Normal Lab Values

Week 6: Genetic Disorders

Suggested readings from
Robbins 8th ed.
pp. 183-258; 510-520

Pathology Cases for Week 6

 

Pathology Case Descriptions

CASE NUMBER 1
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Clinical History: This 45-year-old male had a long history of proteinuria which progressed to end stage renal failure. He was maintained on dialysis but began to experience complications. A transplant donor was identified and a kidney transplant was performed.

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(Summary of Gross Findings - click here)
The kidney is markedly enlarged. The parenchyma has been replaced by multiple cysts which vary in size. The cysts are filled with fluid.
(Summary of Microscopic Findings - click here)
This is a complete hemi section of the kidney. Examination reveals that the entire kidney is replaced by multiple cysts up to several centimeters in diameter. Microscopic examination shows the cysts to be markedly dilated tubules that contain granular eosinophilic material (probably protein) and in some cases, red blood cells. The glomeruli, are compressed.
(Review Normal Histology - click here)
Norm No. 2
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The kidney excretes soluble waste from the body and controls electrolyte balance. It consists of the cortex and the medulla. Within the outer cortex, glomeruli with delicate capillary loops are seen.  The basement membrane is thin and without inflammation or thickening. Bowman’s capsule that surrounds the glomerulus is thin. The interstitium demonstrates no evidence of inflammation or fibrosis.  In the areas between the glomeruli, tubules and arterioles are seen. The tubules are intact.  The vessels exhibit no narrowing or wall thickening. The inner medulla of the kidney contains only tubules and blood vessels. Larger arteries and veins are located at the interface between cortex and medulla.

 

What is the most likely diagnosis?

ANSWER

 

1-1. The pattern of inheritance in this disease is:

  1. Autosomal recessive
  2. Autosomal dominant
  3. X-Linked recessive
  4. X-Linked dominant

ANSWER

 

 

 

 

CASE NUMBER 19
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Clinical History: This 51-year-old male had tuberculosis for many years.  He developed some ankle edema, and was found to have an enlarged liver and 2+ proteinuria.

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(Summary of Gross Findings - click here)
Both kidneys were large, each weighing 250 grams. This chronic renal disease may actually increase the size of the kidney. Pale deposits of amyloid are present in the cortex, most prominently at the upper center. The liver weighed 1900 grams and was firm with a waxy appearance. The heart (not shown) was also large, weighing 470 grams.
(Summary of Microscopic Findings - click here)
Kidney: The same type of hyaline pink material is present in the glomeruli, and is deposited between the endothelial cells and the basement membrane. In some places, it may be present in masses that encroach on the lumen of the capillary. The amyloid can also be recognized in the walls of some small arteries, and in a few places can be seen around the tubules in the interstitial tissue.

Liver: Most of the liver is replaced by homogenous, hyaline pink-staining amyloid which has been laid down between the sinusoids and the liver cells. This would stain with Congo red, or would be metachromatic if stained with crystal violet. The liver cords are replaced or compressed, and appear as widely separated thin cords of cuboidal cells. Bile plugs are present in the bile capillaries.
(Review of Normal Histology- click here)
Kidney:

Norm No. 2 [ImageScope] [WebScope]

The kidney excretes soluble waste from the body and controls electrolyte balance. It consists of the cortex and the medulla. Within the outer cortex, glomeruli with delicate capillary loops are seen.  The basement membrane is thin and without inflammation or thickening. Bowman’s capsule that surrounds the glomerulus is thin. The interstitium demonstrates no evidence of inflammation or fibrosis.  In the areas between the glomeruli, tubules and arterioles are seen. The tubules are intact.  The vessels exhibit no narrowing or wall thickening. The inner medulla of the kidney contains only tubules and blood vessels. Larger arteries and veins are located at the interface between cortex and medulla.

Liver:

Norm No. 3 [ImageScope] [WebScope]

The liver is the organ that metabolizes nutrients received from the digestive tract. These nutrients and processed by tissue hepatocytes which are large polygonal cells. The hepatocyes are separated by portal triads. The triads consist of an artery, a vein and a bile duct. The bile duct is lined by cuboidal epithelium. The artery has a muscular wall and a flat endothelial lining. The sinuses are well defined and contain a small amount of blood.

 

19-1. What is the BEST diagnosis?

  1. Nodular diabetic glomerulosclerosis
  2. Systemic lupus erythematosis
  3. Amyloidosis
  4. Henoch-Schonlein purpura
  5. Diffuse mesangial sclerosis

ANSWER

 

 

19-2. This condition may be associated with:

  1. Rheumatoid arthritis
  2. Bronchiectasis
  3. Chronic osteomyelitis
  4. Multiple myeloma
  5. ALL of the above

ANSWER

 

 

19-3. Deposition of which of the following may produce the same histological appearance?

  1. Transthyretin (pre-albumin)
  2. Lambda immunoglobulin light chains
  3. β2 microglobulin
  4. ALL of the above

ANSWER

 
 

 

 

CASE NUMBER 20
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Clinical History: This 55-year-old female first came to medical attention when she complained of frequent urination, increased thirst and weight loss at age 15. Insulin dependent diabetes was diagnosed. She developed proteinuria at age 20. Her disease progressed until she became dialysis dependent at age 45. She expired due to pneumonia after a below knee amputation

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(Summary of Gross Findings - click here)
The kidneys were small and each weighed 100 grams. The surface was irregular with pits and small cysts.
(Summary of Microscopic Findings - click here)
There are glomerular lesions consisting of diffuse and nodular glomeroslerosis. Nodular glomerulosclerosis or Kimmelstiel-Wilson lesions are ball-like deposits of PAS positive material which contain trapped mesangial cells. These occur in 15-30% of long time diabetics and are virtually pathognomonic of the disease. Diffuse glomeruloslerosis usually appears as global sclerosis of the glomerular tuft. Chronic pyelonephritis, arterio and arteriolo nephrosclerosis as seen here are also typical findings in diabetic kidneys.
(Review Normal Histology - click here)
Norm No. 2
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The kidney excretes soluble waste from the body and controls electrolyte balance. It consists of the cortex and the medulla. Within the outer cortex, glomeruli with delicate capillary loops are seen.  The basement membrane is thin and without inflammation or thickening. Bowman’s capsule that surrounds the glomerulus is thin. The interstitium demonstrates no evidence of inflammation or fibrosis.  In the areas between the glomeruli, tubules and arterioles are seen. The tubules are intact.  The vessels exhibit no narrowing or wall thickening. The inner medulla of the kidney contains only tubules and blood vessels. Larger arteries and veins are located at the interface between cortex and medulla.

 

What is the most likely diagnosis?

ANSWER

 

20-1. The most common cause of end stage renal disease is:

  1. Hypertension
  2. Polycystic kidney
  3. Diabetes mellitus
  4. Glomerulonephritis

ANSWER

 

 

20-2. What type of glomerular lesion is seen characteristically in diabetic nephropathy?

  1. Basement membrane thickening
  2. Nodular glomerulosclerosis
  3. Capsular drop
  4. Fibrin cap
  5. ALL of the above

ANSWER

 

 

 

 

CASE NUMBER 28
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Clinical History: A 47-year-old female with a history of hypertension of at least 8 months duration noted sudden onset of severe inter-scapular pain which rapidly radiated to base of neck but not to abdomen 7 hours prior to admission. On admission her BP was 160/130 (both arms) and pulse was 80 and equal bilaterally. No murmurs were noted. A retrograde aortogram revealed a double channel extending from the root of the aorta to the brachiocephalic artery. Aortotomy was performed for attempted repair of the dissecting aneurysm, but during the procedure there occurred an adventitial tear with subsequent hemopericardium and cardiac tamponade. The patient expired on the operating table 6 hours after surgery had begun.

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(Summary of Gross Findings - click here)
The heart weight was 550 grams and there was left ventricular hypertrophy. The aorta had an intimal tear at the base of the brachiocephalic artery with dissection of the media occurring in the outer 2/3 and extending proximally to within 0.5 cm of the aortic valve. There was an adventitial tear at this point.
(Summary of Microscopic Findings - click here)
There is a blood-filled tear between the inner 2/3 and outer 1/3 of the media. Note necrosis and deposition of fibrin along the margins of the defect. The remainder of the media contains the changes of "cystic medial necrosis."
(Review Normal Histology - click here)
Norm No. 9
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The aorta is a large elastic artery. The luminal surface is lined by flat endothelial cells. This is called the “intima”. Adjacent to the intima is the internal elastic lamina. This is composed of elastin and has a corrugated appearance on histological section. Adjacent to the internal elastic lamina is the tunica media which is composed of smooth muscle. Finally, the outermost layer is the adventitia which is composed of connective tissue.

 

What is the most likely diagnosis?

ANSWER

 

28-1. Most patients with this disease usually have:

  1. Marfan syndrome
  2. Surgical injury to aorta
  3. Hypertension
  4. Syphilis

ANSWER

 

 

 

CASE NUMBER 31
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Clinical History: This 45-year-old man had been well until he was awakened by chest pain that radiated to both arms and neck and was associated with diaphoresis. His blood pressure was 160/110. He was treated with diuretics (Lasix), but he continued to gain weight. Two days after the onset of the chest pain he had a cardiac arrest and died.

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(Summary of Gross Findings - click here)
The heart was slightly enlarged weighing 460gms. There was severe atherosclerosis of all the major coronary arteries with a recent thrombotic occlusion of the proximal left anterior descending coronary artery. A recent transmural infarct was present in the left ventricle that involved the interventricular septum and the papillary muscle.
(Summary of Microscopic Findings - click here)
The slide includes a transmural section of the left ventricle. Nearly the entire section is involved by infarct. However, there is a thin rim (5 to 10 cell layers) of endocardial myocytes which have survived because of diffusion of oxygen and nutrients from the ventricular cavity. Other viable myocytes can be found around larger blood vessels within the section. The intense hypereosinophilia of the necrotic myocytes can best be appreciated by comparing the thin rim of lighter staining subendocardial myocytes with the deeper cells. Note also the karyolysis that is characteristic of coagulation necrosis. In some areas there is little inflammatory response. This observation is explained by microvascular necrosis which does not allow access of circulating leukocytes to these areas. In other areas, especially in the epicardial half of the infarct, there is an intense acute inflammatory response. Many intact neutrophils can be seen. In addition, there are many nuclear fragments from lysed neutrophils. Macrophage activity is not evident. These features of the inflammatory response indicate that the infarct was approximately three to four days old. Note also that the inflammation extends to the epicardial surface and that there are deposits of fibrin on the epicardium. This is called fibrinous pericarditis. The granular grey material seen within some blood vessels is barium sulfate, which was injected to permit post-mortem study of the coronaries by radiography.
(Review Normal Histology - click here)
Norm No. 13
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Normal heart tissue sections demonstrate no evidence of fibrosis or hemorrhage.  Cardiac myocytes have moderately sized centrally located nuclei. Normal myocytes are not brightly eosinphilic. Normally no inflammation is seen.  Normal cardiac myocytes do not show hypertrophy.

 

What is the most likely diagnosis?

ANSWER

 

31-1. The event most likely associated with this patient’s problem was:

  1. Occlusion of a coronary vein
  2. Occlusion of a coronary artery
  3. Stabbed with ice pick
  4. Broken heart

ANSWER

 

 

31-2. What microscopic feature best describes what happened to the nucleus?

  1. Pyknosis
  2. Karyorrhexis
  3. Karyolysis
  4. Apoptosis

ANSWER

 

 

31-3. What molecular events led to the increase eosin staining of the dead myocytes?

  1. Loss of ribosomes
  2. Protein denaturation
  3. Protein synthesis
  4. A & B

ANSWER

 

 

31-4. What microscopic feature in this patient indicates that this infarct is at least 24 hours old?

  1. Coagulation necrosis & loss of nuclei
  2. Wavy fibers
  3. Macrophage infiltrate
  4. Granulation tissue

ANSWER

 

 

31-5. What myocardium is the most vulnerable to ischemic injury in hypovolemic shock?

  1. Subepicardial, left ventricle
  2. Mid-myocardial, left ventricle
  3. Subendocardial, left ventricle
  4. Subendocardial, right ventricle

ANSWER

 

 

 

 

CASE NUMBER 85
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Clinical History: This 64-year-old white female was morbidly obese.

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(Summary of Gross Findings - click here)
The liver weighed 1980 grams. It had a greasy appearance.
(Summary of Microscopic Findings - click here)
The areas of fatty change are readily visible with use of scanning power. They are zonal. Note the peri-portal areas are severely involved and the areas of fatty change extend from one portal area to another. The more severely involved cells have eccentric nuclei and the entire cytoplasm is replaced by a fat globule.
(Review Normal Histology - click here)
Norm No. 3
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The liver is the organ that metabolizes nutrients received from the digestive tract. These nutrients and processed by tissue hepatocytes which are large polygonal cells. The hepatocyes are separated by portal triads. The triads consist of an artery, a vein and a bile duct. The bile duct is lined by cuboidal epithelium. The artery has a muscular wall and a flat endothelial lining. The sinuses are well defined and contain a small amount of blood.

 

85-1. What is the most likely diagnosis?

  1. Metastatic carcinoma
  2. Cirrhosis
  3. Fatty liver
  4. Intrahepatic bile stasis

ANSWER

85-2. What of the following is the least likely to cause this condition?

  1. Excessive alcohol consumption
  2. Malnutrition
  3. Catabolic state from cancer
  4. Chronic right heart failure

ANSWER

 

85-3. If a thin CEO were to develop this disease, you would most likely suspect:

  1. Excessive alcohol consumption
  2. Malnutrition
  3. Catabolic state from cancer
  4. Chronic right heart failure

ANSWER

 

 

 

 

CASE NUMBER 81
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Clinical History: This 62-year-old white male had a history of alcoholism.

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(Summary of Gross Findings - click here)
The liver weighed 1800 grams. The entire organ was uniformly composed of nodules about 0.5 cm in diameter, each surrounded by fibrous tissue. The organ was jaundiced and firm.
(Summary of Microscopic Findings - click here)
The usual architecture present in the liver has been completely disrupted by the bands of connective tissue. In these bands one sees chronic inflammatory cells, mainly lymphocytes and other mononuclear cells. There is some proliferation of the bile ductules.
(Review Normal Histology - click here)
Norm No. 3
[ImageScope] [WebScope]

The liver is the organ that metabolizes nutrients received from the digestive tract. These nutrients and processed by tissue hepatocytes which are large polygonal cells. The hepatocyes are separated by portal triads. The triads consist of an artery, a vein and a bile duct. The bile duct is lined by cuboidal epithelium. The artery has a muscular wall and a flat endothelial lining. The sinuses are well defined and contain a small amount of blood.

 

What is the most likely diagnosis?

ANSWER

 

81-1. What feature of this disease is not seen on microscopic exam in this patient?

  1. Regenerative nodules
  2. Fibrosis
  3. Bile duct proliferation
  4. Fatty change

ANSWER

 

 

81-2. What is a catastophic cause of death often associated with this disease?

  1. Hepatic failure
  2. Ruptured hemorrhoids
  3. Ruptured spleen
  4. Ruptured esophageal varices

ANSWER

 

 

CASE NUMBER 134
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Clinical History: An 81-year-old, asymptomatic female was found to have guaiac positive stool on routine examination. Flexible sigmoidoscopy revealed a rectal mass.

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(Summary of Gross Findings - click here)
A 4 cm fungating, centrally ulcerated mass was found on gross examination.
(Summary of Microscopic Findings - click here)
This section, which includes the edge of the tumor shows invasive adenocarcinoma arising in a villous adenoma. Tall villi lined by neoplastic epithelium replace the normal mucosa at the edge of the mass. Centrally, where the lesion was ulcerated, tumor infiltrates through the muscularis propria and in some sections, enters the subserosal adipose tissue. Irregular glandular spaces are lined by tumor cells and large pools of mucin are seen, as well as desmoplastic (fibrotic) stroma. Although the nuclei of the carcinoma are anaplastic when compared to the normal colon mucosa, the neoplastic epithelium retains a columnar appearance, typically seen in colon carcinoma.
(Review Normal Histology - click here)
Norm No. 27 Colon
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The colon is lined by glandular epithelium with numerous mucin secreting goblet cells. The epithelium is infolded into straight tubular glands of uniform diameter to increase the surface area available for secretion and absorption.

What is the MOST LIKELY diagnosis?

ANSWER

 

 

GENETIC DISORDERS Review Items

Key Vocabulary Terms (click here to search any additional terms on Stedman's Online Medical Dictionary)

agenesis fragile site nondisjunction
aneuploid fragile X syndrome operator gene
aplasia gene operon
autosomal genetic disease organogenesis
balanced polymorphism genetic heterogeneity penetrance
Barr body genotype perinatal
buccal smear haploid phenotype
carrier hemizygous pleiotropy
chromosome hereditary disease polysomy
codon hermaphrodites progeria
congenital abnormality heterozygous pseudohermaphroditism
congenital disease homogeneously stained region recessive
deformation homozygous regulatory gene
deletion inversion replication
developmental anomaly karyotype ring chromosome
diploid linkage RNA
DNA Lyon hypothesis rRNA
dominant malformation sex-linked
double minute meiosis structural gene
dysmorphogenesis mitosis teratogenesis
embryonic period monosomy transcription
embryopathy mosaicism translation
euploid mRNA translocation
expressivity multifactorial inheritance triploid
familial disease mutation trisomy
fetal period neonatal tRNA

LEARNING OBJECTIVES

Absolutely critical information you must know to practice medicine is in bold font.
Important information that will be needed for routine patient care is in regular font.
Information about less common diseases that you may encounter in clinical practice and that will probably appear on examinations is in italics

  1. Identify factors which influence the type and extent of congenital anomalies produced by teratogenic agents.

  2. List a maternal therapeutic agent which has been implicated in each of the following malformations:
  3. Describe the morphologic features of the embryopathies associated with ingestion of the following substances during pregnancy:
    • alcohol
    • hydantoin (dilantin)

  4. Discuss the possible influence on oogenesis and spermatogenesis of maternal and paternal exposure to toxic agents.

  5. Discuss five common genetic abnormalities in terms of: pathogenesis, common features, classification and give examples of each.

  6. List three examples of each of the following types of genetic diseases:
    • simple (autosomal) dominant
    • simple (autosomal) recessive
    • sex-linked recessive
    • multifactorial inheritance

  7. Given a family history or pedigree, indicate the most likely mode of inheritance:
    • autosomal dominant
    • autosomal recessive
    • sex-linked dominant
    • sex-linked recessive

  8. Given the mode of inheritance or a family history involving a disease with classic Mendelian inheritance, predict the likelihood of various phenotypes and genotypes in family members.

  9. Discuss the use of chromatin (Barr) body identification in the recognition and diagnosis of chromosome disorders.

  10. Compare chromosome analysis (karyotyping) and Barr body count (buccal smear)
    • basic steps in performance of test
    • appropriateness in various types of clinical situations
    • costs and time involved
    • accuracy

  11. Outline pathogenetic mechanisms of importance in the production of:
    • mutations
    • acquired congenital anomalies
    • nondisjunction

  12. Discuss chromosomal abnormalities in terms of:
    • pathogenesis
    • classification
    • specific features of the more common examples

  13. List probable causes and examples of mutations and acquired congenital anomalies.

  14. Given photographs of karyotypes, determine the abnormalities in sex or autosomal chromosomes.

  15. Distinguish on the basis of clinical signs, symptoms and karyotype among:

  16. Compare translocation and mosaic types of Down syndrome on the basis of:
    • karyotype
    • maternal factors
    • inheritance

  17. Compare pseudo- and true hermaphroditism on the basis of genetic and gonadal morphology.

  18. Compare rubella infection and thalidomide ingestion in pregnant women in terms of epidemiology and developmental effects on the embryo and fetus.

  19. Discuss the usefulness of the following laboratory tests in regard to genetic disorders and congenital malformations:
    • amnionic fluid analysis
    • tissue culture
    • buccal smear
    • chromosomal analysis

  20. Discuss the following lysosomal storage diseases in terms of enzyme deficiency, stored metabolite and clinical phenotype:

 

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