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• Oncology
• Developmental and Genetic Diseases
• Hemodynamics

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SPECIFIC TUMORS: Only the ones that aren't obvious.

• Striated Muscle Tumors:
• RHABDOMYOMA: Benign
• RHABDOMYOSARCOMA: Malignant (more common)
• Smooth Muscle Tumors:
• LEIOMYOMA: Benign
• Leiomyoma of Uterus: Benign tumor of uterus presents with abdominal pain and dysmenorrhea.
• LEIOMYOSARCOMA: Malignant
• Melanocytes:
• A NEVUS is a benign tumor
• MELANOMA is malignant.
• MIXED TUMORS: Derive from a cell that is multipotent.
• PLEOMORPHIC ADENOMA: BENIGN tumor of the salivary gland. It has epithelial, bone, and cartilage components.
• Malignant Mixed Tumor of Salivary Gland is the name for the malignant tumor.
• WILMS'S TUMOR: NEPHROBLASTOMA. Mixed tumor of renal tissue.
• Germ-Cell Tumors:
• TERATOMA: Tumor composed of tissues derived from all three germ layers. It usually occurs in gonads.
• DERMOID: Benign teratoma of the ovary, having all sorts of strange tissue in it.
• TERATOCARCINOMA: Malignant tumor. Also Seminoma.
• SEMINOMA: A malignant tumor of germ cells.
• DIAGNOSIS: High levels of hCG and AFP are diagnostic of teratoma.
• Neoplastic germ cells secrete hCG
• Neoplastic yolks cells (found in Teratoma) secrete AFP.
• MENINGIOMA: A BENIGN meninges tumor. It can be deadly because it can compress on the brain.

Random Tumor Vocabulary (RTV):

• SARCOMA: A tumor that has arisen from connective tissue or mesothelium.
• CARCINOMA: A tumor that has arisen from epithelial tissue.
• CARCINOMA IN SITU: An epithelial tumor that has not yet penetrated the basement membrane and thus has no current chance of metastasis.
• ADENOMA: Benign tumor of glandular epithelial tissue, such as a tubular adenoma of the colon.
• PEDUNCULATED ADENOMA: An adenoma with a stalk, or peduncle, protruding from the mucosal surface.
• SESSILE ADENOMA: An adenoma without a stalk.
• POLYP: Any growth or mass protruding from a mucous membrane.
• Abnormal cells are elongated and cannot produce mucin anymore.
• PAPILLOMA: Benign tumor of non-glandular epithelial tissue.
• HAMARTOMA: Disorganized, benign tumor-like nodule.
• It contains differentiated cells, but it is disorganized, and one cell type often predominates (although not exclusively).
• CELLULAR MORPHOLOGY / HISTOLOGY:
• METAPLASIA: The replacement of one adult cell by another adult cell. Change of cell-type.

• Squamous Metaplasia: Glandular epithelium ------> squamous epithelium.
• Barrett Esophagus:

• DYSPLASIA: An Altered growth, altered development.
• ANAPLASIA: Lack of differentiated features in a cancer cell, indicative of malignancy.
• DESMOPLASIA: Connective tissue proliferation in response to cancer.
• CHORISTOMA: The presence of normal tissue in an abnormal location.

DIAGNOSIS of MALIGNANCY:

• HISTOLOGICAL DIAGNOSIS:
• ANAPLASIA
• Pleomorphism: Variation in the size and shape of cell nuclei.
• Enlarged and hyperchromatic nuclei
• Prominent nucleoli
• Increased Nuclear to Cytoplasmic Ratio.
• Bizarre Cells and Giant Cells.
• MITOTIC ACTIVITY: Mitotic figures and atypical mitoses.
• GROSS-APPEARANCE: Malignant tumors have irregular edges, or star-shaped jutting borders.
• INVASION: Demonstration of the tumor invading basement membrane, blood vessels, or lymphatics, is diagnostic of malignancy.

GRADING AND STAGING OF TUMORS:

• CANCER GRADING: Histological assessment of malignancy.
• GRADE 1: Well differentiated
• GRADE 2: Medium differentiation.
• GRADE 3: Poorly differentiated.
• CANCER STAGING: Clinical assessment of the spread of the tumor, based on TNM system.
• (T) TUMOR SIZE
• Graded 1-4. 1 is the mildest.
• (N) NODAL: Has it spread to any lymph nodes? Graded 0-3
• N0: It has no spread to lymph nodes.
• N3: Most severe spread to lymph nodes.
• (M) METASTASIS
• M0: No metastases are present.
• M1: Metastases are present.
• DUKE'S CLASSIFICATION: Method of staging colon cancer.

CARCINOGENESIS:

• INITIATION: Irreversible damage to DNA in a critical target gene.
• Initiation is a permanent genetic alteration (mutation) of the cell and is thus irreversible.
• PROMOTION: Single initiated cell is selected for and promoted into a benign tumor.
• Promotion is reversible. It requires continual (or repeated) stimulation, irritation, or treatment, in order to maintain the promoted state.
• PROGRESSION: The process by which a benign neoplasm is transformed into malignant cells.
• INVASION (STAGE I): Contiguous growth of the tumor.
• Carcinoma In Situ: A malignant epithelial tumor that has not yet penetrated the basement membrane.
• PROCESS: Step by step invasion.
• Penetrate Basement Membrane: Collagenases and proteases.
• Binding to the extracellular matrix: integrins, fibronectin.
• Degradation of extracellular matrix.
• Secrete extracellular proteases that break down Collagen IV, Proteoglycans.
• Movement through interstitial tissues: Autocrine motility factor induces movement by pseudopodia.
• METASTASIS (STAGE II): Spread of the tumor to a non-contiguous site, through blood or lymph.
• HEMATOGENOUS METASTASES: Metastasis through blood. Most frequent target sites are liver and lung.
• LYMPHATIC METASTASES: Regional enlargement of lymph nodes can be signs of lymphatic metastasis.
• PROCESS:
• Invasion of Circulation:
• Escape from Circulation: Adherence to endothelia, bind to basement membrane, extravasation.
• Angiogenesis and local growth: Growth of metastatic tumor and its blood supply.

IMMUNODIAGNOSIS of CANCERS: The origin of cancers that are histologically unidentifiable can be diagnosed by immunohistology.

• Keratins: Indicates the presence of epithelial cells: carcinoma or mesothelioma.
• Desmin: Indicates a tumor of muscle origin: myoma.
• Vimentin: Indicates tumors of mesenchymal origin: sarcomas.

AMES TEST: Test for mutagenesis, by measuring the number of backward (reversion) mutations in His^- Salmonella cells grown without Histidine.

• All carcinogens are also mutagens. Most mutagens are also carcinogens.
• Introduce Rat-Liver Microsomal Oxidases into the bacterial culture. These enzymes are added in order to metabolize the potential carcinogens (mutagens), as most require metabolic activation before becoming mutagenic.
• RESULTS: The more bacterial colonies you get, (bacteria living on the His^- bare medium), the greater the mutagenicity of the compound being tested.

ENVIRONMENTAL CAUSES OF CANCER:

• CHEMICAL CARCINOGENS
• DIRECT-ACTING CARCINOGENS: Do not need to be metabolized in liver. They are generally Electrophilic and thus attracted to the negatively charged substituents in the nucleus.
• NITROGEN MUSTARD: A cancer (chemotherapy) drug, that is ironically also carcinogenic itself.
• Benzyl Chloride
• Nitrosylmethylurea
• INDIRECT-ACTING CARCINOGENS:
• CISPLATIN: Chemotherapy drug that is ironically carcinogenic itself.
• Anabolic Steroids can cause brain and liver cancer
• POLYCYCLIC AROMATIC HYDROCARBONS (PAH): Produced by incomplete combustion of organic material. Charred meat, for example.
• METABOLISM: Cytochrome-P450 Mixed Oxidase in liver microsomes.
• Aryl Hydrocarbon Hydroxylase: PAH ------> 7,8-Epoxide
• Epoxide Hydrase: 7.8-Epoxide ------> 7,8-Diol
• Aryl Hydrocarbon Hydroxylase: 7,8-Diol ------> 7,8-Diol-9,10-Epoxide, the reactive carcinogenic product.
• Epoxide: The final reactive carcinogenic product is an epoxide.
• AFLATOXIN-B1: Product of Aspergillus mold, found in moldy grains in other countries.
• RISK: Far increased risk for Hepatocellular Carcinoma.
• METABOLISM: Mixed-Function Oxidase with an Epoxide Intermediate, very much like PAH.
• AROMATIC AMINES, AZO DYES: Their metabolites are excreted in the urine, where they can cause bladder cancer.
• NITROSAMINES:
• METABOLISM: They originate as Nitrites found in food-preservatives. They form nitrosamines by reacting with acids in stomach.
• METALS: Occupational hazards, leading to lung cancer.
• PHYSICAL CARCINOGENS:
• UV-RADIATION
• UV-A: Lower energy UV-light, comprising 97% of UV radiation.
• It is longer wavelength and penetrates the skin to a greater depth than UV-B. It is not innocuous.
• UV-B: Implicated in skin cancer. Wavelength below 400nm.
• This is only about 3% of UV light.
• MECH: Formation of Thymine-Thymine Dimers in DNA, ultimately resulting in a deletion.
• UV-C: Absorbed by the ozone layer, so we don't come into contact with it.
• IONIZING RADIATION
• ASBESTOS: Made of silicates and rigid fibers.
• RISK: Linked to Mesothelioma of the pleural and peritoneal cavities.
• FOREIGN BODIES
• VIRAL CARCINOGENS:
• Animal Viruses: Experimental animals
• Rous Sarcoma Virus: Virus contains an oncogene, induced cancer in chickens.
• Shope Papilloma Virus caused papillomas in rabbits.
• SV40 Virus: Member of the polyoma virus family, which originates from African monkeys. Induces cancer in mice and rats, but not known to in humans.
• HUMAN PAPILLOMA VIRUS (HPV):
• STRUCTURE: Circular double-stranded DNA Virus
• SUBTYPES:
• HPV-1, HPV-2: Lead to epithelial warts.
• HPV 6, 11, 16, 18: All lead to Genital Warts
• HPV 16, HPV 18: Associated with increased risk for Cervical Cancer, and cancer of Penis, Vulva.
• Also, Perianal condylomata are found with HPV.
• MECH: HPV is known to cause cancer by blocking tumor-suppressor genes.
• E6 is an HPV protein that can bind the retinoblastoma gene to inactivate it.
• E7 is an HPV protein that can bind p53 to inactive it.
• EPSTEIN-BARR VIRUS (EBV):
• RISKS:
• NASOPHARYNGEAL CARCINOMA
• BURKITT'S LYMPHOMA: EBV infects B-Lymphocytes.
• Disease is common in childhood.
• It occurs in regions where Malaria is endemic.
• EBV is found in all Burkitt's Lymphoma's in Africa, and about 20% of them in USA.
• Also can be caused by a translocation (see below).
• HODGKIN'S DISEASE: EBV is found in about 50% of these cases.
• INFECTIOUS MONONUCLEOSIS is caused by an acute EBV infection.
• HEPATITIS-B VIRUS (HBV)
• STRUCTURE: Partial double-stranded, partial single-stranded DNA virus.
• RISK: Hepatocellular Carcinoma. Especially in Asia and Africa.
• The level of risk is synergistic with the carcinogenic effects of Aflatoxin-B1.
• MECH: Hepatitis Virus codes for proteins that block Tumor Suppressor proteins.
• HBVX is a protein encoded by HBV. It blocks activation of P53.
• Hepatitis-C Virus is also associated with increased hepatoma risk.
• POLYOMA VIRUSES:
• STRUCTURE: Small circular double-stranded DNA virus.
• BK Virus is being studied for oncogenicity, due to its known relatedness to the SV40 virus.
• JC Virus is also being studied.
• HUMAN T-CELL LEUKEMIA VIRUS I and II (HTLV-I and II): The only known oncogenic Retrovirus. Associated with rare T-Cell Leukemias in Japan and Carribean.

ONCOGENES: These genes show dominant transmission. The presence of only one aberrant copy is sufficient to produce cancer.

• PROTO ONCOGENES:
• c-onc: A human (cellular) proto-oncogene, that codes for proteins that regulate cell division and growth. If these protein lose their regulation or are overexpressed, they become oncogenic.
• v-onc: A proto-oncogene that has been incorporated (via transduction) into a virus, thus making it lose its regulation and become oncogenic.
• TRANSFORMING VIRUSES: Two basic mechanisms of viral oncogenesis.
• ACUTE TRANSFORMING VIRUSES: The virus has transformed a copy of the oncogene (now called v-onc) into its own genome. When the virus spreads, it takes the oncogene with it and can cause aberrant expression of the gene in infected cells.
• SLOW TRANSFORMING VIRUSES: Insertional Mutagenesis of a proto-oncogene. The virus does not have a v-onc, but rather mutates a c-onc by virtue of its insertion into genome.
• Activation of Proto-oncogenes
• ACTIVATION BY MUTATION
• Ras GENES: They code for GTP-binding proteins, G-Proteins
• Ras SUBTYPES:
• Harvey-Ras: Initial discovered Ras, discovered to be mutated in bladder-cancer patient.
• Kirsten-Ras
• N-Ras
• RISK: Colorectal Cancer, Pancreatic Cancer
• p21 PROTEIN is the name of the G-Protein encoded by Ras. It is mutated (point mutation) in 30% of all human cancers.
• ACTIVATION BY TRANSLOCATION
• c-myc: This oncogene (Chrom 8) translocates to Chromosome 14, which codes for an Ig Heavy Chain (C_H) region. This translocation results in over expression of the oncogene.
• MECH: c-myc is activated by its proximity to the heavy-chain gene. This results in a dominant monoclonal colony of B-Cells, which are selected for based on the mutation.
• RISK: BURKITT'S LYMPHOMA is found to have the translocated c-myc gene in ABOUT 75% of cases.
• In the other 25% of cases, an Immunoglobulin light chain is translocated to Chromosome 8, from Chrom 2 or 22, and causes a similar effect.
• PHILADELPHIA CHROMOSOME: abl (Chrom 9) and bcr (Chrom 22) translocation.
• MECH: abl is fused to bcr on Chromosome 22, such that bcr drives the over expression of the abl gene.
• abl codes for Tyrosine Kinase Activity. Hyper activation leads to cancer.
• RISK: CHRONIC MYELOGENOUS LEUKEMIA (CML)
• ACTIVATION BY GENE AMPLIFICATION: Increase in the number of copies of a gene.
• Cytologic Findings: These two chromosomal conditions are interchangeable.
• HOMOGENOUS STAINING REGIONS (HSR's) are visible in double-minute chromosomes.
• DOUBLE-MINUTE CHROMOSOMES are the converse cytological finding, also found.
• RISK:
• N-myc HSR's are seen in Neuroblastoma
• HER-2/neu is a growth-factor receptor. When it is amplified, it is associated with poor prognosis.
• NEUROBLASTOMA:
• Most common tumor in early childhood.
• Tumor arises from sympathetic neural tissue.
• The degree of N-myc
• Different roles of Oncogenes:
• ONCOGENES AND GROWTH FACTORS
• MECH: Genes that code for things like PDGF, which is believed to cause autocrine growth stimulation in neoplastic cells.
• v-sis: Retroviral oncogene that codes for a protein very similar to PDGF beta-chain.
• c-sis: Proto-oncogene that produces the actual PDGF beta-chain.
• RISK: Sarcomas and Glioblastomas produce PDGF, whereas normal cells do not.
• STOMACH CANCER: Fibroblast Growth Factor (FGF) is overexpressed in stomach cancer.
• ONCOGENES AND GROWTH-FACTOR RECEPTORS: Implicated in cancer due to their strong signal-transduction role in promoting cell-growth.
• MECH: Lots of oncogenic receptors are TYROSINE-KINASE RECEPTORS
• EXAMPLES:
• v-erb B: Oncogene that codes for a variant of the EGF-Receptor
• HER2/neu: Codes for NGF-Receptor. It also has Tyrosine Kinase activity.
• RISK: This is overexpressed in BREAST, OVARIAN, ENDOMETRIAL CANCER.
• The protein level in these cancers correlates with prognosis.
• ONCOGENES AND MEMBRANE PROTEIN-KINASES
• TYROSINE KINASE activity is implicated in lots of proto-oncogenes.
• c-abl: Gene codes for a tyrosine kinase.
• It is overexpressed by its translocation next to the bcr gene.
• c-src: Gene codes for a tyrosine kinase.
• ONCOGENES AND G-PROTEINS
• Ras codes for P21 G-Protein.
• MECH: Ras usually undergoes point mutation at codon 12 or 61.
• Ways in which Ras mutation leads to cancer: anything that makes the GTP-bound state more persistent.
• Loss of intrinsic GTPase activity ------> G-Protein is constitutively turned on.
• Loss of sensitivity to GTPase Activating Protein (GAP) ------> G-Protein is constitutively turned on.
• Increased exchange of GDP for GTP.
• RISK: Again, Colorectal and Uterine cancers.
• SIGNAL TRANSDUCTION: Ras ------> Raf ------> Mapk (Mitogen-Activated Protein Kinases)
• ONCOGENES AND NUCLEAR REGULATORY PROTEINS
• MECH: c-myc and c-fos: Competence Proteins. Nuclear regulatory proteins involved in taking the cell out of G₀, thereby enabling it to resume the cell cycle when properly stimulated.
• PDGF stimulation causes these proteins to be expressed ------> making them competent to receive further signals which allow them to undergo mitosis.
• EGF or IGF is then needed to take the cell through S-Phase and mitosis.

TUMOR-SUPPRESSOR GENES: These are recessive cancer genes. Both copies must be defective before cancer results.

• RETINOBLASTOMA GENE
• TWO-HIT HYPOTHESIS: If you inherit one bad copy of the gene, then you will almost inevitably get retinoblastoma in both eyes, by effecting a random mutation of the other copy of the gene.
• A random somatic mutation of one copy is highly likely at some point in life, while a mutation of both copies is unlikely.
• INHERITED RETINOBLASTOMA is thus is both eyes.
• SPORADIC RETINOBLASTOMA is thus in one eye -- sporadic mutation (double-whammy) of both copies of the Rb gene.
• Rb-GENE:
• MECH: Rb-gene codes for a factor that blocks entry of the cell into S-Phase. The Rb-Protein (pRb) blocks the E2F growth factor.
• Normally, pRb gets phosphorylated by cyclins ------> this makes it let go of E2F ------> E2F pushes cell into S-Phase.
• LOCATION: Rb-Gene is located on Chrom 13, band q14.
• P53 GENE: The guardian of the genome, dammit.
• LOCATION: Chrom 17
• MECH: The P53 gene prevents a mutated cell from proliferating. It is induced in response to DNA damage, and it inhibits the cell from entering S-Phase, and ultimately making it undergo apoptosis.
• p53 bind cyclin-dependent kinases ------> induce cyclin-inhibitor WAF ------> inhibit cyclin ------> prevent cell division.
• RISK: P53 mutations are the most common genetic defect found in cancers.
• WILMS'S TUMOR GENE: Childhood form of renal cancer.
• It is known to be a tumor-suppressor gene, because loss of heterozygosity leads to cancer. Function of the gene-product is unknown.
• DCC SUPPRESSOR GENE: Detected in Colon Carcinoma
• MULTIPLE genetic steps in sequence are involved in Colon Carcinoma:
• Adenomatous Polyposis Coli gene is mutated.
• k-Ras gene is mutated.
• DCC suppressor gene then is mutated.
• p53 gene may become mutated.
• BRCA1: Recently identified BREAST-CANCER Tumor-Suppressor gene.
• 85% of breast cancers are sporadic.
• The other 10-15% of familial breast cancers (predisposition) may be due to heterozygosity in this gene.

XERODERMA PIGMENTOSUM: Autosomal-Recessive Disorder, in which people have defective DNA-Repair mechanisms. This leads to a very high incidence of cancer.

CLINICAL LECTURE:

• CLARK'S LEVELS: Five levels for staging Melanomas, according to how deep it goes down.
• LEVEL I: In-Situ Carcinoma. The disease is still confined to the epidermis.
• Measured depth is far less than 0.75mm
• LEVEL II: Early penetration into the Papillary Dermis.
• LEVEL III: Deeper penetration into Papillary Dermis.
• LEVEL IV: Well into the Reticular Dermis.
• LEVEL V: Into subcutaneous tissues.
• Measured depth will be greater than 4mm
• BREAST CANCER:
• Diagnosing Malignancy
• X-RAY: Malignant biopsy shows clustering with linear pattern to branches.
• Stellate shaped calcifications.
• HISTO: Different cell-types on the slide would favor a benign tumor. Singular cell-types would be malignant.
• Ductal Carcinoma In Situ (DCIS): Early Stage I lesion, with no (current) chance of metastasis.
• Cribriform Carcinoma: Low-grade DCIS. Well-differentiated.
• Comedo form Carcinoma: Tremendously enlarged, solid mass with impending necrosis in the middle. High-grade DCIS, but it is still In Situ, so it is still Stage I

CLONAL ORIGIN OF CANCER: Most cancers arise from a single transformed cell.

• Multiple Myelomas arise as a single lineage of B-Cells, with monoclonal antibodies.
• Experimental Evidence: Uterine Tumors in women express only one allele of Glucose-6-Phosphate Dehydrogenase, even though these women normally have two alleles of it.
• G6PD is an X-chromosome gene. Normally in heterozygotes, half of cells will express one isozyme and the other half express the other isozyme.
• In Uterine tumors, all cells express the same isozyme, indicating that they all derived from a single cell.

Cancer as Altered Differentiation:

• Squamous Cell Carcinoma
• Teratocarcinoma
• Leukemias and Lymphomas

TUMOR IMMUNOLOGY: There is little evidence that immunological defenses play a significant role in fighting cancer in humans. Experimental evidence comes mostly from animals.

• TUMOR-SPECIFIC ANTIGENS (TSA): Novel antigens produced only by cancer cells. They differs according to cause of the cancer.
• CHEMICALLY-INDUCED TUMORS: They make a UNIQUE tumor-specific antigen, unique to each tumor.
• VIRALLY INDUCED TUMORS make a COMMON tumor-specific antigen. Each tumor created by the same virus will yield the same antigen.
• TUMOR-ASSOCIATED ANTIGENS: Those expressed initially in the embryo but then arrested in the adult.
• They can then show up again in a tumor, thus they are called Oncodevelopmental Antigens.
• These antigens are measured clinically to test for tumor re-emergence:
• Carcinoembryonic Antigen EA (CEA): Can be measured to follow the re-emergence of a tumor.
• alpha-Fetoprotein is measured in testicular cancers.
• CA125 is measured in ovarian cancers.
• Mechanisms of Cytotoxicity:
• T-Cell mediated Cytotoxicity
• NK-Cell Cytotoxicity: Mediated by lymphokines and lymphokine-activated killer cells.
• Macrophages
• Antibody-dependent Cytotoxicity (ADCC)
• Complement-mediated Cytotoxicity
• IMMUNODEFICIENCY: It increases your risk for B-Cell Lymphomas

PARANEOPLASTIC SYNDROMES: The systemic effects of cancers in the host that are not due primarily to tumor or its metastases.

• FEVER: Especially with Hodgkin's, Renal cell carcinomas, osteogenic sarcomas.
• ANOREXIA AND WEIGHT LOSS
• ENDOCRINE SYNDROMES
• INAPPROPRIATE ANTIDIURESIS
• HYPERCALCEMIA: About ten percent of all patients. Usually attributed to secreted of a PTH-like peptide by an epithelial tumor.
• ECTOPIC HORMONE PRODUCTION is the inappropriate secretion of hormones from a tumor, which can occur in any tumor regardless of its origin.
• CUSHING'S SYNDROME can result from ectopic production of cortisol.
• GONADOTROPIC SYNDROME
• HYPOGLYCEMIA
• NEUROLOGIC SYNDROMES
• SPINAL CORD:
• PERIPHERAL:
• SKELETAL MUSCLE
• HEMATOLOGIC SYNDROMES:
• ERYTHROCYTOSIS
• ANEMIA: Frequently cause is not understood. Sometimes from tumor bleeding.
• THROMBOCYTOSIS occurs in about one third of patients. Cause unknown.
• THE HYPERCOAGULABLE STATE
• VENOUS THROMBOSIS: Often found in mucin-secreting cancers, such as pancreatic cancers.
• DISSEMINATED INTRAVASCULAR COAGULATION (DIC)
• NONBACTERIAL THROMBOTIC ENDOCARDITIS
• MALABSORPTION
• RENAL SYNDROMES
• CUTANEOUS SYNDROMES

EPIDEMIOLOGY OF CANCER

• CAUSE of DEATH:
• Cancer is #2 next to CV disease.
• Lung cancer is biggest killer in both males and now females in USA.
• CANCER PREVALENCE
• Stomach cancer has gone down. Lung cancer has gone up.
• Hepatoma and Esophageal cancer are far more common far east.
• Colorectal and Breast cancer are more common in USA.

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TERATOGEN: Chemical, physical, or biologic agent that causes developmental anomalies.

• FIRST TRIMESTER: Greatest risk. The formation of primordial organ systems is the stage of development most susceptible to teratogenesis.

ERROR of MORPHOGENESIS:

• AGENESIS: The complete absence of an all or part of an organ primordium.
• Examples: Agenesis of Corpus Callosum, Agenesis of Kidneys
• Sertoli Cell Only Syndrome: Absence of germ-cells.
• APLASIA: Absence of an organ, coupled with the persistence of an organ rudiment that never developed completely.
• Example: In aplasia of lung, the bronchi end in a blind pouch of nondescript tissue.
• HYPOPLASIA: Reduced size owing to incomplete development of all or part of an organ.
• Examples:
• Microphthalmia: Small eyes
• Micrognathia: Small chin.
• Microcephaly: Small brain and cranium.
• DYSRAPHIC ANOMALIES: Defects caused by the failure of apposed structures to fuse.
• Two examples = SPINA BIFIDA, CLEFT PALATE
• INVOLUTION FAILURES: Persistence of embryonic or fetal structures that should involute at some stage in development.
• Example = Persistent Thyroglossal Duct. Incomplete involution of thyroglossal duct, which connects base of tongue with thyroid.
• DIVISION FAILURES: Caused by the incomplete cleavage of embryonic tissues, when that process depends on the programmed death of cells.
• Example = Syndactyly
• ATRESIA: Defects caused by the incomplete formation of a lumen.
• Example = Esophageal Atresia = failure to form esophageal lumen.
• DYSPLASIA: Abnormal organization of cells into tissues, resulting in abnormal histogenesis.
• Example = Tuberous Sclerosis, in which brain tissue forms abnormally into visible "tubers"
• ECTOPIA: Anomaly in which an organ is outside its normal anatomic site.
• DYSTROPIA: Retention of an organ at a site where it is located during development.
• Example = Pelvic Kidneys, Abdominal Gonads

CLINICALLY IMPORTANT MALFORMATIONS:

• POTTER COMPLEX: All of the developmental consequences originating from OLIGOHYDRAMNIOS -- a reduced amount of amniotic fluid.
• ETIOLOGY: Potter Complex usually results from failure of development of the fetal mesonephric duct -- renal agenesis.
• CLINICAL: The fetus is usually born with a breeched presentation.
• ANOMALIES:
• Pulmonary Hypoplasia
• External signs of intrauterine fetal compression.
• Morphologic changes of the amnion.
• These morphological features will be found regardless of the cause of the Oligohydramnios.
• ANENCEPHALY: Congenital absence of the cranial vault.
• CAUSE: Dysraphic defect of Neural Tube closure.
• PATHOGENESIS: Genetic factors play a role. Risk of a second one goes up after having one anencephalic fetus.
• NEURAL TUBE DEFECTS: Failure of neural tube to close.
• CRANIORACHISCHISIS: Neural tube open from cranium into the spinal cord and vertebral column.
• SPINA BIFIDA: Incomplete closure of the spinal cord and vertebral column.
• PATHOGENESIS:
• Usually localized to lumbar region.
• It is the mildest of the dysraphic anomalies.
• alpha-FETAL PROTEIN (AFP): It is often HIGH in Spina Bifida, although this is not a sensitive test. It is a good initial screening test, to test for possibilities of Spina Bifida. AFP can be high for other reasons, too.
• MENINGOCELE: Hernial protrusion of meninges through the vertebral column.
• MYELOMENINGOCELE: Hernial protrusion of meninges and neural tissue through the vertebral column.
• FETAL ALCOHOL SYNDROME: Anomalies resulting from consumption of alcohol during pregnancy.
• SYMPTOMS:
• Characteristic Facial Dysmorphologies
• Microcephaly, Micrognathia
• Thin upper lip
• No Philtrum
• Epicanthal folds
• Mental Retardation.
• Growth retardation.
• Septal heart defects
• TORCH COMPLEX: Cluster of similar symptoms occurring from infectious diseases.
• TORCH:
• TOXOPLASMOSIS: Cat shit. Not too common intrauterine, although mothers commonly have Toxoplasma antibodies.
• Others
• RUBELLA: Very rare due to vaccine.
• CYTOMEGALOVIRUS: Fairly common. Up to 2% of newborns infected.
• HERPES VIRUS: HSV-II is most often contracted by exposure to open infection passed through birth canal, which can be prevented by C-Section. Infection in-utero is more rare.
• SYMPTOMS: Common TORCH Symptoms
• Inflammatory lesions of Brain: Most serious problems.
• HISTO: Early necrotic lesions later become calcified and visible on CT, esp. in Toxoplasmosis.
• SYMPTOMS: Psychomotor retardation, neurological defects, seizures.
• Ocular Defects: Particularly in Rubella. Cataracts and microphthalmus.
• Cardiac Defects: Septal defects, patent ductus arteriosus.

CHROMOSOMAL ABNORMALITIES:

• RECIPROCAL TRANSLOCATIONS: Recombination between non-homologous chromosomes, in which whole parts of a chromosome are moved to a different location.
• BALANCED TRANSLOCATIONS occur when there is no less of genetic material. These translocations may be silent, although the mother has the risk of passing visible chromosomal abnormalities to offspring.
• ROBERTSONIAN TRANSLOCATIONS: Translocation in which division occur near centromere.
• PRODUCTS: One very long metacentric chromosome and a small chromosome fragment.
• CHROMOSOMAL DELETIONS: Related to several cancers in humans.
• CHROMOSOMAL INVERSIONS: DNA is flipped around and inserted backwards.
• Pericentric inversions are breaks on opposite sides of the centromere (around the centromere).
• Paracentric inversions are breaks on the same side of the centromere.
• RING CHROMOSOMES:
• ISOCHROMOSOMES: Faulty division of the chromosome in which it divides in a plana transverse to the mitotic spindle, rather than parallel to it, during Anaphase.
• Results are chromosomes consisting of two identical arms.
• Numerical Abnormalities:
• HAPLOID
• DIPLOID
• EUPLOID
• POLYPLOID
• ANEUPLOID
• MONOSOMY
• TRISOMY
• MOSAICISM: Condition caused by Non-disjunction in which the body contains two or more karyotypically different cell lines.
• NONDISJUNCTION: Failure for homologous chromosomes to divide in Anaphase I of Meiosis, resulting in one Monosomic and one Trisomic daughter cell.
• The monosomic daughter cell is inviable, except for Monosomy X.
• The trisomic daughter cell may be silent or may result in a variety of abnormalities, depending on which chromosome it is.
• p: The short arm of a chromosome
• q: The long arm of a chromosome

CHROMOSOMAL DISORDERS:

• DOWN'S SYNDROME:
• CAUSE: TRISOMY 21 is most common cause, although other chromosomes can cause it too.
• Trisomy 21 usually occurs from non-disjunction, but it can also occur as a result of a Robertsonian Translocation involving chromosome 21.
• RISK: Risk for Down's Syndrome increases sharply with increased age at parturition.
• Risk goes form 1:1000 at normal, to 1 in 30 by age 45.
• SYMPTOMS:
• MENTAL RETARDATION, worsening with age (from 70 in childhood to 30 in adulthood).
• Craniofacial Features: Characteristic
• Brushfield Spots are characteristic speckles in eyes.
• Simian Crease: Horizontal crease on hands
• Epicanthal folds
• CONGENITAL HEART DISEASE: 30% of patients.
• GI TRACT: Duodenal stenosis, atresia
• IMMUNE SYSTEM: Unusually susceptible to disease
• HEMATOLOGIC:
• Higher risk for Leukemia.
• NEUROLOGICAL: They show strong histological likeness to Alzheimer's Disease by age 35. Similar brain atrophy pattern. Interesting finding.
• KLINEFELTER'S SYNDROME: XXY. Tall, sterile, hypogonadic male.
• SIGNS: Low testosterone, High FSH and LH
• Extra X chromosome will generate the female-typical Barr Body (silent X chromosome), visible in most nuclei.
• SYMPTOMS: Gynecomastia, infertility, female pattern pubic hair, testicular atrophy.
• TURNER SYNDROME: XO (Monosomy X). Masculine Woman.
• PATHOGENESIS: Many woman are only missing part of the other X chromosome -- not the whole thing.
• SYMPTOMS:
• No menarche, sterility
• STREAK GONAD: Abnormal development of ovary, resulting in a fibrous streak.
• Webbed neck
• They are short.
• Horseshoe kidney is often seen
• Coarctation of Aorta seen in 15% of cases.
• TRISOMY 18 (Edward's Syndrome): Increased maternal age is a risk for this.
• SYMPTOMS: Sever congenital abnormalities
• Prominent occiput, small jaw, clenched hands, rocker bottom feet
• Profound CNS and heart abnormalities
• Prognosis only to 1 year of life.
• CLINICAL: If you have a baby with congenital heart problems and you can diagnose this abnormality, then that is good cause not to treat the heart problems too aggressively.
• TRISOMY 13 (Patau Syndrome): Increased maternal age is a risk for this.
• SYMPTOMS: Similar to trisomy 18, but rarer and more severe.
• Polydactyly and bilateral cleft lip.
• PRADER-WILLI SYNDROME: Deletion of part of short arm of the Paternal copy of Chromosome 15.
• An example Genomic Imprinting, where the maternal or paternal copy of a chromosome directs different genetic expression, as shown by the different symptoms in their deletion.
• SYMPTOMS:
• Mental retardation
• Short stature
• Hypotonia
• Obesity and huge appetite after infancy.
• Small hands and feet
• Hypogonadism
• ANGELMAN (Happy Puppet) SYNDROME: Deletion of part of short arm of the Maternal copy of Chromosome 15.
• An example Genomic Imprinting, where the maternal or paternal copy of a chromosome directs different genetic expression, as shown by the different symptoms in their deletion.
• SYMPTOMS:
• Mental retardation
• Ataxic gait
• Seizures
• Inappropriate laughter
• CRI DU CHAT SYNDROME: Classical deletion syndrome. Deletion in the short art of Chromosome 5.
• SYMPTOMS:
• Infants have a "Cry of the Cat."
• Mental retardation.

AUTOSOMAL DOMINANT DISORDERS:

• Heritability:
• If one parent has it, the child has a 50% chance of getting it.
• Gene defects often code for structural proteins, where one allele is sufficient to result in deficiency or malformation.
• The disorder is usually seen in every generation on a pedigree.
• MARFAN SYNDROME: Connective tissue disorder.
• PATHOGENESIS: Mutation in the gene for FIBRILLIN, which serves as a scaffold for the deposition of elastin. Fibrillin is practically gone from tissues.
• LOCATION: Long arm of Chromosome 15.
• SYMPTOMS: Tall and slender
• Arachnodactyly = spider finger, long fingers
• SKELETAL: Concave sternum
• Hyperextensible, weak tendons and joints.
• CARDIOVASCULAR: Most common cause of death.
• Faulty media of the Aorta leads to DISSECTING AORTIC ANEURYSMS.
• Heart valvulopathies.
• EYES: Connective tissue problems.
• Subluxation of lens, severe myopia, retinal detachment.
• EHLERS DANLOS SYNDROME: Group of connective tissue disorders.
• SYMPTOMS: Hyper plasticity and fragility of skin.
• Joint hypermobility.
• Thin scars; bruise very easily
• Arthritis
• PATHOGENESIS: Collagen Defect, in some type of collagen depending on the subtype.
• Subtypes:
• EDS I is the most common. Normal life-expectancy
• EDS IV: Type-III (Reticular) Collagen defect. Most dangerous due to potential for rupture of arteries or GI tract.
• EDS VII: Type-I Collagen defect.
• OSTEOGENESIS IMPERFECTA: Brittle bone disease.
• SYMPTOMS: Group of disorders with generalized fragility of bone, easy fractures.
• PATHOGENESIS: All subtypes involve Type-I Collagen.
• Subtypes:
• OI Type I: Normal appearance at birth, but fractures starting in infancy.
• Only half the normal amount of Procollagen I is made.
• Blue Sclerae as a consequence of deficiency of collagen fibers.
• OI Type II: Fatal in utero.
• OI Type III: Progressively deforming.
• NEUROFIBROMATOSIS: Development of Neurofibromas, benign tumors of Schwann cell origin.
• NEUROFIBROMATOSIS TYPE I: Van Recklinghausen Disease. Relatively common, 1/3500 persons.
• PATHOGENESIS: defect in NF1 Gene, which codes for a GTPase-Activating Protein (GAP), involved in regulation of the Ras protein.
• Normally, the NF1 gene probably suppresses Ras. Defect allows Ras to continue unabided.
• SYMPTOMS:
• Neurofibromas are soft pedunculated tumors. There can be many or few of them.
• Plexiform Neurofibromas are large, invasive neurofibromas.
• NEUROFIBROSARCOMA appears in 3%-5% of patients, usually of plexiform type.
• Cafe 'Au Lait Spots: Six or more such lesions, greater than 1.5cm each in adulthood.
• Lisch Nodules: Pigmented nodules of iris, which are masses of melanocytes.
• Skeletal lesions
• Mental Status: Mild intellectual impairment sometimes, but not retardation.
• NEUROFIBROMATOSIS TYPE II: Central Neurofibromatosis. Has a separate genetic origin and is really a different disease. Chromosome 22.
• SYMPTOMS: Bilateral Acoustic Neuromas.
• ACHONDROPLASIA: Dwarfism.
• PATHOGENESIS: Inadequate endochondral bone formation.
• SYMPTOMS: Short limbs, normal head and trunk, flat nose.
• FAMILIAL HYPERCHOLESTEROLEMIA: Codominant phenotypes. Defect in LDL-Receptor. Chromosome 19.
• HETEROZYGOTE: Cholesterol around 250-350 mg / dL
• CHD by age 40.
• HOMOZYGOTE: Cholesterol over 600 mg / dL
• Die of MI by age 30.
• SYMPTOMS:
• Atherosclerosis at a very young age.
• Xanthomas: Fatty benign tumors, resulting from accumulation of fat. Nodules of lipid-laden macrophages.
• WILLIAM'S SYNDROME: Recently classified as autosomal dominant.
• PATHOGENESIS: Absence of one of the Elastin genes.
• SYMPTOMS:
• Characteristic facial features.
• Growth deficiency
• CARDIAC: Super valvular Aortic Stenosis, leading to a stenotic aorta. Contrast to Marfan's where you get a widened Aorta.

AUTOSOMAL RECESSIVE DISORDERS: The majority of heritable diseases are autosomal recessive.

• Heritability:
• Rare autosomal recessive disorders often occur with consanguineous marriages.
• Disease occurs when two heterozygotes have children -- neither parent has the disease when child gets the disease.
• Disease shows up in one fourth of offspring of such parents.
• Gene usually codes for a metabolic or regulatory enzyme, where one allele is sufficient to carry forth activity of the enzyme.
• CYSTIC FIBROSIS:
• PATHOGENESIS: Defect in the CFTR (CF Transmembrane Conductance Regulator) Cl^- channel. It can no longer be activated by cAMP and thus never secretes Cl^-.
• Inadequate or no excretion of Cl^- in glandular cells ------> little or no secretion of water ------> viscous mucous.
• Deltaf508 is the most severe mutation. Complete absence of CFTR function. There are intermediate forms.
• SYMPTOMS:
• Chronic Pulmonary Disease ------> Bronchiectasis, widening and hypertrophy of bronchioles.
• High risk for infection.
• Most common source of morbidity and mortality
• Deficient Exocrine Pancreatic Function ------> Malabsorption
• Pancreatitis results from plugged pancreatic ducts.
• Liver: Plugged mucous in biliary system can result in biliary cirrhosis and jaundice.
• Meconium Ileus: Obstruction of the small bowel in the newborn. Caused by failure to pass meconium in neonate. Has been attributed to failure of pancreatic secretions to digest meconium.
• DIAGNOSIS: Sweat test.
• Sweat gland cell cannot reabsorb Cl^- due to CFTR defect, therefore sweat is hypertonic rather than normal hypotonic.
• EPIDEMIOLOGY: The most common lethal genetic disorder.
• Carrier state is estimated to be 1 in 25 people.
• LYSOSOMAL STORAGE DISEASES: Group of diseases in which you accumulate unmetabolized substances in lysosomes.
• GAUCHER DISEASE: Most common storage disease.
• PATHOGENESIS: Deficiency in GLUCOCEREBROSIDASE (beta-Glucosidase) ------> accumulation of Glucosylceramidee in the lysosomes of macrophages.
• GAUCHER CELLS are lipid-laden macrophages, characteristically present in spleen, liver sinusoids, lymph nodes, bone marrow.
• They have foamy cytoplasm and eccentrically located nuclei.
• Stain positive for PAS.
• SYMPTOMS / SIGNS:
• Splenomegaly: Virtually universal in the disease, with infiltrates of Gaucher cells in the red pulp.
• Presence of Gaucher Cells
• EPIDEMIOLOGY: Ashkenazi Jews principally.
• PROGNOSIS: They lead a normal life; usually present with Splenomegaly in adulthood.
• TAY-SACH'S DISEASE:
• PATHOGENESIS: Defect in beta-HEXOSAMINIDASE, resulting in failure to break down Ganglioside GM₂
• Ganglioside: A sphingolipid, containing ceramide and N-Acetylneuraminic acid.
• EPIDEMIOLOGY: Famously, Ashkenazi Jews.
• PATHOGENESIS: Gangliosides accumulate in all organs, but especially in brain and retina.
• Lipid-laden macrophages show up in gray matter of cortex in late disease.
• SYMPTOMS:
• Progressive mental deterioration
• Blindness
• Cherry Red Spot shows up on macula in funduscope. This is involvement of retinal ganglion cells.
• NIEMAN-PICK LIPIDOSES: Heterogenous group of disorders relating to lysosomal storage of sphingomyelin, cholesterol, and glycolipids in macrophages, in many organs.
• PATHOGENESIS:
• Type-I: Defect in Sphingomyelinase
• Sphingomyelinase hydrolyzes Sphingomyelin ------> Ceramide + Phosphorylcholine
• Type-II: Defect is uncertain.
• FOAM CELL is characteristic: Enlarged macrophage with uniform vacuoles of lipid and cholesterol.
• SYMPTOMS: BRAIN accumulation of sphingomyelin. Neurologic problems are most common cause of death. Brain atrophy.
• HURLER'S SYNDROME (MUCOPOLYSACCHARIDOSES): Accumulation of Glycosaminoglycans (GAG's) in many organs.
• PATHOGENESIS: Failure of any of then 10 enzymes involved in GAG breakdown.
• GAG's: Chondroitin Sulfate, Heparin Sulfate, Keratin Sulfate.
• Undegraded GAG's accumulate in macrophages in neurons, liver, and endothelial cells.
• SYMPTOMS: Death occurs in childhood, from pulmonary infections or cardiac complications.
• Coarse facial features and dwarfism give them the nickname of Gargoylism.
• CNS: Progressive gliosis and cortical atrophy.
• SKELETAL: Deformities are a consequence of accumulation of GAG's in chondrocytes.
• CARDIAC: Thickening and distortion of valves, chordae tendineae, and endocardium. Atherosclerosis.
• Hepatosplenomegaly.
• HUNTER'S SYNDROME: An X-Linked Mucopolysaccharidoses. Death earlier than 15 yrs of age.
• GLYCOGENOSES: Glycogen storage disease.
• VON GIERKE'S DISEASE (TYPE I GLYCOGENOSIS): Accumulation of glycogen in the liver.
• PATHOGENESIS: Defect in GLUCOSE-6-PHOSPHATASE, such that glycogen can't be broken down in liver.
• SYMPTOMS: Good prognosis with modern treatment.
• Hepatomegaly
• Hypoglycemia
• POMPE'S DISEASE (TYPE II GLYCOGENOSIS): All organ systems involved.
• SYMPTOMS: Death from heart failure by age 2.
• PATHOGENESIS: Deficiency in enzyme Acid alpha-Glucosidase ------> inexorable accumulation of glycogen in many different cells.
• MCARDLE'S DISEASE (TYPE V GLYCOGENOSIS): Accumulation of glycogen in skeletal muscle, inability to break down muscle glycogen.
• PATHOGENESIS: Deficiency in enzyme Muscle Phosphorylase, which breaks down Glycogen ------> Glucose-1-Phosphate in skeletal muscle.
• SYMPTOMS: Muscle cramps with exercise, possible myoglobinuria.
• ERRORS OF AMINO ACID METABOLISM
• PHENYLKETONURIA (PKU): The leading preventable cause of mental retardation.
• PATHOGENESIS: Deficiency in enzyme Phenylalanine Hydroxylase, which converts Phenylalanine to Tyrosine and also helps to break it down ------> Inability to breakdown phenylalanine.
• Phenylalanine and its metabolites (Phenyl ketones) accumulate. It impairs development of neurons and growth of myelin in early childhood development.
• The symptoms have been proven to originate from Phenylalanine itself.
• SYMPTOMS: Progressive retardation in first few years of life, if diet is not restricted of phenylalanine.
• ALCAPTONURIA (OCHRONOSIS): Excretion of Homogentisic Acid in the urine.
• PATHOGENESIS: Deficiency in Homogentisic Acid Oxidase.
• SYMPTOMS:
• Generalized pigmentation
• Arthritis
• Urine darkens rapidly upon standing.
• Historical Significance: It was one of the first heritable diseases described.
• Ochronosis: Referring to brown-appearing pigment of tissues.
• ALBINISM: Heterogenous group of disorders, all having absent or reduced biosynthesis of Melanin.
• OCULOCUTANEOUS ALBINISM: Most common form of albinism. There are two major types.
• Tyrosinase-Positive OCA: Most common form.
• Complete Albinism early on, but some pigment accumulates later.
• PATHOGENESIS: Basic biochemical defect is not known.
• Tyrosinase-Negative OCA: Complete absence of Tyrosinase and therefore melanin.
• SYMPTOMS:
• Snow-white hair, pink eyes, pink skin
• Severe Ophthalmic Problems: Photophobia, decreased visual acuity, nystagmus, strabismus
• SMITH-LEMLI-OPITZ SYNDROME: No blood cholesterol.
• PATHOGENESIS: Defective enzyme in the cholesterol synthesis pathway.
• Virtually no endogenous cholesterol.
• Buildup of 7-Dehydrocholesterol due to blocked biosynthesis pathway.
• SYMPTOMS: Death at age of six weeks.
• Some polydactyly and syndactyly
• Club foot
• Heart defects

X-LINKED DOMINANT TRAITS: Very rare.

• Females would be affected twice as often as males.
• Familial Hypophosphatemia (Rickets)
• Ornithine Transcarbamylase Deficiency:
• SYMPTOMS:
• Babies will have very high ammonia levels in newborn period.

X-LINKED RECESSIVE:

• DUCHENNE/BECKER MUSCULAR DYSTROPHY: Severe muscle-wasting disease.
• PATHOGENESIS: Deficiency of enzyme DYSTROPHIN, a membrane cytoskeletal protein, like spectrin, found in muscle.
• Dystrophin molecules form an intracellular network (anchored to cytoplasm), important in forming mechanical properties of muscle.
• FLEXIBILITY is lacking MD.
• SYMPTOMS: Death by 17 years
• Failure to walk by 18 months
• Pseudohypertrophy of calf muscles.
• Progressive retardation.
• Cardiac problems (frequent cause of death)
• HEMOPHILIA-A (FACTOR VIII DEFICIENCY): No clotting; spontaneous bleeding into joints, muscles, internal organs.
• PATHOGENESIS: The Factor VIII gene is very large.
• SYMPTOMS: Deforming arthritis is common complication, caused by bleeding into joints.
• TREATMENT: Recombinant Factor VIII
• FRAGILE-X SYNDROME:
• PATHOGENESIS: Expansion of trinucleotide repeats on the X chromosome. The more the repeats, the greater the level of retardation.
• Inheritance tends to amplify the number of repeats.
• CGG is the repeated triplet in Fragile X syndrome.
• SYMPTOMS: Second only to Down's Syndrome as a cause of mental retardation.
• Frequently seen with Autism as well as mental retardation.

MULTIFACTORIAL DISEASES: Multiple genes and environmental factors.

• Heritability:
• Probability of affecting later offspring is affected by whether older siblings are affected.
• The more severe the defect, the greater the risk of transmission.
• The expression of symptoms is proportional to the number of mutant genes.
• CLEFT LIP and CLEFT PALATE: Failure of closure of frontal prominence with maxillary process, either unilaterally or bilaterally.
• PATHOGENESIS: Multifactorial inheritance. Multiple genes direct it, and environmental factors at the time can influence it.
• Having one Cleft-Lip baby
• Common examples of adult diseases
• HYPERTENSION
• DIABETES TYPE II
• PSORIASIS
• SCHIZOPHRENIA
• ATHEROSCLEROSIS
• GOUT
• ANKYLOSING SPONDYLITIS
• Common Examples of Childhood Diseases:
• CONGENITAL HEART DISEASE
• PYLORIC STENOSIS

Diseases of Infancy and Childhood:

• PREMATURE BIRTH:
• Appropriate for Gestational Age (AGA): Premature Birth
• Risk Factors:
• Maternal Illness
• Uterine Incompetence
• Fetal Disorders
• Placental Abnormalities
• SYMPTOMS: IRDS, metabolic disturbances (jaundice), anemia, bacterial sepsis
• Small for Gestational Age (SGA): Low Birth-Weight Babies
• Risk Factors
• Impaired maternal health and nutrition
• Interference with placental circulation or function
• Disturb the growth or development of the fetus.
• SYMPTOMS: Much more heterogenous. Congenital birth defects.
• PREMATURE ORGANS:
• LUNGS: Amniotic Fluid Aspiration is actually retained amniotic fluid (it never evacuates the lungs) in premature infants.
• LIVER: Premature infant is deficient in Glucuronyl Transferase, which results in accumulated bilirubin ------> Neonatal Jaundice.
• BRAIN: Incomplete CNS development at birth.
• INFANT RESPIRATORY DISTRESS (IRDS): Premature infants have no Pulmonary Surfactant at birth, leading to infant Hyaline Membrane Disease, or atelectasis of the alveoli.
• SYMPTOMS: HYPOXIA ------> Pulmonary Vasoconstriction ------> Increased Right to Left shunting through Foramen Ovale and Ductus Arteriosus
• Cyanosis
• ERYTHROBLASTOSIS FETALIS:
• PATHOGENESIS: Most commonly, an Rh^-, sensitized mother giving birth to her second Rh⁺ child. Rh⁺ child will then elicit antibodies from maternal circulation ------> massive fetal anemia.
• There are other more minor form of erythroblastosis, involving other antigenic incompatibilities.
• SYMPTOMS:
• HYDROPS FETALIS: Severe edema and secondary congestive heart failure in fetus, caused by severe anemia. Fatal.
• KERNICTERUS: Bilirubin Encephalopathy results from fetal jaundice. Bilirubin staining of brain, particular pontine nuclei, basal ganglia, dentate nucleus.
• Any infant with jaundice is susceptible to Kernicterus

BIRTH INJURY:

• CEPHALOHEMATOMA: Subperiosteal hemorrhage defined to a single cranial bone.
• SYMPTOMS: They usually resolve without complications.
• INTRACRANIAL HEMORRHAGES: May lead to Cerebral Palsy. Can result from traumatic delivery.

SUDDEN INFANT DEATH SYNDROME (SIDS): Leading cause of death during first year of life.

• PATHOGENESIS: Unknown, although sleep apnea may play a role.
• RISK-FACTORS: Sleeping in prone position, smoking parents, socioeconomic status

NEOPLASMS OF INFANCY and CHILDHOOD:

• HAMARTOMAS: Focal, benign overgrowths of one or more of the mature cellular elements of normal tissue.
• HEMANGIOMAS: Either a hamartoma or a true neoplasm.
• Port Wine Stain: Dark purple color to affected area, capillary hemangioma, like a bruise.
• They may regress spontaneously.
• LYMPHANGIOMAS: Cystic Hygromas
• MORPHOLOGY: Unilocular or multilocular cysts along lymphs vessels in head and neck region.
• They do not regress spontaneously and should be resected.
• SACROCOCCYGEAL TERATOMAS: Germ cell neoplasm, the most common solid tumor in the newborn.

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HEMORRHAGE:

• PURPURA: Diffuse superficial hemorrhage, up to 1cm in diameter.
• ECCHYMOSIS: Bruise.
• PETECHIA: Pinpoint hemorrhage, esp. in conjunctivae and skin.

HYPEREMIA

• PHYSIOLOGIC (ACTIVE): Exercise
• PASSIVE: Congestive
• Lung: Heart Failure Cells have hemosiderin.
• Liver: Nutmeg Liver
• Spleen
• Edema and Ascites

THROMBOSIS: Clot. Technically a thrombus is adherent to vascular endothelium.

• LINES OF ZAHN: Help distinguish a thrombus from a post-mortem clot which is where blood coagulates post-mortem and separates into layers.

EMBOLISM: Anything that knocks loose and lodges in the blood.

• AIR EMBOLUS: As in Decompression Disease
• AMNIOTIC FLUID EMBOLUS: Can lead to Disseminated Intravascular Coagulopathy (DIC), due to the presence of Thromboplastin in amniotic fluid.
• BONE MARROW EMBOLUS
• FAT EMBOLUS: Large bone fractures
• FOREIGN BODY EMBOLUS: Bullet
• PARADOXICAL EMBOLUS: Emboli originally from venous side go to arterial side and cause an infarct, due to a patent foramen ovale or other septal defect.
• THROMBO EMBOLUS: Most common.

ANASARCA: Profound, generalized edema.

DISSEMINATED INTRAVASCULAR COAGULOPATHY (DIC): Usually fatal. Thousands of intravascular micro-clots which consume all platelets and result, paradoxically, in uncontrolled bleeding in certain areas.

• CAUSES:
• Amniotic Fluid Embolus, release of Thromboplastin into blood.
• Gram negative endotoxic shock

TROUSSEAU SYNDROME: Paraneoplastic syndrome of hypercoagulable state. Classically associated with pancreatic cancer

INFARCTION: Acutely, it leads to Coagulative Necrosis.

• RED INFARCT: Pulmonary infarct, or infarct of an organ that has dual blood supply.
• PALE INFARCT: Single blood supply, as in kidney.

EDEMA: OK?

SHOCK:

• CARDIOGENIC SHOCK
• SEPTIC SHOCK
• TOXIC SHOCK: Due to Staph and Strep exotoxin, TSS. These bugs are induced to make TSS by the presence of a rare phage.
• HYPOVOLEMIC SHOCK
• NEUROGENIC SHOCK: ANS failure.
• STAGES:
• REVERSIBLE: High vasoconstriction, vascular tone.
• CRITICAL: Very high TPR
• IRREVERSIBLE: Pooling and stagnation, interstitial edema, severe acidosis.

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