Questions and Answers
What is the definition of tall stature in terms of standard deviation?
What is the most common chromosomal cause of short stature?
What is the name of the syndrome characterized by short stature, development delay, and congenital cardiac anomaly?
What is the name of the gene mutation that causes achondroplasia?
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What is the term for short stature caused by an unknown etiology?
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What is the name of the new drug that has an effect on growth and possibly spinal stenosis in achondroplasia?
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What is the characteristic feature of skeletal dysplasia?
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What is a characteristic of osteosarcoma (OS)?
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Which genes are involved in hereditary Paget's disease of bone?
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What is the result of a p53 mutation in a cell?
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What is the incidence of osteosarcoma in Li-Fraumeni syndrome?
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What is the result of a conditional knockout for Rb1 and Tp53 in osteoblastic precursor cells?
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What is characteristic of Paget's disease of bone?
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What is the percentage of children with germline mutations in a cancer-predisposing gene in pediatric cancer?
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What is the association between Paget's disease of bone and osteosarcoma?
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What is the role of TP53 and RB1 genes in osteosarcoma?
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What is the type of tumors that occur in retinoblastoma?
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What is the main effect of the vosoritide on the growth of children with achondroplasia?
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What is the characteristic feature of Leri-Weill dyschondrosteosis?
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What is the function of osteoclasts in bone remodeling?
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What is the primary site of occurrence of giant cell tumor of bone?
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What is genetic instability?
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What is the main criterion for evaluating the response to chemotherapy in giant cell tumor of bone?
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What is a driver event?
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What is the mode of inheritance of Leri-Weill dyschondrosteosis?
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What is the effect of vosoritide on blood pressure?
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What is the difference between inherited cancer and familial clustering?
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What is the characteristic feature of hyperachondroplasia?
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What is a phenocopy?
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What is the role of osteoblasts in bone remodeling?
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What is retinoblastoma?
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What is the percentage of risk of a baby having achondroplasia if one parent is affected?
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What is the function of the shelterin complex?
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What is the most common type of polyp that can lead to colon carcinoma?
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What is the characteristic of hyperplastic polyp?
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What is the difference between tubulovillous adenoma and tubular adenoma?
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What is the characteristic feature of adenocarcinoma colon?
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What is the name of the gene that is mutated in Familial Adenomatous Polyposis (FAP)?
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What is the percentage of endometrial cancers in Lynch syndrome?
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What is the name of the condition characterized by fibrotic scarring of glomeruli?
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What is the name of the autosomal recessive polyposis syndrome caused by mutations in both alleles of the MUTYH gene?
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What is the name of the type of glomerulosclerosis characterized by less than 50% of all glomeruli being involved with majority showing sclerosis?
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What is the name of the test used to screen for cancers in Lynch syndrome?
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What is the name of the gene that is often methylated in sporadic MSI-high CRC?
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What is the term used to describe the process of accumulation of mutations leading to colon carcinoma?
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What is the percentage of the population that possesses a mutated copy of the MUTYH gene?
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What is the result of granulocytes degranulating and producing proteases?
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What is the characteristic of the immune complex in the sub-endothelial location?
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What is the cause of sub-epithelial deposits?
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What is the result of frustrated chemotaxis?
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What is the characteristic of membranous glomerulopathy?
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What is the result of abnormal basal membrane production in membranous glomerulopathy?
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What is the treatment for membranous glomerulopathy?
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What is the characteristic of the mesangial space?
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What is the cause of deposits in the mesangial space?
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What is the result of deposits in the mesangial space?
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What is the primary mechanism by which the immune response is slowed in IgA nephropathy?
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What is the characteristic of the basement membrane in diabetic nephropathy?
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What is the result of the loss of glycocalyx in diabetic nephropathy?
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What is the role of VEGF in maintaining the microvasculature?
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What is the advantage of using animal models in diabetic nephropathy research?
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What is the effect of VEGF knockout on the glomerulus in diabetic mice?
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What is the role of podocytes in the production of VEGF?
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What is the effect of streptozotocin on beta cells in the pancreas?
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What is the characteristic of the glomerulus in diabetic mice?
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What is the effect of VEGF on the endothelial cells in the glomerulus?
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What is the primary mechanism by which alloantigens contribute to the formation of immune complexes in the kidney?
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What is the result of granulocyte degranulation in the kidney?
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What is the term for the syndrome characterized by hematuria, renal dysfunction, and hypertension?
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What is the primary location of immune complex deposition in the first type of glomerular localization?
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What is the role of antibody in the formation of immune complexes in the kidney?
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What is the consequence of increased blood pressure in the kidney due to proliferation of cells?
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What is the term for the abnormal casts formed in the urine due to the presence of blood?
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What is the effect of VEGF inhibition in animal models of diabetic nephropathy?
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What is the primary cause of glomerulosclerosis?
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What is the location of the immune complex deposition in the second type of glomerular localization?
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What is the role of sFlt-1 in reducing renal complications in diabetic nephropathy?
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What is the role of granulocytes in the inflammatory response in the kidney?
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What is the primary function of the kidneys in regulating blood pressure?
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What is the characteristic feature of nephritic syndrome?
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What is the effect of VEGF-A on endothelial cells?
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What is the role of M2 macrophages in the context of sFlt-1 treatment?
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What is the characteristic feature of membranous nephropathy?
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What is the result of a mutation in the mismatch repair genes in Lynch syndrome?
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What is the primary function of the kidneys in regulating electrolyte balance?
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What is the characteristic feature of acute renal insufficiency?
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Study Notes
Height and Stature
- Height is 60-80% genetic, influenced by feeding, health, and medication
- Low penetrance genes have a small influence on height, while high penetrance genes have a significant effect
- Causes of short stature:
• Primary growth disorder
- Syndromes
- Small for gestational age (SGA) without catch-up growth
- Skeletal dysplasia
- Disorder of bone metabolism • Secondary growth disorders
- Malnutrition
- Celiac disease
- Hormonal disorder
- Metabolic disorder • Idiopathic short stature (unknown cause)
- Chromosomal causes of short stature: • Down syndrome • Turner syndrome (1 X chromosome or missing short arm of one X chromosome)
Noonan Syndrome
- Features:
• Short stature
• Development delay (mean IQ 86)
• Facial features:
- Broad neck
- Low set ears
- Hypertelorism, ptosis • Congenital cardiac anomaly • Pectus deformity • Lymphatic abnormalities • Coagulation defect • Cryptorchidism
Skeletal Dysplasia
- Abnormalities of epiphysis, metaphysis, and/or diaphysis
- Causes disproportionate short stature (limbs too short for trunk or vice versa)
- Examples:
• Achondroplasia (Lili putian)
- Features:
- Short stature
- Large head
- Short arms and legs
- Skin creases
- Pronounced lumbar lordosis (bent back)
- Deep nasal bridge
- Frontal bossing (pronounced forehead)
- Short hands with trident
- Treatment: symptomatic, possibly Vosoritide (new drug with effect on growth and spinal stenosis) • Leri-Weill dyschondrosteosis
- Features:
- Short stature
- Short arms and legs
- Madelung deformity
- Muscle hypertrophy
- Short 4th metacarpal bone
- Features:
Disorders of Bone
- HC/13 Giant cell tumour of bone:
• Histology: giant cells, osteoclast-like cells
• Location: end of bone, mostly epiphysis or metaphysis
• Cells involved in bone remodeling:
- Osteoprogenitor cells (MSC), osteoblast, lining cells, osteocytes, osteoclast • Osteoclast normal function: resorbs bone, pumps hydrogen into environment, acidic environment
- Malignancy in giant cell tumor:
• High-grade sarcoma arising in/next to giant cell tumor
• Rare: resection and chemotherapy response
• Primary osteosarcoma:
- Rb and p53 mutations
- High genetic instability, chromothripsis, and kataegis
Hereditary Forms of Cancer
- Germline genetics: hereditary disease and mendelian inheritance patterns
- Somatic genetics: acquired DNA changes during tumor development
- The multistep nature of cancer: time is an enemy, and cells are exposed to intrinsic mutation processes
- Genetic instability: when a cell has a mutation in a gene important for DNA protection
- Countermeasures: DNA damage repair mechanisms
- Driver events: • Activated oncogenes • Defective tumor suppressor genes (Rb and p53) • Cancer usually develops during later decades of life
- Inheritance patterns: • Autosomal dominant • Autosomal recessive • X-linked
Paget's Disease of Bone
- Increased bone resorption and formation
- Primary abnormality resides in osteoclasts
- Dense, inactive, and largely acellular bone
- Increased risk of osteosarcoma (0.15-1%)
Hereditary Colorectal Cancer
- 10% of patients with melanoma have a positive family history
- Familial clustering of melanoma is caused by pathogenic gene variants in CDKN2A, BAP1, POT1, TERT, TERF2IP, ACD, MITF, NEK11
- Understanding the genetic basis of melanoma susceptibility gives insight into tumor suppressor mechanisms and provides opportunities for personalized surveillance, prevention, and treatment
- Normal histology: • Layers: epithelial, lamina propria, muscularis mucosa, submucosa • Polyps: almost all colon carcinomas start with a polyp • Hyperplastic polyp: serrated lumina, no dysplasia • Tubulovillous adenoma: darker morphology, no dysplasia • Dysplasia: hyperchromasia, enlarged nuclei, disturbed growth patterns, mitosis • Adenocarcinoma colon: submucosal proliferation of glands
- Development of colon carcinoma: • Stepwise process • Accumulation of mutations • Morphologic features increasing during progression
- Hereditary colon cancer: • Familial Adenomatous Polyposis (FAP) • Lynch syndrome (non-polyposis syndrome) • MUTYH-associated polyposis (MAP)
Microscopy and Pathology of Nephrosclerosis
- Glomerulosclerosis: fibrotic scarring of glomeruli
- Most common cause of end-stage renal disease is aging
- Glomerulosclerosis: nomenclature • Focal: <50% of all glomeruli involved, majority showing sclerosis • Segmental: majority of involved glomeruli show sclerosis in <50% of cut surface
- Incidence of focal global glomerulosclerosis with age
- Causes: • Ischemia • Inflammation • Endocrine • Epithelial damage • Infection • Hyperperfusion • Unknown ('primary FSGS')
Immune Complexes and Glomerulosclerosis
- Relation between glomerular localization of immune complexes and clinical picture
- Antibodies play a major role in inflammation
- Anatomy of the kidney: • Glomerulus: a ball with one big/long capillary • Bowman capsule: capsel around the capillary
- 4 localizations for deposits of immune complexes: • Under the sub-endothelium • Under the epithelium • In the mesangium • In the glomerular basement membrane### Nephritic Syndrome
- Characteristics:
- Hematuria
- Renal dysfunction
- Hypertension
Immune Complex Deposits
- Sub-endothelial deposits:
- Antibodies bind to molecules in the glomerular basal membrane (auto- or allo-antigens)
- Antibodies bind to the FC tail, attracting and activating complement precursors
- Complement attracts granulocytes, leading to degranulation and protease production
- Proliferation, blocking blood flow, and activating the renin-angiotensin system (RAS)
- Leading to renal dysfunction and hypertension
- Sub-epithelial deposits:
- Antibodies bind to epitopes in the sub-epithelial space (auto- or allo-antigens)
- Fc tail sticks out of the membrane, attracting complement precursors
- Frustrated chemotaxis, leading to granulocyte accumulation and irritation
- Eventual proteinuria, hypo-proteinemia, and edema
Membranous Glomerulopathy
-
Stages:
- Sub-epithelial deposits
- Thickening of the basal membrane due to abnormal production
- Basal membrane encapsulation of complexes
- Scarred basal membrane with holes
-
Treatment:
- Anti-inflammatory drugs
- Protein-free diet
Mesangial Deposits
-
Causes:
- Abnormal antibodies (e.g. IgA nephropathy)
- Auto-antibodies against molecules in the mesangium (e.g. laminin)
-
Characteristics:
- Microscopic hematuria
- Slow inflammation leading to scarring, accumulation of extracellular matrix, and decreased filtration area
- Hypertension and renal dysfunction
Diabetic Nephropathy
-
Characteristics:
- High glucose levels and oxygen radicals harm endothelial cells and podocytes
- Thickening of the basal membrane, increasing blood pressure, and albuminuria
- Vascular alterations: loss of fenestrae, glycocalyx, and fenestrae, endothelial swelling, and arteriolar hyalinosis
-
Vascular Endothelial Growth Factor (VEGF) role:
- Fundamental regulator of microvasculature
- Produced by podocytes and diffuses to endothelium
- Binding to VEGF receptor 2 on endothelial cells maintains endothelial cells and glycocalyx
- Upregulation in diabetic mouse, but downregulation in human diabetic nephropathy
Treatment of Diabetic Nephropathy
-
VEGF inhibition:
- In diabetic mice, VEGF inhibition reduces proteinuria and improves renal function
- In humans, sFlt-1 treatment reduces albuminuria, hypertrophy, and mesangial matrix expansion
- sFlt-1 binds to M2 macrophages, reducing inflammation and endothelial activation
Kidney Function and Failure
-
Kidney function:
- Production of urine
- Excretion of wastes
- Blood pressure regulation
- Production of erythropoietin
- Activation of vitamin D
- Acid/base regulation
-
Kidney failure:
- Volume overload
- Accumulation of toxic waste
- Hypertension
- Anemia
- Bone mineral disease
- Metabolic acidosis
Acute Renal Insufficiency
-
Tubule-interstitial:
- Allergic, autoimmune, hypoxic, or allograft rejection
-
Glomerular:
- Nephritic (red blood cells in the urine)
- IgAN, TBMN, Alport, vasculitis, and allograft glomerulitis
- Nephrotic (no red blood cells in the urine)
- DM-N, FSGS, minimal change, and allograft glomerulopathy
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Description
This quiz covers the basics of human growth and development, including measurements, genetic and environmental factors affecting height, and definitions of tall and short stature.