Xeroderma Pigmentosum - Key Clinical Features

General features are:

(1) History of acute sunburn reaction on minimal UV exposure.

(2) Numerous freckle-like hyperpigmented macules on sun-exposed area of the skin, followed by increased pigmentation, and development of premalignant actinic keratosis.

(3) Early onset of skin cancer in photoexposed areas.

(4) Photophobia and ophthalmologic abnormalities in the UV-exposed structures of the eye (i.e. conjunctiva, cornea, and lids).

(5) Neurologic abnormalities including hyporeflexia, acquired microcephaly, sensorineural hearing loss beginning with high frequencies, spasticity, ataxia, seizures, and progressive intellectual impairment.

Of note, a few points with significant implications in clinical practice have recently emerged from studies on large XP cohorts at National Institutes of Health in the USA and at the National XP Service in UK (Bradford et al., Journal of Medical Genetics 48: 168-176, 2011; Sethi et al., British Journal of Dermatology 169:1279-1287, 2013; Fassihi et al., PNAS 113: E1236-1245, 2016):

i) Most patients in XP-A, -B, -D, -F, and -G groups have severe sunburn reactions from an early age. In contrast, XP-C, -E, and -V patients have normal sunburn reactions for skin type.

ii) XP patients with extreme sunburn reactions are likely to be diagnosed very early and therefore photo-protected from a young age. As a consequence, in such cases pigmentary changes are relatively mild and skin cancers are relatively uncommon.

iii) In contrast, the first symptoms in XP-C patients are freckles that appear around the age of 2 years. They have a later age of XP diagnosis and therefore accumulate more UV-induced damage, leading to an earlier age of first skin cancer.

iv) XP-E and XP-V patients may have two decades or more without any symptoms. During this period, they accumulate UV-induced mutations that can result in hundreds of skin tumors in later life.

v) Paradoxically, therefore, the XP-C, -E, and -V groups, which have generally been described as milder on the basis of their cellular sensitivity to UV and lack of neurological abnormalities, tend to develop more skin cancers than the groups classified as more severe using the same criteria.

vi) XP-C patients are particularly susceptible to ocular problems relative to their skin changes compared with the other groups.

vii) Within the XP population, XP-F and XP-G patients seem to be remarkably resistant to the development of skin cancers.