DISEASE CARD

Definition

Xeroderma pigmentosum (XP) is an autosomal recessive disorder first described by Moriz Kaposi in Ferdinand von Hebra's textbook of Dermatology published in 1870. It is a syndrome with defective DNA nucleotide excision repair (NER). The term “xeroderma pigmentosum” refers to the dry and pigmented skin typically present in affected individuals. The disorder is characterized by hypersensitivity to sun exposure, pigmentary alterations high incidence of skin neoplasm, photophobia, keratitis and increased incidence of tumors in several other organs.¹ Most patients show defects in one of seven proteins (XPA to XPG) involved in nucleotide excision repair (NER) of UV- and other types of DNA damage. A minority of cases with the so-called XP variant form (XP-V) fail to correctly replicate UV-damaged DNA as a consequence of mutations in DNA polymerase eta.²

Clinical Description

Cutaneous symptoms. The median age at onset of the cutaneous symptoms is between 1-2 years of age. Approximately 50% of XP patients have a history of acute sunburn reaction on minimal UV exposure (even through windows). The healing takes longer than in normal healthy individuals (4-6 days). The remaining tan normally without excessive burning or blister development. In all patients, numerous freckle-like hyper-pigmented macules, atrophic hypopigmented patches and teleangiectasias (poikiloderma) appear on sun-exposed areas. Continued sun exposure causes the skin to become dry and parchment-like, with increased pigmentation, and development of premalignant actinic keratosis, usually in early childhood.³ The appearance of sun-exposed skin in children with XP is similar to that occurring in farmers and sailors after many years of severe sun exposure. Therefore, XP represents an example of accelerated photo-aging.^{2, 4 5}

Ophthalmologic abnormalities are found in nearly all patients. They develop in the first decade of life and are usually limited to the anterior, UV-exposed structures of the eye (i.e. conjunctiva, cornea, and lids). Photophobia is often present and may be associated with prominent conjunctival injection. Continued UV exposure of the eye may result in severe keratitis leading to corneal opacification and vascularization. The lids progressively develop increased pigmentation and loss of lashes. Atrophy of the skin results in ectropion, entropion, or, in severe cases, complete lid loss.⁴

Neurologic abnormalities have been reported in approximately 30% of XP patients. The onset can be early in infancy or delayed until the second decade or even later. The spectrum of these complication is wide, ranging from isolated hyporeflexia to acquired microcephaly, sensorineural hearing loss beginning with high frequencies, spasticity, ataxia, seizures, and progressive intellectual impairment. In the past, an XP patient with any neurologic abnormality was considered affected by De Sanctis-Cacchione syndrome. This term is now reserved for rare XP patients showing severe neurologic manifestations, dwarfism and immature sexual development.²

Cutaneous neoplasias. XP patients often develop skin cancer in the first decade of life. The median age of onset of the first skin neoplasm is 8 years for basal and squamous cell carcinoma, nearly 50 years earlier than that of the general population, and 19 years for malignant melanoma. In XP patients under 20 years of age, the frequencies for melanoma and for basal and squamous cell carcinoma are respectively 2,000- and 4,800-fold higher than in the general U.S. population. 80-90% of skin cancers (basal cell carcinomas, squamous cell carcinomas, melanomas) occur on the face, head and neck. Most affected people die of malignancy early in adulthood.^{5, 6}

Other neoplasias. Tumors of the anterior portion of the eyes (epithelioma, squamous cell carcinoma, and melanoma) and of the oral cavity (particularly squamous cell carcinoma of the tip of the tongue) are common. It has been estimated that all sites exposed to ultraviolet radiation have about a thousand-fold increased risk of developing tumors. Furthermore, an approximate 10- to 20-fold increase in various internal neoplasms (gliomas, leukemia, lung, uterus, breast, pancreas, stomach, +

kidney, and testicles tumors) has been reported in XP.^{2, 4, 5}

Based on clinical findings and family history, XP patients are classified in seven complementation groups (from XP-A to XP-G), together with a XP variant (XP-V), consisting of a condition with a functional NER but a lacking DNA polymerase (Pol η), that is involved in the replication of damaged DNA.

Table: clinical signs of Xeroderma pigmentosum complementation groups and XP variant²

^{“+”: symptomatic manifestations; “-“: absence of symptoms}

Pathogenesis

Most XP patients exhibit defective repair of the damage generated in cellular DNA by ultraviolet (UV) light due to faulty nucleotide excision repair (NER). NER is the most versatile DNA repair system and can repair a variety of bulky DNA damage including UV-induced DNA damage. XP is caused by mutations in one of seven genes (XPA to XPG) whose products are NER components, involved in the repair cascade.⁷ The XPC and XPE proteins are needed to recognise the photoproducts in DNA. XPB and XPD are part of a protein complex TFIIH, which opens up the structure of the DNA around the site of the photoproduct. XPA verifies that proteins are in the correct position and then the nucleases XPG and XPF cut the DNA on either side of the damage, so that the damaged section can be removed and replaced with intact DNA.

Defects in the eighth XP gene (POLH) do not affect NER. These so-called XP variants (XP-V) have problems in DNA polymerase eta that is involved in replication of damaged DNA by a process called trans-lesion synthesis (TLS).⁸

The molecular defects in XP cells result in a greatly elevted induction of mutations in sun-exposed skin of affected individuals. This increased mutation frequency probably accounts for the pigmentation changes and the skin cancers. The causes of the neurological abnormalities are poorly understood. They are clearly not connected with exposure to UV light. Current theories suggest that oxidative DNA damage is generated during normal metabolism in the central nervous system, and that some types of this damage must be repaired by NER. In the absence of functional repair, the lesions persist and result in neuronal death.^{8, 9}

Diagnosis

The diagnosis of XP is made clinically based on skin, eye, and neurologic manifestations. The occurrence of consanguinity in the family history may aid in diagnosis. XP can usually be conclusively diagnosed by analyzing patient's skin fibroblasts (obtained from a small skin biopsy) for the appropriate DNA repair defect. Specific functional assays allow discrimination between the XP classical form, that is defective in NER, and the variant form of XP (XP-V), that is defective in TLS. Molecular genetic diagnostics can affirm the diagnosis.⁸

Treatment

There is no cure for XP. The main goals of management/treatment are making an early diagnosis and long-life rigorous protection from UV exposure. Since 5% of daylight comprises ultraviolet radiation (UVR), this necessitates rigorous avoidance of and protection from UVR in daylight. XP patients should follow general precautionary measures that include:

• To adopt sun avoidance methods that include i) the use of protective clothing (long sleeves and pants, shirts with collars, tightly woven fabrics that don't let light through), hats (wide-brimmed) and eyewear (face shields specifically made to protect from UV light), ii) the application of sunscreens with SPF of 30 (UVA and UVB) or greater in all sun-exposed areas, iii) the avoidance of outdoor activities or performing them night time if possible.
• To undergo skin examinations by a dermatologist every 3 to 6 months.
• To report immediately to the doctor any suspicious spots or growths
• To undergo frequent eye examinations by an ophthalmologist.
• To undergo yearly evaluation (through to age 20) regarding neurological problems.

Treatment of choice for skin tumors in XP patients is surgical resection and in progressive lesions according to guidelines. As XP patients may need to undergo hundreds of excisions over a lifetime, removal of undamaged skin should be minimized. Further treatment options include chemical peeling (trichloroacetic acid) that may lead to a tumor-free period of 2-5 years, administration of retinoids (especioally isotretinoin) for prevention of BCC and SCC development, photodynamic therapy and full-face resurfacing and topical application of 5-Fluorouracil or Imiquimod. Some patients profit from high-dose isotretinoin with regard to reduction of skin cancers. However, side effects limit this treatment. Some new therapies are in the pipeline, like a liposomal topical lotion containing T4N5 (Dimericine) that used in a daily basis is able to reduce the frequency of actinic keratosis and basal cell carcinomas. (NCT00002811). 2, 10

Some patients show hypersensitivity to X-ray, therefore a test with low dose radiation should be performed ahead of an investigation with X-ray. With respect to neurologic symptoms, there is unfortunately currently no effective the­rapy besides supportive measures.2

References

^{1. Bradford PT, Goldstein AM, Tamura D, et al. Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair. J Med Genet. 2011;48(3):168-176.}

^{2. Piccione M, Belloni Fortina A. Xeroderma Pigmentosum: General Aspects and Management. 2021;11(11).}

^{3. Masaki T, Wang Y, DiGiovanna JJ, et al. High frequency of PTEN mutations in nevi and melanomas from xeroderma pigmentosum patients. Pigment Cell Melanoma Res. 2014;27(3):454-464.}

^{4. Hengge UR, Emmert S. Clinical features of xeroderma pigmentosum. Molecular Mechanisms of Xeroderma Pigmentosum. 2008:10-18.}

^{5. Kraemer KH, Lee M-M, Andrews AD, Lambert WC. The role of sunlight and DNA repair in melanoma and nonmelanoma skin cancer: the xeroderma pigmentosum paradigm. Arch Dermatol. 1994;130(8):1018-1021.}

^{6. Hadj-Rabia S, Oriot D, Soufir N, et al. Unexpected extradermatological findings in 31 patients with xeroderma pigmentosum type C. Br J Dermatol. 2013;168(5):1109-1113.}

^{7. De Boer J, Hoeijmakers JH. Nucleotide excision repair and human syndromes. Carcinogenesis. 2000;21(3):453-460.}

^{8. Bootsma D, Hoeijmakers J, editors. The genetic basis of xeroderma pigmentosum. Annales de genetique; 1991.}

^{9. Chen H, Weng QY, Fisher DE. UV signaling pathways within the skin. J Invest Dermatol. 2014;134(8):2080-2085.}

^{10. de Andrade FAG, Cavalcanti CEO, Isoldi FC, Ferreira LM. Therapeutics of xeroderma pigmentosum: A PRISMA-compliant systematic review. Indian J Dermatol Venereol Leprol. 2021;87(2):176-189.}