Xeroderma pigmentosum is an autosomal recessive condition and hence family history will be generally absent. Patients often present with severe sunburn that is often persistent. The onset and course is dependent on exposure to sun [9]. There are three stages in the course of the disease. The first stage of the disease is found in sun-exposed areas like the face and is characterized by diffuse erythema, scaling and freckles. As disease progresses, changes can be noted on the legs, neck and occasionally in the trunk. In most of the cases, these changes decrease with reduced exposure to sun. But, gradually these changes may become permanent.

The second stage of xeroderma pigmentosum is characterized by poikiloderma. Uneven hyper-or hypopigmentation, atrophy of the skin, and telangiectasias are the clinical features of poikiloderma. Telangiectasias may be seen in both sun exposed and non-exposed areas of the skin.

The third stage is characterized by appearance of malignancies. Patients with xeroderma pigmentosum may develop squamous cell carcinomas, basal cell carcinomas, and malignant melanomas. Malignancies may develop in children in the age group of 4-5 years.

Photosensitivity is the most common manifestation of this condition, and it generally appears in the wavelength range of 290-320 nm. About 80% of the patients present with ocular defects like conjunctivitis [4]. Solar lentigines are noted in the first few years which may later develop into melanomas. Vascular pterygia, ectropion, infections, epithelioma of the lid, cornea, and conjunctivae, are also seen as ocular problems in these patients.

About 20% of the patients present with neurologic problems. Neurologic manifestations are more common in XPA and XPD patients. Severity of the symptoms often depends on sensitivity of the cells to sun. Some of the common neurologic problems include spasticity, ophthalmoplegia, microcephaly, areflexia, hyporeflexia, chorea, sensorineural deafness, and mental retardation. In some patients neurologic problems may be more prominent than the usual clinical symptoms. Older patients may show scarring and mutilation, particularly in the nasal and orbital regions.

• Dysgeusia

  […] sum diameter of lesions showed a 61% decrease after 16.5 months of treatment, although after 18.5 months of treatment, a persistent lesion showed progression and metatypical characteristics; adverse events included persistent alopecia muscle cramps, dysgeusia [ncbi.nlm.nih.gov]

• Hearing Impairment

  […] abnormality Cognitive defects Cognitive deficits Intellectual impairment Mental impairment [ more ] 0100543 Conjunctival telangiectasia Small dilated blood vessels near membrane covering front of eye and eyelids 0000524 Cutaneous photosensitivity Photosensitive [rarediseases.info.nih.gov]

• Photosensitivity

  Xeroderma pigmentosum (XP) is a genetic photosensitive disorder in which patients are highly susceptibe to skin cancers on the sun-exposed body sites. [ncbi.nlm.nih.gov]

  Differential diagnosis There are other causes of photosensitivity - eg, congenital erythropoietic porphyria. [ 1 ] Other genetic conditions with photosensitivity due to defective DNA repair - eg, Cockayne's syndrome, the XP-CS complex, trichothiodystrophy [patient.info]

  In xeroderma pigmentosum, the photosensitivity is acute in nature. [emedicine.medscape.com]

• Hyperpigmentation

  Both patients had marked lentiginous hyperpigmentation and multiple skin cancers at an early age. Their cultured fibroblasts showed similar hypersensitivity to killing by UV and reduced repair of DNA photoproducts. [ncbi.nlm.nih.gov]

  Note the mottled hyperpigmentation and atrophy. Courtesy of Neil S. Prose, MD, Duke University Medical Center, Durham, North Carolina. [emedicine.medscape.com]

  Hyperpigmentation of the cells is not usually accompanied by an increase in the number of melanocytes. Both hyperkeratosis and hyperpigmentation is more pronounced in the second stage of the disease. [symptoma.com]

• Photosensitive Skin Rash

  Photosensitive skin Photosensitive skin rashes Photosensitivity Sensitivity to sunlight Skin photosensitivity Sun sensitivity [ more ] 0000992 Developmental regression Loss of developmental milestones Mental deterioration in childhood [ more ] 0002376 [rarediseases.info.nih.gov]

• Eczema

  Types & treatments Childhood eczema Adult eczema Insider secrets Types of hair loss Treatment for hair loss Causes of hair loss Hair care matters Insider secrets What is psoriasis Diagnosis & treatment Skin, hair & nail care Triggers Insider secrets What [aad.org]

• Photophobia

  Ocular changes apart from photophobia may include ectropion, entropion, conjunctivitis, keratitis and ocular neoplasms. [medcaretips.com]

  He also had photophobia and both eyes showed corneal opacities. Histopathological examination of the excised growth showed features consistent with melanoma. [ncbi.nlm.nih.gov]

• Conjunctival Injection

  The most common abnormalities were in the periocular skin and ocular surface, including interpalpebral conjunctival melanosis (44%) and conjunctival injection (43%). [ncbi.nlm.nih.gov]

  Ocular abnormalities include photophobia, ectropion, conjunctival injection, keratitis, and tumours (which usually occur on the areas of the eye that are exposed to ultraviolet light, such as the conjunctiva, cornea, and eyelids). [bmj.com]

  Photophobia is often present and may be associated with prominent conjunctival injection. [doi.org]

• Abnormal Eye Movement

  […] response/abnormal eye movements (1 point) Assisted gait (1 point) (or wheelchair-bound 2 points) Note that ( i ) this severity score is based on the neurological systems affected in XP; and ( ii ) a functional score to reflect baseline mobility is also [pnas.org]

• Nystagmus

  Eye movements exhibited rolling nystagmus, but were able to track large objects. [doi.org]

• Myoclonus

  Here we describe a sister and a brother presenting chorea, dystonia, myoclonus, ataxia and polyneuropathy related to XP. [ncbi.nlm.nih.gov]

Clinical manifestation of xeroderma pigmentosum is the most suitable method of diagnosis and identification. Standard laboratory methods are not suggested in the workup as no consistent anomalies in laboratory studies are recorded. Specialized laboratory studies are suggested to check for hypersensitivity of fibroblasts to UV radiation. Molecular defects associated with the disease are identified using chromosomal breakage and complementation studies along with gene sequencing. This aids in identifying the affected gene complementation group in a particular patient. Complementation group of genes can also be detected using cell-fusion techniques. This method is followed by gene sequencing or DNA repair assessment test for confirmatory diagnosis.

Xeroderma pigmentosum can be detected prenatally using amniocentesis and subjecting the cells to unscheduled synthesis of DNA [10]. Alkaline comet assay is a faster and safer way of diagnosing prenatally [11]. Although in some cases, abnormal electroencephalographic recordings are noted, the recording may be normal even in patients with neurologic manifestations. Electromyography and nerve conduction studies are useful in case of axonal polyneuropathy [12].

In the first stage of the disease, hyperkeratosis and hyperpigmentation of the basal cell layer can be observed in the histologic studies. Rete ridges may show atrophy. Hyperpigmentation of the cells is not usually accompanied by an increase in the number of melanocytes. Both hyperkeratosis and hyperpigmentation is more pronounced in the second stage of the disease. Atrophy increases with disease progression and telangiectasia also becomes notable. Histology of the dermis may now resemble actinic keratosis. Third stage of xeroderma pigmentosum is characterized by the presence of various tumors.

• Cytopenia

  To the rs2228000 polymorphism, the CT and TT polymorphic genotype were associated with increased odds ratio (OR) of more profound cytopenia (hemoglobin and neutrophils count). [ncbi.nlm.nih.gov]

Preventing exposure to sunlight is a very important step towards controlling the symptoms. Sun protection methods like use of sunscreens, and sun protective clothing like hats and eyewear, will help in reducing the damage caused by radiation. Patients should take care to apply sunscreen in all exposed areas including face, hands, ears, and back of neck. Regular visits to the doctor are also equally important for early detection and treatment of malignancies, if any.

Oral retinoids are reported to decrease the chance of skin cancer in patients with xeroderma pigmentosum [13]. In case of actinic keratosis, 5-flurouracil is recommended. A recent discovery is the use of DNA repair enzymes, delivered using specially engineered liposomes, to correct DNA damage caused by UV rays. Gene therapy is being tried as a treatment modality and is still in experimental stage. Surgery is suggested for removal of malignancies.

Prognosis of this condition is grim in many cases. Those who have mild forms of the disorder may survive till middle age. Completely avoiding exposure to UV radiation may improve the outlook for patients with mild forms of the disease. The risk of developing skin cancer is many times greater than that of the general population. The mean age of developing first tumor is around 8 years. The risk of internal malignancies is also increased considerably in patients with xeroderma pigmentosum. A study on survival curves of several patients’ show that the probability of surviving to 13 years of age is around 90%, while the probability of surviving to 28 years is approximately 80% [4]. The life expectancy of a patient with xeroderma pigmentosum reduces by 30 years. Cancer, infections and other diseases are the major causes of death. About 33%of the patients die due to various types of cancer, while in another 11%, infections are the major reason for death.

The major etiological factor implicated in the development of this disorder is the ultraviolet (UV) light component of sunlight. The cells are unable to correct the DNA damage induced by UV radiation leading to accumulation of defective DNA. UVB component of light is considered to be more important than UVA. Deficiency in DNA repair is caused by a defect in nucleotide excision repair [2]. Defect in post-replication repair may also lead to this condition [3]. UVB component of light may result in immunosuppressive effects that lead to xeroderma pigmentosum. The mutations are then inherited in an autosomal recessive pattern. Eight complementation groups of genes, XPA to XPG, have been implicated in the development of this condition. An XP variant is also described as an etiological factor.

Xeroderma pigmentosum is a rare disorder in United States and Europe. The estimated incidence in these two countries is 1 in 250,000 people. But, this skin disorder is found to be more common in Japan, North Africa and Middle East. In Japan, the incidence is approximately 1 in 40,000 people. It is found to affect people of all races. Further, the prevalence is equal in both genders. Disease onset occurs around one to two years of age. Parental consanguinity is present in some variants of xeroderma pigmentosum [4]. About one third of the patients with this condition belongs to XPC group, whereas XPA is the most common group in Japan. In Europe XPA and XPC are the most common groups.

When exposed to sunlight, the cells of individuals affected by xeroderma pigmentosum show a dose-dependent decrease in survival rate when compared to normal cells [5]. This because of reduced rate of DNA synthesis in the presence of UV light. Reduced DNA synthesis is due to defect in repairing DNA damaged by UV rays. Seven genes XPA to XPG are implicated in the repair of DNA in xeroderma pigmentosum. These genes play an important role in global genome nucleotide excision repair (GG-NER) and transcription-coupled nucleotide excision repair (TC-NER) [6]. The corresponding defects in the gene products of the mutated genes result in the clinical features of xeroderma pigmentosum. The genes differ in different types, severity and manifestations of the disease. For example, XPF results in mild clinical features while XPG is associated with severe form of the disease. Presence of abnormal repair proteins at the site of unrepaired DNA damage site may also result in cutaneous cancer [7].

Immunosuppression induced by UVB rays are also implicated in the pathogenesis of this skin condition. Patients with xeroderma pigmentosum are found to have many immunologic abnormalities including that of cell mediated immunity. This result in defective cutaneous responses to infections, reduced number of circulating T-helper cells, impaired lymphocyte production and function. Activity of natural killer cells is also considerably reduced. Abnormal transcription of DNA is noted in one form of XPG mutation [8].

Xeroderma is a genetic disorder and the presence of two copies of abnormal genes leads to the development of this condition. Those who have a family history of xeroderma pigmentosum should take up genetic counseling. The overall preventive measure that is suitable in xeroderma pigmentosum is limiting sun exposure. Sun blocks should be regularly used and exposed areas should be protected with appropriate clothing and hats. Eye wear, particularly UV absorbing sunglasses, are very useful.

Xeroderma pigmentosum (XP) is a disorder characterized by dry, pigmented skin, and hypersensitivity to sunlight. It is also marked by premature aging of the skin, and cutaneous malignancy in childhood [1]. It is a rare autosomal recessive disorder, first described by Hebra and Kaposi in 1874. The condition mostly affects the areas exposed to the sun, including the eyes. Onset of the disease occurs in early childhood or infancy. Children affected by this condition may have severe symptoms even with few minutes of exposure to the sun. Most of the people with this disease develop skin cancer later in life. They also have an increased risk of developing other forms of cancer, including brain tumors. In addition to the skin problems, people with xeroderma pigmentosum may develop neurological abnormalities like hearing loss, poor coordination, and loss of intellectual functions.

Xeroderma pigmentosum is a rare form of genetic disorder characterized by high sensitivity to sunlight and premature aging of skin. This disease is caused by inheriting two abnormal genes from parents, who generally do not show any symptoms of the condition. Eight different gene abnormalities are implicated in the development of this disease. These gene abnormalities impair the DNA repair system that corrects the DNA damage caused by UV radiations of the sun. Accumulation of DNA damage results in cell death and even cancer. Couples who are carriers of abnormal gene are at an increased risk of producing children who have two abnormal genes, resulting in xeroderma pigmentosum. This condition is found in all races and both genders have equal risk.

The disease progresses in three stages. The first stage occurs around 6 months after birth and is characterized by scaling, reddishness and freckles on the skin, particularly in exposed areas like face and neck. Irregular dark spots may also be seen. This may gradually spread to hands and legs. The changes may diminish in cold seasons as sun exposure is less. The second stage is characterized by thinning of the skin and the development of web-like collection of spots and blood vessels dispersed through the skin. Irregular patches of light and dark skin also may be noted. Third stage of the disease is characterized by development of skin cancers. Some patients may also develop eye problems and neurologic symptoms.

The disease is diagnosed around 1-2 years of age. It is confirmed by checking for UV hypersensitivity and then following it up with chromosomal breakage studies. It is also diagnosed prenatally using amniocentesis. Complete cure for xeroderma pigmentosum is not available. Any treatment focuses on preventing UV exposure and its damage on DNA. Sun damage can be avoided using sunscreen and protective clothing, particularly in exposed areas. Regular visits to the doctor is important to diagnose and treat malignancies. The disease has a poor outcome and many people die at an early age due to skin cancers. Those who have a mild variant of the disease and takes adequate protection against sun exposure may live beyond middle age.

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