oncology nursing brown bag lunch september 9, 2014 deborah
TRANSCRIPT
Oncology Nursing Brown Bag Lunch September 9, 2014
Deborah Tamura MS, RN, APNG
NCI, Dermatology DNA Repair Section
No Conflict of Interest
Learning Objectives At the completion of this presentation the participant will be able to: • Name a minimum of 3 diseases caused by
defective DNA repair. • List 3 symptoms of xeroderma pigmentosum and
trichothiodystrophy. • Describe patient education strategies to reduce
the risk of skin cancer in xeroderma pigmentosum patients.
Ultraviolet Radiation CAUSES
DNA Damage
Still trying to convince my daughter to protect her skin from the sun
UV DEFENSE MECHANISMS
Skin Cancer
Pigmentation & Skin Thickening
UV-Exposure
DNA Repair Cell Cycle Arrest
Apoptosis
DNA Damage DNA photoproducts
Mutation
Removal of Mutated Cells (Immune-Surveillance)
The Process of Nucleotide Excision
Repair
DNA Damage Identified
Damaged DNA Removed
Synthesize a New Segment of DNA and attach it to the Original strand of DNA
Genes Involved in Nucleotide Excision Repair
Identify Damage
Damaged DNA Removed
New DNA Segment Spliced into Place.
New Segment of DNA is Synthesized
TFIIH
XPE
CSA CSB
XPV (Variant)
G= Normal Gene
g= Mutated Gene
g= Mutated Gene
Function of normal gene compensates for mutant gene.
Autosomal Recessive Inheritance Males and Females Equally Affected Recurrence risk for each child is 1 in 4 or 25% Parents are not clinically affected and have no symptoms but are carriers for the condition
Carrier Father
Carrier Mother
Gg Gg Gg
Gg gg
Normal Carrier Carrier Affected
GG Gg
Means ‘Dry Pigmented Skin’ Caused by mutations in genes of NER (7) and Pol Eta – by pass polymerase (XP-Variant) One in million in the U.S. More common in Japan and the Middle East Occurs in all ethnic groups 10,000 fold increased risk of skin cancer
32 y/o >200 skin cancers died age 35 glioblastoma
2 y/o diagnosed at daycare center KA on lip
Xeroderma Pigmentosum
Signs and Symptoms Freckling before age 2 years Severe UV sensitivity (50% of patients have severe blistering sunburns) Early onset of skin cancers – often before age 10 Eye – photophobia; dry eyes, cancer on eye surfaces Neurodegeneration in approximately 25% of patients. More common in XP-A, XP- B, XP-D, XP-F and XP-G. Progressive hearing loss, loss of DTRs, ataxia, cognitive decline, recurrent aspiration
Nine month old in shade for 45 minutes
The Eye Complications in Xeroderma Pigmentosum
Severe Photosensitivity
Corneal Clouding, Pterigium
Malignancy on eye surface
Progressive Neuro-degeneration in Xeroderma Pigmentosum - Patient with
XP-A Mutations
Age 4 Age 17 Age 41 Died age 45
Neuro-Degeneration in Xeroderma Pigmentosum
Age 33 Died age 35
Died age 36 Age 17 Died age 20
XP-A XP-D
The Well Dressed XP Person Sun block >SPF 30
applied several times per day
Hood covering ears back of neck with UV blocking face shield
Sunglasses – UV blocking with side shields
Long sleeved shirts Long pants or tights
under skirts Gloves Shoes and long socks Sun Protective Suit
Environmental Protection Avoiding the sun – stay indoors during daylight hours UV meter to measure ambient UV levels UV blocking window tints: house and car Avoid unshielded florescent lights and all halogen lighting Handicapped parking permit Avoid Cigarette smoke
The goal of UV protection is to have the lowest amount of UV exposure as possible
Patient Care Management Cancer Detection and Treatment Frequent self skin exams – at least weekly Regular dermatologic visits Photographs of lesions Prompt biopsy and surgical removal of suspicious
lesions Pharmacologic Interventions Aldara 5 FU Oral Retinoids
Referral to Patient Support Groups
Trichothiodystrophy
About 100 patients reported in medical literature May be called PIBIDS, IBIDS, Tay Syndrome or Pollet Syndrome Mutations in XPD, XPB, TTDA and TTDN1 cause disease Disease symptoms caused by faulty gene transcription Severe Sun Sensitivity in Half of Patients
Collodion Membrane
Tiger Tail Banding of Hair
Ichthyosis - Dry Skin
Brittle Nails Short Hair - Sparse
Eyebrows
TrichothiodystrophySymptoms
High Rate of Pregnancy and neonatal complications
Trichothiodystrophy
Severe Delay
Autism Age 14 TTDN1
Age 25 Moderate
Delays
TTDA
Normal Development Age 5
Short Stature Severe Delay Age
Died age 9 yr
XP-D Mutations
Complications of Trichothiodystrophy
Ophthalmologic Immune Dysfunction –
Frequent Infections Endocrine Abnormalities
– Hypogonadism (?) Poor Growth – bone
abnormalities 20 fold increased risk of
death before age 10
Patient Care Management of Trichothiodystrophy
Benefit from Multidisciplinary Approach Dermatology – follow skin and hair symptoms Neurology – assess for developmental delay Immunology – if frequent infections – IVIG Ophthalmology – follow cataracts and myopia
Advocate for rehabilitative and support services Refer to Patient Support Group
Cockayne Syndrome Approximately 140 Patients Reported in
Literature Caused by Mutations in Genes: CSA or CSB CS/XP Overlap Mutations in XPB, XPD, XPG Defective Transcription Coupled Repair – Faulty
Repair of Actively Transcribing Genes Necessary for Normal Cell Function
Significantly Reduced Life Span
Cockayne Syndrome: Physical Features
Severe Growth Deficiency – Cachetic Dwarfism Wizened Face – Deep Set Eyes Sensorineural Hearing Loss Retinal Pigmentation – Corneal Opacity – Cataracts Slender Beak-Like Nose Photosensitive - Dry Skin, Senile Appearance
Cockayne Syndrome: Associated Complications
Cardiovascular Problems – arrhythmias hypertension Hepato-splenomegaly Skeletal Abnormalities Neurologic – Progressive Neurodegeneration and Cerebral Atrophy
Cockayne Syndrome Patient Care Issues
Supportive Interventions Rehabilitative Therapies PT, OT, Speech Therapy Special Education Classes
Feeding Tube for Failure to Thrive Hearing Aids Surgery for Cataracts Use of Sunscreens for Photosensitivity Refer to Patient Support Group
XP CS TTD Sun sensitivity + + + or -
Skin pigmentation \ cancer + - -
Ocular abnormalities + + +
Neurological abnormalities - or + + +
NER defect + + +
Environmental influence ++ - -
Developmental defect + ++ ++
Comparison of NER Diseases+
Diagnosis of DNA Repair Diseases
Clinical Features Detailed Medical History – How bad was the sunburn? Laboratory Testing
UV sensitivity Host cell reactivation assay Mutation analysis Polarizing light microscopy exam of hair
Family History – Autosomal Recessive Inheritance
• Age 2 months • Outside in covered stroller for 20 minutes
When the Diagnosis is a Bad Gene – Not a Bad Parent
UV Sensitivity Testing: Fibroblasts Exposed to Ultraviolet Radiation
Before Exposure Normal Cells After
UVC XP Cells After
UVC
What Have We Learned in 40 years?
• Over 250 articles published relating to laboratory and clinical research of NER and DNA repair diseases
• There are more genes and more pathways to be identified in DNA repair
• Patients with TTD, XP and CS have mutations in the same genes but very different clinical features (Pleiotropy)
• UV protection works to prevent skin and ocular cancer in XP patients; does not prevent neurodegeneration
• XP patients may be at risk for multiple types of internal cancers
The Kraemer Lab
Principal Investigator: Dr. Ken Kraemer Associate Investigator: Dr. John DiGiovanna Senior Scientist: Dr. Sikandar Khan Visiting Post Doc: Dr. Christianne Kuschal Research Nurse: Debby Tamura MS, RN
All the post docs, medical students and post bacs who have worked in the lab for the past 35 years.