Xeroderma pigmentosum Q82.1

Author: Prof. Dr. med. Peter Altmeyer

All authors of this article

Last updated on: 27.01.2021

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Synonym(s)

atrophodermia pigmentosa (Crocker); Light shrink skin; Lioderma essentialis congenita (Auspitz); Melanosis lenticularis progressive; Moonlight Sickness; OMIM 278700; OMIM 278720; OMIM 278730; OMIM 278740; OMIM 278750; OMIM 278760; OMIM 278780; OMIM 610651

History
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Kaposi, (1863)1882 - Comment: Moriz Kaposi described the first patient with dry skin and pigmentary disorders in 1863. It was not until 20 years later that the term "xeroderma pigmentosum" was coined. In 1968, it was demonstrated by James Cleaver that the cells of these patients had a defect in DNA repair genes, the nucleotide excision repair (NER) system.

Definition
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Rare, genodermatosis with abnormal reaction of the skin to UV rays with advanced development of aging skin and formation of malignant skin tumors as a result of disorders of DNA repair in the process of nucleotide index repair (NER). This repair mechanism corrects major DNA damage caused by UV radiation.

Classification
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Depending on the defect of the excision repair mechanism, 8 complementation groups are distinguished: type A-G (see table).

Clinical manifestations in the individual types (XP-A - XP-V) of Xeroderma pigmentosum (XP) (varies according to Herouy et al.)
Types Dermatological symptoms Dermatological tumors Neurological symptoms Ocular symptoms
XP-A

+++

SK

++

++

XP-B

+++

SK/B

+

++

XP-C

+

SK/B

+

-

XP-D

++

MM

++

+

XP-E

+

B

-

-

XP-F

++

SK/B

+

-

XP-G

++

SK/B

+

-

XP-V

+

B

-

-

KS = carcinoma, spinocellular; B = basal cell carcinoma; MM = malignant melanoma; + = mild; ++ = moderate; +++ = severe

Occurrence/Epidemiology
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Worldwide occurrence; all breeds; incidence in Europe and North America about 1/250,000 inhabitants/year, in Japan about 1/22,000 inhabitants/year. The parents of XP patients are obligatory carriers of a mutation in one of the XP genes.

Etiopathogenesis
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Autosomal recessive inherited disorder of the nucleotide excision repair system. The mutations are distributed across different chromosomes. (XP-A: 9q22; XP-B: 2q21, XP-C: 3p25; XP-D: 19q13; XP-E: 11; XP-F: 19q13; XP-G: 13q32; XP-V: 6p12-21). Thus, there is a so-called heterogony of a phenotype, i.e. defects of versch. This means that there are defects in different genes (XP-A / XP-G and the VXP-V gene polymerase) that cause the same clinical picture. The individual gene segments encode repair proteins that are involved in different substeps of the nucleotide excision repair system.

Affected repair systems in xeroderma pigmentosum and their original function (varied n. Herouy et al.)
Repair proteins Function
XP-A, XP-C, XP-E DNA damage recognition
XP-B, XP-D helicase, local unwinding of DNA
XP-G, XP-F Incision of the DNS
XP-V Polymerase

In contrast to the other variants, XP-V has a defect in DNA polymerase, i.e. in transläsional DNA synthesis.

Manifestation
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Earliest childhood: 6 to 18 months of age, for type E only 6 to 9 years of age. No gender preference, manifestation of malignant tumours in the 2nd to 20th year of life.

Clinical features
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Acute early clinical leading symptom: At first, only the severe sensitivity to sunlight is impressive, which is already noticeable in the first weeks of life. However, XP-C, XP-E XP-V patients can also tan without sunburn. All other types are characterized by severe sunburn with blistering even behind glass panes during the first sun exposure. After exposure to the sun, regular healing takes place within 4-6 days with scaling and formation of light brown to black, ephelid-like or lentiginous melanotic spots. The sensitivity to sunlight remains for the rest of the life.

Chronic sequelae (progression over years): poikiloderma, dyschromas and malignancies. Further: skin atrophy with eyelid ectropion and microstomy, keratosis actinica as cumulative long-term effects of (normal) sunlight exposure. Infestation of eyelids, conjunctiva, cornea and iris.

Malignancies of the skin; development of:

Neurological disorders: with about 20% involvement of the nervous system (especially type A, hyper- and areflexia). As the disease progresses, increasing inner ear hearing loss, speech, gait and balance disorders develop.

Miscellaneous: Typically more frequent caries development, less frequent development of leukaemia.

Laboratory
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Detection of the absence of endonuclease in fibroblast culture (also prenatally).

Histology
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  • Light-damaged cells in the epithelium, increased melanin storage in the stratum basale. Pigment incontinence with intra- and extracellular pigment accumulation in the upper corium. Long-term damage depends on the clinical constellation (tumour formation, lentiginous changes).
  • The pathologically anatomical substrate of the neurological disorders is a primary neuronal degeneration with loss of neurons.

Diagnosis
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Suspected clinical diagnosis. Typical anamnesis and clinic with extreme sensitivity to sunlight already in the first days of life! The later poikilodermatic clinical picture is pioneering.

Human genetic examination with molecular genetic diagnostics.

Differential diagnosis
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  • A distinction must be made between the early infantile state, in which acute sun damage is at the forefront of the pathophysiological process. Only the later
  • Polymorphic light dermatosis: first manifestation much later (between 10 and 30 years of age). Women are affected about 10 times more frequently than men. No detectable pigmentation disorders, no increased carcinogenesis.
  • Lupus erythematosus, more systemic: "butterfly erythema" as persistent, blurred erythema on the face. Furthermore, erythemato-papulo-vesicular foci, pityriasiform, firmly adhering scaling or atrophy occur. The light reaction will rarely occur as acute "Dermatitis solaris" but only after a time delay of days. Histology, immunohistology and serology are conclusive.
  • Urticaria pigmentosa: Here the signs of excessive light sensitivity are generally absent. Discovered in infancy rather as an "accidental finding". Darian sign positive in Urticaria pigmentosum. No increased carcinogenesis. Histology is conclusive.
  • Peutz-Jeghers syndrome (important DD): No excessive sensitivity to light. Perioral and also periorbital lentigines are typical in early childhood; intestinal polyps in adolescence. Lentiginosis also of the oral mucosa and the conjunctiva.
  • Hidroa vacciniformia: Sudden circumscribed erythema, usually a few hours after exposure to the sun, with formation of partially umbilical blisters up to 2.0 cm in size with serous or hemorrhagic content. Bowl-shaped, varioliform, often depigmented scars are characteristic. No pigmentation disorders; no increased carcinogenesis.
  • Erythropoietic porphyria (CEP): onset in infancy, itching, burning, edematous erythema, vesicles, possibly haemorrhagic ulcerations. Formation of varioliform scars, severe mutilation, hyper- and depigmentation, scarred alopecia, sclerosis, hypertrichosis, hemolytic anemia, splenomegaly, red urine. Laboratory evidence: red urine, red fluorescence, uroporphyrin I highly elevated.
  • Goltz-Gorlin syndrome: very rare, poicilodermatic lesions and scars and pigmentation anomalies or pigmentation disorders. Characteristic extracutaneous manifestations are: skeletal involvement (90% of cases): syn- and polydactylia, hypo- and aplasia of fingers and toes.
  • FAMM Syndrome(Familial Atypical Multiple Birthmark and Melanoma Syndrome): Uniform clinic with multiple melanocytic nevi and malignant melanomas. Genetic detection of the gene mutation.
  • Progeria (Werner syndrome): Very rare syndrome of senescence. Occurs mainly between 20 and 30 years of age; not before 10 years of age. Postpubertal growth retardation with premature graying of the hair (20 to 30 years), regressive laryngeal changes (hoarseness) and complete atrophy of the subcutaneous fatty tissue in the distal tibia and in the entire foot area. Clinical premature senescence (bird face), lack of excessive light sensitivity and the poicilodermatic picture of XP.
  • Bloom Syndrome: Extremely rare clinical picture. Symptoms beginning in the 1st year of life. Androtrophy. Typical is a butterfly-shaped, teleangiectatic (reminiscent of lupus erythematosus) facial erythema. Intensification under the influence of sunlight, possibly blistering of the lips and eyelids. Often café-au-lait stains. Proportioned dwarfism with a final size of less than 150 cm. Frequent infections. Early development of neoplasia, especially lymphatic and myeloid leukaemias, lymphomas, carcinomas of the oral cavity and gastrointestinal tract.

General therapy
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Lifelong, absolute avoidance of UV rays by shifting the day-night rhythm. Complete physical and chemical sun protection (clothing, sun protection preparations). Skin check-ups in 3-6 month intervals. Specialist medical supervision of the patients. Genetic counselling!

External therapy
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Systematic light protection with application of all necessary measures.

Internal therapy
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Prophylactic success is described with the oral administration of retinoids: Acitretin (e.g. neotigason) or isotretinoin (e.g. isotretinoin-ratiopharm; acne normin) 0.5-2 mg/kg bw/day.

Cave! Due to high dosage often early incompatibilities (see AI or NW under Acitretin or Isotretinoin).

Operative therapie
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Timely surgical removal of malignant tumours already formed by means of excision, curettage, cryosurgery.

Progression/forecast
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The risk of developing skin tumours is 1000 times higher! Furthermore, XB patients have an increased risk of developing internal neoplasia (CNS tumors, sarcomas, leukemias, lung carcinomas - Note: Smoking - sun for the lungs - leads to DNA damage (see below DNA repair), which is also repaired by the NER).

Note(s)
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Self-help group D (www.xerodermapigmentosum.de)

Literature
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  1. Berking C (2007) Photocarcinogenesis. dermatologist 58: 398-405
  2. Berneburg M, Krutmann J (2003) Xeroderma pigmentosum and related syndromes. dermatologist 54: 33-40
  3. Cox SE et al (1993) Prevention of skin cancer in xeroderma pigmentosum: the physician as advocate. J Am Acad Dermatol 29: 1045-1046
  4. Dupuy A et al (2015) DNA damage and gene therapy of xeroderma pigmentosum, a human DNA repair-deficient disease. Mutate Res 776: 2-8.
  5. Emmert S et al (2002) Relationship of neurologic degeneration to genotype in three xeroderma pigmentosum group G patients. J Invest Dermatol 118: 972-982
  6. Emmert B et al (2011) Xeroderma pigmentosum. dermatologist 62: 91-97
  7. Ettinger M et al (2017) Light protection for Xeroderma pigmentosum. dermatologist 68:359-363
  8. Fassihi H et al(2016) Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect. Proc Natl Acad Sci U S A 113:E1236-1245.
  9. Herouy Y et al (2003) Xeroderma pigmentosum: Moonshine children. JDDG 3: 191-198
  10. Kaposi M (1882) About Xeroderma pigmentosum. Medical Yearbooks (Vienna) 619-633
  11. Khatri ML et al (1992) Xeroderma pigmentosum. J Acad Dermatol 26: 75-78
  12. Kraemer KH et al (1987) Xeroderma pigmentosum. Cutaneous, ocular and neurologic abnormalities in 830 published cases. Arch Dermatol 123: 241-250
  13. Lindenbaum Y et al (2001) Xeroderma pigmentosum/cockayne syndrome complex: first neuropathological study and review of eight other cases. Eur J Paediatr Neurol 5: 225-242
  14. Lynch HT et al (1984) Xeroderma pigmentosum. Arch Dermatol 120: 175-179
  15. Moriwaki S, Kraemer KH (2001) Xeroderma pigmentosum--bridging a gap between clinic and laboratory. Photodermatol Photoimmunol Photomed. 17: 47-54
  16. Moriwaki S (2016) Human DNA repair disorders in dermatology: A historical perspective, current concepts and new insight. J Dermatol Sci 81:77-84.
  17. Poblete-Gutiérrez P et al (2006) Hereditary photodermatoses. Dermatologist 57: 1067-1082
  18. Stone N et al (2000) Xeroderma pigmentosum: the role of phototesting. Br J Dermatol 143: 595-597

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Last updated on: 27.01.2021