This is a rare autosomal recessive disorder characterized by increased sensitivity to cellular injury. This manifests itself as photosensitivity, photophobia, early onset of freckling, xerosis, corenal opacities, and early development of sun-induced cancers. Neurological abnormalities occur in 20% of patients and are particularly severe in some variants. The cellular defect is defective DNA repair replication. Thus, UV induced damage leads to faulty repair and cellular injury.
It involves both sexes and all races with an incidence of 1:250,000 and a gene frequency of 1:200. A history of consanguinity is common. Prenatal diagnosis can be made by an analysis of DNA repair of cultured amniotic cells. There is genetic heterogeneity identified by somatic cell fusion studies or complementation groups.
Complementation Group Skin Cancer Neurologic Abnormalities DNA repair
% of Normal
A Yes Severe or mild <2 (Most severe) B with CS Yes XP/CS 3-7 B-TDD No TDD C Yes No 10-25 D Yes Moderate 25-50 D-TDD No TDD D Yes XP/CS E Yes No 40-50 (Mildest) F Yes No 10-20 G Yes Yes <5 G with CS No CS XP Variant Yes No 100
CS is Cockayne syndrome characterized by short stature, photosensitivity, deafness, mental deficiency, large ears and nose and sunken eyes. TTD is trichothiodystrophy is also known as Tay syndrome or IBIDS syndrome and is not associated with cancer. This also has abnormal DNA repair. In the XP variant, DNA excision repair is normal but there is defective ability to convert newly synthesized DNA from low to high molecular weight after UV irradiation (postreplication repair). There is a very severe form of the disease which is a variant of XP-A called De Sanctis-Cacchione syndrome. In this variant, there is microcephaly, dwarfism, choreoathetosis, and mental deficiency.
All of these patients develop skin related changes before the age of 2 years with severe sunburns and variable freckling. There is a 1000 fold increased risk for developing cutaneous basal cell, squamous cell carcinoma, or melanoma before the age of 20 years. As progressive damage of the eyes occurs, corneal opacities and ectropion and entropion may occur.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/
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Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
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EPIDEMIOLOGY CHARACTERIZATION SYNONYMS INCIDENCE/
AGE SEX GEOGRAPHY
- Incidence of xeroderma pigmentosum in Larkana, Pakistan: a 7-year study.
Bhutto AM, Shaikh A, Nonaka S.
Department of Dermatology, Chandka Medical College Larkana, Pakistan.
Br J Dermatol. 2005 Mar;152(3):545-51. Abstract quote
Xeroderma pigmentosum (XP) is a rare autosomal recessive inherited disorder caused by a defect in the normal repair of DNA of various cutaneous cell types damaged by exposure to ultraviolet radiation.
We present our 7-year experience with 36 XP patients who either visited the Department of Dermatology or were seen in the medical camps arranged in remote areas for patients' welfare, from 1995 to 2001. For ease of discussion we classified all cases into the following subgroups on clinical grounds only: mild, those with light brown freckles on the face alone; moderate, those with dark brown freckles with burning on the face, neck, ears, chest, hands and photophobia but without other associated obvious cutaneous and ocular changes; severe, those with extensive dark brown freckles with burning on the exposed parts as well as on the unexposed parts of the body, i.e. the chest, back, abdomen and arms including other associated cutaneous and ocular changes such as ulcers and malignancy.
Of 36 patients, three (8.3%) were classified as mild, nine (25%) moderate and 24 (66.7%) severe; there were 18 males and 18 females, age range 2-30 years (mean 8.9 years). Seventeen patients had cutaneous changes: actinic keratosis, keratoacanthoma, fissures and ulcerative nodules on the exposed parts of the body. Four patients had wide ulcers, along with mass formation and severe pigmentation on the face, neck and head. Twenty-nine patients developed ocular symptoms: photophobia, conjunctivitis, corneal keratitis and lid ulcer. One patient had complete loss of vision.
Histopathological findings revealed that six patients had squamous cell carcinoma (SCC) on the face, head, ear or lip. More than one sibling (two to four) was affected in four families. The majority of cases (20/36, 55.6%) were from the Brohi tribe (skin type III), while the remaining cases (16/36, 44.4%) were from the Sindhi population (skin type IV). The large number of XP patients seen in those with skin type III (Brohi tribe) compared with skin type IV (Sindhi population) indicates that the skin type and the race has a considerable value in the pathogenesis of XP. Furthermore, 24 of 36 patients were in the severe group and six of these had SCC. Moreover, no neurological abnormalities were observed in our patients.
All patients were treated according to disease severity by prescribing oral antibiotics, local steroids, sunscreens and/or chemotherapy followed by irradiation in malignant cases. Two patients died because of extensive SCC.
DISEASE ASSOCIATIONS CHARACTERIZATION
PATHOGENESIS CHARACTERIZATION GENERAL
- The role of UV induced lesions in skin carcinogenesis: an overview of oncogene and tumor suppressor gene modifications in xeroderma pigmentosum skin tumors.
Daya-Grosjean L, Sarasin A.
Laboratory of Genetic Instability and Cancer, UPR2169 CNRS, IFR 54, Institut Gustave Roussy, 39, rue Camille Desmoulins, 94805 Villejuif Cedex, France.
Mutat Res. 2005 Apr 1;571(1-2):43-56. Epub 2005 Jan 25. Abstract quote
Xeroderma pigmentosum (XP), a rare hereditary syndrome, is characterized by a hypersensitivity to solar irradiation due to a defect in nucleotide excision repair resulting in a predisposition to squamous and basal cell carcinomas as well as malignant melanomas appearing at a very early age. The mutator phenotype of XP cells is evident by the higher levels of UV specific modifications found in key regulatory genes in XP skin tumors compared to those in the same tumor types from the normal population.
Thus, XP provides a unique model for the study of unrepaired DNA lesions, mutations and skin carcinogenesis. The high level of ras oncogene activation, Ink4a-Arf and p53 tumor suppressor gene modifications as well as alterations of the different partners of the mitogenic sonic hedgehog signaling pathway (patched, smoothened and sonic hedgehog), characterized in XP skin tumors have clearly demonstrated the major role of the UV component of sunlight in the development of skin tumors. The majority of the mutations are C to T or tandem CC to TT UV signature transitions, occurring at bipyrimidine sequences, the specific targets of UV induced lesions. These characteristics are also found in the same genes modified in sporadic skin cancers but with lower frequencies confirming the validity of studying the XP model.
The knowledge gained by studying XP tumors has given us a greater perception of the contribution of genetic predisposition to cancer as well as the consequences of the many alterations which modulate the activities of different genes affecting crucial pathways vital for maintaining cell homeostasis.
CHARACTERIZATION RADIOLOGIC LABORATORY MARKERS
- DNA-based diagnosis of xeroderma pigmentosum group C by Whole-genome scan using single-nucleotide polymorphism microarray.
Lam CW, Cheung KK, Luk NM, Chan SW, Lo KK, Tong SF.
Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.
J Invest Dermatol. 2005 Jan;124(1):87-91. Abstract quote
In this study, we have established the molecular basis of xeroderma pigmentosum (XP) in two unrelated Chinese families.
In the first patient with consanguineous parents, we mapped the disease-causing locus XPC using single-nucleotide polymorphism microarray. Mutational analysis of the XPC gene showed that the patient is homozygous for a nonsense mutation, E149X. After developing DNA-based diagnosis of XPC, we screened another XP patient for XPC mutations.
We found that the second patient is a compound heterozygote of 1209delG and Q554X in this gene. These are the first XPC-causing mutations identified in Chinese patients.
- Dermoscopy of skin lesions in two patients with xeroderma pigmentosum.
Malvehy J, Puig S, Marti-Laborda RM.
Department of Dermatology, Hospital Clinic, IDIBAPS, C/Villarroel 170, 08036 Barcelona, Spain.
Br J Dermatol. 2005 Feb;152(2):271-8. Abstract quote
BACKGROUND: Xeroderma pigmentosum (XP) is a rare disorder produced by a genetic defect in the repair of DNA damage caused by ultraviolet radiation. The early diagnosis of malignant skin tumours is crucial in the survival of patients with XP, but this is not easy even for experienced dermatologists due to the presence of a high number of actinic lesions. Dermoscopy is a new diagnostic method that increases the diagnostic accuracy for skin tumours.
OBJECTIVES: To describe the clinical and dermoscopic features of different benign and malignant lesions [focusing on malignant melanoma, basal cell carcinoma (BCC) and benign melanocytic naevi] in two patients with XP.
METHODS: Three dermatologists with experience in pigmented skin lesions and dermoscopy examined two siblings with XP over a period of 54 months. Diagnosis of skin tumours was obtained using clinical examination and dermoscopy with 10-fold magnification and digital images. All the tumours with criteria of malignancy were excised for further histopathological analyses.
RESULTS: Multiple skin tumours showing some degree of pigmentation were detected in the patients. Clinical and dermoscopic examination allowed the discrimination of four melanomas (three of them in situ), 26 BCCs and five dysplastic naevi from other pigmented skin lesions. The features and parameters previously described for dermoscopy were shown to be appropriate for the recognition of tumours in our patients with XP. Generalized actinic lentigos were distinguished from BCCs by the presence of a delicate brown pigmented network. Fine vessels from poikiloderma were differentiated from the arborizing telangiectasia of BCC.
CONCLUSIONS: The dermoscopic findings in the tumours were similar to those previously described in patients not affected by XP. Diagnosis by dermoscopic pattern analyses allowed a correct classification of malignant tumours in these cases.
CHARACTERIZATION GENERAL VARIANTS LARYNGEAL DYSTONIA
- Laryngeal dystonia in xeroderma pigmentosum.
Muto A, Matsui A, Saito Y, Iwamoto H, Kaneko K, Masuko K, Chikumaru Y, Saito K, Kimura S.
Department of Pediatrics and Pediatric Neurology, Yokohama Ryo-iku Medical Center, 557-2 Ichizawa-cho, Asahi-ku, Yokohama 241-0014, Japan; Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan.
Brain Dev. 2005 May 27; [Epub ahead of print] Abstract quote
We report on three patients with xeroderma pigmentosum group A (XPA) who showed laryngeal stridor in their 20s. The stridor appeared on feeding and emotional excitation, was exaggerated during respiratory infection and was life-threatening on some occasions.
Adduction of the vocal cords during inspiration, observed by laryngoscopy, confirmed laryngeal dystonia in all cases.
This type of focal dystonia may be characteristic in XPA and requires special attention during the management of these patients to avoid serious complications.
PROGNOSIS CHARACTERIZATION SKIN
- Assessment of 3 xeroderma pigmentosum group C gene polymorphisms and risk of cutaneous melanoma: a case-control study.
Blankenburg S, Konig IR, Moessner R, Laspe P, Thoms KM, Krueger U, Khan SG, Westphal G, Berking C, Volkenandt M, Reich K, Neumann C, Ziegler A, Kraemer KH, Emmert S.
Department of Dermatology and Department of Occupational and Social Medicine, Georg-August-University, Goettingen, Germany, Institute of Medical Biometry and Statistics, University Hospital Schleswig-Holstein-Campus Lubeck, Germany, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute/NIH, Bethesda, MD, USA and Department of Dermatology, Ludwig-Maximilians-University, Munich, Germany.
Carcinogenesis. 2005 Jun;26(6):1085-1090. Epub 2005 Feb 24. Abstract quote
Individuals with the rare DNA repair deficiency syndrome xeroderma pigmentosum (XP) are sensitive to the sun and exhibit a 1000-fold increased risk for developing skin cancers, including cutaneous melanoma. Inherited polymorphisms of XP genes may contribute to subtle variations in DNA repair capacity and genetic susceptibility to melanoma.
We investigated the role of three polymorphic alleles of the DNA repair gene XPC in a hospital-based case-control study of 294 Caucasian patients from Germany who had cutaneous melanoma and 375 healthy cancer-free sex-matched Caucasian control subjects from the same area.
We confirmed that the XPC intron 9 PAT+, intron 11 -6A, and the exon 15 2920C polymorphisms are in a linkage disequilibrium. Only 1.6% of the 669 donors genotyped were discordant for these three polymorphisms. The allele frequencies (cases: controls) were for intron 9 PAT+ 41.7%:36.9%, for intron 11 -6A 41.8%:37.0% and for exon 15 2920C 41.3%:37.3%. Using multivariate logistic regression analyses to control for age, skin type and number of nevi, the three polymorphisms were significantly associated with increased risks of melanoma: OR 1.87 (95% CI: 1.10-3.19; P = 0.022), OR 1.83 (95% CI: 1.07-3.11; P = 0.026), and OR 1.82 (95% CI: 1.07-3.08; P = 0.026), respectively. Exploratory multivariate analyses of distinct subgroups revealed that these polymorphisms were associated with increased risks for the development of multiple primary melanomas (n = 28).
The results of our case-control study support the hypothesis that the intron 9 PAT+, intron 11 -6A and exon 15 2920C haplotype may contribute to the risk of developing cutaneous melanoma by increasing the rate of an alternatively spliced XPC mRNA isoform that skips exon 12 and leads to reduced DNA repair. Our results should be validated in independent samples in order to guard against false positive findings.
TREATMENT CHARACTERIZATION GENERAL
Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
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