Pediatric diseases A39-44

Question 1

A/39. Congenital anomalies

Terminology and definitions

Answer 1

Congenital anomalies: 1 in 33 births will have some congenital anomaly. Congenital does not imply a genetic basis one way or the other. They may be genetic or may not, they may or may not be heritable.

1. Malformations: primary errors of morphogenesis; intrinsically abnormal developmental process. Usually multifactorial.
2. Disruptions: Disruptions arising from an external source damaging the fetus. Amniotic bands - which may wrap around some part and constrict it.
3. Deformations: also an extrinsic source. Usually compression induced deformation. Common (2% of newborns are affected). Usually due to localized or generalized compression of the growing fetus, e.g. uterine constraint (during weeks 35‐38) compression from a twin.
4. Sequence: Multiple errors that occur after an initiating malformation, deformation, or disruption.
5. Malformation syndrome: presence of many defects that cannot be explained on the basis of localizing one error in morphogenesis.
6. Agenesis: complete absence of an organ or its anlage.
7. Aplasia: incomplete development of an organ.
8. Hypoplasia: underdevelopment of an organ.
9. Atresia: absence of an opening (hollow visceral organ or duct).

Question 2

A/39. Congenital anomalies

Agenesis

Aplasia

Hypoplasia

Atresia

Answer 2

Agenesis: complete absence of an organ or its anlage.

Aplasia: incomplete development of an organ.

Hypoplasia: underdevelopment of an organ.

Atresia: absence of an opening (hollow visceral organ or duct).

Question 3

A/39. Congenital anomalies

Question 4

A/39. Congenital anomalies

Malformations

Disruption

Deformation

Answer 4

Malformations: primary errors of morphogenesis; intrinsically abnormal developmental process. Usually multifactorial.

Disruptions: Disruptions arising from an external source damaging the fetus. Amniotic bands - which may wrap around some part and constrict it.

Deformations: also an extrinsic source. Usually compression induced deformation. Common (2% of newborns are affected). Usually due to localized or generalized compression of the growing fetus, e.g. uterine constraint (during weeks 35‐38) compression from a twin.

Question 5

A/39. Congenital anomalies

terms:

Sequence

Malformation syndrome.

Answer 5

Sequence: Multiple errors that occur after an initiating malformation, deformation, or disruption.

Malformation syndrome: presence of many defects that cannot be explained on the basis of localizing one error in morphogenesis.

Question 6

A/39. Congenital anomalies

The main etiologies of congenital abnormalities

Answer 6

1. Genetic
2. Environmental
3. Multifactoral

Genetic:

• Tons of possibilities. Downs, Turner,
• Single gene defects causing major malformations are of the Homeobox genes, HOX genes.

Environmental

1. Viral infections during pregnancy: the TORCH complex of viruses. can be passed from infected mother to the fetus.
   
   • ​Toxoplasma
   • Other
   • Rubella
   • Cytomegallovirus
   • Herpes
2. Toxins.
   
   • Thalidomide
   • Smoking, NO
   • Alcohol, fetal alc synd
3. Chronic Maternal diseases.
   
   1. ​Diabetes - organomegaly and increased fat. neural tube defects.

Question 7

A/39. Congenital anomalies

The time windows of fetal development and susceptibility

Answer 7

0-3 weeks: embryogenesis

• insults in the first 3 weeks typically cause abortion

3-9 weeks: Organogenesis

• Major congenital organ malformations

after 9 weeks: Growth and maturation of organs.

• Growth retardation, mental retardation
• Decreased weight
• Organ injury

Question 8

A/39. Congenital anomalies

The TORCH infections and what they cause

Answer 8

1. Toxoplasma
2. Other
3. Rubella
4. Cytomegallovirus
5. Herpes virus

If they infect early in gestation 3-9 weeks: growth and mental retardation, cataracts, cardiac malformations.

Later, infection and inflammation, ecephalitis, myocarditis, pneumonia, hepatosplenomegaly,

Question 9

A/40. Diseases of prematurity

Definition of prematurity

Reasons for prematurity

Answer 9

Prematurity: as in premature babies: less than 37 weeks, or less than 2.5 kg.

2nd highest cause of fetal mortality (after congenital anaomalies)

Reasons for prematurity

1. Fetal problems
   
   • ​​chromose disorders
   • any of the congenital anomalies
   • congenital infections: TORCH
2. Placental causes​
   
   • ​​Placenta Previa: Abnormal localization or attachement of the placenta to the uterus.
   • Placenta Abruption: Early separation of the placenta.
   • Placental Infarction
3. Maternal causes
   
   • ​​pre-eclampsia - high blood pressure caused by the pregnancy, usually developing after 20 weeks. Can be very serious, even fatal to both.
   • chronic hypertension
   • drugs, alcohol, cigarettes

Question 10

A/40. Diseases of prematurity

Clinical consequences of prematurity

Answer 10

IRDS: Infant Resp. Distress Syndrome:

• Insufficient Surfactant production causing lung insufficiency.
  
  • ​hypoxia and CO2 buildup => acidosis -> endothelial damage -> hyaline formation in the lungs, further pulmonary failure.
• 60% of infants born before 28 weeks.
• Cesaerian section increases the risk.
• Maternal Diabetes increases
• Twins increases
• Corticosteroids stimulate surfactant production.

Necrotizing enterocolitis

• Occurs in 1 of 10 children with very low birth weight <1.5kg
• Is more associated with normal, enteral feeding. Suggesting that it invovles an infectious agent, but none have been identified specifically.
• Cytokines, and specifically PAF, platelet activating factor, is part of the pathogenesis, by inducing enterocyte apoptosis and compromising the intetstinal tight junction integrity - GI perforation, sepsis.
• The terminal illeum and right colon are most often affected but can be anywhere.
• intestine becomes distended, congested, thin, and weak. It may be gangrenous and clearly necrotic. Perforation and peritonitis occur after this.
• Bloody stool -> abdominal distention -> hypovolemic collapse.
• High mortality, and surviving infants develop intestinal strictures of fibrotic scars from the lesions.

Question 11

A/41. Sudden infant death syndrome

Definition,

Causes: the main major risk factors

Other risk factors

Clinical morphology (postmortem)

Answer 11

SIDS: The death of infants between 1 month and 1 year old that cannot be explained after a complete autopsy, examination of the death scene, and review of the clinical history.

These typically occur while the infant is asleep, giving the colloquial name, crib death.

Usually 2-4 months old. And it is considered to be of multi-factoral origin.

Triple risk model

1. A vulnerable infant
   
   • ​​Delayed development of the Sympathetic Arousal, Cardiac, and pulmonary reflexes. Arcuate nucleus of the brain stem not yet adequately responding to hypoxia, acidosis, or thermal stresses occuring during sleep.
   • Gene polymorphisms in the serotonergic or autonomic systems pathways that may be pre-disposing.
2. Critical developmental period in homeostatic control
3. One or more exogenous stressors.
   
   • ​​Laying on their belly (prone position) may present greater hypoxia, thermal risk.
   • Soft surfaces may also increase these risks
   • Thermal stress
   • Sleeping in bed with parents (thermal stress)
   • “Back to sleep”

​​Clinical morphology of the post-mortem.

1. Petechia in ~80%
2. Lung congestion, pulmonary vascular swelling, May or may not have pulmonary edema
3. Frequent hypoplasia of brain stem nuclei.

Other risk factors:

• Mother less than 20 years
• Smoking during pregnancy
• Other drug abuse during pregnancy
• Low prenatal care
• Poverty
• Brain stem
• Males are more at risk
• Twins, triplets
• Rapidly following a previous pregnancy.

Question 12

A/42. Fetal hydrops

definition, causes

Answer 12

Fetal Hydrops: Generalized edema of the fetus that occurs in the uterus

Causes: immune or non-immune hydrops

Immune hydrops:

• RH or ABO incompatibility.

Non-immune

1. Cardiovascular malformations causing heart failure, leading to Heart Failure, and the corresponding edema from backward failure.
2. Chromosomal anomalies. - “TED” Turners, Edwards, and Down syndromes
   
   • ​​Trisomy 21 Downs
   • Trisomy 18 Edwards
   • Turner XO
   • All of them cause edema due to various cardiac malformations.
3. Genetic anemias or Viral induced anemias
   
   • Anemia causes hypoxia and excessive work for the heart, causing eventual heart failure in the infants weak heart, the circulatory failure and generalized hypoxia, dilation, causes edema.

Question 13

A/43. Cystic fibrosis

Cause and the major systems affected.

Answer 13

The most common lethal genetic disease of caucasians. Less common in asians and africans. Autosomal recessive with no effect in heterozygote carriers.

Epethilial Chloride channel malfunction of the exocrine glands. A huge number of genetic defects can cause it, and it can range from mildly less active to totally absent or non-functional. Severity correlates to its action.

1. GI tract - intestines, pancreas, liver
2. Respiratory tract
3. Rerproductive tracts
4. Sweat glands - Don’t cause any pathology, but are consitently a good diagnostic, as they produce excessively salty sweat (high Na+ content).

The most important clinical problems are:

1. Recurrent pulmonary infections, and the resulting changes of the bronchii and lung
2. Pancreatic insufficiency
3. Bile canaliculi obstruction and eventual liver cirrhosis

Question 14

A/43. Cystic fibrosis

Pancreas and Liver problems.

Answer 14

Pancreas affected in >85% of patients.

• Viscous secretion plugs ducts, causes chronic pancreatitis and fibrosis
• Pancratic insufficiency and Bile duct insufficiency
• Malabsorption syndrome.
• Especially fat malabsorption.

Liver

• Bile canaliculi obstruction
• Hepatic Steatosis
• progressing to Cirrhosis, and all of the problems going along with that.

Question 15

A/43. Cystic fibrosis

Genital system impairments

Answer 15

95% of males are sterile,

1. Due to the increased viscocity of the seminiferous tubules fluid.
2. And, more importantly, often a congenital bilateral absence of the vas deference.

Question 16

A/43. Cystic fibrosis

Pulmonary dysfunctions

Answer 16

The viscous mucous causes:

1. Chronic persistent lung infections -> pseudomonas aeruginosa, heamophilus influenza, and staph aureus.
2. Chronic bronchitis causing ->
3. Bronchiectasis
4. Fibrosis of the lung, and COPD
5. Generating Cor pulmonale.

Question 17

A/43 Cystic fibrosis

Major morbidities

Major causes of death

Answer 17

Major morbidities: Reulst from the malabsorption syndrome, chronic lung infections, and eventual liver cirrhosis

Malabsorption:

• hypoalbuminemia -> generalized edema
• coagulation problems Vit K
• bone problems Vit D
• recurrent diarrhea and rectal prolapse/damage
• general malnutrition

Most common causes of death:

1. Cardiorespiratory problems from the lung infections and resulting Cor Pulmonale
2. Transplantation related complications
3. Liver cirrhosis and liver failure.

Question 18

A/44. Tumors of infancy and childood

What are the main benign tumors

Answer 18

Accidents are the 1st cause of death in children age 4-14.

Tumors are the 2nd. Any kind of tumor MAY occur, but 3 major ones are common.

Benign tumors:

1. Hemangioma - May be C_avernous hemangiomas_ or Capillary hemangiomas.
   
   1. Cavernous ones are made of very dilated capillaries, while capillary hemangiomas just have normal sized capillaries
   2. _​_These usually form at or shortly after birth.
   3. They often spontaneously regress, but they may actually get larger over the next few years.
   4. They are basically just cosmetic.
2. Lymphangiomas - The lymphatic version of a hemangioma.
   
   1. These can cause clinical problems, not from being malignant, but because..
   2. They can form in deeper structures, in the neck, the mediastinum, and may compress nerves or other vessels.
3. Sacrococcygeal teratomas
   
   1. ​The most common germ cell tumor of children
   2. 10% of them are associated with congenital midline, hindgut, or neural tube defects.
   3. 75% of these are benign, while about 12% are malignant and lethal, and 12% are benign but will become malignant.

Question 19

A/44. Tumors of infancy and childhood

Malignant tumors:

What are the general characteristics of childhood vs adult tumors?

Answer 19

Infant tumors are mainly in the: blood, brain, and soft tissue.

• Infant tumors are often related to abnormal development - teratogenesis produces oncogenesis.
• Are related to genetic defects the predisopse them to early cancer development.
• Have a much higher chance of spontaneous regression or differentiation into mature, benign cells.
• Many of them can be cured, and so the importance of minimizing the effects of the chemo or radiation treatment to produce secondary malignancies.

Question 20

A/44. Tumors of infancy and childhood

Neuroblastoma

Answer 20

Neuroblastoma-

• Tumor arising from Neural Crest Cells within the developing Sympathetic Nervous System ganglia or the Adrenal medulla (most frequently). Can be catecholamine secreting.
• The most frquent infant tumor, about 50% of the total infant malignancies
• The majority of these tumors spontaneously regress and there is also very high rates of spontaneous maturation as well as high therapy induced matruation. Leaving behind only a fibrous scar.
• If it differentiates, Ganglion cells and Schwann cells form, and it progresses from a neuroblastoma, to a ganglioneuroblastoma, and finally to a ganglioneuroma.
• It only metastasizes to the bone, liver, and skin.
• Histology:
  
  • Small cell tumor which secretes a fine neuropil (fibrillar extracellular matrix).
  • Forms characteristic pseudo-Rosettes of cells around a central neuropil core.

Prognosis:

• Stage 1, 2, and 4S have a very favorable prognosis of spontaneous regression.
• Particularly if the child is younger than 18 months.
• Schwann or ganglion cell differentiation is also very favorable.
• Increasing amplification and high copy number of the NMYC (MYC oncogene) has a very negative prognosis, regardless of any other factors.

Staging of neuroblastoma:

• Stage 1: a localized tumor, which has been completely excised by surgery, and with its sentinal lymph nodes negative for the tumor
• Stage 2A: localized tumor which can’t be totally resected. local sentinel tumors are positive for tumor cells.
• Stage 2B: Localized tumor with ispilateral sentinel lymph nodes positive, and enlarged contralateral lymph nodes that are negative for tumor histologically.
• Stage 3: Unilateral tumor that can’t be resected at all, infiltrating across the midline. With or without regional lymph nodes positive. OR. unilateral tumor with positive contralateral lymph nodes
• Stage 4: Any primary tumor with disseminated tumor cells in distant lymph nodes, bone, bone marrow, skin, or liver.
• Stage 4S: localized tumor with metastasis to the bone, marrow, skin, or liver, which has specific cellular characteristics, and is in infants younger than 1 year.

Question 21

A/44. Tumors of infancy and childhood

Retinoblastoma

Answer 21

Retinoblastoma: The most common intraocular malignancy of all children.

• 40% have a heritable germ line mutation of RB1. - often produces multiple, bilateral tumors
• 60% have a spontaneous somatic RB1 mutation. - unilateral tumors.
• Present usually around 2 years, but may occur at birth.
• They are highly treatable, almost total survival, with excision and chemo/radiotherapy.
• Untreated they are fatal.
• Patients with familial retinoblastoma are at higher risk of Osteosarcoma and other soft tissue tumors.

Histology

• Small round cell tumor with large nuclei and very little cytoplasm. Look like undifferentiated retinoblasts.
• Differentiated cells also exist within the tumor mass, some of them form Flexner-Wintersteiner Rosettes. These are true rosettes, because they are short columnar cells around a central lumen, and not a central ECM deposit, like the pseudorosettes seen in Neuroblastoma.

Question 22

A/44. Tumors of infancy and childhood

Wilms tumor, causes and clinical course

Answer 22

Aka Nephroblastoma.

Most common kidney tumor of children.

Occurs between 2-5 years.

• It commonly occurs in children with 3 main genetic disorders
• WAGR syndrome, Denys-Drash syndrome,
  
  • I_nactivation or deletion mutations of the WT1 gene_. Which is a critical gene in normal gonadal and renal development.
  • Abnormal imprinting at a locus near the WT1 gene, involving the IGF-2 gene. Predisposes the whole body segments to grow abnormally large, as well as general enlargement of the organs.

Clinical course

• Usually presents because the tumor is huge and palpable on the abdomen.
• Sometimes it presents because of a fever and abdominal pain, or GI obstruction.
• It is also highly treatable, with resection and chemotherapy, except in diffuse anaplasia of the cells.

Question 23

A/44. Tumors of infancy and childhood

Wilms tumor, histology

Answer 23

A large tumor with well defined border, with a Triphasic combination of cells plus one more kind, which are recapitulating the different stages of kidney development.

1. Tightly packed cells with large nuclei and small cytoplasm - the blast cells
2. Tubular epethilial cells, organized into primitive tubules or glomeruli.
3. Fibrocyte-like or myocyte-like stromal cells.

About 5% of the tumors contain Anaplastic cells undifferentiated cells with large, pleomorphic nucle and abnormal mitotic figures. This is a negative prognostic feature.

Nephrogenic rests: are often found near the tumors, and are masses of undifferentiated embryonic tissue within the kidney.

By the time it is diagnosed, it is very frequently bilateral or multicentric.