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Questions and Answers
What is the result of a promoter swap in Ewing sarcoma?
What is the result of a promoter swap in Ewing sarcoma?
The break in EWSR1 is specific to Ewing sarcoma.
The break in EWSR1 is specific to Ewing sarcoma.
False
What are the two main techniques used for translocation detection in Ewing sarcoma?
What are the two main techniques used for translocation detection in Ewing sarcoma?
Conventional cytogenetic (fresh tissue) and RT-PCR (frozen tissue, paraffin)
Ewing sarcoma is typically found in young people, in _______ and soft tissue.
Ewing sarcoma is typically found in young people, in _______ and soft tissue.
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Match the following techniques with their descriptions:
Match the following techniques with their descriptions:
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What is the characteristic of osteochondroma?
What is the characteristic of osteochondroma?
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Ewing sarcoma can occur in older people.
Ewing sarcoma can occur in older people.
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What are the three main components used in pathological diagnosis of bone tumors?
What are the three main components used in pathological diagnosis of bone tumors?
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IDH mutants convert ____________ to D2HG.
IDH mutants convert ____________ to D2HG.
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Match the following bone tumors with their characteristic features:
Match the following bone tumors with their characteristic features:
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What is the effect of LWD treatment on growth?
What is the effect of LWD treatment on growth?
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DNA analysis is always necessary in making a diagnosis of syndromic growth disorder.
DNA analysis is always necessary in making a diagnosis of syndromic growth disorder.
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What is the importance of recognizing the inheritance pattern of a specific syndrome?
What is the importance of recognizing the inheritance pattern of a specific syndrome?
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The presence of giant cells in bone tumors is not unique to _______________________.
The presence of giant cells in bone tumors is not unique to _______________________.
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Match the following characteristics with the correct diagnosis:
Match the following characteristics with the correct diagnosis:
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What is the most common chromosomal cause of short stature?
What is the most common chromosomal cause of short stature?
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Turner syndrome only occurs in boys.
Turner syndrome only occurs in boys.
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What is the mean IQ of individuals with Noonan syndrome?
What is the mean IQ of individuals with Noonan syndrome?
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The frequency of skeletal dysplasia is approximately ______________ live births.
The frequency of skeletal dysplasia is approximately ______________ live births.
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Match the following syndromes with their characteristics:
Match the following syndromes with their characteristics:
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What is the frequency of Achondroplasia?
What is the frequency of Achondroplasia?
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What is the definition of tall stature in terms of standard deviation?
What is the definition of tall stature in terms of standard deviation?
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Short stature is defined as a height less than -1 SDS.
Short stature is defined as a height less than -1 SDS.
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What are the factors that influence height, aside from genetics?
What are the factors that influence height, aside from genetics?
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Armspan measurement is typically the same as ______________ in adults.
Armspan measurement is typically the same as ______________ in adults.
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Match the following measurements with their descriptions:
Match the following measurements with their descriptions:
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What is the effect of upregulation of PDGF-C, CCDN1, c-MYC in cell proliferation?
What is the effect of upregulation of PDGF-C, CCDN1, c-MYC in cell proliferation?
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Tall stature is always a sign of overgrowth.
Tall stature is always a sign of overgrowth.
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What is the difference between syndromic and non-syndromic growth disorders?
What is the difference between syndromic and non-syndromic growth disorders?
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Downregulation of cyclin-dependent kinase inhibitors (p21, p57) leads to ______________ of growth inhibition.
Downregulation of cyclin-dependent kinase inhibitors (p21, p57) leads to ______________ of growth inhibition.
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Match the following features with their corresponding syndromic growth disorders:
Match the following features with their corresponding syndromic growth disorders:
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VEGF expression is a characteristic of evading growth inhibition.
VEGF expression is a characteristic of evading growth inhibition.
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What is the role of hTERT in escaping from senescence?
What is the role of hTERT in escaping from senescence?
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Repression of IGFBP-3 promoter leads to ______________ of apoptosis.
Repression of IGFBP-3 promoter leads to ______________ of apoptosis.
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Study Notes
Osteochondroma and Chondrosarcoma
- Mutant cells grow out and form an osteochondroma with some normal cells.
- Osteochondroma is not entirely clonal.
- Osteochondromas can progress to secondary peripheral chondrosarcoma.
- Chondrosarcoma is clonal, and some cells may not have EXT mutations.
- Other mutations that inactivate cell cycle genes, such as INK4 or Trp53, can also occur.
Central Cartilaginous Tumors
- Enchondromatosis (Ollier disease) is a rare, non-hereditary condition with a unilateral predominance.
- It occurs during skeletal formation in young patients and has a 40% risk of malignant transformation.
- IDH1 or IDH2 mutations are often found in Ollier, secondary chondrosarcoma, and primary central chondrosarcoma.
- These mutations convert α-KG to D2HG, affecting DNA methylation and histone modifications.
Ewing Sarcoma and Molecular Diagnostics
- Pathological diagnosis involves immunohistochemistry, molecular analysis, morphology, and clinical and radiological information.
- Ewing sarcoma has a specific translocation, EWSR1-ETS, which is essential for tumor formation.
- Immunohistochemistry is used to detect antigens in tissue sections, determine diagnosis, and predict prognosis.
- Molecular testing is necessary to confirm the diagnosis, as immunohistochemical profiles may overlap.
- Techniques for translocation detection include conventional cytogenetic, RT-PCR, FISH, and next-generation sequencing.
Molecular Alterations in Small Blue Round Cell Tumors
- Ewing sarcoma specific translocations involve EWSR1-ETS fusion proteins.
- Specific translocations in sarcomas involve chimeric gene formation, promoter swap, and truncation.
- These translocations lead to transcriptional deregulation, deregulated signaling, and altered expression.
Diagnosis and Treatment
- Diagnosis involves a combination of immunohistochemistry, molecular analysis, and radiological information.
- Treatment for Ewing sarcoma involves resection, chemotherapy, and radiation, with a 5-year survival rate of about 60-65%.
- Genetic testing is essential for diagnosis, but not sufficient on its own, as some tumors share the same fusion but are entirely different.
- Antibodies against chimeric proteins, such as SS18-SSX, can be used for diagnosis.
Giant Cell Containing Tumors of Bone
- Giant cells in bone tumors are not necessarily indicative of a giant cell tumor.
- GCTB (giant cell containing tumors of bone) is a specific type of tumor with a distinct biology and therapy.
- GCTB is characterized by the presence of giant cells and mononuclear cells.
- Treatment for GCTB involves understanding its biology and therapy.
Height Measurement and Definition
- Height is measured in relation to the standard deviation (SDS) from the mean height
- Tall stature: height > 2 SDS or > 1.6 SDS above target height based on parent's height
- Short stature: height < -2 SDS or > 1.6 SDS under target height based on parent's height
Guideline for Measuring
- Measure height, weight, head circumference, arm span, and sitting height
- Measure parents' height only when armspan and sitting height are abnormal in the child
Height Determinants
- 60-80% of height is determined by genetics
- Feeding, health, and medication are other important factors influencing height
Syndrome Definition and Recognition
- A syndrome is a group of signs and symptoms that occur together and characterize a particular abnormality or condition
- Syndrome recognition involves pattern recognition
Causes of Short Stature
Primary Growth Disorders
- Syndromes
- SGA (small for gestational age) without catch-up growth
- Skeletal dysplasia
- Disorders of bone metabolism
Secondary Growth Disorders
- Malnutrition
- Celiac disease
- Hormonal disorders
- Metabolic disorders
- Idiopathic short stature (unknown cause)
Syndromes with Short Stature
- Down syndrome (trisomy 21)
- Turner syndrome
- Noonan syndrome
Turner Syndrome
- Occurs only in girls
- Characterized by a single X chromosome or an isochromosome X (missing short arm)
- Often have heart conditions and are infertile
- Benefit from growth hormone therapy
Noonan Syndrome
- Caused by a gene mutation, affecting both boys and girls
- Short stature (mean height: 169 cm in males, 154 cm in females)
- Developmental delay (mean IQ: 86)
- Facial features: hypertelorism, ptosis, low-set ears, and broad neck
- Congenital cardiac anomaly, pectus deformity, lymphatic abnormalities, coagulation defects, and cryptorchidism
- Genetics: mutations in genes in the RAS-MAPK pathway
Skeletal Dysplasia
- Frequency: 1:3000 live births, 1:110 perinatal mortality
- Characterized by short limbs for trunk, epiphysis, metaphysis, and/or diaphysis abnormalities
- Causes disproportionate short stature
- Heterogeneity (clinical and genetic), non-uniform terminology
Skeletal Dysplasia: Achondroplasia
- Frequency: 1:15,000 - 1:40,000
- Clinical features: short stature with large head, short arms and legs, skin creases, pronounced lumbar lordosis, and short hands with trident fingers
- X-ray features: normal or small bone size, no increase in bone width with age
Objectives
- Define short stature and tall stature
- Recognize and describe the clinical features of common syndromes with short stature
- Understand the molecular background of specific syndromes
- Interpret the inheritance pattern of a specific syndrome and its implications for the patient and their family
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Description
This quiz covers the growth of mutant cells, formation of osteochondroma, and its progression to secondary peripheral chondrosarcoma. It also explains how normal cells can acquire mutations leading to malignancy.
