Lakhasly

Clinical Description
There are many reviews of the clinical features of XP [1,4-6]. In about 60% of cases, the first signs are extreme sensitivity to sunlight [6], which takes many days or weeks to resolve. In these individuals, this sunburn reac- tion can happen in the first weeks of life and is often blamed on neglect or labelled wrongly as cellulitis or impetigo. The other 40% of cases do not show any sun- burn reaction. In these cases, the first manifestation, often by two years of age, is an unusually increased number of lentigines (freckle-like pigmentation) in sun- exposed areas. They are present on the nose, zygoma and forehead and then appear on the sides of the neck, sparing the area under the chin. Photophobia is often present. In the absence of sun protection, the skin ages, becoming dry, rough and atrophic. Lentigines increase in number and darken and are difficult to distinguish clinically from the many, flat, pigmented seborrhoeic warts, which also proliferate and become warty. Small, hypopigmented macules are commonly seen amongst the lentigines and may even be the first presentation. Telangiectasia can be a late feature. Stucco keratoses may be present and are readily distinguishable from solar keratoses. As all the skin changes are the result of exposure to UV radiation, the severity of these changes is absolutely dependent on the amount of sun-exposure, the Fitzpatrick skin type and the degree of protection of the skin from sunlight. The effects vary a great deal between individuals. In the absence of rigorous protec- tion from the sun, areas of hyper- and hypo-pigmenta- tion will result, followed by accelerated photo-ageing, warty lesions, in-situ melanocyte and keratinocyte malig- nancy, and eventually multiple basal cell carcinomas and invasive squamous cell carcinomas and melanomas. It has been estimated that XP patients have a 10, 000-fold increased risk of non-melanoma skin cancer and a 2, 000-fold increased risk of melanoma under the age of 20 [6]. The early age of onset and the frequency of skin cancers in an otherwise normal individual should trigger further assessment for XP. In addition to the very large increase in skin cancer there is an approximately 50-fold increase in internal neoplasms, especially of the central nervous system.
Ocular abnormalities are almost as common as the cutaneous abnormalities, but they are strikingly limited to the anterior, UV-exposed structures of the eye (lids, cornea, and conjunctiva). Photophobia is often present and may be associated with prominent conjunctival injection. Continued sunlight exposure may result in
Page 2 of 6
severe keratitis, leading to corneal opacification and vas- cularization, and in neoplasms (epithelioma, squamous cell carcinoma, and melanoma) [5,7].
In XP patients there is also a greatly increased fre- quency of cancer of the oral cavity, particularly squa- mous cell carcinoma of the tip of the tongue, a presumed sun-exposed area [5].
20-30% of patients have neurological problems and intellectual deficiency [1,6,8]. The time of onset can vary from the age of two to middle age. The neurological abnormalities are the result of progressive neuronal degeneration resulting in sensorineural deafness, ataxia, areflexia, microcephaly and intellectual deficiency as well as impaired eyesight.
The clinical features are dependent on exposure to sunlight, the complementation group, the precise nature of the mutation as well as unknown factors. Conse- quently there is a huge variation in clinical features. Sunny climates, outdoor living, fair skin, smoking, poor availability of diagnostic facilities, delayed diagnosis and poor protection from sunlight will exacerbate the cuta- neous features, resulting in multiple pigmentation changes, multiple skin cancers and early death. Conver- sely, less sunny climates, indoor living, pigmented skin, early diagnosis and good solar protection, can result in relatively mild skin features. However even allowing for these factors, there is much variability, especially in cases that do not show the acute sunburn reaction. The abnormal freckling may become apparent by the age of two, but may occur much later.
It might be expected that the patients with the most severe repair defects would show the most extreme sun- burn reactions and the highest incidence of skin cancer. Paradoxically, however, those patients with acute sun- burn reactions develop fewer skin cancers than those who do not. This is probably the result of earlier diag- nosis of the former group and a disinclination of this group to go out in sunlight without protection.
The XP variant (XP-V) sub-type refers to patients with a somewhat different molecular defect (see below). These patients may display relatively mild features, but some have severe skin problems. Individuals with XP-V do not have neurological problems and, like those with XP-C, their sunburn pattern conforms to their skin type.
There are a few rare cases with combined features of XP and Cockayne Syndrome. These individuals have the severe neurological and developmental problems charac- teristic of Cockayne Syndrome together with the solar- induced pigmentation changes of XP.