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GENODERMATOSES WITH PHOTOSENSITIVITY

This category includes several very rare disorders, which will not be discussed in detail, such as Rothmund–Thomson syndrome (poikiloderma congenitale), Bloom syndrome, Cockayne syndrome, trichothiodystrophy, and Hartnup disease (which causes a pellagra-like eruption). Porphyrias are discussed later. Xeroderma pigmentosum is considered separately here.

Xeroderma pigmentosum

Etiology and pathogenesis

Xeroderma pigmentosum (XP) is the term used for eight clinically similar autosomal recessive diseases in which there are different defects of DNA repair.

    Ultraviolet B causes pyrimidine dimer production within the DNA molecule, especially thymidine dimers. Normally, these are excised and replaced by thymine, a process known as excision repair. This causes ‘unscheduled' DNA synthesis (i.e. DNA is synthesized at times other than for cell replication), which can be detected by autoradiography. In seven of the XP types, the defect involves defective endonuclease-mediated excision repair, manifested as low levels of unscheduled DNA synthesis following exposure to UVR.

    Fusion of fibroblasts from different XP strains can normalize the level of unscheduled DNA repair in UV-exposed cell cultures, so cells from patients with XP can be assigned to different types. These are known as complementation groups, as they depend on which cell strain is complementary and corrects the defect, and are labeled groups A–G. The most frequent are XP-A and XP-C.

    The final type of XP, known as XP variant, accounts for about 30% of patients who have XP. It is characterized by normal levels of unscheduled DNA repair and may be due to a defect of postreplication repair.

Clinical features

All types share some common features that are perennial and progressive; they may also be apparent to a minor degree in heterozygotes. Features may vary in severity within groups, but are typically severe in the commonest (XP-A) type.

    Age of onset may be from the first few months of life, usually in the first few years, but is occasionally in the second decade. There may be episodes resembling prolonged sunburn, with associated freckling and dryness of exposed skin (Fig.17.27). Skin tumors develop subsequently, usually in large numbers, and include basal cell carcinomas, squamous cell carcinomas, and melanomas. Mucous membranes, especially the conjunctivae and lower lip, are also affected; photophobia is common. In some of the subtypes, particularly XP-A and XP-D, progressive neurologic abnormalities are a significant feature, with an onset in the first two decades. These may be mild, especially sensorineural deafness, but a severe disorder of mental retardation, peripheral neuropathy, and cerebellar abnormalities may occur (De Sanctis–Cacchione syndrome).

    Phototesting is characterized by abnormal photosensitivity, which produces prolonged erythema compared with the usual 24-h peak erythemaComplementation group is determined by cell culture and may be prognostically important (e.g. neurologic disease is not a feature of XP variant but is often severe in XP-A).

Figure 17.27 Xeroderma pigmentosum. This shows freckling and wrinkling of the dorsa of the hands in a child. These changes are similar to those normally seen in much older patients. See also Fig. 19.67.

Differential diagnosis

In most instances, where there are established skin changes, the differential diagnosis is between the different types of XP rather than from other disorders. The rare photosensitivity genodermatoses may also need to be considered. Early or milder cases, especially in patients who have freckles but no gross photosensitivity, may be difficult to distinguish from those with prominent ordinary freckles or with various disorders featuring facial lentiginosis (all rare).

Treatment

Once the diagnosis has been established, strict sun avoidance and high protection factor sunscreens are essential to delay the development of tumors. Antenatal diagnosis is possible by culturing amniotic fluid cells. Topical endonucleases to replace the deficient repair enzymes are being investigated. Tumors are treated by excision. Systemic retinoids reduce the frequency of epidermal tumors.

White/Cox: Diseases of the Skin, 2ed.(c) 2006, Elsevier Inc. All rights reserved.