Topics A39-44 Pediatric Diseases: Congenital anomalies, prematurity, SIDS, hydrops, CF, Childhood Tumors

Question 1

What does “congenital” mean?

Answer 1

Structural defects present at birth. May be cosmetic or functional. Many may not be apparent until later in life.

Incidence is as high as 1 in 33.

Question 2

Definitions of:

• Malformation
• Disruption
• Deformation

[Note that these definitions are really bitchy and I hope no one cares about this]

Answer 2

Malformation: primary errors of morphogenesis, intrinsically abnormal developmental process. Not usually one gene or chromosomal defect, but many factors.

Disruption: secondary destruction of organ/region, so by contrast to malformation they arise from an extrinsic disturbance. Classic example is “amniotic bands” that encircle and compress developing fetus. Not heritable. In contrast to deformation, a previously-formed organ is destroyed, not just malformed.

Deformation: also extrinsic disturbance of development, but via abnormal biomechanical forces such as uterine constraint.

Question 3

Definitions:

• Sequence
• Malformation Syndrome

Answer 3

Sequence: a single aberration that snowballs and leads to many secondary effects. Example is oligohydramnios sequence (decreased amniotic fluid). Many things can cause decreased amniotic fluid, but the low fluid leads to fetal compression, which makes a fetus with a flattened face, positional abnormalities of the limbs, poor growth of chest, etc.

Malformation Syndrome: several defects that cannot be explained by a single localizing error in morphogenesis. May be chromosomal abnormality or viral infection that affects several tissues

Question 4

Definitions:

• Agenesis
• Aplasia/Hydroplasia
• Atresia

Answer 4

Agenesis: complete absence of organ

Aplasia/Hypoplasia: incomplete development or under-development

Atresia: absence of an opening, usually a hollow visceral organ or duct like the intestine or bile duct

Question 5

3 major categories of causes for human malformations

Answer 5

1. Genetic
2. Environmental
3. Multifactorial

Question 6

Genetic causes of malformation:

-Which ones are inheritable?

Answer 6

Chromosomal disorders (Down syndrome, Klinefelters) are not usually inheritable because they arise during gametogenesis, not spread. But single gene mutations undergo Mendelian inheritance.

Question 7

Can you give 3 examples of specific environmental factors that cause fetal disruptions of development? (listing more than 3 on the answers but at least try to get 3)

Answer 7

1. Infections like Rubella (rare due to vaccine)
2. Medications like thalidomide (tranquilizer and cancer treatment)
3. Alcohol

Others: radiation, cigarettes, 13-cis-retinoic acid (acne treatment), warfarin, anticonvulsants, maternal hyperglycemia

Question 8

During which weeks of development is the embryo most susceptible to teratogens?

Answer 8

Weeks 3-9, and the peak sensitivity is between weeks 4 and 5.

Question 9

What is multifactorial inheritance?

What are 3 common defects that occur?

Answer 9

Multifactorial inheritance: interaction of environmental influences with 2 or more genes, commonly causing congenital defects

Examples:

1. Cleft Lip
2. Cleft Palate
3. Neural tube closure defects

Question 10

What are the two ways that perinatal infections can occur?

Answer 10

1. Transcervical (Ascending) infections: spread of infection from vaginal canal upwards. The fetus may “inhale” infected amniotic fluid, or contract it while passing thru birth canal. Some viruses but mostly bacteria like S. agalactiae
2. Transplacental: crosses placenta via chorionic villi. Mostly viruses and parasites, some bacteria

Question 11

What is the common acronym for the most important transplacental infections?

Answer 11

TORCH

T: Toxoplasma
O: Other (Listeria, Trepenoma, Malaria)
R: Rubella virus
C: Cytomegalovirus
H: Herpes virus

Question 12

If an embryo/fetus gets a TORCH infection, what is the difference if they get it early in pregnancy vs late?

Answer 12

Early: growth restriction, mental retardation, cardiac abnormalities

Late: Inflammatory tissue injury (pneuomonia, myocarditis, encephalitis…)

Question 13

A baby is considered premature if it is born at a gestational age of how many weeks?

How much do they normally weigh?

Answer 13

Less than 37 weeks.

Usually weigh less than 2500 g

Question 14

What is the pathogenesis of the respiratory disease associated with premature birth?

Answer 14

Infant Respiratory Distress Syndrome (IRDS) aka Hyaline Membrane Disease

Fundamental problem is that type II pneumocytes have not matured and cannot produce surfactant. Without surfactant, the surface tension is too high and the alveoli collapse on expiration. The neonate has to exert more effort to inhale again, gets tired, and generalized atelactasis sets in (airlessness, “collapsed lung”).

If the baby was able to live for a short time after birth but then died, it may show eosinophilic “hyaline membrane” lining inner surface of alveoli. It’s fibrin preciptate and necrotic epithelial cells. Worsens effectiveness of oxygen exchange.

Question 15

What are the major treatments for the respiratory problems of prematurely born babies? What are 2 complications that can occur as a result?

Answer 15

Respiratory Treatments
1. Surfactant supplemented (has greatly improved prognosis since it’s been implemented)

2. High-frequency oscillatory ventilator (HFOV) gives small jet streams of air that open up alveoli. Provides high oxygenation (80-100%)

Complications of High Oxygenation:

1. Bronchoplulmonary dysplasia: decrease in alveolar separation
2. ROS from oxygen may damage retina, causing blindness

Question 16

Why do premature babies often have intraventricular hemorrhage?

Answer 16

Brain reacts to hypoxia by dilating its vessels. However, the vessels are not fully mature in the neonate and so hemorrhage can occur.

Question 17

What is the syndrome that commonly affects the colon of very low birth weight premature babies?

Answer 17

Necrotizing Enterocolitis (NEC) - 1 in 10 VLBW infants

May be related to premature introduction of GI bacteria, but nothing specific has been identified. Inflammatory mediators like PAF may be related by increasing mucosal permeability, causing enterocyte apoptosis.

Can develop gangrenous intestinal perforations and peritonitis. May require bowel resection. If these babies survive, they may have post-NEC structures and fibrosis.

Question 18

What must be done before a diagnosis of SIDS?

Answer 18

The infant <1 year of age must have a full autospy, death scene examined, and clinical history reviewed, and then the cause of death must still be unexplainable. Multiple petechiae is the most common finding in SIDS autopsies.

Question 19

When and at what age are babies most at risk for SIDS?

What region of the brain may be related to SIDS deaths?

In what position should babies lay to prevent SIDS?

Answer 19

Babies are most at risk when they are sleeping, also between the 2nd and 4th month.

The arcuate nucleus may be related to SIDS as it has a critical role in arousal and response to noxious stimuli. SIDS babies may have delayed development of arousal reflexes and cardiorespiratory control.

Babies should lay on their back; babies who died of SIDS were often found laying prone. There is also some correlation between laying on soft surfaces and being too warm. Also a correlation between mothers who smoke or parents who use drugs.

Question 20

What does “hydrops foetalis” mean?

What are the two major categories of fetal hydrops?

Answer 20

Fetal hydrops: accumulation of edema in fetus during intrauterine growth.

1. Immune Hydrops: usually results from hemolysis as a result of Rh or ABO incompatability. Less common nowadays with good prophylaxis.
2. Non-immune Hydrops: associated with cardiovascular defects, chromosomal abnormalities, and fetal anemia.

Question 21

When can Rh- mothers have antibodies that attack an Rh+ fetus?

When is ABO incompatibility most likely a problem during pregnancy?

Answer 21

Rh- mothers may get large dose of Rh+ fetal blood with one pregnancy, providing enough antigens to lead to formation of IgG antibodies that can later cross the placenta in the next pregnancy.

ABO incompatibility is rarely a problem because most people just form IgM antibodies against other blood groups, and they can’t cross the placenta. However, type O mothers can sometimes have IgG antibodies against A and B antigens. Even then, the effects are more mild than Rh incompatibility.

Question 22

What are some chromosomal abnormalities that can cause fetal hydrops (non-immune kind)?

Answer 22

45X (Turner), Trisomies 21 and 18.

The basis is usually cardiac anomalies. Turner syndrome may have impaired lymph drainage from the neck, causing nuchal fluid accumulation and “cystic hygroma” (an isolated effusion that can be compatible with life)

Question 23

What are 2 non-immune causes of fetal anemia that may lead to fetal hydrops?

[may not be too important, just feel I should put more as fetal hydrops is an entire topic. The main thing to know for this topic is Rh incompatibility, which I didn’t want to fully explain because you probably know it]

Answer 23

1. α-thalassemia: genetic defect causing impaired production of hemoglobin. More common in Southeast Asia
2. Parvovirus transplacental infection

Question 24

What is the prevalence of Cystic Fibrosis?

What type of inheritance does it follow?

What is the most common gene mutation?

Answer 24

1 in 3200 births in the U.S., commonly affecting Caucasian people. It’s the most common lethal genetic disease in white people

Follows autosomal recessive inheritance

CFTR gene change F508 (CFTRΔF508) is the most common mutation (70%), located on chromosome 7

Question 25

What is the result of having the cystic fibrosis mutation?

What is the most frequent cause of death?

Answer 25

Results from an impaired chloride channel (CFTR), preventing reabsorption of salt in most exocrine glands like sweat glands (characteristic salty sweat). However, in the lung and intestines, CFTR mutation leads to poor secretion of Cl- into the lumen, and so not enough water follows with it - the secretions are isotonic but low volume. Severe respiratory, pancreatic, and liver complications

Most frequent cause of death is from the low volume in lungs making viscous, concentrated secretions that obstruct the airway and are prone to infections.

Question 26

Definition: Heterotopia / choristoma

Answer 26

Heterotopia / choristoma: microscopically normal cells or tissues, but they’re present in abnormal locations. E.g. pancreatic tissue found in stomach or small intestines

Question 27

3 notable benign tumors that are common in childhood:

Answer 27

1. Hemangiomas: normally located on skin of face and scalp. Red-blue masses, with flat lesions called “port wine stains.” Mostly cosmetic issue.
2. Lymphangiomas: same thing but with lymph regions.
3. Sacrococcygeal teratomas: Most common germ cell tumors of childhood. Around 10% are associated with congenital abnormalities like spina bifida.

Question 28

What are the top 3 most common childhood tumors?

Answer 28

1. CNS tumors, especially medullablastoma
2. Solid tumors, especially of kidneys like Wilms (nephroblastoma)
3. Neuroblastoma

(note this was what was said in my histo class, and I’ve seen some slight variations.. most sources say Leukemia is the most common childhood cancer, and maybe that’s not included because leukemia is not properly a “tumor”)

Question 29

In which organs do childhood neuroblastomas usually arise?

What are some things to note histologically?

Answer 29

40% arise in adrenal medulla (like our slide for histo), remainder are along the sympathetic chain.

See small, round, blue cells (characteristic for many childhood tumors). May also see Homer-Wright rosettes: neuroblastoma cells concentrically arranged around a lumen and that has neuropil fibrillary network around it.

Question 30

Which protooncogene is associated with neuroblastoma?

If neuroblastoma cells are able to mature a bit more, what do they become?

Answer 30

Protooncogene: N-Myc

Neuroblastoma cells can differentiate into ganglion cells, forming ganglioneuroma

Question 31

What lab tests might be able to indicate for neuroblastoma?

How is the survival rate?

Answer 31

Test VMA or HVA in urine because these cells cause overproduction of catecholamines, and VMA/HVA are breakdown products of catecholamines.

Tumor responds well to treatment and commonly detected. 5 year survival rate is ~90%.

Question 32

Which gene mutation may lead to retinoblastoma?

What are the 2 forms of retinoblastoma?

Answer 32

RB1 gene. But need “double-hit” for tumor formation.

Forms:
1. Inherited: usually both eyes are affected. Inherit one faulty gene and then a somatic mutation knocks out the other.

2. Acquired/sporadic: just one eye affected. Less common because both alleles have to have a somatic mutation.

Question 33

What is notable histologically in Retinoblastoma?

Answer 33

Small round blue cells again (typical for childhood tumor).

Flexner-Wintersteiner Rosettes: again concentric blastoma cells, but in this one the center usually has a vessel.

Question 34

What other tumor is associated with retinoblastoma?

What is a major symptom of retinoblastoma?
How is the prognosis of retinoblastoma?

Answer 34

Associated tumor: osteosarcoma (Matolcsy apparently likes to ask)

Major symptom: Poor vision with “leukocoria” - white eyes. Usually appears around 2 years old.
Prognosis is relatively good because it is so noticeable that it can be caught early. Treatment may save vision. Untreated it leads to malignancy.

Question 35

What 3 groups of congenital malformations are associated with increased risk for Wilms tumor (nephroblastoma)? Which genes are associated?

Answer 35

1. WAGR Syndrome: Wilms, Aniridia (no iris), Genital abnormality, mental Retardation. 1 in 3 with WAGR go on to form Wilms (I guess the others are just AGR). WT1 gene (Wilms Tumor 1, 11p13) abnormalities
2. Denys-Drash Syndrome: 90% get Wilms. Have gonadal dysgenesis and renal abnormalities. Also WT1 gene is abnormal.
3. Beckwith-Wiedermann Syndrome: WT2 gene affected, this disease is an example of genomic imprinting. Insulin-like growth factor 2 (IGF2) is overproduced, causing hypoglycemia, organ enlargement, and tumorigenesis.

Question 36

What is the “classic triphasic combination” of cells seen in histology slides of Wilms tumor?

Answer 36

1. Blastemal cells: Small round blue cells like the other childhood tumors, but they also show some tendency for differentiation
2. Stromal cells: mostly into fibrocytes, but may also see cartilage, muscle, bone
3. Epithelial elements: takes form of “abortive tubules” or glomeruli

Question 37

How does a Wilms tumor appear on gross examination?

How old are children who usually get it? What are some other signs? How treatable is it?

How does it usually originate?

Answer 37

Large, solitary, well-circumscribed mass. Usually arises in the middle of the kidney. Grows quickly, destructive.

Appears between 2 and 5 years old. May be palpable from abdomen. May cause hematuria. Very treatable if you catch it early.

Despite all that about WAGR and Denys-Drash, most cases of Wilms tumor are not related to the WT genes and are completely sporadic.