A/39-44 PEDIATRIC DISEASES (Leiel)

Question 1

congenital anomalies is meaning….

Answer 1

Structural defects that are present at birth (does not imply or exclude a genetic basis for the defect).

In 3% of newborns, it is defined as a major anomaly (cosmetic or a functional significance).

Question 2

Define the following:

• malformation:
• disruption:
• deformation:
• sequation:
• agenesis:
• aplasia/hypoplasia:
• atresia:

Answer 2

• malformation: intrinsically abnormal developmental process. Usually it is multifactorial
• disruption: results from secondary destruction of an organ or body region that was previously normal in development. An extrinsic disturbance in morphogenesis.
• deformation: an exogeneous influence which alters the growing of the fetus.
• sequation: one alteration which is followed by another
• agenesis: complete absence of an organ or its anlage
• aplasia/hypoplasia: incomplete development or underdevelopment of an organ.
• atresia: the absence of an opening (usually of a hollow visceral organ or duct)

Question 3

What are the categories of causes of human malformations?

Answer 3

• Genetic
• Environmental influences:
• Multifactorial inheritance

Question 4

Give an example of a genetic cause of human malformations.

Answer 4

all chromosomal syndromes are associated with congenital malformations (e.g. Down Syndrome, Turner syndrome etc)

Single gene mutations:

• e.g. HOX (homeobox) genes. These genes are responsible for the regulation of other genes and the development of organs. They are switched on at the beginning of organogenesis and switched off when it is terminated. Agents that alter HOX gene expression are known to produce malformations.

Question 5

What are the environmental influences that cause malformations?

Answer 5

1. viral infections

• transplacentally: TORCH complex (Toxoplasma; Other (zika); Rubella; Cytomegallovirus; Herpes)
• transcervically: inhaling infected amniotic fluid / passing through the infected birth canal.

2.drugs: thalidomide, warfarin, anticonvulsants, 13-cis-retinoic-acid

3. alcohol: leads to “fetal alcohol syndrome” –> pre and postnatal retardation, facial abnormalities, pshycomotor disturbances.

4. cigarrete smoking: low birth weight, spontaneous abortions, placental abnormalities

5. maternal conditions: such as diabetes mellitus, which can lead to organomegaly and increased body fat and muscle mass, cardiac anomalies and neural tube defects.

Question 6

Multifactorial inheritance What means that?

Answer 6

the interaction of environmental influences with two or more genes of small effect.

Question 7

Please describe the 3 phases of intrauterine development and how insult at each phase affects the type of malformation produced.

Answer 7

The intrauterine development of humans can be divided into 3 phases:

• 0-3: embryogenesis
• 3-9: organogenesis. At the end of this period (9th week) the baby is “ready”.
• 9-42: fetal period. Growth and maturation of the organs.
• Noxa between 0-3 weeks: causes death or abortion in case many cells are involved but if only few cells are involved the embryo has the chance to recover.
• Noxa between 3-9 weeks: congenital malformation
• Noxa between 9-42 weeks: reduced susceptibility for teratogenic agents –> growth retardation, injury to organs, decreased size and weight.

The same agent can lead to different affects if occurs at different timing.

Question 8

Pathogenesis??

Question 9

Define prematurity

Answer 9

Prematurity is defined as:

• gestational age of less than 37 weeks

​​​or

• weight < 2500 gm

Prematurity is the 2^nd most common cause of neonatal mortality.

Question 10

What are the reasons for prematurity?

Answer 10

Fetal factors

• Chromosomal disorders
• Congenital anomalies
• Congenital infections: the TORCH group of infections being a common cause.

The growth retardation is symmetric

Placental causes

• Placenta previa: abnormal localization of the placenta. No proper attachment.
• Placenta abruption: early separation of the placenta from the decidua
• Placental infarction

The growth retardation is asymmetric

Maternal factors -

• Preeclampsia: toxemia of the pregnancy
• Chronic hypertension
• Drug, alcohol consumption, cigarette smoking

Question 11

Give 2 examples of diseases of prematurity

Answer 11

• IRDS (infant respiratory distress syndrome)
• Necrotizing enterocolitis

Question 12

IRDS

• In one scentance, what is IRDS
• What are the contributing factors for developing it?

Answer 12

Inability of the immature lung to synthesize sufficient surfactant.

• Occurs in 60% of the infants born before 28 weeks of gestation (the percentage decreases with increasing gestational age)
• Other contributing factors are cesarean section, maternal diabetes and twin gestation.
  
  • labor increases surfactant synthesis; if cesarian section is done prior to labor it might increase the risk for RDS
  • Infants of diabetic mother have a higher risk for developing RDS, since insulin suppresses corticosteroids effect (corticosteroids stimulate surfactant formation.)

Question 13

What is Surfactant?

• Which cell produces it?
• What is it composed of?
• What is it’s function?

Answer 13

Produced by type 2 pneumocytes

composed of a phospholipid called lecithin and at least 2 groups of SAP (surfactant associated proteins).

When the baby breath for the 1st time, the surfactant coats the alveoli. Surfactant is responsible for reducing surface tension and decreasing the pressure required for keeping the alveoli open (reducing the effort required for inflating the alveoli).

Question 14

Describe the pathogenesis of IRDS

Answer 14

No surfactant → surface tension increases → higher effort is required to keep the alveoli open → infant gets tired → atelectasis (Partial or complete collapse of the lung) → hypoventilation, uneven perfusion → hypoxia + CO2 retension → acidosis → pulmonary vasoconstriction → pulmonary hypoperfusion → endothelial and epithelial damage → plasma leakage into the alveoli → formation of hyaline membrane (fibrin and necrotic cells).

The hyaline membrane further decreases the oxygenation → acidosis further increases and the situation becomes more and more severe.

Question 15

Morphology

Answer 15

Macroscopic:

• Lung of normal size, heavy, mottled purple color with poorly developed or collapsed alveoli.

Microscopic:

• If the baby dies within the several hours, only necrotic cellular debris are present in the terminal bronchioles and alveolar ducts.
• If it persists more than this, the eosinophilic hyaline membrane appears, and it lines the respiratory bronchioles, alveolar ducts and the alveoli.

Question 16

Clinical features

Answer 16

• oxygen is required
• high concentration of ventilator-administered oxygen for prolonged periods is associated with 2 complications:
  
  1. Retinopathy of prematurity (e.g. retrolental fibroplasia)
     
     • Has 2 phases:
       
       • Hyperoxic phase: the expression of VEGF is decreased, leading to endothelial cell apoptosis.
       • VEGF increases in relatively hypoxic conditions, inducing retinal vessel proliferation characteristic for lesions of the retina.
  2. bronchopulmonary dysplasia: characterized by alveolar hypoplasia

Question 17

What are 3 other conditions that IRDS patients are predisposed to?

Answer 17

Other problems:

1. Lung resistance increases, and this restricts the inflow from the superior vena cava → stasis → increased pressure, hypoxia → subependymal bleeding (the glial cells are underdeveloped, and together with the hypoxic condition and the increased resistance, bleeding is favored).
2. The inflow from the inferior vena cava Is also restricted → bacteria colonizes in the intestine → necrotizing enterocolitis. In NEC, the involved segment is distended, friable and congested. Intestinal perforations with peritonitis may be seen macroscopically.
3. The increased resistance results in a patent ductus arteriosus

Question 18

How can lung maturation be assessed?

AND

What is th therapy for IRDS?

Answer 18

• Lung maturation can be assessed by analysis of amniotic fluid phospholipid level.
• Prevention by delaying labor (inducing lung maturation).
• There is a possibility for administration of an exogeneous surfactant.
• giving steroid treatment

Question 19

What are the causes of Necrotizing enterocolitis?

Answer 19

• incidence of the disease is inversely proportional with the gestational age
• causes:
  
  1. Intestinal ischemia is a prerequisite
  2. Agents which aggravate mucosal injury: bacterial colonization and administration of formula feeds.

Question 20

What is the morphology of necrotizing enterocolitis?

Answer 20

• any part of the intestine might be involved, but typically it is the terminal ileum, cecum and right colon
• macroscopically: the involved segment is distended, friable and congested or it can be frankly gangrenous
• microscopically: coagulative necrosis, ulceration, bacterial colonization and submucosal bubbles.
• appearance of reparative changes as granulation tissue and fibrosis.

Question 21

What is the clinical course of necrotizing enterocolitis?

Answer 21

• Onset of bloody stool, abdominal distension and development of circulatory collapse.
• Gas can be demonstrated within the intestinal wall.
• NEC can lead to resection of the necrotic segment, death or in those who survive → development of post-NEC strictures from fibrosis of the healing process.

Question 22

What is SIDS?

Answer 22

sudden infant death syndrome

Refers to a death of an infant under 1 year age which remains unexplained after thorough investigation, including a complete autopsy, death scene and review of the clinical history. The death usually occurs during sleep

Question 23

What is the pathogenesis of SIDS?

Answer 23

It is suspected that a maldevelopment of the arcuate nucleus is involved in SIDS syndrome. This nucleus plays a role in the arousal response to noxious stimuli such as hypoxia, thermal stress etc. it also contains regions that regulate breathing, HR and body temperature. The maldevelopment impairs the function of those regions

Question 24

What are the risk factors for SIDS?

Answer 24

When certain environmental factors exist, such as prone sleeping position, sleeping on soft bed and over-dressing (hyperthermia) the baby is exposed to the noxious stimuli without an ability to react properly.

Triple risk model for the SIDS: the intersection of three risks:

1. a vulnerable infant
2. a critical developmental period in homeostatic control
3. an exogenous stressor(s).

Question 25

What is the morphology of SIDS?

Answer 25

1. Hypoplasia of the arcuate nucleus 2. Multiple petechiae 3. Congested lungs 4. _Microscopically_: vascular engorgement, with or without pulmonary edema

Question 26

What are some cases which can result in sudden death?

Answer 26

Sudden death can be the result of other causes, such as: * **infections**: viral myocarditis * **fatty acid oxidation** disorders * **mutations** in cardia **Na/K channels**

Question 27

What is fetal hydrops? * Waht are the 2 types of hydrops

Answer 27

**Accumulation of edema fluid during intrauterine growth.** The fluid accumulation can be **localized**, a condition which is usually **compatible with life**, or it can be a **generalized** **edema** of the fetus (hyrops fetalis), which is usually a **lethal** condition. Can be devided to: * **Immune** and **nonimmune** hydrops.

Question 28

Immune hydrops pathogenesis:

Answer 28

**Rh incompatibility** (fetal is +, mother is -) → antibody-induced hemolytic disease in the newborn → anemia of the fetus → ischemia → * Pumping function decreases → edema * Liver → hypo-proteinemia → * → Jaundice * → pumping function decreases → edema Due to the success in preventing Rh hemolysis, ABO incompatibility is now the most common cause of immune hemolytic disease in the newborns. It is a much milder disease which develops in infants of group A or B who are born to group O mothers. The anti-A and anti-B haemagglutinins of the mother are of IgM type so they cant cross the placenta,

Question 29

What are the 3 major causes of nonimmune hydrops?

Answer 29

Major causes: 1. **cardiovascular defects**: lead to cardiac failure and hydrops 2. **chromosomal abnormalities**: most common is Turner syndrome and trisomies 3. **fetal anemia** (other than Rh and ABO incompatibility) due to parvovirus B19, which replicated inside normoblasts and leads to erythrocytes maturation arrest. Other reason is homozygous alpha-thalassemia.

Question 30

What is the morphology of fetal hydrops?

Answer 30

* Anatomic findings are **variable**. Most severe is hydrops fetalis. * The presence of **dysmorphic features** suggest underlying constitutional **chromosomal abnormalities**. * In hydrops associated with **fetal anemia**, the **placenta and the fetus appear pale**. * **Cardiac** failure and congestion lead to **hepato and splenomegaly**. * The **bone marrow** shows compensatory **hyperplasia of erythroid precursors**. * Extramedullary hematopoiesis in the spleen, liver and other tissues, which leads to the **presence of immature cells in the circulation** * Hemolysis due to Rh or ABO incompatibility leads to increased **circulating bilirubin**, which might exert a **toxic effect on the brain**. When the bilirubin Is deposited in areas of the brain it imparts a characteristic yellow hue to the parenchyma called **kernicterus**.

Question 31

Describe the clinical course of fetal hydrops * Tests, Therapy, Prevention

Answer 31

Early recognition is imperative. * **amniotic fluid** obtained by amniocentesis can show high **levels of bilirubin** * **positive antiglobulin test** in case fetal red cells are coated by maternal antibody. * _therapy_ * by **antenatal exchange transfusion** * postnatally: **phototherapy** * administration of anti-D globulins to the mother can prevent the occurrence of immune hydrops in subsequent pregnancies.

Question 32

Describe CYSTIC FIBROSIS * How is it acquired? * What does it affect?

Answer 32

* It is the most common lethal genetic disease that affects Caucasian population * **autosomal recessive** (affects only homozygotes) * a disorder of epithelial transport affecting fluid secretion in **exocrine** **glands** and the **epithelial lining** (**GI**, **respiratory** and **reproductive** tracts). * a **more viscous mucus** is produced which blocks the airways and pancreatic ducts and is responsible for recurrent and **chronic pulmonary infections** and **pancreatic insufficiency** * **High NaCl in the sweat**

Question 33

Describe the Gene defect that results in cystic fibrosis

Answer 33

* the primary defect is of **epithelial Cl^- channels** encoded by **CFTR** gene on chromosome **7q31.2**. * The most common CFTR gene mutations lead to a **deletion** of the **codon** coding for **phenylalanine** at amino acid in position **508**. * Depending on the location of the mutation in the gene sequence, the mutations are either **severe**, in which there is a **complete loss** of the protein function (as the 508 case) or they are **mild** in which there is **only a partial loss**. * the consequence of the defect in the CFTR gene product is different between the tissue

Question 34

Describe the role of CFTR in the sweat glands and Respiratory+GI and what will happen in case that there is a mutation in the gene coding for CFTR.

Answer 34

1. _sweat glands_: * Normally: CFTR protein is responsible for reabsorption of Cl from the GI lumen, followed by Na. * defect in CFTR **decreases the reabsorption of NaCl** → hypertonic sweat 2. _respiratory and GI_: * Normally: CFTR has an opposite function: it is responsible for Cl excretion into the lumen. * a mutation in the CFTR decreases the Cl excretion, and this is followed by an increased Na and H₂0 reabsorption. The net result is that the fluid inside the lumen remains isotonic, but the volume of it is reduced. Dehydrated mucus → defective mucociliary action → accumulation of viscous secretion → obstruction of the lumen → recurrent infections. -the presence of other genetic defects can modulate the frequency and severity of the organ-specific manifestation. An example to this is a defect in mannose-binding lectin which reduces survival chance if a CF patient is gets a bacterial infection.

Question 35

Describe the morpholgy of the different organs affected by CF

Answer 35

_Pulmonary changed_ * There is a viscous mucus secretion by cells in which **hyperplasia** and **hypertrophy** is seen. This mucus **obstruct** the **air passages**, which become distended and infected (severe bronchitis and bronchiectasis). Most common bacteria are *_pseudomonas aeruginosa, haemophilus influenza and staphylococcus aureus_*. _Pancreatic changes_ * are present in 85-90% of the patients with CF * *_mild cases_*: **accumulation of mucus in the ducts** and **dilation of exocrine glands** * more *_severe cases_*: **ducts are plugged** → gland becomes **atrophied** → **fibrosis**. * Due to the loss of pancreatic exocrine secretion, the **fat absorption is impaired** → squamous metaplasia of the lining epithelium of the pancreatic ducts. * Plugs are also found in the small intestine of infants, causing an obstruction called meconium ileus. _Liver changes_ * bile canaliculi are plugged with mucinous material * ductular proliferation * portal inflammation * steatosis, cirrhosis _Genital system_ * In 95% of the adult males: azoospermia and infertility * bilateral absence of the vas deference

Question 36

Clinical course of CF * What is the diagnosis based on? *

Answer 36

_The diagnosis is based on:_ 1. salty sweat of the infant 2. characteristic clinical findings 3. family history 4. CFTR gene mutation The symptoms are extremely variable with respect to severity, onset and and organ involvement. * In 5-10%, meconium ileus appears in approximation to birth, which actually leads to the diagnosis of the disease * In 85-90% of patients with severe mutations on both alleles, an **exocrine pancreatic insufficiency develops**. This has several complications: 1. **malabsorption** of **proteins** → can cause **generalized** **edema** 2. **malabsorption** of **fat** → deficiency of fat soluble **vitamins** (A,K,D,E) + **diarrhea** * The rest 10-15% are classified as pancreatic sufficient phenotypes, which have an excellent growth and development. Idiopathic chronic pancreatitis occurs in some of those patients and is associated with recurrent abdominal pain and life threatening complications. * The most common cause of death are:

Question 37

What are 3 the most common causes of death in CF patients?

Answer 37

The most common causes of death are: 1. **cardiorespiratory complications**, such as persistent lung infections, obstructive pulmonary disease and **cor pulmonale** 2. **transplantation related** complications 3. **liver** **disease**: recurrent sinonasal polyps in 10-25% of the patients

Question 38

What are the 2 types of tumor like lesions?

Answer 38

have to be distinguished from tumor-like lesions of 2 types: 1. **heterotopia** or choristoma: normal tissue In an abnormal location. For example: adrenal cells in the kidney 2. **hamartoma**: excessive focal overgrowth of cells and tissues in an organ

Question 39

Benign tumors of infancy and childhood?

Answer 39

1. **hemangioma** * Cavernous and capillary hemangioma, usually located in the skin of the face and scalp. * Morphology: flat/elevated, irregular shape, red-blue colour. The larger flat ones are called port wine stains. * The superficial are usually of cosmetic significance. 2. **lymphangiomas** * The lymphatic counterpart of hemangiomas. Fluid filled spaces lined by endothelial cells and surrounded by lymphoid aggregates which occur in the skin or the deep regions of the neck, axilla, mediastinum and retroperitoneum 3. **sarcococcygeal teratomas:** in 10% of the cases it is associated with congenital anomalies, primary defects of the hindgut and cloacal regions and other midline defects. 75% are mature and benign tumors.

Question 40

What are the differences between adult malignant tumor and infancy and childhood malignant tumors?

Answer 40

There are several differences between an adult and infancy/childhood malignant tumors: 1. **location**: in infancy it occurs in the **hematopoietic** system, **neural** tissue and **soft** tissue (in contrast to lung, heart, prostate and colon) 2. **biologic and histologic** defferences. In infancy: 1. are related to an **abnormal development** 2. related to **constitutional genetic abnormalities** 3. tendancy for **spontaneous regression** 4. **block of maturation** 5. small abnormal cells → **blastema** (un-differentiated cells) 6. **secondary** chance for **malignancy**

Question 41

Give 3 examples of malignant tumord of infancy and childhood. (names only)

Answer 41

* Neruoblastoma * Retinoblastoma * Nephroblastoma (Wilms' tumor)

Question 42

Describe neruoblastoma * Localization, source.

Answer 42

* tumor of the sympathetic ganglia (60% paravertebral region and posterior mediastinum and 40% adrenal medulla ) * 50% of malignancies diagnosed in infancy * _features_: **spontaneous regression** and **spontaneous or therapy induced maturation**. * sporadic or genetic background (autosomal dominance)

Question 43

Describe the morphology of neruoblastoma

Answer 43

_macroscopic featurs:_ * Small (more common, usually regress) or large (\<1kg) * Encapsulated or infiltrative * On transection: **graish**, **brain-like tissue**. The larger can have necrotic zones, cystic softening and hemorrhage. _microscopic features:_ * **Small dark nuclei, scant cytoplasm, poorly defined borders** * **Mitotic** activity, **neuclear breakdown**, pleomorphism * **Eosinophilic** fibrillary background called neuropil * Rosette formation: neuropil surrounded by tumor cells * It is called **ganglioneuroblastoma** when ganglion cells, in addition to primitive neurblasts are present. The maturation of neuroblasts to ganglion cells is accompanied by the appearance of Schwann cells * If no neuroblasts are found but only mature ganglion cells → **ganglioneuroma**

Question 44

What does the prognosis of neuroblastoma depends on?

Answer 44

Depends on the **stage of the tumor** (classified from 1 to 4, better prognosis in low stage tumor) and **the age of the patient**. * Stage 4S (special): primary tumor at stage 1 or 2 + metastasis to the liver, skin and/or bone marrow. excellent prognosis, minimal therapy, spontaneous regression. * Age: the prognosis is better under 1 year.

Question 45

What is the clinical course of neuroblastoma patients?

Answer 45

* *_neonates_*: metastasis to the skin with blue discoloration * *_below 2 years_*: protruberant belli, fever, weight loss * *_above 2 years_*: metastasis with resultant hepatomegaly, ascites, bone pain. Diagnostic feature: the tumor produces catecholamines, thus, **VMA and HVA can be detected in the urine**. Although cateholamines are elaborated, **hypertension is not frequent** is those patients

Question 46

What differs retinoblastoma from other tumors?

Answer 46

has several characteristics that differ it from other tumors: 1. it is frequently a **congenital** tumor 2. **multifocal and bilateral** 3. undergoes **spontaneous** **regression** 4. high incidence for a **second primary tumors** 5. the **incidence decreases with age** * **familial cases:** multifocal + bilateral * **sporadic cases:** unifocal + unilateral * germline or somatic mutation in **RB1 gene**

Question 47

What is the morphology retinoblastoma

Answer 47

* probably arise from cells of **neuroepithelial origin**, **usually** in the **posterior retina** * **nodular masses** * undifferentiated areas of the tumor are composed of **small round cells** with **hyperchromatic nucleus** and **few cytoplasm** * Differentiated structures are also found, one of them is called **Flexner-Wintersteiner rosette**, which consist of **cuboidal or columnar cells** arranged around a **central lumen** _{(this is in contrast to the pseudo-rosette seen in neuroblastoma, which consist of cells arranged around space filled with neuropil (=neuritic processes of the primitive neuroblasts)}. * **dissemination** **of the tumor cells from the eye** through the optic nerve or subarachnoid space **to** the **CNS**, **skull**, **bones** and **lymph nodes**

Question 48

What are the clinical features of retinoblastoma?

Answer 48

Usually presented at 2 years of age, may appear at birth. **Poor vision**, **strabismus**, pain and tenderness of the eye, whitish hue to the pupil. Survival of the patient if treated.

Question 49

Nephroblastoma=Wilms' tumor * Age * Which congenital malformation groups increase the risk for developing Wilms' tumor?

Answer 49

* most common primary tumor of the kidney, usually during 2-5 years of age * the presence of congenital malformations of 3 groups increase the risk for developing Wilms' tumor: 1. **WAGR syndrome** 2. **Denys-Drash syndrome** * Both 1+2 are associated with abnormality of Wilms' tumor 1 (WT1), which is critical to normal renal and gonadal development 3. **Backwith-Wiedemann syndrome**, which is an example of genomic imprinting. In some wilms tumors there is a loss of maternal imprinting of IGF-2, leading to overexpression of IGF2 protein → organ enlargement, tumorigenesis

Question 50

What is the morphology of nephroblastoma? What are the Nephrogenic rests?

Answer 50

* **large, solitary, well-circumscribed mass** * **soft**, **homogeneous**, tan to **gray** color * foci of hemorrhage, **cystic degeneration** and **necrosis** can be seen * _histologically_: we can observe the triphasic combination: blastemal + stromal + epithelial cell types. 5% of the tumors contain foci of anaplasia (cells with large hyperchromatic pleomorphic nucleus and abnormal mitosis) which is related to p53 mutations and resistance to chemotherapy. ***_Nephrogenic rests_*** are **putative precursors of Wilms' tumors** which might be present in the kidney, next to the tumor. * Its appearance is versatile: * it might resemble the tumor or can consist of fibrous tissue with immature kidney structures. * The presence of the nephrogenic rest means **high risk for developing wilms tumor** at the contralateral kidney.

Question 51

Clinical course of nephroblastoma * Findings in the physical examination * Symptoms * What improves the prognosis?

Answer 51

* **Palpable abdominal mass** which might extend to the pelvis. * *_Not often_* we see **fever**, **abdominal pain,** **hematuria**, **intestinal obstruction**. * **Nephrectomy** **and** **chemotherapy** makes the prognosis very good for wilms tumor patients, except in the case of the presence of diffuse anaplasia (rather than focal).