementation is not required.

This insufficiency is associated with malabsorption of protein and fat and increased fecal loss. (foul-smelling stools, abdominal distension, poor weight gain).
Faulty fat absorption may induce deficiency states of the fat-solube vitamins A,D,K.
NOTE endocrine insufficiency (diabetes) is uncommon in CF and occurs late int he course of the disease.

Question 20

Describe phenylketonuria?

Answer 20

PKU results from mutations that cause a severe lack of the enzyme phenylalanine hydroxylase (PAH)

Question 21

symptoms of the autosomal recessive disease of phenylketonuria?

Answer 21

-Homozygotes have lack of PAH (phenyalanine hydroxylase). Infants are normal at birth, but a few weeks later they exhibit a rising plasma phenylalanine level which impairs brain development. 6 months severe mental retardation becomes evident.
Children loose ability to walk and talk. loss of pigmentation in skin and hair.

Hyperphenylalaninemia and the resultant mental retardation can be avoided by restricting phenylalanine intake early in life. With this treatment children develop normally. But during adulthood if dietary restriction is not met, women could bear children who are mentally retarded. thus dietary restrictions should be kept up during conception.

Question 22

what happens in phenylketonuria when the enzyme PAH (phenylalanine hydroxylase) is missing?

Answer 22

there is an inability to convert phenylalanine into tyrosin.

• 50% of dietary intake of phenylalanine is necessary for protein synthesis rest is made into tyrosine by PAH.
• lack of PAH creates a shunt into intermediates that are excreted in the urine and sweat and can cause brain damage. Can be treated with enzyme replacement therapy (in trials)
• 2% of this disease is do to synthesis or recycling of the cofactor tetrahydrobiopterin, this cannot be treated with dietary restrictions, but require Terahydrobiopterin supplementations.

Question 23

Describe galactosemia?

Answer 23

autosomal recessive, mutation in the gene encoding the enzyme galactose-1-phosphate uridyltransferase (GALT).

Normally this enzyme breaks down lactase into glucose and galactose, galactose is broken down further.
metabolites like galactose-1-phosphate accumualte in liver, spleen, lens, eye, kidney, cerebral cortex.

Question 24

symptoms of galactosemia?

Answer 24

• non-specific CNS damage with little understanding
• liver enlarges (hepatomegaly) and cirrosis occurs
• opacification of the lens (cataract) develops.

at birth infants fail to thrive, vomiting and diarrhea appear withing a few days of milk ingestion, Jaundice appears at 1st week. Galactose-1-phosphate in the liver impair amino acid transport = aminoaciduria.

Dietary restriction are needed. Though even with diet speech abnormalities can develop.

Question 25

Lysosomal storage disease?

Answer 25

the breakdown of complex substrates like sphingolipids into soluble end products. The lose of lyzosoaml enzymes there is a accumualtion of insoluble metabolites.
Primary storage: accumulation of metabolites inside lyzosomes become big enough to affect cell
Secondary storage: impaired autophagy

Lack of quality control mechanisims causes dysfunctional mitochondria and free radical generation and apoptosis.
Niemann pick C and gaucher disease are connected to the risk of Alzheimer disease.

• Autosomal recessive transmission
• patient population consisting of infants and young children
• storage of insoluble intermediates in the mononuclear phagocyte system, giving rise to hepatosplenomegaly
• frequent CNS involvement and associated neuronal damage
• cellular dysfunction caused not only by storage of undigested material, but also by a cascade of secondary events, for example, macrophage activation and release of cytokines.

Question 26

Describe tay-sacks disease (GM2 gangliosidosis: deficiency in hexosaminidase B subunit)

Answer 26

• GM1 and GM2 subclassifications
• most common
• loss of function of beta subunit of hexosaminidase A needed for GM2 degradation.
• GM2 accumulates in nerves, the unfolded proteins are degraded and this results in the accumulation of toxic substrates and intermediates within neurons.
• normal birth
• motor weakness at 3-6 months
• neurological impairment
• onset of blindness
• death at 2-3 years of age.

Question 27

Describe Niemann-pick disease Types A and B?

Answer 27

Niemann-pick disease are related entitites characterized by a primary deficiency of acid sphingomelinase (accumulation of sphingomyelin).

Type A = sphingomyelinase deficiency; sphingomeylin in lyzosomes that look like “zebra bodies”. Excessive lipid accumulation in neurons, death by age 3. Type B = some enzyme activity remains.
Type C = APC mutation causing cholesterol accumulation in cells.

Question 28

Describe Gaucher disease?

Answer 28

mutation in the gene that encodes glucocerebrosidase (glucocerebroside accumulation, an intermediate in glycolipid metabolism in mononuclear phagocytic cells.
3 autosomal recessive variants of gaucher disease.
The accumulation of glucocerebrosides in macrophages become enlarged and have a cytoplasmic appearance characterized as wrinkled tissue paper.

Question 29

Describe the types of glycogen storage diseases?

Answer 29

• dysfunction of enzymes involved in glycogen metabolism can result in storage of normal or abnormal forms of glycogen predominantly in liver or muscles or in all tissues.
• Hepatic form (von gierke disease) liver cells store glycogen because of a lack of hepatic glucose-6-phosphatase)
• Myopathic forms McArdle disease, lack of muscle phosphorylase causing cramps in muscle after excersize do to lack of glycogen storage.
• pompe disease there is a lack of lysosomal acid maltase (all organs affected).

Question 30

Describe Karyotyping?

Answer 30

a photographic representation of a stained metaphase spread in which the chromosomes are arranged in order of decreasing length.
The most common is Giemsa (G-banding stain).
Each chromosome can be seen to possess a distinctive pattern of light and dark bands of variable widths.
-The use of banding techniques allows identification of each chromosome and can detect and localize structural abnormalities large enough to produce changes in banding pattern.

Question 31

Define euploid and polyploid and aneuploid?

Answer 31

Euploid: Haploid number multiple (n) 23 for humans.

polyploid: 3n and 4n
aneuploid: any number that is not an exact multiple of n.

monosomy of an autosome is incompatible with life, while trisomoy of certain autosomes and monosomy involving sex chromosomes are compatible with life.

Question 32

Describe structural abnormalities of chromosomes?

Answer 32

chromosomes are designated by short arm (letter p) and long arm (letter q). and then numbered from the centromere outward.

• Translocation (reciprocal translocation = exchange DNA).
• Robertsonian translocation (centric fusion type) translocation; break near the centromere causing one very long and one very short chromosome.
• Isochromosomes: the break occurs vertically; one chromosome has 2 short arms and one has 2 long arms.
• Deletion
• inversions: gene may be read backwards
• ring chromosomes: after a break at both ends of the chromosomes the 2 end reunite to form a ring.

Question 33

Trisonomies?

Answer 33

Trisomy 21: down syndrome (mental retardation, abundant neck skin, heart defect, umbilical hernia, hypotonia, intestinal stenosis, Gap between 1st and 2nd toes)
Trisomy 18 Edwards syndrome (prominent occiput, mental retardation, micrognathia, low set ear, short neck, overlapping fingers, heart and renal defect)
Trisomy 13: patau syndrome (Microphthalmia, microcephaly and mental retardation, cleft lip and palate, cardiac, umbilical hernai, rectal defects, rocker-bottom feet.

Question 34

Describe the disorders related to sex chromosomes?

Answer 34

a number of sex chromosomes ranging from 45x to 49XXXXY are compatible with life. Because some X-chromosomes can be inactivated (lyonization), and small amount of genetic info on the Y-chromosome.
Y-chromosomes ONLY code for the male determination (SRY, sex determing region of the Y) no matter how many X-chromosomes are present.

Question 35

how can females be described as mosaics?

Answer 35

Mosaic means the presence of two different genotypes in an individual which developed from a single fertilized egg. Females have to X chromosomes but one is inactivated.

Question 36

what is the method of X-chromosome inactivation in females?

Answer 36

long non-coding RNA encoded by the XIST gene which is retained in the nucleus where it coasts the X chromosome that it is transcribed from and other XIST allele is switched off in the active X allowing genes to be expressed on that chromosome.

Question 37

describe the 2 disorders related to X-chromosomes?

Answer 37

-Klinefelter syndrome: male hypogonadism that develops where there are at least 2 X chromosomes and one or more Y chromosome. (nondisjuction of sex chromosomes). Irradiation of parents or advanced age, and mosaic patterns in parents can cause this. small testis, low testosterone, reduced facial body, gynecomastia: male breasts. autoimmune disease and breast cancer frequency increases.
-turner syndrome: primary hypogonadism in FEMALES do to monosomy of the short arm of the X chromosomes. 45X karyotype is seen in 57% of patients
short stature webbing of the neck, cubitus valgus, aortic coarctation.

Question 38

what are the 3 types of disease resulting from mutations affecting single genes that do not follow the mendelian rules of inheritance?

Answer 38

• diseases caused by triplet repeat mutations,
• diseases caused by mutations in mitochondrial genes
• diseases associated with alteration of imprinted regions of the genome.

Question 39

what are triple repeat mutations? examples?

Fragile X syndrome

Answer 39

Fragile repeat mutations:
Fragile X syndrome: the causative mutation occurs in a long repeating sequence of 3 nucleotides.
all are associated with neurodegenerative changes.
Huntington disease and myotonic dystrophy.
Fragile x-syndrome results from a mutation in the FMR1 gene
Clinical features: long face, large mandible, large everted ears, large testicles.

Question 40

what are the not typical X-linked recessive disorders of Fragile-X-syndrome?

Answer 40

• Carrier males: 20% of males are carriers with no symptoms
• Affected females: 30-50% of women carriers show mild symptoms which is unusual for an X-linked recessive disease.
• Anticipation: clinical feature of fragile X-syndrome worsen with successive generation. Expansion of the trait occurs during oogenesis (in huntigtons disease it occurs during spermatogenesis)

this may be related to the number of CGG repeats, longer repeats 200-4000 “full mutation” cause worse symptoms.

Question 41

what is the pathogeneis of Fragile-X-syndrome?

Answer 41

the FMR1 gene has CGG repeats normally but if these repeats are extended then the area of the gene will be heavily methylated and silenced.
FMR1 is expressed in all tissues but its heavily present in the brain and testis.
FMR1 is translocated from the cytoplasm to the nucleus where it binds mRNA. The FMRP-mRNA complexes perform critical roles in regulating the translation of specific mRNAs involved in synapses of neurons.

Question 42

describe fragile X tremor/Ataxia?

Answer 42

the CGG “premutations” in the FMR1 gene can cause a disease that is phenotypically different from fragile X syndrome. this involves a toxic gain of function mechanism;

the premutations (few CGG repeats) form a toxic accumulation in the nucleus.
Expansion can affect any part of the gene;
-untranslated region: Fragile X (gene is silenced) loss of function
-coding region: huntigtons disease. (misfolded protein but no silenced)

Question 43

Mutations in mitochondrial genes?

Answer 43

can only be transmitted via the mother since the mitochondrial comes from the mother.
The affect is mostly on the cells that rely heavily on the mitochondria: CNA, skeletal muscle, cardiac muscle, liver, kidney.
progressive bilateral loss of central vision that leads in due course to blindness.

Question 44

describe diseases that are caused by alterations of imprinted regions: Prader-Willi and Angelman Syndromes.

Background info on imprinting.

Answer 44

all human (except sex chromosomes) come in pairs, one maternal and a paternal. Most genes are the same. The biggest difference is epigenetic process called genomic imprinting where homologous genes are differentially "inactivated" during paternal and maternal gametogenesis.
-Maternal imprinting is silencing of maternal allele and paternal imprinting implies the paternal allele is inactivated via METHYLATION and histones.
imprinting occurs in ova or sperm and stably transmitted to all somatic cells derived from the zygote.

Question 45

describe diseases that are caused by alterations of imprinted regions: Prader-Willi and Angelman Syndromes.

The actual diseases.

Answer 45

Parder-willi syndrome: mental retardation, short stature, hypotonia, obesity, small hands and feet, hypogonadism.
A deletion affects the paternally derived chromosome 15.

Angelman syndrome affects the same chromosomal region but from the mother. Mentally retarded and ataxic gait, seizures and inappropriate laughter.

if the paternal allele is expressed; genes involved in mRNA processing and UBE3A which codes for ubiquitin protein needed for protein degradation.
in maternal allele expression the ubiquitin gene is poorly expressed.

Question 46

Define uniparental disomy?

Answer 46

when 2 chromosomes come from one parent

in the case of angelman syndrome, the cause of the syndrome can also be from 2 paternal chromosomes 15.

Question 47

overview of pediatric diseases?

Answer 47

diseases of infancy and childhood are of genetic origin. the 1st year of life is the most risky. with the 1st 4 weeks being the most hazardous.

Question 48

Define the following:

• malformations
• disruptions
• deformations
• sequence
• malformation syndrome
• agenesis, atreisa.

Answer 48

• Malformation: primary errors of morphogenesis (abnormal development)
• disruptions: result form secondary destruction of an organ or body region that was previously normal in development. (not heritable) amnionic bands wrapping around limbs of fetus is one example.
• deformations: extrinsic disturbance of development; such as uterine compression
• sequence: multiple congenital anomalies that result from secondary effects of a single localized aberration in organogenesis.
• malformation syndrome: several defects that cannot be explained on the basis of a single localizing initiating error in morphogenesis.
• agenesis: no development, Aplasia: incomplete development, hypoplasia: underdevelopment. Atresis: absence of an opening of a hollow visceral organ or duct such as intestines and bile ducts.

Question 49

what are the 3 groups of error causes in human malformations?

Answer 49

• Genetic: chromosomal abnormalities and mutations.

- environmental influences: infections, drugs and radiation that the mother is exposed to during pregnancy.

Question 50

what are some of the environmental causes of congenital diseases?

Answer 50

Rubella
Zika virus can cause CNS malformations
thalidomide was used to treat cancers caused limb malformations
alcohol: retardation, facial anomalies, (microcephaly, short palpebral fissure, maxillary hypoplasia)
smoking: low birth weight do to affects on placenta.
Diabetes mellitus: high birth weight.

Question 51

Describe the pathogenesis of congenital anomalies?

Answer 51

1. timing of the prenatal teratogenic insult is important impact on the occurrence and type of anomaly produced. 2 stages: embryonic period and fetal period of development.
   During embryonic period (9 weeks), insults could cause death and abortion of the fetus.
   During 3-9th week the embryo is susceptible to teratogenesis, peak sensitivity occurs between the 4th and 5th weeks when organs are made.
   during the fetal period the maturing organs are susceptible to growth retardation or injury to already formed organs.
2. complex interplay between environmental teratogens and intrinsic genetic defects is exemplified by the fact that features of dysmorphogenesis caused by environmental insults often can be recapitulated by genetic defects in the pathways targeted by these teratogens.
   - cyclopamine: in plants and inhibits the hedgehog gene causing cyclopia (one fused eye).
   - Valproic acid: disrupts expression of HOX (homobox genes) that are needed for skeletal and limb development and placement
   - Vitamin A (retinol): in the absence multiple organs are affected, eyes, genitourinary system, cardiovascular system, diaphragm, lungs. cleft lip and cleft palate.

Question 52

2 forms of perinatal infections:

Answer 52

• Transcervical or ascending infections: can ascend into uterus up the cervix, or given to fetus during birth through infected canal
• Transplacental infections: through placenta: Zika, Rubella virus.

Question 53

Describe prematurity and fetal growth restriction

Answer 53

-prematurity is defined by a gestational age less than 37 weeks and is the second most common cause of neonatal mortality. premature birth, the fetus is underweight.
Birth can be because: premature rupture of membranes, intrauterine infection, abnormalities of uterus, cervix, placenta. Immature organs makes the fetus vulnerable to the following complications:
-respiratory distress syndrome (hyaline membrane disease)
-necrotizing enterocolitis
-sepsis
-intraventricular and germinal matrix hemorrhage
-long-term sequelae, including developmental delay.
infants born underweight suffer from FETAL growth restriction:
-fetal abnormalities: conditions that intrinsically reduce growth potential of the fetus despite adequate supply of nutrient from the mother, (symmetrical growth loss)
-Placental abnormalities: placenta previa (low implantation of the placenta), placental abruption (separation of placenta from the decidua, placental infraction. (asymmetrical growth; brain is spared relative to organs for example).
-Maternal factors: drug, alcohol, hypertension, inherited disorders.

Question 54

Describe Respiratory distress syndrome of the newborn?

RDS = respiratory distress syndrome.

Answer 54

Also called hyaline membrane disease because of the membranes that form in the airways of the infants.
Causes: excessive sedation of mother, fetal head injury during delivery, aspiration of blodd or amniotic fluid and intrauterine hypoxia secondary to the complession of coiling the umbilical cord around the neck.
The infant has no surfactant as a result made by the type II pneumocytes. The increased effort needed to breath causes the infant to tire and atelectasis sets in (collapse of the lung). The result is a sequence of events that leads to epithelial and endothelial damage and eventually to the formation of hyaline membranes.
High insulin levels suppress surfactant synthesis by supressing the corticosteroid that that stimulate surfactant (diabetic mothers have high risk for RDS). Labor increases surfactant thus Cesarean section birth is associated with RDS.
Treatment focuses on prevention: delay birth until lungs form. ventilators can be used on premature births.

2 problems develop with older ventilation techniques:

• retinopathy since the VEGF needed for vasculogenesis is low during ventilation no vessels form, but once taken of ventialtion vessels can grow in the retina causing lesions.
• bronchopulmonary dysplasia: hyperoxemia, hyperventilation, prematuriy, inflammatory cytokine, vascular maldevelopment cause this.

Question 55

in RDS what can be seen in microscope specimens?

Answer 55

infants who dies from RDS have characteristic eosinophilic hyaline membranes line the respiratory bronchiles, alveoli.
The membranes contain necrotic epithelial cells admixed with extravasated plasma proteins. Inflammation of neutrophilis can be seen. Proliferation of type 2 pneumocytes and interstitial fibrosis is seen.

Question 56

what are infants who recover from RDS (respiratory distress syndrome) have an increased risk for?

Answer 56

• patent ductus arteriosus
• intraventricular hemorrhage
• necrotizing enterocolitis.

Question 57

what is RDS treated with?

Answer 57

administration of steroid, surfactant therapy

Question 58

define sudden infant death syndrome (SIDS)?

Answer 58

“the sudden death of an infant under 1 year of age whcih remains unexplained after a through case investigation, including performance of the complete autopsy, examination of the death scene and review of the clinical history.
If there is an anatomical or biochemical cause of death found upon autopsy then its called a: SUID (sudden unexpected infant death).

mostly the hypothesis is that SIDS reflects a delayed development of arousal and cardiorespiratory control.

Question 59

what is the pathogenesis of SIDS? sudden infant death syndrome?

Answer 59

multifactorial condition, with a mixture of contributing cases in a given case. 3 interacting variables have been proposed:

1. vulnerable infant
2. critical developmental period in homeostatic control
3. one or more exogenous stressors.

There is a delay in the arousal of the cardiorespiratory control in the brain stem (medulla oblongata) in response to stresses such as hypoxia and thermal stress encountered during sleep.
the medullas serotonergic (5-HT) system of the medulla is implicated in these “arousal” responses as well are regulation of other critical homeostatic functions such as respiratory drive, blood pressure and upper airway reflexes. SIDS develop upon malfunction of theses systems.

Laying infants in the prone position to sleep has been linked to SIDS, so its recommended that they lie on their back. since lying prone exposes the infant to the noxios stimuli (hypoxai, hypercarbia (too much CO2 in the blood and thermal stress)

victims of SIDS have: multiple petechiae in the thymus visceral and parietal pleura and epicardium. pulmonary edema and hypoplasia of the arcuate nucleus

Question 60

Describe Fetal hydrops?

Answer 60

accumulation of edema fluid in the fetus during intrauterine growth.
Originally this was thought to be only caused Rh incompatibility between mother and fetus however with treatment with prophylaxis other disorder during pregnancy other causes were discovered. Such as:
cardiovascular malformations, tachyarrhtythmia, syphilis, (infections). Turner syndrome, Trisomy 21, 18.

Question 61

what causes the immune hydrops between fetus and mother?

Answer 61

The fetus inherits red cell antigenic determinants from the father that are foregin to the mother.
The RBC of the fetus may make it into the mother during the last trimester of development as the cytotrophoblast is no longer present. Antibodies are made against the fetal RBCs that may affect future pregnancies.
-dose of transfused blood plays a role in the immune response.
-IgG can cross the placenta. upon 1st exposure IgM is formed to upon 1st pregnancy the response is unlikely, however with subsequent exposure the IgG antibodies will be produced.

Hemolysis can also occur in ABO incompatibility between the fetus and the mother, however the condition is less severe since other cells express A and B antigens acting as a sponge of anitbodies. These conditions mostly occur to A or B infants born to O blood type mother who have antigens against both A and B antibody.

Question 62

what are some of the non-immune hydrops causing events?

Answer 62

-cardiovascular defects, chromosomal anomalies, and fetal anemia.
-turner syndrome may be associated with lymph drainage abnormaliteis. Thought cardiac abnormalities such as arrhythmias also cause fetal hydrops.
-fetal anemias caused by homoxygous a-thalassemia
-Transplacental infections such as parvovirus b19. Liver failure can also cause hypoalbuminemia reducing osmotic pressure.
the hemolysis of RBCs cause bilirubin which can cause CNS damage.

Question 63

Treatment of fetal hydrops?

Answer 63

RhIG administration which masts the antigens of fetal RBCs. postnatally phototherapy is helpful because visible light breaks down billirubin.

Question 64

Describe tumors and tumorlike lesions of infancy and childhood.and tissues native to the organ in which it occurs. (benign tumor of blood vessels)

Answer 64

malignant neoplasms constitute the second most common cause of death in children between the ages of 4 and 14 years. (benign tumors are even more common than cancers). 2 special categories exist:

• Heterotopia or choristoma: microsopically normal cells or tissues that are present in abnormal locations. (pancreatic tissue can be present in the stomach for example) This has NO clinical significance but can be mistaken for neoplasms.
• Hamartoma: excessive but focal overgrowth of cells and tissues native to the organ in which it occurs.

Question 65

describe benign neoplasms of infants?

Answer 65

in the pediatric age group and type of neoplasm may be encountered, 3 are the most common:

• hemangiomas: (benign tumor of blood vessels)
• lymphangiomas: lesions in the lymphatic system.
• teratomas: tumor made of cells not normally present at the site (sites are typically n the gonads)

Hemangiomas can produce flat or elevated lesions on the face and scalp. the flat to elevated irregular red-blue masses are called port-wine stains. These may recess spontaneously.
lymphangiomas show up as cystic and cavernous spaces lined by endothelial cells and surrounded by lymphoid aggregates. These may grow large enough after birth to affect surrounding structures.
Tetratomas: produce various well differentiated structures do to the omnipotent nature of the cells.

Question 66

describe malignant neoplasms in infants?

Answer 66

organs involved in hematopoietic system, neural tissue, and soft tissue are the most commonly affected. the differences between infantile and adult tumors are as follows:

• frequent demonstration of a close relationship between abnormal development (teratogenesis) and tumor induction (oncogenesis) suggesting a common stem cell defect.
• genetic abnormalities that predispose to cancer may be present
• Tendency of fetal tumors to regress and turn into mature elements spontaneously.
• better survival or cure of many childhood tumors

the 3 special types that you need to know are:

• neuroblastoma
• retinoblastoma
• wilms tumor

Question 67

Describe the neuroblastoma infant neoplasm?

Answer 67

tumor of the sympathetic ganglia and adrenal medulla that are derived from primordial neural crest cells populating these sites.
some spontaneously regress and therapy induced maturation can occur. most occur sporadically but some are autosomal dominant. mutated anaplsatic lymphoma kinase (ALK) gene have been linked to it an blockers for therapy are being tested. 40% arise from the adrenal cortex.
Children younger then 18 months of age are more likely to survive then older patient with the same neoplasm.
Amplification of the MYCN gene has been linked to impacting the prognosis. the greater amplification leads to worse prognosis.

age, stage, MYCN status and ploidy are used to clinically determine the prognosis of a neoplasm.
PLOIDY: number of sets of homologous chromosomes in the genome of a cell or an organism. Each set is designated by n

neuroblastomas are undifferentiated.
neuroblastomas can secrete tumors that secrete catecholamines that can be used fro screening patients.

Question 68

Describe retinoblastoma?

Answer 68

most common primary intraocular malignancy of children. 40% are germline
60% are sporadic
familial cases typically are associated with development of multiple tumors that are bilateral.

CLINICAL: poor vision can occur;
-strabismus: cannot align eyes properly.
-whitish hue to the pupil (cats eye reflex)
if untreated can be fatal.

Question 69

Describe wilms tumor?

Answer 69

also called nephroblastoma is the most common primary tumor of the kidney in children.
3 groups of congenital malformations are associated with an increased risk of wilms tumors
-WAGR (wilms tumor, aniridia, genital abnormalities and mental retardation) ANIRIDIA = no iris.
-denys-drash syndrome (DDS):
-beck with wiedemann syndrome (BWS)

the 1st 2 are associated with abnormalities to the wilms tumor 1 (WT1) gene on 11p13. the method of abnormality is different; WAGR: loss of genetic material (delations), DDS patients have dominant negative inactivating mutations in WT1.
WT1 is critical for gonadal development.
In BWS and upstream region called WT2 is affected. in BWS enlarged organs can be seen that are linked to one of the upstream genes that is affected IGF2 (insulin growth factor 2) that is overexpressed.

Question 70

morphology of retinoblastomas?

Answer 70

nodular masses on the posterior retina. the tumor is made of undifferentiated retinoblasts.
Flexner-wintersteiner rosettes are the most characteristic structure.
made of cuboidal or short columnar cells arranged around a central lumen.

Question 71

what are some of the molecular diagnosis of mendelian and complex disorders?

Answer 71

for genetic screening FISH, cytogenetics, molecular diagnostics techniques can be used. this should be done to all patients at risk of cytogenetically abnormal progeny. such as: advanced age, 34

Question 72

in diagnostics what is used to detect molecular diagnosis of copy abnormalities?

Answer 72

-G-banding is used for karyotype analysis of chromosomes, this has low resolution.
-FISH (fluorescence in situ hybridization) is used fro chromosomal regions.
In FISH probes a compliment probe is attached to the chromosomes in metaphase and thus with a fluorescence microscope.
in FISH we need to know about which region may be affected by a mutation.
Array comparative genomic hybridization (aCGH); Normal DNA is labeled with a red and a reference DNA is labeled with green. The labeled samples are then cohybridized to an array spotted with DNA probes that span the human genome at regularly space intervals. and usually cover all 22 autosomes and the sex chromosomes. the labeling is compared, if the 2 samples are equal then it will appear yellow. Similar thing can be done with SNP (single nucleotide polymorphisms)

Question 73

describe PCR (polymerase chain reaction) in terms of genetic diagnosis?

Answer 73

PCR = exponential amplification of DNA. 2 primers are used to isolate a DNA sequence of interest and thermal cycling with polymerases are used to amplify them.
ANALYSIS: Sanger sequencing: dead end nucleotides A,T,G, and C labeled with different fluorescent tags can be used to end the PCR at different length and thus the sequence of the DNA can be read.