Pediatric Disorders

What is a Sequence?

A sequence refers to multiple-congenital anomalies that result from secondary effects of a single localized aberration in organogenesis. The initiating event may be a malformation, deformation or disruption. One of the best examples being oligohydramnios, or Potter sequence

What chemicals leads to teratogenic effects?

A variety of drugs and chemicals have been suspected to be teratogenic (<1% of congenital malformations are caused by these agents). These include thalidomide (limb abnormalities), alcohol (fetal alcohol syndrome), anticonvulsants, warfarin (oral anticoagulant), and 13-cis-retinoic acid (used in the treatment of severe acne).

What is the pathology and histopathology of Necrotizing Enterocolitis (NEC)?

Abdominal radiographs show gas within intestinal wall (pneumatosis intestinalis). Involved segment (typically involves ileum, cecum, and right colon but other parts of the small and large bowel may be affected) is distended, friable, congested, gangrenous, or may have intestinal perforation (free air) with peritonitis. Microscopically, shows (mucosal or transmural) coagulative necrosis, ulceration, bacterial colonization, and submucosal gas bubbles.

What is the Classification by Histology of Neuroblastic Tumors?

According to neural differentiation, classified as: • Neuroblastoma, or primitive stroma, • Ganglioneuroblastoma, or primitive stroma and ganglion cells, and • Ganglioneuroma, or schwannian stroma and ganglion cells

Detail Anaplasia in Wilms tumor.

Anaplasia is in 5% of Wilms tumors. • Characterized by cells with large, hyperchromatic, pleomorphic nuclei and abnormal mitoses (underlying p53 mutations). • Harbringer of poor prognosis, but if anaplasia is focal/confined, same as non-anaplasia tumors • Tumors with diffuse anaplasia (especially with extrarenal spread) have the least favorable outcome.

Why is Wilms Tumor also known as a triphasic tumor?

Because Wilms Tumor has three aspects: 1. Stromal (mesenchyme) 2. Epithelial/glandular 3. Blastemal

At what point is the fetus most susceptible to teratogenesis?

Between the third and the ninth weeks, when organs formed from germ cell layers, the embryo is extremely susceptible to teratogenesis (peak between the fourth and fifth weeks). During the fetal period there is reduced susceptibility to teratogenic agents.

What cardiovascular and chromosomal abnormalities are associated with Fetal Hydrops?

Cardiovascular Associations are: -Malformations -Tachyarrhythmia -High-output failure Chromosomal Associations are: -Turner syndrome -Trisomy 21 (Down syndrome) -Trisomy 18 (Edward syndrome)

What are some causes for Fetal Hydrops?

Causes for Fetal Hydrops are: Twin Gestation -Twin-twin transfusion Infection of erythroblasts -Cytomegalovirus -Syphilis -Toxoplasmosis Fetal Anemia -Homozygous alpha-thalassemia -Parvovirus B19 (invades the nucleus of normoblasts (erythroid precursors) where it replicates) causes aplastic anemia -Immune hydrops (Rh and ABO)

What are the clinical presentations of Cytomegalovirus?

Clinical presentations of Cytomegalovirus: • Mental retardation • Microcephaly • Deafness • Hepatosplenomegaly

What are common Metastatic Sites for Neuroblastoma?

Common sites are: • Lymph nodes • Liver • Lungs • Bone marrow • Bones • Skin

What are Congenital Anomalies?

Congenital Anomalies are: • Structural defects present at birth • Most common cause of mortality in the first year of life. • Include: malformations, disruptions, deformations, sequence and syndromes.

What are Deformations?

Deformations are changes from the normal size or shape of an anatomic structure due to mechanical forces that distort an otherwise normal structure. • Represent an extrinsic disturbance of development. • They affect approximately 2% of newborn infants to varying degrees.

What is are Disruptions?

Disruptions result from secondary destruction of an organ or body region that was previously normal in development. They represent an extrinsic disturbance in morphogenesis (i.e, amniotic bands). They are not heritable, so there is no risk of recurrence in a subsequent pregnancy.

What are the pathological effects of fetal hydrops?

Effects of hydrops in fetal anemia (of both immune and nonimmune etiology) is tissue ischemia with secondary myocardial dysfunction and circulatory failure. Liver failure occurs (with loss of synthetic function) contributing to hypoalbuminemia, reduced oncotic pressure, and edema. Increased immature red cells (reticulocytes, normoblasts, and erythroblasts) is known as erythroblastosis fetalis.

What Entities are Associated with Prematurity?

Entities Associated to Prematurity are: • Respiratory distress syndrome of the Newborn (RDS) (Hyaline membrane disease) • Necrotizing enterocolitis (NEC) • Sepsis • Intraventricular and germinal matrix hemorrhage • Long-term complications, including developmental delay.

What are some examples of Malformations?

Examples of Malformations are: • Cleft lip and cleft palate • Polydactyly, or extra digits, and • Syndactyly, or fusion of digits

What is the pathogenesis of excessive all-trans-retinoic acid?

Excessive exposure to retinoic acid (vitamin A) is also teratogenic. Infants born to mothers treated with retinoic acid for severe acne present a recognized phenotype known as retinoic acid embryopathy that includes central nervous system, cardiac, and craniofacial defects, such as cleft lip and cleft palate.

What are the teratogenic effects of Radiation?

Exposure to heavy doses of radiation during the period of organogenesis leads to malformations, such as microcephaly, blindness, skull defects, and spina bifida.

What is Fetal Hydrops?

Fetal hydrops refers to accumulation of edema fluid in fetus during intrauterine growth. Causes of fetal hydrops include hemolytic anemia due to Rh blood group incompatibility between the mother and fetus (immune hydrops) and nonimmune hydrops. Both lead to generalized edema of fetus (hydrops fetalis), usually lethal condition, (or to isolated pleural and peritoneal effusions, postnuchal fluid accumulation cystic hygroma which are compatible with life).

Describe Germinal Matrix/Intraventricular Hemorrhage.

Germinal Matrix-Intraventricular Hemorrhage: • In the beginning, brain is underdeveloped (called germinal matrix) • With less O2, vessels break off easily, leads to hemorrhage • Subependymal (germinal matrix) hemorrhage, with secondary bleeding into the ventricles, is particularly prone to occur in preterm infants.

What are Hemangiomas?

Hemangiomas are the most common tumors of infancy • Two types Exist : capillary and cavernous. • In children most hemangiomas are located in the skin, particularly on the face and scalp. • Many instances they spontaneously regress. • Associated to von Hippel-Lindau and Sturge Weber syndromes

What are multifactorial causes of congenital defects?

Implies the interaction of environmental influences with two or more genes of small effect. E.g. cleft lip and palate, and neural tube defects. Folic acid reduces neural tube defects

What is Blueberry Muffin Baby?

In neonates, disseminated neuroblastomas may present with multiple cutaneous metastases with deep blue discoloration to the skin, often referred to as blueberry muffin baby.

What can be done for the premature infants with RDS?

In uncomplicated cases, recovery occurs within 3 or 4 days. High concentrations of oxygen (positive pressure ventilation) administered for prolonged periods of time create oxygen-derived free radicals, causing retrolental fibroplasia (retinopathy of prematurity) and bronchopulmonary dysplasia (BPD).

What are genetic causes of congenital abnormalities?

Karyotypic abnormalities are present in approximately 10% to 15% of live-born infants with congenital anomalies. Examples include trisomy 21 (Down syndrome), Klinefelter syndrome, Turner syndrome, and trisomy 13 (Patau syndrome). Single gene mutations may underlie major congenital anomalies, (which follow mendelian patterns of inheritance).

What are Lymphangiomas?

Lymphangiomas represent lymphatic counterpart of hemangiomas. Microscopically consist of cystic and cavernous spaces with pale fluid content lined by endothelial cells surrounded by lymphoid aggregates. Predominantly occur in deeper regions of the neck, axilla, mediastinum and retroperitoneum.

What are the major causes of Non-Immune Hydrops?

Major causes of Non-Immune Hydrops are: - Cardiovascular defects - Chromosomal anomalies - Fetal anemia

What are the major risk factors of Prematurity?

Major risk factors of Prematurity include: - Premature rupture of placental membranes. - Intrauterine infection (such as be streptococcus). - Uterine, cervical, and placental structural abnormalities (E.g. Uterine fibroids or leiomyoma, a smooth muscle benign tumor). - Multiple gestation (twin pregnancy)

What are Malformations?

Malformations are primary errors of morphogenesis, or structural defects, with intrinsically abnormal embryonic or fetal development. • Associated with multiple genetic loci, i.e. multifactorial • Not the result of a single-gene or chromosomal defect.

How are Malformations usually presented?

Malformations may present in several patterns: • Single body systems: congenital heart defects and anencephaly, or absence of brain, and • Multiple malformations: involving many organs

What is N-myc amplification?

N-myc amplification has profound impact on prognosis. Greater the number of copies, worse prognosis. N-myc amplification is most important genetic abnormality used in risk stratifications of neuroblastomas and automatically renders a tumor as high risk irrespective of stage or age.

Describe Necrotizing Enterocolitis (NEC).

Necrotizing Enterocolitis (NEC) • Incidence of disease inversely proportional to gestational age. • Clinical presentation: • Abdominal distention • Absent bowel sounds • Bloody stools

What are Nephrogenic Rests?

Nephrogenic rests are precursor lesions of Wilms tumors (A fragment of embryonic tissue in the kidney retained after the period of embryonic development; Remnants of early glomeruli is a risk factor for Wilms tumor) • Sometimes seen in the renal parenchyma adjacent to the tumor. • Important to document the presence of nephrogenic rests in resected specimen, since these patients are at increased risk of developing Wilms tumors in contralateral kidney.

What are the teratogenic effects of Nicotine?

Nicotine (? teratogen) is associated to spontaneous abortions, premature labor, and placental abnormalities; babies often have a low birth weight and may be prone to sudden infant death syndrome.

What is oligohydramnios, or Potter sequence?

Oligo means little of it, and Hydramnios means amniotic fluid. Caused by: • Chronic leakage of amniotic fluid • Amniotic fluid helps development of lungs (leads to pulmonary hypoplasia) • Uteroplacental insufficiency (maternal hypertension, severe toxemia) • Absence of kidney in child, will not be producing urine, will have reduced fluid

What are the effects of Oligohydramnios, or Potter Sequence?

Oligohydramnios, or Potter sequence causes fetal surface of placenta to be very rough, or amnion nodosum (lack of lubricant, i.e. amniotic fluid, tissue accumulation on placental face is amnion nodosum) • Baby no longer floating in uterus, staying in one position • Baby will have alterations in body • Try to accommodate via fetal position, face will flatten

What is the pathogenesis of Deformations?

Pathogenesis includes localized or generalized compression of growing fetus by abnormal biomechanical forces, leading eventually to variety of structural abnormalities. • The most common underlying factor responsible for deformations is uterine constraint.

Describe Prematurity.

Prematurity is a gestational age of less than 37 weeks and weight less than 2500 grams (lungs developed by 34 weeks). It is the second most common cause of neonatal mortality (primary cause: congenital anomalies).

What is the Prognosis of Wilms tumor?

Prognosis of Wilms tumor is currently very good, and excellent results are obtained with a combination of nephrectomy and chemotherapy in most cases.

What is Respiratory Distress Syndrome of the Newborn (RDS)?

RDS is: • Commonly observed in preterm infants, and those delivered by cesarean section (Birth canal offers convenience to infant -compresses chest, helps lung to expand, easier for baby to breath). • Incidence of disease inversely proportional to gestational age. • Physical exam: dyspnea and fine rales heard on both lung fields. • Maternal history of diabetes (surfactant synthesis inhibited by high levels of insulin in infants of diabetic mothers). Chest XR "ground glass picture"

What other risks are associated with Retinoblastoma patients?

Risk to develop osteosarcoma and soft tissue tumors in familial retinoblastoma patients

What are the clinical presentations of Rubella infection?

Rubella embryopathy includes cataracts, heart defects (persistent ductus arteriosus, pulmonary artery hypoplasia or stenosis, ventricular septal defect, tetralogy of Fallot), deafness, and mental retardation.

What are some proposed causes for SIDS?

SIDS autopsy usually fails proving cause of death (multiple petechiae are the most common findings present on the thymus, visceral and parietal pleura, and epicardium). • Infections (e.g., viral myocarditis or bronchopneumonia) are most common causes of sudden unexpected death, followed by unsuspected congenital anomaly. • Considered multifactorial condition that reflects a delayed development of arousal and cardiorespiratory control. • (Back to sleep campaign.)

What is Sudden Infant Death Syndrome (SIDS)?

SIDS is a disease of unknown cause. SIDS is the leading cause of death between age 1 month and 1 year in the USA and the third leading cause of death overall in infancy, after congenital anomalies and diseases of prematurity and low birth weight.

Describe Stage 1 of Neuroblastoma.

Stage 1: Localized tumor with completely excised, with or without microscopic residual disease; representative ipsilateral non-adherent lymph nodes negative for tumor (nodes adherent to the primary tumor may be positive for tumor).

Describe Stage 2A of Neuroblastoma

Stage 2A: Localized tumor with incomplete gross resection; representative ipsilateral non-adherent lymph nodes negative for tumor microscopically.

Describe Stage 2B of Neuroblastoma

Stage 2B: Localized tumor with or without complete gross excision, ipsilateral non-adherent lymph nodes positive for tumor; enlarged contralateral lymph nodes, which are negative for tumor microscopically

Describe Stage 3 of Neuroblastoma

Stage 3: Unresectable unilateral tumor infiltrating across the midline with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement.

Describe Stage 4 of Neuroblastoma

Stage 4: Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs (except as defined for stage 4S).

Describe Stage 4S of Neuroblastoma

Stage 4S ("S" = special): Localized primary tumor (as defined for Stages 1, 2A, or 2B) with dissemination limited to skin, liver, and/or bone marrow (<10% of nucleated cells are constituted by neoplastic cells; >10% involvement of bone marrow is considered a stage 4). Stage 4S is limited to infants <1 yr.

What are the teratogenic effects of Diabetes in the mother?

The incidence of major malformations in infants of diabetic mothers is between 6% and 10%. Maternal hyperglycemia-induced fetal hyperinsulinemia results in increased body fat, muscle mass, and organomegaly (fetal macrosomia), cardiac anomalies, and neural tube defects.

What is the most serious consequence of fetal hydrops?

The most serious consequence of fetal hydrops in the central nervous system is kernicterus. The brain is enlarged and edematous and on cut section shows deposit of (bright yellow pigment from) bilirubin, particularly in the basal ganglia and brain stem.

What is the Staging of Neuroblastoma?

The staging of Neuroblastoma is as follows: • Stage 1 • Stage 2A • Stage 2B • Stage 3 • Stage 4 • Stage 4S

What are the three major Benign Tumors of infancy?

The three major Benign Tumors of infancy are Hemangiomas, Lymphangiomas, andSacrococcygeal Teratomas.

What is Valproic acid and what is its pathogenesis?

Valproic acid is an anti-epileptic and teratogen during pregnancy. Disrupts homeobox (HOX) proteins that are involved in patterning limbs, vertebrae, and craniofacial structures. Mutations produce syndactyly (fusing of digits), polydactyly (extra digits) and hand-foot-genital syndrome, (characterized by distal limb and distal urinary tract malformations).

What is the pathogenesis of insufficient all-trans-retinoic acid?

Vitamin A (retinol) derivative, all-trans-retinoic acid, is essential for normal development/differentiation, absence during embryogenesis results in constellation of malformations affecting multiple organ systems, including the eyes, genitourinary system, cardiovascular system, diaphragm, and lungs.

What is Wilms Tumor, or Nephroblastoma, and what do its major pathogenesis include?

Wilms Tumor (nephroblastoma) is the most common primary renal tumor of childhood. Diagnosed between ages 2 and 5 years. Pathogenesis of Wilms Tumor includes: • WAGR Syndrome • Denys-Drash Syndrome • Beckwith-Wiedemann syndrome

What is the Prognois for Neuroblastoma?

• Age and stage are most important: • Infants with localized primary tumors and widespread metastases (to liver, bone marrow, and skin) represent special 4S subtype; (not uncommon for primary or metastatic tumor to) spontaneously regresses • (Outlook for these 4S patients is excellent). • Children younger than 18 months of age have best outlook.

Describe the Pathogenesis of Wilms Tumor relative to Beckwith-Wiedemann Syndrome.

• Beckwith-Wiedemann patients have increased risk to develop: - Wilms tumor - Hepatoblastoma - Adrenocortical tumors - Rhabdomyosarcomas (skeletal muscle cancer) - Pancreatic tumors (pancreatoblastoma)

Describe Beckwith-Wiedemann Syndrome.

• Beckwith-Wiedemann syndrome patients have increased risk for Wilms tumor. • Exhibit enlargement of individual body organs (organomegaly: tongue, kidneys or liver) or entire body segments (hemihypertrophy), and enlargement of adrenal cortical cells (adrenal cytomegaly). • (Genomic imprinting). The genetic locus is in band p15.5 of chromosome 11 distal to the WT1 locus (WT2).

Describe Denys-Drash Syndrome.

• Denys-Drash Syndrome patients have an extremely high risk for Wilms tumor (~ 90%). • Characterized by gonadal dysgenesis and renal abnormalities. • They demonstrate germline abnormalities in WT1 11p13.

What are unfavorable or favorable genetic factors in Neuroblastoma?

• Gain of the distal long arm of chromosome 17 is unfavorable. • Deletion of the distal short arm of chromosome 1 is unfavorable. • Overexpression of telomerase unfavorable. • Expression of TrkA, differentiation toward sympathetic ganglia lineage is favorable.

Elaborate on Congenital Capillary Hemangiomas.

• Hemangioma of the liver can bleed easily, even from biopsy • Skin is vascularized, bleeds easily - Forms scabs, resolved into scars over a few years

What are the common malignant neoplasms of ages 10-14?

• Hepatocellular carcinoma • Soft tissue sarcoma • Osteogenic sarcoma • Thyroid carcinoma • Hodgkin disease

What is the pathogenesis of RDS?

• Immaturity of lungs is the most important substrate on which this condition develops. • Main defect is deficiency of pulmonary surfactant. • Leads to collapsed lungs, progressive atelectasis and reduced lung compliance. • Results in deposition of protein/fibrin-rich exudate in alveolar spaces (hyaline membranes).

What are the common malignant neoplasms of ages 5-9?

• Leukemia • Retinoblastoma • Neuroblastoma • Hepatocellular carcinoma • Soft tissue sarcoma • Ewing tumor • Central nervous system tumors • Lymphoma

What are the common malignant neoplasms of ages 0-4?

• Leukemia • Retinoblastoma • Neuroblastoma • Wilms Tumor • Hepatoblastoma • Soft tissue sarcoma (especially rhabdomyosarcoma) • Teratomas • Central Nervous System Tumors

What are Sacrococcygeal Teratomas?

• Most common germ cell tumors of childhood with 40% or more of cases. • 10% are associated with congenital anomalies, defects of hindgut and cloacal region (and other midline defects, e.g., meningocele, spina bifida). • 75% are mature (benign course) and 12% are malignant (and lethal). • Remainder are immature teratomas • (Malignant potential correlates with amount of immature tissue elements i.e, immature neuroepithelial elements, present).

What is Retinoblastoma?

• Most common primary intraocular malignancy of children. • Cell of origin is neuronal. • 40% of cases associated with germ-line mutation of RB1 allele located on chromosome 13q14. • (Tumor cells may disseminate through the optic nerve or subarachnoid space). • Sites of distant metastases are the central nervous system, skull, distal bones and lymph nodes.

What is a Neuroblastoma?

• Tumor of sympathetic ganglia and adrenal medulla (derived from primordial neural crest cells populating these sites). • Natural history includes spontaneous regression and spontaneous or therapy induced maturation. • 90% of neuroblastomas produce catecholamines: - Vanillylmandelic acid (VMA) - Homovanillic acid (HVA)

Describe WAGR Syndrome.

• WAGR Syndrome is characterized by Wilms tumor, Aniridia, Genital anomalies, and mental Retardation. • Patients with WAGR syndrome carry constitutional germline deletions of WT1 11p13.