Xeroderma pigmentosum Q82.1

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.

Rare, genodermatosis with pathological reaction of the skin to UV radiation with advanced development of senile skin and formation of malignant skin tumors as a result of disorders of DNA repair in the process of nucleotide excision repair (NER). This repair mechanism repairs major DNA damage caused by UV radiation.

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

• Type A = de Sanctis-Cacchione syndrome
• Type V = so-called pigmented xerodermoid.

Worldwide occurrence; all ethnicities; incidence in Europe and North America approximately 1/250,000 population/year, in Japan approximately 1/22,000 population/year. The parents of XP patients are obligate carriers of a mutation in one of the XP genes.

Autosomal recessive inherited disorder of the nucleotide excision repair system. The mutations are distributed to different genes on 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).

There is therefore a so-called heterogony of the phenotype, i.e. mutations in different genes (XP-A / XP-G). genes (XP-A / XP-G as well as the VXP-V gene (=REV1 gene is involved in the translesion synthesis/TLS of damaged DNA) polymerase), which trigger an identical phenotype. The individual gene segments encode repair proteins that are involved in different steps of the nucleotide excision repair system.

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

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:

• spinocellular carcinomas (especially type C, E, V- remark: these patients have a normal sunburn reaction and are therefore diagnosed late!)
• malignant melanomas (especially type D)
• Basal cell carcinomas (especially type E, V)
• Sarcomas.
• In 80% eye involvement (mainly type C)

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.

Light-damaged cells in the epithelium, increased melanin deposition in the stratum basale. Pigment incontinence with intra- and extracellular pigment accumulation in the upper corium. The long term damage is according to the clinical constellation (tumor formation, lentiginous changes).

The pathological anatomical substrate of the neurological disorders is a primary neuronal degeneration with loss of neurons.

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.

• 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.

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

The risk of developing skin tumors is increased 1000 times! Furthermore, XB patients have an increased risk of developing internal neoplasms (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).

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