Cancer prone diseases
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recessive autosomal; occurrence is favored by consanguinity; frequency is 0.3\/10
5 with large geographical variations; higher frequenciy observed in Tunisia (10\/10
5, role of consanguinity) and in Japan (1\/10
5); rare in black people
278700 , 278720 , 278730 , 278740 , 278750 , 278760 , 278780 , 278800 , 208900 , 610651 , 194400
910 Xeroderma pigmentosum
xeroderma pigmentosum (XP) is caused by a defect in nucleotide excision repair mechanisms; various clinical aspects and intensity of signs are described according to the gene involved (7 known complement groups) and type of mutation
Phenotype and clinics
severe sun photosensitivity (poikilodermia): induced precocious cutaneous lesions, concomitant to first sun exposures, on the exposed areas (hands, arms, face); dry skin, senile-like, cutaneous retractions (premature aging of the skin)
photophobia, often the first sign, before cutaneous lesions; followed by bilateral cataract; increased risk of ocular benign and malign tumors
neurological signs (14 to 40% of patients): mental retardation, pyramidal syndrome, peripheral neuropathia; more severe central nervous system (CNS) disorders are observed when mutations occur in XPA DNA binding site
clinical heterogeneity: related to genetic heterogeneity of the disease (7 known complementation groups A, B, C, D, E, F, G and 7 characterized genes). Intensity and precocity of signs are dependent on the gene involved; groups A, C, D and G are associated with a more severe disease.
the same genes are implicated in two related diseases: Cockayne syndrome (groups B, D and G) and trichothiodystrophy (groups B and D)
Above: characteristic aspect of evolved lesions of the face in an XP patient. To be noted multiple scars of carcinomas and an aged aspect of the skin with poikilodermia. Below: multiple basocellular carcinomas on the face of an XP patient. Thick arrow points to a recent lesion, and thin arrow to a scar of an old lesion - Courtesy Daniel Wallach
propensity to cutaneous tumors after sun exposure ( risk X 1000 to develop cancer on sun -exposed areas of the skin): benign lesions, multiple basal cell carcinomas and spinal carcinomas (occuring in 2 to 40 year old patients, median age 8 yrs), malignant melanomas slightly later than carcinomas (risk x 2000 compared to normal population), rarely other skin tumors (fibrosarcomas, angiosarcomas).
propensity to various solid tumors (mainly brain tumors, x 10 to 20 fold in comparison with general population )
photoprotection; genetic counseling; treatment of malignant tumors
progressively increasing number of cutaneous, ocular and other solid tumors; cutaneous atrophy with numerous scars and aesthetic damage; skin abnormalities comparable to what is clinically and histologically observed with aging; blindness; severe mental retardation
2\/3 death before adult age
hypermutability after UV irradiation in cell cultures; no increased of spontaneous chromosome abnormalities in lymphocytes of fribroblastes; however, after UV-exposure an increased number of sister chromatid exchanges (SCE) and chromosome aberrations are observed (mainly chromatid-type abnormalities); fibroblasts express an increased sensitivity to chemical mutagens; there is no cytogenetic feature useful for XP diagnosis
Genes involved and Proteins
the clinical and cytologic XP heterogeneity is the consequence of the genetic heterogeneity: 7 complementation groups (XPA to G) plus an additional variant form, evidenced by somatic cell fusion experiments
the genes involved are:
, located in 9q22,
, also called ERCC3 (ERCC for Excision-Repair Cross Complementing rodent repair deficiency), located in 2q21,
, located in 3p25,
, also called ERCC2, located in 19q13,
, located on chromosome 11
, also called ERCC4, located in 19q13
, also called ERCC5, located in 13q32, and
, also called Pol eta, and located in 6p12-21
all XP genes are implicated in various steps of the
NER (nucleotide excision repair) system
, except the XP variant that is mutated in a mutagenic DNA polymerase (POL H) able to bypass the UV-induced DNA lesions; various alterations of the same gene may involve various phenotypes Cockayne syndrome , trichothiodystrophy )
To be noted
http:\/\/www.xps.org\/home.htm Xeroderma Pigmentosum Society, USAhttp:\/\/www.icondata.com\/health\/pedbase\/files\/XERODERM.HTM University of Western Ontario, London, Canada.
Common pathways for ultraviolet skin carcinogenesis in the repair and replication defective groups of xeroderma pigmentosum.
Cleaver JE et al
A summary of mutations in the UV-sensitive disorders: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy.
Cleaver JE et al
Helicases and aging.
Nakura J et al
The relative expression of mutated XPB genes results in xeroderma pigmentosum/Cockayne's syndrome or trichothiodystrophy cellular phenotypes.
Riou L et al
Nucleotide excision repair and human syndromes.
de Boer J et al
Xeroderma pigmentosum and the role of UV-induced DNA damage in skin cancer.
van Steeg H et al
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