Human Growth and Development

Questions and Answers

What is the definition of tall stature in terms of standard deviation?

Height > 1.6 SD above target height (correct)

Height > 2 SD above target height (correct)

Height > 3 SD above target height

Height > 1 SD above target height

What is the most common chromosomal cause of short stature?

Noonan syndrome

Klinefelter syndrome

Down syndrome (correct)

Turner syndrome

What is the name of the syndrome characterized by short stature, development delay, and congenital cardiac anomaly?

Turner syndrome

Down syndrome

FGFR3 syndrome

Noonan syndrome (correct)

What is the name of the gene mutation that causes achondroplasia?

FGFR3 Signup and view all the answers

What is the term for short stature caused by an unknown etiology?

Idiopathic short stature Signup and view all the answers

What is the name of the new drug that has an effect on growth and possibly spinal stenosis in achondroplasia?

Vosoritide Signup and view all the answers

What is the characteristic feature of skeletal dysplasia?

Disproportionate short stature Signup and view all the answers

What is a characteristic of osteosarcoma (OS)?

There is no benign precursor for OS. Signup and view all the answers

Which genes are involved in hereditary Paget's disease of bone?

SQSTM1 and TNFRSF11A Signup and view all the answers

What is the result of a p53 mutation in a cell?

The cell cycle stops until DNA repair occurs. Signup and view all the answers

What is the incidence of osteosarcoma in Li-Fraumeni syndrome?

40% before age 50 Signup and view all the answers

What is the result of a conditional knockout for Rb1 and Tp53 in osteoblastic precursor cells?

The mice develop osteosarcoma. Signup and view all the answers

What is characteristic of Paget's disease of bone?

Increased bone resorption and formation. Signup and view all the answers

What is the percentage of children with germline mutations in a cancer-predisposing gene in pediatric cancer?

8.5% Signup and view all the answers

What is the association between Paget's disease of bone and osteosarcoma?

Paget's disease increases the risk of developing osteosarcoma. Signup and view all the answers

What is the role of TP53 and RB1 genes in osteosarcoma?

They are tumor suppressor genes that are often mutated in osteosarcoma. Signup and view all the answers

What is the type of tumors that occur in retinoblastoma?

Malignant tumors of the retina. Signup and view all the answers

What is the main effect of the vosoritide on the growth of children with achondroplasia?

Increases the growth rate by 1.5 cm per year Signup and view all the answers

What is the characteristic feature of Leri-Weill dyschondrosteosis?

Madelung deformity and short 4th metacarpal bone Signup and view all the answers

What is the function of osteoclasts in bone remodeling?

To resorb bone Signup and view all the answers

What is the primary site of occurrence of giant cell tumor of bone?

Epiphysis or metaphysis of long bones Signup and view all the answers

What is genetic instability?

When a cell has a mutation in a gene that is important for DNA protection. Signup and view all the answers

What is the main criterion for evaluating the response to chemotherapy in giant cell tumor of bone?

Percentage of necrosis Signup and view all the answers

What is a driver event?

A mutation that leads to cancer development. Signup and view all the answers

What is the mode of inheritance of Leri-Weill dyschondrosteosis?

Pseudo-autosomal Signup and view all the answers

What is the effect of vosoritide on blood pressure?

Decreases blood pressure Signup and view all the answers

What is the difference between inherited cancer and familial clustering?

Inherited cancer has a known genetic basis, while familial clustering does not. Signup and view all the answers

What is the characteristic feature of hyperachondroplasia?

Severe short stature Signup and view all the answers

What is a phenocopy?

A person who develops cancer but does not have a mutated gene. Signup and view all the answers

What is the role of osteoblasts in bone remodeling?

To form new bone Signup and view all the answers

What is retinoblastoma?

The first cancer for which genetic inheritance was elucidated. Signup and view all the answers

What is the percentage of risk of a baby having achondroplasia if one parent is affected?

50% Signup and view all the answers

What is the function of the shelterin complex?

It protects telomeres. Signup and view all the answers

What is the most common type of polyp that can lead to colon carcinoma?

Tubulovillous adenoma. Signup and view all the answers

What is the characteristic of hyperplastic polyp?

It has serrated lumina and no dysplasia. Signup and view all the answers

What is the difference between tubulovillous adenoma and tubular adenoma?

Tubulovillous adenoma has darker morphology, while tubular adenoma has lighter morphology. Signup and view all the answers

What is the characteristic feature of adenocarcinoma colon?

Submucosal proliferation of glands Signup and view all the answers

What is the name of the gene that is mutated in Familial Adenomatous Polyposis (FAP)?

APC Signup and view all the answers

What is the percentage of endometrial cancers in Lynch syndrome?

50% Signup and view all the answers

What is the name of the condition characterized by fibrotic scarring of glomeruli?

Glomerulosclerosis Signup and view all the answers

What is the name of the autosomal recessive polyposis syndrome caused by mutations in both alleles of the MUTYH gene?

MUTYH-associated polyposis Signup and view all the answers

What is the name of the type of glomerulosclerosis characterized by less than 50% of all glomeruli being involved with majority showing sclerosis?

Focal global glomerulosclerosis Signup and view all the answers

What is the name of the test used to screen for cancers in Lynch syndrome?

Colonoscopy Signup and view all the answers

What is the name of the gene that is often methylated in sporadic MSI-high CRC?

MLH-1 Signup and view all the answers

What is the term used to describe the process of accumulation of mutations leading to colon carcinoma?

Stepwise process Signup and view all the answers

What is the percentage of the population that possesses a mutated copy of the MUTYH gene?

1-2% Signup and view all the answers

What is the result of granulocytes degranulating and producing proteases?

Creating holes in the wall, resulting in hemorrhage Signup and view all the answers

What is the characteristic of the immune complex in the sub-endothelial location?

Linear binding pattern with immunofluorescence Signup and view all the answers

What is the cause of sub-epithelial deposits?

Antibodies against epitopes in the sub-epithelial space Signup and view all the answers

What is the result of frustrated chemotaxis?

No inflammation and no symptoms for a long time Signup and view all the answers

What is the characteristic of membranous glomerulopathy?

Thickening of the basal membrane and spike-like structures Signup and view all the answers

What is the result of abnormal basal membrane production in membranous glomerulopathy?

Hyperproteinuria and edema Signup and view all the answers

What is the treatment for membranous glomerulopathy?

Protein-free diet and anti-inflammatory drugs Signup and view all the answers

What is the characteristic of the mesangial space?

Mesangial cells and mesangial matrix Signup and view all the answers

What is the cause of deposits in the mesangial space?

Circulating antibodies that are abnormal in their structure Signup and view all the answers

What is the result of deposits in the mesangial space?

Hematuria and nephritic syndrome Signup and view all the answers

What is the primary mechanism by which the immune response is slowed in IgA nephropathy?

The granulocytes cannot reach the immune complexes with their podia Signup and view all the answers

What is the characteristic of the basement membrane in diabetic nephropathy?

Thickening of the basement membrane Signup and view all the answers

What is the result of the loss of glycocalyx in diabetic nephropathy?

Pro-inflammatory and pro-thrombotic changes Signup and view all the answers

What is the role of VEGF in maintaining the microvasculature?

It is a positive regulator of vascular function Signup and view all the answers

What is the advantage of using animal models in diabetic nephropathy research?

They are fast to develop and genetically identical Signup and view all the answers

What is the effect of VEGF knockout on the glomerulus in diabetic mice?

It leads to an increase in extracellular matrix Signup and view all the answers

What is the role of podocytes in the production of VEGF?

They are one of the producers of VEGF Signup and view all the answers

What is the effect of streptozotocin on beta cells in the pancreas?

It inhibits the production of insulin Signup and view all the answers

What is the characteristic of the glomerulus in diabetic mice?

It is enlarged Signup and view all the answers

What is the effect of VEGF on the endothelial cells in the glomerulus?

It maintains the endothelial cells Signup and view all the answers

What is the primary mechanism by which alloantigens contribute to the formation of immune complexes in the kidney?

Alloantigens come from micro-organisms and are introduced to the bloodstream through infection. Signup and view all the answers

What is the result of granulocyte degranulation in the kidney?

The creation of literal holes in the capillary walls, leading to leakage of blood into the urine. Signup and view all the answers

What is the term for the syndrome characterized by hematuria, renal dysfunction, and hypertension?

Nephritic syndrome Signup and view all the answers

What is the primary location of immune complex deposition in the first type of glomerular localization?

Under the sub-endothelium Signup and view all the answers

What is the role of antibody in the formation of immune complexes in the kidney?

Antibodies bind to specific antigens, leading to the formation of immune complexes. Signup and view all the answers

What is the consequence of increased blood pressure in the kidney due to proliferation of cells?

Hypertension Signup and view all the answers

What is the term for the abnormal casts formed in the urine due to the presence of blood?

Erythrocyte cast Signup and view all the answers

What is the effect of VEGF inhibition in animal models of diabetic nephropathy?

Reduction of proteinuria Signup and view all the answers

What is the primary cause of glomerulosclerosis?

All of the above Signup and view all the answers

What is the location of the immune complex deposition in the second type of glomerular localization?

In the glomerular basal membrane Signup and view all the answers

What is the role of sFlt-1 in reducing renal complications in diabetic nephropathy?

Inhibiting VEGF-induced tube formation Signup and view all the answers

What is the role of granulocytes in the inflammatory response in the kidney?

To recognize and respond to immune complexes, leading to inflammation Signup and view all the answers

What is the primary function of the kidneys in regulating blood pressure?

Regulating blood pressure through fluid balance Signup and view all the answers

What is the characteristic feature of nephritic syndrome?

Presence of red blood cells in the urine Signup and view all the answers

What is the effect of VEGF-A on endothelial cells?

Inducing endothelial activation Signup and view all the answers

What is the role of M2 macrophages in the context of sFlt-1 treatment?

Binding to sFlt-1 Signup and view all the answers

What is the characteristic feature of membranous nephropathy?

Immune complex deposition in the glomerulus Signup and view all the answers

What is the result of a mutation in the mismatch repair genes in Lynch syndrome?

Increased microsatellite instability Signup and view all the answers

What is the primary function of the kidneys in regulating electrolyte balance?

Regulating potassium levels Signup and view all the answers

What is the characteristic feature of acute renal insufficiency?

Sudden decline in renal function Signup and view all the answers

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

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:
1. Sub-epithelial deposits
2. Thickening of the basal membrane due to abnormal production
3. Basal membrane encapsulation of complexes
4. 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:
1. Production of urine
2. Excretion of wastes
3. Blood pressure regulation
4. Production of erythropoietin
5. Activation of vitamin D
6. Acid/base regulation
Kidney failure:
1. Volume overload
2. Accumulation of toxic waste
3. Hypertension
4. Anemia
5. Bone mineral disease
6. 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.