Xeroderma pigmentosum

Xeroderma pigmentosa, or XP, is an autosomal recessive genetic disorder of DNA repair in which the ability to repair damage caused by ultraviolet (UV) light is deficient. This disorder leads to multiple basaliomas and other skin malignancies at a young age. In severe cases, it is necessary to avoid sunlight completely. The two most common causes of death for XP victims are metastatic malignant melanoma and squamous cell carcinoma. XP is about six times more common in Japanese people than in other groups.

Cause

Xeroderma pigmentosum has an autosomal recessive pattern of inheritance.

The most common defect in xeroderma pigmentosum is a genetic defect whereby nucleotide excision repair (NER) enzymes are mutated, leading to a reduction in or elimination of NER. Unrepaired damage can lead to mutations, altering the information of the DNA in individual cells. If mutations affect important genes, like tumour suppressor genes (e.g. p53) or proto oncogenes then this disorder may lead to cancer. Patients exhibit elevated risk of developing cancer, such as basal cell carcinoma.

Normally, damage to DNA in epidermal cells occurs during exposure to UV light. The absorption of the high energy light leads to the formation of pyrimidine dimers, namely CPD's (cyclobutane-pyrimidine-dimers) and 6-4PP's (pyrimidine-6-4-pyrimidone photoproducts). The normal repair process entails nucleotide excision. The damage is excised by endonucleases, then the gap is filled by a DNA polymerase and "sealed" by a ligase.

Types

There are 7 complementation groups, plus one variant form :

Type	Diseases Database	OMIM	Gene	Locus	Also known as/Description
Type A, I, XPA	29877	278700	XPA	9q22.3	Xeroderma pigmentosum group A. Classical form of XP.
Type B, II, XPB	29878	133510	XPB	2q21	Xeroderma pigmentosum group B.
Type C, III, XPC	29879	278720	XPC	3p25	Xeroderma pigmentosum group C.
Type D, IV, XPD	29880	278730 278800	XPD ERCC6	19q13.2-q13.3 , 10q11	Xeroderma pigmentosum group D or De Sanctis-Cacchione syndrome. De Sanctis-Cacchione syndrome can be considered a subtype of XPD.
Type E, V, XPE	29881	278740	DDB2	11p12-p11	Xeroderma pigmentosum group E.
Type F, VI, XPF	29882	278760	ERCC4	16p13.3-p13.13	Xeroderma pigmentosum group F.
Type G, VII, XPG	29883	278780 133530	RAD2 ERCC5	13q33	Xeroderma pigmentosum group G.
Type V, XPV		278750	POLH	6p21.1-p12	Xeroderma pigmentosum variant. XPV patients suffer from mutation in a gene that codes for a specialized DNA polymerase called polymerase-η (eta). Polymerase-η can replicate over the damage and is needed when cells enter S-phase in the presence of a DNA-damage.

Symptoms

Some of the most common symptoms of XP include:

• An unusually severe sunburn after a short sun exposure. The sunburn may last for several weeks. The sunburn usually occurs during a child's first sun exposure.
• Development of many freckles at an early age .
• Irregular dark spots on the skin .
• Thin skin .
• Excessive dryness of skin .
• Rough-surfaced growths (solar keratoses), and skin cancers .
• Eyes that are painfully sensitive to the sun and may easily become irritated, bloodshot, and clouded, .
• Blistering or freckling on minimum sun exposure.
• Premature aging of skin, lips, eyes, mouth and tongue.
• Crusting skin
• Spidery blood vessels
• Scaly skin
• Oozing raw skin surface
• Limited growth of hair on chest and legs.

Treatment

The most important part of managing the condition is reducing exposure to the sun. The number of keratoses can be reduced with Isotretinoin (though there are significant side-effects.) Existing keratoses can be treated using cryotherapy or fluorouracil.

In Popular Culture

Christopher Snow, the protagonist and narrator of Dean Koontz' Moonlight Bay Trilogy of novels (Fear Nothing, Seize The Night and the to-be-completed Ride The Storm), has severe enough XP that he must avoid sunlight and as much artificial light as possible at all costs, living his life at night and then only by dim bulbs and candlelight, though always maintaining a positive and envigorated attitude about life, even authoring a best-selling autobiographical book on living with XP.

In Jodi Picoult's novel 'Second Glance' nine year old character Ethan Wakeman suffers from XP so severe he can only leave the house after sunset.

Alejandro Amenábar's Award-winning film, The Others, centers around a woman (Nicole Kidman) whose children suffer from XP and must be kept indoors, behind closed curtains, at all times.

Yui stars in a romantic Japanese movie Taiyō no Uta, where she plays the lead character, a street musician named Kaoru Amane, who is diagnosed with Xeroderma Pigmentosum and only performs at night because of this disease. Even with this diagnosis, she chases her dreams of becoming a singer and meets Kōji Fujishiro (Takashi Tsukamoto), who also has a passion for music and whom Kaoru eventually falls in love with. This story was also the basis for a Japanese TV drama series, also called "Taiyō no Uta", starring Erika Sawajiri and Takayuki Yamada in the roles of Kaoru and Kōji.