DISEASE CARD

Disease group DNA repair disorders
DISEASE NAME XERODERMA PIGMENTOSUM
Synonymous De Sanctis Cacchione syndrome
Estimated prevalence 1:1,000,000 (United States). A higher prevalence (≤1:100,000) has been reported in Japan, North Africa (Tunisia, Algeria, Morocco, Libya, and Egypt), Middle East (Turkey, Israel, and Syria) and in communities in which consanguineous marriage is common. The incidence of XP has been established at 2.3 per million livebirths in West-Europe and at 0.9 per million livebirths in the autochthonic Western Europe population (Kleijer et al., DNA Repair 7:744-750, 2008).
OMIM 278700, 610651, 278720, 278730, 278740, 278760, 278780, 278750
Inheritance Autosomal recessive
Gene (s) XPA (611153), XPB/ERCC3 (133510), XPC (278720), XPD/ERCC2 (126340), XPE/DDB2 (600811), XPF/ERCC4 (133520), XPG/ERCC5 (133530), POLH (603968)

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. 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 and premalignant lesions in the sun-exposed area of the skin, photophobia, ophthalmologic abnormalities in the sun-exposed portion of the eyes, extremely high incidence of skin cancer and ocular neoplasms, and increased incidence of tumors in other organs and tissues. About 30% of XP patients have neurologic manifestations that usually become manifest later than the cutaneous changes. The neurologic abnormalities are progressive and include acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and cognitive impairment. XP results from an inability to handle damage generated in cellular DNA by ultraviolet (UV) light. Most patients are defective 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. The different XP defects show different frequencies: the majority of XP patients described in the literature belong to XP-A -C, -D and -V groups. XP-A is very frequent in Japan, XP-C is the most common group in the United States and in Europe, and in Germany also XP-D is frequent.

 

Clinical Description

Cutaneous symptoms. Approximately 50% of XP patients have a history of acute sunburn reaction on minimal UV exposure. The remaining tan normally without excessive burning. In all patients, numerous freckle-like hyper-pigmented macules appear on sun-exposed areas. The median age at onset of the cutaneous symptoms is between 1-2 years of age. Continued sun exposure causes the skin to become dry and parchment-like, with increased pigmentation, and development of premalignant actinic keratoses. 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.

Ophthalmologic abnormalities are almost as common as the cutaneous abnormalities. They may begin 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.

Neurologic abnormalities have been reported in approximately 30% of XP patients. The onset may 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.

Cutaneous neoplasias. If extreme UV avoidance is not introduced early, 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. Most affected people die of malignancy early in adulthood.

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.

 

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). These cases are mutated in one of seven genes (XPA to XPG) whose products are NER components involved in the repair cascade. 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).

The molecular defects in XP cells result in a greatly elevated 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.

 

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 may be employed in a complementary and, in terms of genotype/phenotype correlation, also consulting fashion. The results of these analyses are fundamental for proper patient management and genetic counselling of the families involved.

 

Treatment

There is no cure for XP. The main goal of treatment is to protect oneself from UV exposure and thus prevent the damaging effects it can have on the skin. XP patients should follow general precautionary measures, such us: - 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 or greater in all sun-exposed areas, iii) the avoidance of outdoor activities that should be kept to a minimum if at all necessary and carried out at night time if possible. - To undergo skin examinations by a dermatologist at least 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 testing (through to age 20) for potential neurological problems.

Treatment of choice for skin tumors in XP patients is surgery. With respect to neurologic symptoms, there is unfortunately currently no effective the­rapy besides supportive measures.