Xeroderma Pigmentosum (XP) is a rare genetic disorder caused by a defect in nucleotide excision repair that results in an inability to repair UV-induced DNA damage. This leads to skin cancers developing at a very young age after only minimal sun exposure. Signs include severe sunburn, freckling, and development of skin cancers. Diagnosis is based on clinical findings and measuring DNA repair factors. Treatment focuses on protecting the skin from UV exposure and promptly removing cancerous growths. Most patients die young from skin cancers, but increased awareness and protection can improve prognosis.
Rare inherited skin disorder due to defective repair of DNA
characterized by; photosensitivity, pigmentary changes, premature skin aging, early malignant tumor development
Rare genetic disorder that occurs worldwide in all races and ethnic groups.
First described by Hebra and Kaposi in 1874.
Photosensitivity and premature onset of all major types of skin cancer .
Inability of a cell to repair damage caused by UV leading to genetic instability and skin cancer.
Responsible for removing the damaged segments of DNA and restoring the original sequence of DNA.
The NER mechanism is composed of two types:
Transcription coupled(TCR): Which rapidly repairs areas of DNA that are "active" and being transcribed into RNA
Global genome(GGR): Which repairs damage in the rest of the genome more slowly
Seven XP genes are central to NER which includes many other accessory proteins
The term “complementation group” is based on cell fusion experiments.
Cells from different XP patients are fused to investigate if the DNA repair defect in the fused cells is corrected.
If DNA repair in the fused cell is increased, each cell provides proteins that the other is lacking and the cells “complement” each other and are in different complementation groups.
If DNA repair in the fused cells is not normalized, the cells do not “complement” each other, meaning that both cells harbor mutations in the same DNA repair gene.
Seven such complementation groups have been identified (XP-A to XP-G), which correspond with mutations in seven distinct genes that can cause XP.
Severity changes is dependent on the amount of sun exposure and the degree of UVR protection
Acute and severe sunburn on minimal sun exposure takes weeks to resolve.
50% of XP patients suffer from severe and prolonged sunburn reactions.
Rest 50% have sunburn reactions that are normal and present with lentigines as well as hypopigmented macules.
Development of many freckles at an early age.
• Rough-surfaced growths (solar keratoses), and skin cancers
• Blistering or freckling on minimum sun exposure
• Telangiectasia (spider veins)
• Limited growth of hair on chest and legs
•
Xeroderma pigmentosum is a rare genodermatosis inherited as an autosomal recessive trait and caused by one of several defects in the excision repair mechanism of DNA. As a result numerous cutaneous malignancies develop at a very early age 1000 to 2000 times more than which is expected for normal individuals. It starts with markedly increased tendency to skin burns in first few years of life. Skin changes such as atrophy, depigmentation soon follows. Since repair mechanism is impaired in DNA, UV rays from sunlight causes damage and makes them prone to get actinic keratosis which progresses into a carcinoma. This presentation is about a girl of very young age suffering from xeroderma pigmentosa with squamous cell carcinoma of lower lip.
Rare inherited skin disorder due to defective repair of DNA
characterized by; photosensitivity, pigmentary changes, premature skin aging, early malignant tumor development
Rare genetic disorder that occurs worldwide in all races and ethnic groups.
First described by Hebra and Kaposi in 1874.
Photosensitivity and premature onset of all major types of skin cancer .
Inability of a cell to repair damage caused by UV leading to genetic instability and skin cancer.
Responsible for removing the damaged segments of DNA and restoring the original sequence of DNA.
The NER mechanism is composed of two types:
Transcription coupled(TCR): Which rapidly repairs areas of DNA that are "active" and being transcribed into RNA
Global genome(GGR): Which repairs damage in the rest of the genome more slowly
Seven XP genes are central to NER which includes many other accessory proteins
The term “complementation group” is based on cell fusion experiments.
Cells from different XP patients are fused to investigate if the DNA repair defect in the fused cells is corrected.
If DNA repair in the fused cell is increased, each cell provides proteins that the other is lacking and the cells “complement” each other and are in different complementation groups.
If DNA repair in the fused cells is not normalized, the cells do not “complement” each other, meaning that both cells harbor mutations in the same DNA repair gene.
Seven such complementation groups have been identified (XP-A to XP-G), which correspond with mutations in seven distinct genes that can cause XP.
Severity changes is dependent on the amount of sun exposure and the degree of UVR protection
Acute and severe sunburn on minimal sun exposure takes weeks to resolve.
50% of XP patients suffer from severe and prolonged sunburn reactions.
Rest 50% have sunburn reactions that are normal and present with lentigines as well as hypopigmented macules.
Development of many freckles at an early age.
• Rough-surfaced growths (solar keratoses), and skin cancers
• Blistering or freckling on minimum sun exposure
• Telangiectasia (spider veins)
• Limited growth of hair on chest and legs
•
Xeroderma pigmentosum is a rare genodermatosis inherited as an autosomal recessive trait and caused by one of several defects in the excision repair mechanism of DNA. As a result numerous cutaneous malignancies develop at a very early age 1000 to 2000 times more than which is expected for normal individuals. It starts with markedly increased tendency to skin burns in first few years of life. Skin changes such as atrophy, depigmentation soon follows. Since repair mechanism is impaired in DNA, UV rays from sunlight causes damage and makes them prone to get actinic keratosis which progresses into a carcinoma. This presentation is about a girl of very young age suffering from xeroderma pigmentosa with squamous cell carcinoma of lower lip.
Mitochondrial disease includes a group of neuromuscular diseases caused by damage to intracellular structures that produce energy, the mitochondria; disease symptoms usually involve muscle contractions that are weak or spontaneous.
Leber's hereditary optic neuropathy (LHON)
Leigh syndrome,
Myoneurogenic gastrointestinal encephalopathy (MNGIE)
KSS – (Kearns-Sayre Syndrome)
Role of Flow Cytometric Immunophenotyping in Plasma Cell DyscrasiasApollo Hospitals
Immunophenotyping is being routinely used for the diagnosis of leukemias. With the advent of specific markers for plasma cells, it has become possible to differentiate between benign and malignant plasma cells based on their immunophenotypic profile. The enhanced use of immunophenotyping in plasma cells dyscrasias may help to categorize the borderline cases which can not be done with morphology alone. Also the immunophenotypic profiling of plasma cells would help in Minimal Residual Disease (MRD) evaluation of patients on treatment of multiple myeloma (MM).
refsum disease its a genetical disorder which is autosomal recessive phytanoyl-CoA-hydroxylase is the enzyme location of this enzyme is chromosome 10p13
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.
Mitochondrial disease includes a group of neuromuscular diseases caused by damage to intracellular structures that produce energy, the mitochondria; disease symptoms usually involve muscle contractions that are weak or spontaneous.
Leber's hereditary optic neuropathy (LHON)
Leigh syndrome,
Myoneurogenic gastrointestinal encephalopathy (MNGIE)
KSS – (Kearns-Sayre Syndrome)
Role of Flow Cytometric Immunophenotyping in Plasma Cell DyscrasiasApollo Hospitals
Immunophenotyping is being routinely used for the diagnosis of leukemias. With the advent of specific markers for plasma cells, it has become possible to differentiate between benign and malignant plasma cells based on their immunophenotypic profile. The enhanced use of immunophenotyping in plasma cells dyscrasias may help to categorize the borderline cases which can not be done with morphology alone. Also the immunophenotypic profiling of plasma cells would help in Minimal Residual Disease (MRD) evaluation of patients on treatment of multiple myeloma (MM).
refsum disease its a genetical disorder which is autosomal recessive phytanoyl-CoA-hydroxylase is the enzyme location of this enzyme is chromosome 10p13
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.
Abstract:
Xeroderma pigmentosum with squamous cell carcinoma of skin has been
infreqently reported .Is a rare autosomal recessive disease characterized by defective
DNA repair. . A seven year old boy having xeroderma pigmentosa presented with
extensive ulceration of the face . On investigation, the ulceration was found to be
squamous cell carcinoma. The details of the case are presented and its pathological
findings are discussed
Analyze the Molecular Genetics of a Solitary Causative Genetic Material behin...ijtsrd
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Xeroderma pigmentosum
1. Under the guidance of
Dr. K.Eswar Kumar
M.Pharm, Ph.D.
Pharmacology Division
A.U. College of Pharmaceutical Sciences.
Presenting by
K. Manasa Thriveni
B.Pharm
614209505004
2/4/2017 Pharmacology Division 1
3. We owe our lives to light from the sun, which provides the
energy captured during photosynthesis.
But the sun also emits a constant stream of Ultraviolet rays that
ages and mutates the cells of our skin.
The hazardous effects of the sun are most dramatically
illustrated by the rare recessive genetic disorder , Xeroderma
Pigmentosum(XP) .
2/4/2017 Pharmacology Division 3
4. Xeroderma Pigmentosum (XP) is a rare genetic disorder that
occurs worldwide in all races and ethnic groups.
First described by Hebra and Kaposi in 1874 the disorder is
characterised by marked photosensitivity and premature onset
of all major types of skin cancer [1].
Definition:
It is characterised by inability of a cell to repair damage
caused by UV leading to genetic instability and skin cancer.
2/4/2017 Pharmacology Division 4
5. Incidence:
Usually found at very young age(1-2yrs).
XP affects approximately one in 1,00,000 individuals
worldwide.
One in 250,000 persons in the United States and Europe (2)
Six times more common in Japanese people than in any other
groups (3)
2/4/2017 Pharmacology Division 5
9. Nucleotide Excision Repair(NER)
This system is responsible for removing the damaged
segments of DNA and restoring the original sequence of DNA.
The NER mechanism is composed of two types:
Transcription coupled(TCR):Which rapidly repairs areas of
DNA that are "active" and being transcribed into RNA
Global genome(GGR): Which repairs damage in the rest of the
genome more slowly
Seven XP genes are central to NER which includes many other
accessory proteins.
2/4/2017 Pharmacology Division 9
11. SKIN
The POL H gene
(encoded DNA polymerase eta
(Pol η))
Protecting cells from UV rays
Repairing of
DNA damage
Xeroderma
pigmentosum
UV
2/4/2017 Pharmacology Division 11
12. Causes of XP
Autosomal recessive genetic disorder
Nucleotide excision repair(NER) enzymes are mutated
Reduced or eliminated number of NER enzymes
Metastatic malignant melanoma
Squamos cell carcinoma
2/4/2017 Pharmacology Division 12
14. Autosomal Recessive Genetic Disorder
In recessive disorders, the condition does not appear
unless a person inherits the same defective gene for the
same trait from each parent.
If an individual receives one normal gene and one gene
for the disease, the person will be a carrier for the disease.
The risk of transmitting the disease to the children of a
couple, both of whom are carriers for a recessive
disorder, is 25 percent. Fifty percent of their children risk
being carriers of the disease.
2/4/2017 Pharmacology Division 14
15. Aetiology
The products of seven of these genes (XP-A through G) are involved
in the repair of ultraviolet-induced photoproducts in DNA by the
process of nucleotide excision repair (NER)5.
The XPC and XPE proteins are needed to recognise the photoproducts
in DNA.
XPB and XPD are part of a protein complex TFIIH, which opens up
the structure of the DNA around the site of the photoproduct.
XPA protein verifies that proteins are in the correct position and then
the nucleases XPG and XPF cut the DNA on either side of the damage,
so that the damaged section can be removed and replaced with intact
DNA.
2/4/2017 Pharmacology Division 15
16. Complementation groups for XP:
XPA
XPB
XPC
XPD
XPE
XPF
XPG
XPV
2/4/2017 Pharmacology Division 16
XPA,XPC,XPE
XPB,XPD
XPF,XPG
17. Patients defective in the XPC or XPE genes do not, in general,
have the extreme sunburn reactions or neurological abnormalities.
Defects in the eighth XP gene do not affect NER 7.
The DNA polymerases that normally replicate DNA cannot deal
with damage in the DNA template and specialised polymerases
have to be employed to get past the damage (translesion
synthesis).
For UV damage, the cell uses DNA polymerase η, encoded by the
gene POLH and this gene is mutated in XP-V patients 8.
Like XP-C and XP-E patients, XP-V patients rarely have extreme
sunburn reactions or neurological problems.
2/4/2017 Pharmacology Division 17
18. Signs and Symptoms of
Xeroderma Pigmentosum
Severe sunburn.
Development of many freckles at an early age.
Rough-surfaced growths (solar keratoses), and skin cancers.
Eyes that are painfully sensitive to the sun and may easily
become irritated, bloodshot and clouded.
Blistering or freckling on minimum sun exposure.
2/4/2017 Pharmacology Division 18
19. Cont…
Spider Veins
Limited growth of hair on chest and legs
Scaly skin
Dry skin
Irregular dark spots on the skin
Corneal ulcerations
2/4/2017 Pharmacology Division 19
21. Diagnosis
Before birth:
Amniocentesis
Chorionic villous sampling
After birth:
Severe sunburn after first exposure to the sunlight
Based on clinical findings and family history,
skin, eye, and nervous system
By measuring the DNA repair factor from skin or blood sample
2/4/2017 Pharmacology Division 21
22. Treatment of XP
Cryotherapy
Removal of heat from the body.
Fluorouracil
Pyrimidine analogue used to treat cancer
Reduced exposure to sun’s UV rays
2/4/2017 Pharmacology Division 22
23. 2/4/2017 Pharmacology Division 23
Protection from
UV
Eye and skin
exam
Prompt removal
of cancerous
tissue
Neurological
exam
Psychososial
care
24. prognosis
Many patients die at an early age from skin cancers but if a person is
diagnosed early, does not have severe neurological symptoms and takes all
the precautionary measures to avoid exposure to UV light, they may survive
beyond middle age.
Less than 40% of individuals with the disease survive beyond age 20.
Some with less severe cases manage to live well up to 40 years.
Prevention
Genetic counseling for those with Family history.
2/4/2017 Pharmacology Division 24
25. Conclusions
Though there is no cure for XP, increased awareness and
early diagnosis, followed by protection from daylight and
careful patient management, can improve the quality of
life and life expectancy of affected individuals.
A major challenge for the future is to increase
understanding of the aetiology of the neurological
problems associated with the disorder in some individuals.
This should enable the development of treatments to
alleviate the neurological degeneration.
2/4/2017 Pharmacology Division 25
26. References
1) Halpern, J.; Hopping, B.; Brostoff, J. (2008)“Photosensitivity,
corneal scarring and developmental delay: Xeroderma Pigmentosum
in a tropical country”.. Cases journal. 1:254.doi:10.1186/1757-1626-
1-254.PMC 2577106. PMID 18937855
2)Robbins JH, Kraemer KH, Lutzner MA, Festoff BW, Coon HG:
Xeroderma pigmentosum: an inherited disease with sun-sensitivity,
multiple cutaneous neoplasms, and abnormal DNA repair. Annals
Internal Med 1974, 80:221-248.
2/4/2017 Pharmacology Division 26
27. 3) Hirai Y, Kodama Y, Moriwaki S, Noda A, Cullings HM, Macphee
DG, Kodama K, Mabuchi K, Kraemer KH, Land CE, Nakamura N.
Heterozygous individuals bearing a founder mutation in the XPA
DNA repair gene comprise nearly 1% of the Japanese population.
2006 ;Mutat Res, 601:171-178.
4)Lehmann AR, McGibbon D, Stefanini M (2011). Xeroderma
pigmentosum. 2011 ;Orphanet J Rare Dis. 6: 70. Nov 1;6:70. doi:
10.1186/1750-1172-6-70.
5)Stefanini M, Kraemer KHK: Xeroderma pigmentosum. In
Neurocutaneous Diseases Edited by: Ruggieri M, Pascual-
Castroviejo I, Di Rocco C 2008, Chapter 51:771-792.
2/4/2017 Pharmacology Division 27
28. 6) Mieran Sethi,1 Alan R. Lehmann,1,2 Hiva Fassihi1: XERODERMA
PIGMENTOSUM: A MULTIDISCIPLINARY APPROACH,
2013;EMJ Dermatol. 1:54-63.
7) Lehmann AR, Kirk-Bell S, Arlett CF, Paterson MC, Lohman PHM,
de Weerd- Kastelein EA, Bootsma D: Xeroderma pigmentosum cells
with normal levels of excision repair have a defect in DNA synthesis
after UV- irradiation. 1975; Proceedings of the National Academy of
Sciences of the United States of America, 72:219-223.
8) Masutani C, Kusumoto R, Yamada A, Dohmae N, Yokoi M, Yuasa
M, Araki M, Iwai S, Takio K, Hanaoka F: The XPV (xeroderma
pigmentosum variant) gene encodes human DNA polymerase eta.
1999 ;Nature, 399:700-704.
2/4/2017 Pharmacology Division 28
29. 9) Dr. Fawzia M. A. BUTT, Dr. Jeremiah R.MOSHI, DR.Siva
OWIBINGIRE. Xeroderma pigmentosum: a
Review and case series, 2010; Elsevier Ltd, 38(7):534-7
10) https://en.wikipedia.org/wiki/Xeroderma pigmentosum
11) http://rarediseases.org/rare-diseases/xeroderma pigmentosum/
2/4/2017 Pharmacology Division 29