7 research outputs found
[Letter] A distinct genotype of XP complementation group A: surprisingly mild phenotype highly prevalent in Northern India/ Pakistan/ Afghanistan
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Xeroderma pigmentosum:A disease model for clinical, cellular and molecular consequences of ultraviolet radiation-induced damage
Ophthalmic Manifestations of Xeroderma Pigmentosum:A Perspective from the United Kingdom
Xeroderma pigmentosum: a multidisciplinary approach
Xeroderma pigmentosum (XP) is a rare, autosomal recessive disorder of DNA repair. Affected
individuals are unable to repair ultraviolet radiation (UVR)-induced DNA damage, leading to a variety
of clinical manifestations: a dramatic increase in mucocutaneous malignancies, increased lentigines,
extreme photosensitivity (in approximately 50% of cases), and neurodegeneration (in approximately
30% of affected individuals). Incidence in Western Europe is recorded as 2.3 per million live births. There
are eight different complementation groups, XP-A to XP-G, and XP-variant (XP-V) corresponding to the
eight affected genes. Classically, XP patients were identified by clinicians for their tendency to develop
severe and exaggerated sunburn on minimal sun exposure, however recently it has been shown that
XP-C, XP-E and XP-V patients have normal sunburn reactions for skin type compared to the other
groups, who suffer not only with severe, exaggerated sunburn, but also have an increased incidence
of neurodegeneration.
A diagnosis of XP should be considered in a child with either severe sunburn, increasing lentigines at
exposed sites, or development of multiple skin cancers at an early age. Skin biopsy and subsequent
testing in cell cultures for defective DNA repair, confirms or excludes the diagnosis. Mean life expectancy
is reduced; the two main causes of mortality are skin cancer and neurodegeneration. These clinical
features distinguish XP from other disorders of DNA repair, namely Trichothiodystrophy and Cockayne
syndrome, although overlapping syndromes do occur. Instigation of meticulous photoprotection for
all XP patients has been shown to reduce both the lentigines and number of skin cancers dramatically
and would be presumed to increase life expectancy. Compliance with photoprotection is a recognised
problem amongst XP patients, particularly in those without easy sunburn. This is further accentuated by
lack of social acceptance for people who wear UVR-protective visors. Increased awareness of XP,
both within the medical and media spheres will benefit current and future XP patients; this will
aid earlier diagnosis and timely photoprotection, with better compliance, and therefore, result in an
improved prognosis
Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect
Xeroderma pigmentosum (XP) is a rare DNA repair disorder characterized by increased susceptibility to UV radiation (UVR)-induced skin pigmentation, skin cancers, ocular surface disease, and, in some patients, sunburn and neurological degeneration. Genetically, it is assigned to eight complementation groups (XP-A to -G and variant). For the last 5 y, the UK national multidisciplinary XP service has provided follow-up for 89 XP patients, representing most of the XP patients in the United Kingdom. Causative mutations, DNA repair levels, and more than 60 clinical variables relating to dermatology, ophthalmology, and neurology have been measured, using scoring systems to categorize disease severity. This deep phenotyping has revealed unanticipated heterogeneity of clinical features, between and within complementation groups. Skin cancer is most common in XP-C, XP-E, and XP-V patients, previously considered to be the milder groups based on cellular analyses. These patients have normal sunburn reactions and are therefore diagnosed later and are less likely to adhere to UVR protection. XP-C patients are specifically hypersensitive to ocular damage, and XP-F and XP-G patients appear to be much less susceptible to skin cancer than other XP groups. Within XP groups, different mutations confer susceptibility or resistance to neurological damage. Our findings on this large cohort of XP patients under long-term follow-up reveal that XP is more heterogeneous than has previously been appreciated. Our data now enable provision of personalized prognostic information and management advice for each XP patient, as well as providing new insights into the functions of the XP proteins