Professional Documents
Culture Documents
Problem Based Learning (PBL) for Large Groups Medical Students: e-Problem Solving Test: A Mutation Causing Retinoblastoma (Rb)
*International Medical University (IMU),
ST Matthews School of Medicine (SMU),
AIMST-U, MSU, Vinayaka Missions Med School
Acknowledgements: The Authors Gratefully Acknowlwdges All On-Line Resources Including Google.com, PubMed, Elsieviers Ltd, Eye Cancer Network, Scriibd.com., ect.,.
Retinoblastoma (Rb): Problem Based Learning (PBL) for Large Groups Medical Students:
e-Problem Solving Test: A Mutation Causing Retinoblastoma (Rb). Abstract: Problem Based Learning (PBL) is an innovative
approach and emerging advances in the integrated medical curriculum to achieve the effective measurable outcomes for the large group of medical students in small groups with the on-line resources available (OLRA). Integrated
PBLs covers the clinical relevance of the particular disease with different disciplines of medicine which includes anatomy, pathophysiology, biochemistry-genetic basis of the disease, pathology, laboratory diagnosis, pharmacology,
community medicine, behavioural issues at the must know level of phase-1 medical students with much emphasize on self-directed learning with the OLRA and encourage the students to acquire up to date knowledge and clinicalcommunication skills right from the beginning of the medical curriculum and inculcate life-long learning. This present article emphasizes the achievement of the measurable learning outcomes with the reusable-on-line resources
available with the structured PBLs on a particular disorder which are not covered by any other mode of teaching-learning activities including didactic lectures and/or seminars and so on. Begining of the semester 1 hands-on
workshop on PBL-process to be provided to the students by the content experts of medical education. In this article provided with the case study on Retinoblastoma (Rb). Rb is a rare eye tumor of childhood that arises in the retina.
Rb is caused by a deletion of chromosomes 13, 14, 15, 21, and 22 and is a frame-shift deletion mutation. It is the most common intraocular malignancy of infancy and childhood; with an incidence of 1/15,00020,000 live births. The
two most frequent symptoms revealing Rb are leukocoria and strabismus. Pleotropy includes iris rubeosis, hypopyon, hyphema, buphthalmia, orbital cellulites and exophthalmia may also be observed. Sixty per cent of
retinoblastomas are unilateral and most of these forms are not hereditary (median age at diagnosis two years). Rb is bilateral in 40% of cases (median age at diagnosis one year). All bilateral and multifocal unilateral forms are
hereditary. Hereditary Rb constitutes a cancer predisposition syndrome: a subject constitutionally carrying an RB1 gene mutation has a greater than 90% risk of developing retinoblastoma but is also at increased risk of developing
other types of cancers. The PBL Process: Day-1:PBL-Induction: Step 1: Release of the digital copy of figure 1 shows the phenotype of patients with Rb and brain storming. Step-2: Figure-2-display of k aryotype of a person affected
by Rb and brain storming. Day 1-Step-3: Figure 3-display of pedigree chart-inheritance of Rb and discussion and division of labour. Day 1-Step 4: Research component on Rb-Review Article:
URLhttp://www.sciencedirect.com/science/article/pii/S0140673611611379 : Day 1- Step 5: Matching and fine tuning of the learning outcomes arrived by the team, facilitated by tea leader. Day 2-Step 1: Presentations and
Summarization on RB: Day 2-Step 2: Display of video clip on RB, U Tube URL: https://www.youtube.com/watch?v=FOnZKtupBYg [5]. Day 2-Step 3: Construction of cognitive concept mapping and discussion, Day 2-Step 4: Spot
test on matching questions. Terms to be familiar with before you start to solve the test: Retinoblastoma (Rb), RB1 gene on chromosome 13 (first tumor suppressor gene discovered), genetic disorder, Oncogenes, tumor suppressor
genes, DNA-repair genes, epidemiology, mode of inheritance-X-linked, autosomal dominant (AD) transmission, penetrance, pedigree analysis, karyo-type of Rb, frame shift-deletion-mutation, deletion of parts of chromosomes at 13,
14, 15, 21, and 22 [1]. Alfred Knudsons two-hit hypothesis (1971) [2], biochemical-molecular basis of retinoblastoma, sporadic (non-hereditary) Rb, familial (hereditary) Rb, consanguinity, risk factors of Rb, signs and symptoms,
pathophysiology, clinical presentation of RB, congenital anomalies-dysmorphism, differential diagnosis, molecular etiopathogenesis, bridge to pharmacology, management of Rb, treatment options, preventive medicine, prenatal
diagnosis, amniocentesis, genetic counselling, behavioural issues, ethics, referral to Ssspeciality clinics URL [3]:http://edit.mskcc.org/pediatrics/childhood/retinoblastoma Memorial Sloan-Kettering Cancer Center, Research
component in Rb, model review article on Retinoblastoma URL: http://www.sciencedirect.com/science/article/pii/S0140673611611379[4].
PBL Process Keywords: Problem based learning, USMLE-Preparatory curriculum, learning outcomes, on-line reusable resources, clinical skills, BIO-GEN Inno-vision, content experts, PBL-process, PBL-facilitation, group leader
as facilitator, small group learning, integrated medical curriculum, measurable learning outcomes, on-line resources, e-learning, self-directed learning, audio-visual facility, medical dictionary, group dynamics, brain storming, team
work, peer value-review, division of labour, group dynamics, leadership quality and team player, group leader as a facilitator, communication skills, time-management, mono-acting as a simulated patient, parts of the PBLs: Step
wise release of the parts of the PBL-Step 1, 2 and 3, video clips, construction of high-yield cognitive concept mapping, spot test-matching questions. Learning Outcomes: Retinoblastoma, karyo-type of Rb, Alfred Knudsons two-hit
hypothesis, risk factors of Rb, histopathology of Rb, differential diagnosis of leukocoria, genetic counselling on Rb and ethics.
Osteosarcoma
Leukocoria
4
5
FISH
Variable expressivity
Germinal retinoblastoma
Mosaicism
G
M
10 Germline mutation
11 Cytogenetic Location of Retinoblastoma
12 Pleotrophy
13 Penetrance
L M. 13q14.2.
Ans: 1-H ; 2-A ; 3-I ; 4-C ; 5-B ; 6-E ; 7-J ; 8-F ; 9-D ; 10-G; 11-M; 12-K; 13-M .
Bridge to Mol-Biology
& Genetics
Secondary glaucoma
Orbital inflammation
Orbital invasion
3 4
The left eye is enlarged. The cornea is
opacified, the conjunctiva is injected,
while tumor cells can be seen on the
corneal endothelium (arrows).
CT demonstrates intratumoral
calcifications consistent with Rb
(black arrows). The left optic nerve
is enlarged and retrobulbar
opacities suggest extrascleral
extention (white arrow).
Leukocoria or
White Pupil
Rb is either sporadic or familial
Sporadic cancer in 55-65% of all cases.
Sporadic cancers are unilateral.
Hereditary childhood cancer
bilateral tumors in ~75% of cases.
unilateral tumors in ~25% of cases.
1/20,000 children; 300 /yr Average
age is 18 months. Treatment:
enucleation. Prognosis is good after
enucleation over 90% survival with
early detection and treatment.
Molecular Pathogenesis of Rb
MANAGEMENT
Step 4: MCQ 1. 6-24. A newborn child is being Eye Cancer Network Case #13: Retinoblastoma
History: This 16-month old patient was referred for bilateral leukocoria (white pupil),
examined. During ophthalmologic evaluation, acute glaucoma OS, with evidence of anterior chamber seeding and possible optic
it is noticed that the red reflex is absent.
nerve/orbital invasion. The left pupil was nonreactive. Impression: Retinoblastoma.
Which of the following could this indicate?
*Note* This risks and benefits of observation, enucleation, chemotherapy and external
beam radiation therapy were discussed in detail. Single agent cisplatinum chemotherapy (3
A.Congenital cataracts.
cycles due to definite choroidal and possible orbital and optic nerve involvement) and
B.Chorioretinitis.
enucleation of the left eye was performed. Histopathologic evaluation of the left eye
C.Retinitis pigmentosa.
revealed retinoblastoma without optic nerve or orbital extension. The right eye was
D.Optic atrophy.
enucleated after failure of systemic chemoreduction to produce a treatable tumor.
E.Holoprosencephaly.
PATHOGENESIS
6-24. The answer is A. (Swaiman, p 82.) On shining a light through the pupil of the normal newborn, the normal color of the retina is perceived as an orange-red reflection of the light. Failure to perceive
that reflection usually indicates opacification of the pathway of light transmission. Several types of intrauterine infections, including rubella and CMV infection, may produce congenital cataracts and impair
light transmission in this way. The presence of a distinctive white reflex usually indicates disease behind the lens, such as a scar from retinopathy of prematurity or a retinoblastoma. Reference: Pre Test:
Clinical Vignettes for the USMLE Step 2 CK, PreTestTM Self-Assessment and Review, 5th Edition.
19. A 5-month-old girl has bilateral retinoblastoma. Neither parent has a history of having had retinoblastoma. Chromosomal analysis of the patient's stimulated peripheral blood lymphocytes is
done; the photograph is of a representative karyotype. Which of the following critical events has most likely resulted Genetic Counselling on Rb: Parents having a child with RB (at the time of
from an aberration involving chromosome 13? Biochemical Calculation:
enucleation or during treatment) & patients with family history of Rb should
A.Proto-oncogene activation
undergo genetic counselling (blood sample only).
1+1=1; 1+2=2; 5+5=5
B.Proto-oncogene amplification
Recommendation: examination at birth & 4-mo thereafter until
Can U Solve This?
C.Proto-oncogene loss
4 yrs of age. Tumor tissue & blood required in sporadic cases w
GOD Cant Come in Person to Help You. He Will Send Some One in the
D.Tumor-suppressor gene activation Form of Homosepian, Believe it. The Only Thing What You Are Going to
hile only blood sample sufficient in inherited cases.
Take Away is Karma _Educate_Dr P Kumar, BIO-GEN.
E.Tumor-suppressor gene loss
Molecular tests: Direct analysis of the constitutional mutation of
RB11. The following are true about retinoblastoma (Rb):
gene performed on constitutional DNA. Indirect analysis of the allele
A. in familial retinoblastoma, the hereditary pattern is that of an AD mutation.
carrying the mutation. Tumor cell LOH evaluation. Patients should be
B. the genetic defect is recessive at the cellular level.
informed about the risk of transmission and of second primary malignant
C. retinoblastoma results from a dominant mutant onco-gene
tumor development (20% at 10 years , 50% at 20 years & 90% at 30 years).
D. both germinal or somatic mutation can give rise to retinoblastoma
E. osteosarcoma is associated with retinoblastoma containing deletion of chromosome 13. Answers: TTFTT.
11
Strabismus - 20%
PATHO -PHYSIOLOGY
or mutation of the RB gene occurs in either the germline or a somatic cell (eg, retinoblast). The second hit, which is always a somatic event that disrupts the remaining RB allele,
usually involves one of the indicated mechanisms (their approximate frequencies in retinoblastoma tumors are indicated). The predicted result of the 2 hits (tumor vs no tumor)
is indicated when the first hit involves a full-penetrance vs a low-penetrance mutation. These predictions are based on the assumption that 2 copies of a low-penetrance mutation
are sufficient to suppress tumorigenesis. This mechanism could help to explain the phenomenon of low-penetrance retinoblastoma, since approximately 60% of second hits that
are tumorigenic with full-penetrance mutations may not cause tumors with low-penetrance mutations. RB indicates RB gene mutation; wt, wild type.
Ans
Column B
H A. Associated with retinoblastoma containing
deletion of chromosome 13.
A B. Variation in clinical features (type and
severity) of a genetic disorder between affected
individuals, even with n same family.
I C. A technique used to identify the presence of
specific chromosomes or chromosomal regions
through hybridization (attachment) of
fluorescently-labelled DNA probes to denatured
chromosomal DNA. Examination under
fluorescent lighting detects the presence of the
hybridized fluorescent signal (and hence
presence of the chromosomal material) or
absence of the hybridized fluorescent signal (and
hence absence of the chromosome material).
C
B
Leukocoria - 60%
Knudsons Double Hit Hypothesis:Chromosomal events leading to tumorigenesis in retinoblastoma (Rb) according to the Knudsen 2-hit hypothesis. The first hit
No
Column A
1 Alfred Knudsons two-hit hypothesis
GENETICS : ETIOLOGY
12
GENETICS
The PBL Process: Day 1-Step 1-Trigger 1: Release of the Digital Copy of
Fig.1 Shows the Presentations of Retinoblastoma Phenol Type URL: Google Images:
DIAGNOSIS
10
ETHICS: GENETIC
COUNSELING & REFERRAL
TO SPECILITY CLINICS
RB SUPPORT GROUPS.
Rb Inheritance: Rb is inherited as a
13
References: [1] [1]. Isabelle Aerts, Livia Lumbroso-Le Rouic, Marion Gauthier-Villars, Herv Brisse 4, Franois Doz and Laurence
Desjardins. Review. Retinoblastoma. Orphanet Journal of Rare Diseases 2006, 1:31, 1-11.
[2]. Alfred G. Knudson, JR. Mutation and Cancer: Statistical Study of Retinoblastoma. Proc. Nat. Acad. Sci. USA Vol. 68, No. 4, 820-823.
[3]:http://edit.mskcc.org/pediatrics/childhood/retinoblastoma Memorial Sloan-Kettering Cancer Center.
[4] Helen Dimaras, Kahaki Kimani, Elizabeth A O Dimba, Peggy Gronsdahl, Abby White, Helen S L Chan, Brenda L Gallie. Retinoblastoma.
is the ONLY Visible GOD I Know.
Lancet 2012; 379: 14361446. http://www.sciencedirect.com/science/article/pii/S0140673611611379 Mother
The Most Beautiful Woman in This World is Mother Therasa
The Most Handsome Man in This World is Nelson Mondala
[5]. Retinoblastoma-U Tube URL: https://www.youtube.com/watch?v=FOnZKtupBYg