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Xeroderma pigmentosum (XP) is a group of rare inherited skin disorders characterized by a heightened reaction to sunlight (photosensitivity) with skin blistering occurring after exposure to the sun. In some cases, pain and blistering may occur immediately after contact with sunlight. Acute sunburn and persistent redness or inflammation of the skin (erythema) are also early symptoms of XP. In most cases, these symptoms may be apparent immediately after birth or occur within the next three years. In other cases, symptoms may not develop until later in childhood or, more rarely, may not be recognized until adulthood. Other symptoms of XP may include discolorations, weakness and fragility, and/or scarring of the skin.
Xeroderma pigmentosum affects the eyes as well as the skin, has been associated with several forms of skin cancer, and, in some cases, may occur along with dwarfism, mental retardation, and/or delayed development.
Several subtypes of XP (i.e., XP complementation groups) have been identified, based upon different defects in the body's ability to repair DNA damaged by ultraviolet light (UV). According to the medical literature, the symptoms and findings associated with the classic form of xeroderma pigmentosum, known as XP, type A (XPA), may also occur in association with the other XP subtypes. These include: XP, type B (XPB); XP, type C (XPC), XP, type D (XPD); XP, type E (XPE); XP, type F (XPF); and XP, type G (XPG). These XP subtypes are transmitted as an autosomal recessive trait. In addition, another subtype of the disorder, known as XP, dominant type, has autosomal dominant inheritance.
In addition to the XP subtypes discussed above, researchers have identified another form of the disorder known as XP, variant type (XP-V). As with the other XP subtypes, symptoms and findings associated with the classic form of XP may also be seen in individuals with XP-V. XP-V cells have a normal or near normal ability to repair UV-induced DNA damage (nucleotide excisional repair), however, they are defective in replicating UV-damaged DNA during the division and reproduction of cells. Although the disorder's mode of inheritance is unknown, most researchers suspect that XP-V is transmitted as an autosomal recessive trait.
The earliest signs of xeroderma pigmentosum (XP) include excessive freckling and an extremely heightened reaction to sunlight (photosensitivity), with skin blistering occurring after exposure to the sun. In some cases, pain and blistering may occur immediately after contact with sunlight. Acute sunburn and persistent redness or inflammation of the skin (erythema) are also early symptoms of XP. In most cases, these symptoms may be apparent immediately after birth or by the age of three years. However, in some cases, symptoms may not be apparent until later in childhood, or more rarely, during adulthood.
Additional skin abnormalities often develop, including abnormal darkening of the skin (hyperpigmentation), diminished pigmentation of the skin (hypopigmentation), and/or excessive scarring. Small red skin lesions (telangiectasias) may develop due to abnormal widening of blood vessels. In addition, the skin may become weakened and excessively fragile, degenerative (atrophic) changes may occur, and the skin may appear unusually dry and smooth.
Most affected individuals also have abnormalities of the eyes, most notably an extreme intolerance to light (photophobia). Additional symptoms and findings often include inflammation of the corneas (keratitis), inflammation of the transparent membrane lining the insides of the eyelids and covering the whites of the eyes (conjunctivitis), excessive tearing (lacrimation), and clouding of the lens of the eyes (opacities). In addition, in many individuals with XP, the eyelids may abnormally turn outward (ectropion) or inward (entropion).
Several types of benign and malignant tumors may be associated with XP, with onset possible before the age of five in some cases. Sunlight-induced skin cancers (e.g., malignant melanoma, basal cell carcinoma, and squamous cell carcinoma) commonly develop in individuals with XP, most often affecting the head, neck, and face. (For more information on these forms of skin cancer, please see the "Related Disorders" section below.) Individuals with XP may also be prone to developing certain pre-malignant or benign (non-cancerous) skin tumors, such as tumors consisting of blood vessels (angiomas) or certain cells that cover particular bodily surfaces (keratoacanthomas), as well as tumors of the eyelids, corneas, and/or tip of the tongue. In individuals with XP, the severity of associated skin and eye abnormalities may depend on the amount of exposure to ultraviolet light.
Unusually slow development, dwarfism, mental retardation, and neurological impairments may also be associated with some cases of XP. Such neurological impairments may include absent or weakened reflexes (areflexia or hyporeflexia); an abnormally small head (microcephaly); hearing impairment (sensorineural deafness); increased rigidity in certain muscles, causing stiffness and limitation of movement (spasticity); and/or loss of voluntary coordination (ataxia). (For more information on ataxia, please see the "Related Disorders" section of this report.)
When XP occurs in association with mental retardation, dwarfism, abnormal gonadal function (hypogonadism), and, in some cases, neurological abnormalities, the disorder is referred to as De Sanctis-Cacchione syndrome. (For more information on De Sanctis-Cacchione syndrome, please see the "Related Disorders" section of this report below.)
The range and severity of associated abnormalities may vary dramatically among affected individuals. The previously mentioned symptoms and findings may occur in association with any of the subdivisions (i.e., complementation groups) of XP.
More specifically, in XP, type B (XPB), the neurological defects and skin damage associated with classic XP (XPA) may occur along with Cockayne syndrome. (For more information on "Cockayne syndrome," please see the "Related Disorders" section of this report.)
In some cases, XP, type C (XPC) may be associated with an inflammatory autoimmune disorder of the connective tissues (lupus). In addition, individuals with this type of XP are particularly prone to developing a certain type of skin cancer (malignant melanoma). (For more information on these disorders, please see the "Related Disorders" section of this report.)
XP, type D (XPD) may be characterized by sparse and brittle hair (trichothiodystrophy), short stature, unusual facial features, abnormal sexual development (hypogonadism), and scaling of the skin (ichthyosis). Some individuals with XPD may also experience a late onset of neurological symptoms, such as mental deterioration and/or loss of voluntary coordination (ataxia). (For more information on ichthyosis, please see the "Related Disorders" section of this report below.)
XP, type E (XPE) has been associated with minimal or no neurological symptoms, and most people with this XP subtype have a less severe form of skin disease. However, individuals affected by XPE may be susceptible to early onset of some types of skin cancer (e.g., basal cell carcinoma, squamous cell carcinoma, malignant melanoma).
XP, type F (XPF) has been associated with minimal or no occurrence of skin cancer, neurological abnormalities, or disorders of the eyes.
XP, type G (XPG) has been associated with normal physical and neurological development and mild skin changes.
Little is known about XP, dominant type other than that it is transmitted as an autosomal dominant trait and is a milder form of the classic type of XP.
As with the other subtypes of xeroderma pigmentosum, XP, variant type (XP-V) may be characterized by symptoms and findings seen in those with the classic form of XP. However, XP-V has been associated with no neurologic symptoms. In addition, affected individuals may be prone to the early onset of certain sunlight-induced skin cancers (e.g., basal cell carcinoma, squamous cell carcinoma, malignant melanoma).
Xeroderma pigmentosum (XP), types A through G as well as XP, variant type are thought to have autosomal recessive inheritance. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.
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, but usually will not show symptoms. 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, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.
In some cases, the parents of individuals with XP have been closely related by blood (consanguineous). In these cases, if both parents carry the same disease gene, there is a higher-than-normal risk that their children may inherit the two disease genes necessary for the development of the disease.
One rare form of xeroderma pigmentosum, known as XP, dominant type, is transmitted as an autosomal dominant trait. In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed "dominating" the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
In most subtypes of XP, associated symptoms and findings result due to the body's inability to repair deoxyribonucleic acid (DNA) damaged by exposure to ultraviolet light (UV). DNA is the carrier of the genetic code within cells. The coded DNA instructions within genes consist of different arrangements of four basic chemicals (nucleotide bases) known as adenine (A), cytosine (C), guanine (G), and thymine (T). In many individuals with XP, cells are unable or have a reduced capacity to carry out "nucleotide excision repair" (NER), a complex process during which nucleotides with UV-induced damage are removed. As a result, as damaged DNA replicates itself during the division and reproduction of cells, errors or "mutations" within the coded DNA instructions continue to accumulate. Researchers have classified the different XP complementation groups (e.g., XPA, XPB, etc.) based upon specific defects in the body's ability to repair UV-damaged DNA.
In addition, researchers have classified XP, variant type (XP-V) based upon the fact that XP-V cells have a normal or near normal ability to repair UV-induced DNA damage. However, such cells are defective in replicating UV-damaged DNA, in other words, genetic material within the XP-V cells is significantly more likely to mutate due to exposure to UV radiation than otherwise expected (hypermutability).
Disease genes that may be responsible for causing XP subtypes A through G have been mapped to particular chromosomes. The affected genes are all thought to play some role in the repair of UV-damaged DNA (i.e., nucleotide excision repair). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q". Chromosomes are further subdivided into bands that are numbered.
A disease gene has been located on the long arm (q) of chromosome 9 (9q22.3) in the classic form of XP, on the long arm (q) of chromosome 2 (2q21) in XP, type B, and on the short arm (p) of chromosome 3 (3p25) in XP, type C. In addition, abnormal changes (mutations) of a DNA repair gene (known as ERCC2), mapped to the long arm of chromosome 19 (19q13.2-q13.3), are thought to play a role in causing XP, type D. XP, type E is thought to be caused by mutations of a gene linked to the short arm of chromosome 11 (11p12-p11). Mutations of the "ERCC4" gene, which has been mapped to the short arm of chromosome 16 (16p13.2-p13.1), have been identified in individuals with XP, type F. In addition, abnormal changes of a DNA repair gene on the long arm of chromosome 13 (13q33) have been implicated in cases of XP, type G.
In individuals with XP-V, researchers have identified mutations in a gene known as hRAD30 (also known as the DNA polymerase eta gene), which is the human counterpart (homologue) of a similar gene in yeast (RAD30). According to researchers, the hRAD30 gene (like its yeast counterpart) appears to encode an enzyme (i.e., DNA polymerase) that enables error-free cellular replication by "bypassing" UV-induced damage (thymine dimers). As a result, proper functioning of this so-called "damage-bypass replication protein" plays an important role in helping to minimize the occurrence of certain skin cancers that may be induced by exposure to sunlight. Accordingly, in individuals with XP-V, mutations of the hRAD30 gene appears to result in impaired replication of UV-damaged DNA and an increased susceptibility to UV-induced skin cancers.
Xeroderma pigmentosum (XP) appears to affect males and females in equal numbers. The onset of symptoms usually occurs immediately after birth or within the next three years of life. However, in some cases, symptoms may not develop until later childhood. In addition, rare cases of adult onset have been reported in the medical literature.
XP affects approximately one in 100,000 individuals worldwide and about one in 250,000 persons in the United States and Europe. The disorder appears to occur more frequently in Japan.
Symptoms of the following disorders may be similar to those of xeroderma pigmentosum (XP). Comparisons may be useful for a differential diagnosis:
Cockayne syndrome is a rare inherited disorder characterized by growth retardation, abnormal sensitivity to light (photosensitivity), an abnormally small head (microcephaly), and a prematurely aged (progeroid) appearance. Children with this disorder may scar easily and have an increased amount of color (pigmentation) in the skin. Cockayne syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose "Cockayne" as your search term in the Rare Disease Database.)
De Sanctis-Cacchione syndrome is an extremely rare disorder in which XP occurs in association with dwarfism, inadequate functioning of the testes or ovaries (hypogonadism), and one or more neurological abnormalities. Symptoms of XP include a heightened reaction to sunlight (photosensitivity), skin discoloration, and the possible development of several types of eye disorders and skin cancer. The most common neurological abnormalities associated with De Sanctis-Cacchione syndrome are deficient intelligence, an abnormally small head (microcephaly), and/or absent (areflexia) or weakened (hyporeflexia) reflexes. De Sanctis-Cacchione syndrome is inherited as an autosomal recessive trait.
The following disorders may be associated with XP as secondary characteristics. They are not necessary for a differential diagnosis:
Lupus (systemic lupus erythematosus) is an inflammatory disease of the connective tissue. Tissue damage occurs when the body's own immune system inappropriately attacks healthy tissue, causing inflammation and malfunction of various organ systems. The range and severity of associated symptoms and findings may be extremely variable, depending upon the specific tissues and organ systems affected. However, in many cases, initial, generalized symptoms may include excessive fatigue, skin rash, fevers, swollen glands, loss of appetite (anorexia), weight loss, headaches, and swelling due to fluid retention (edema). (For more information on this disorder, choose "lupus" as your search term in the Rare Disease Database.)
Malignant melanoma is a form of skin cancer that develops from the melanin cells of the upper layer of the skin (epidermis) or from similar cells that may be found in moles (nevi). In early stages, most melanomas do not produce any specific symptoms. They may later appear as a lesion that does not heal or an existing mole that shows changes in size or color. This type of skin cancer eventually spreads to the lower skin levels and adjacent tissue and may result in new tumor growths in vital organs of the body. (For more information on this disorder, choose "melanoma" as your search term in the Rare Disease Database.)
Basal cell carcinomas are tumors that occur in the basal cells on the surface of the skin and may appear as small, shiny, firm masses of tissues (nodules), flat, scar-like lesions (plaques); or red patches covered by thick, dry, silvery scales. If left untreated, basal cell carcinoma may spread (metastasize) to other parts of the body, causing further disease. This type of skin cancer is difficult to differentiate from psoriasis or localized dermatitis without a biopsy. Overexposure to sunlight or ionizing radiation may be causes of this type of skin cancer.
Squamous cell carcinomas are tumors that usually appear on sun-exposed areas of the skin, but may occur anywhere on the body. This form of skin cancer is characterized by lesions that may appear to have a scaly or crusted surface. The lesions may spread to underlying tissue. (For more information on this disorder, choose "squamous cell carcinoma" as your search term in the Rare Disease Database.)
Ichthyosis is a general term describing a group of disorders characterized by abnormal dryness, thickening, and scaling of the skin. Such symptoms are thought to result from abnormalities in the production of a protein that is a major component of the skin (keratin). Depending upon the form of the disorder present, additional symptoms and findings may include unusual redness of the skin, severe itching (pruritus), unusually rough and/or thickened skin in certain areas of the body (such as the palms and soles), defects of the nails, sparse hair, and/or other abnormalities. Most known forms of ichthyosis are genetic disorders. (For more information on this disorder, choose "ichthyosis" as your search term in the Rare Disease Database.)
Ataxia is a neurological condition characterized by an impaired ability to coordinate voluntary movement. Associated symptoms and findings may vary, depending upon the specific underlying cause of the condition and other factors. However, in many cases, ataxia may result in impaired balance, an abnormal manner of walking (gait), speech difficulties, and/or other abnormalities. Ataxia may have many different causes, including certain genetic, neurologic, metabolic, and/or other disorders; injury to certain areas of the central nervous system (e.g., cerebellum); and/or other factors.
In some cases, a diagnosis of xeroderma pigmentosum (XP) may be suspected before birth (prenatally) based upon the results of specialized tests, such as amniocentesis. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and studied. Such prenatal screening procedures may be conducted for families with a history of XP.
In many cases, XP is diagnosed or confirmed during infancy or childhood based upon a thorough clinical evaluation, characteristic physical findings, a detailed patient and family history, and certain specialized laboratory tests. For example, in some cases, samples of certain cells, such as white blood cells (lymphocytes) and skin cells (fibroblasts), may be exposed to UV radiation and studied microscopically to detect impaired DNA repair or defective replication of UV-damaged DNA.
Affected individuals should be regularly monitored by physicians to ensure prompt detection and appropriate treatment of skin lesions, eye abnormalities, and/or other symptoms and findings potentially associated with the disorder.
For individuals with XP, it is essential to minimize sun exposure as much as possible to protect against ultraviolet radiation. Appropriate measures include limiting time outdoors during daylight hours, using special (e.g., broad-spectrum) topical sunscreens, wearing sunglasses and double layers of clothing, and shielding glass in windows to prevent the passage of sunlight. In addition, affected individuals should take appropriate precautions to avoid exposure to certain chemical carcinogens, such as those in cigarette smoke.
Early surgical removal of and/or other appropriate treatment measures for skin tumors (neoplasms) are essential for individuals with XP.
Genetic counseling will be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
A plastic surgery procedure (dermabrasion), chemical peels, or grafting of skin from areas that have not been exposed to sunlight have been used in some individuals with XP. In addition, dermabrasion and the use of topical 5-fluorouracil may be effective in treating premalignant or early lesions in some cases. In some children with XP, application of a catalase cream may help to prevent tumor development. Topical ointments that contain vitamin A derivatives are also being investigated.
T4 endonuclease V.B. liposome encapsulated (Dimericine) is being investigated as a possible therapy for preventing the development of skin malignancies and other skin abnormalities that may occur in association with XP. Further studies are needed to determine the long-term safety and effectiveness of this therapy for individuals with XP. For more information, contact:
Applied Genetics, Inc.
205 Buffalo Ave.
Freeport, NY 11520
Tel: (516) 868-9026
For carefully selected individuals, a procedure may be conducted during which part of the corneas are removed and replaced (keratoplasty). Further studies are needed to determine the long-term safety and effectiveness of keratoplasty in carefully selected individuals with XP. Artificial tears and soft contact lenses have also been used in affected individuals with certain eye abnormalities occurring in association with XP.
According to the medical literature, imiquimod 5% (Aldara) has been used to treat cutaneous malignancies sometimes associated with XP. Imiquidmod 5% was used to treat facial basal cell carcinomas. Initial results demonstrated improvement in the affected areas. More research is necessary to determine the long-term safety and effectiveness of this potential treatment for cutaneous malignancies associated with XP.
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FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 278700; Last Update: 7/30/99. Entry No: 133510; Last Update:7/30/99. Entry No: 278720; Last Update:7/21/99. Entry No: 278730; Last Update:7/30/99. Entry No: 278740; Last Update:7/30/99. Entry No: 278760; Last Update:7/30/99. Entry No: 278780; Last Update:10/16/98. Entry No: 194400; Last Update:6/16/99. Entry No: 278750; Last Update:7/12/99.
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Report last updated: 2008/01/12 00:00:00 GMT+0