Pseudoxanthoma elasticumQ82.8

Rare, metabolic, autosomal inherited systemic disease(OMIM 264800) with consecutive mineralization disorder of the elastic connective tissue, manifesting on skin, eyes and cardiovascular system. Very few cases have also been reported of acquired Pseudoxanthoma elasticum.

Classification according to Plomp et al (2010)

• Main criteria
  • Skin: Irregular, scar-like skin relief due to flatly elevated, symptomless yellow papules/plaques laterally on the neck and/or in the large joint flexures (especially axillary); histopathologically fragmentation, agglutination and calcification of elastic fibres.
  • Eye: Peau d'orange (retina); "angioid streaks".
  • Genetics: Bi-allelic ABCC6 mutations; a 1st degree relative which meets the diagnostic criteria of PXE.
• Secondary criteria
  • Eye: Retinal comets and/or "wing signs
  • Genetics: Heterozygote ABCC6 mutation

Incidence: Approx. 0.5-1.0/100,000 inhabitants/year. Prevalence is currently given as 1.0:25,000/100,000.

The inheritance is mostly autosomal recessive (90% of cases), rarely autosomal dominant.

It is caused by mutations in the ABCC6 gene (syn.: MRP6 gene = multidrug resistance protein 6), which is mapped on chromosome 16p13.1. The ABCC6 gene encodes the transmembrane protein MRP6, which is responsible for a number of physiologically important processes. MRP6 belongs to the family of so-called "multidrug resistance-associated proteins (MRP)". MRPs are also involved in drug resistance, especially in combination with chemotherapy. The result is the production of non-functional MRP6, (S.u. ABC transporter). MRP6 proteins are preferentially expressed in the liver and kidney. They are responsible, among other things, for the transport of bilirubimetabolites from hepatocytes. So far, 32 PXE mutations have been detected.

In PXE, this dysfunction can no longer prevent calcification, fragmentation and degeneration of the elastic fibres. Ultimately, the exact mechanism has not been elucidated.

The cause of the few cases of acquired PXE that have become known worldwide is still unknown.

A significant number of patients with beta thalassemia develop clinical signs of PXE. Occasionally, a pseudoxanthoma-elasticum-like clinical picture has been described under therapy with penicillamine.

Skin: Regionally circumscribed, round or oval, symmetrically arranged, striped, spotted or focal, slightly raised, soft, possibly confluent papules. Color: Primarily purple, later white to yellowish, "ivory". In the "mature" stage of development, yellowish papules and plaques appear with a granular surface relief reminiscent of a plucked chicken skin (also cobblestone-like humped).

Increased wrinkling of the chin is considered a characteristic feature (farewell sign).

Oral mucosa: rarely, analogous lesions are also found in the oral mucosa.

Eyes: visual disturbances in the 3rd to 4th decade of life, papillary "angioid streaks" of the fundus of the eye. Calcification of elastic fibers causes tears of the lamina vitrea of the choroid and pigment epithelium(angioid streaks) and macular degeneration. There is a risk for retinal hemorrhages and loss of central vision.

Cardiovascular and other symptoms: hypertension (25%), arteriosclerotic changes (calcifications of the elastica of the vessels) with intermittent claudication (20%) and angina pectoris (20%). Less common are:

• Myocarditis
• aortitis
• cerebral insults
• bleeding of the gastrointestinal tract as well as of the kidneys (here also calcifications).
• Bleeding tendencies: spontaneous vascular ruptures are the most frequent cause of death.

Symptoms of disease often appear only in the second decade of life; slow development.

• Partially swollen, broken, mineralised, elastic fibres rich in calcium salts and acidic proteoglycans.
• Electron microscopy: enlargement, cavern formation and fragmentation of the elastic fibres. Enlargement of a variable proportion of collagen fibrils with a flower-like structure in cross-section. Granulo-filamentary material and small calibre collagen.

• Clinical:
  • elastosis actinica
  • lax cutis
  • Colloidalmilium
  • elastic nevus
  • Buschke-Ollendorf syndrome
  • mediodermal elastolysis
  • Pseudoxanthoma-elasticum-like syndrome
• Histological:
  • The histological picture is conclusive in the context of the clinic.

Symptomatic, possibly surgery for cosmetic indication.

Prevention of consequential damages due to nicotine withdrawal, avoidance of atherogenic lipid metabolism disorders.

Therapy attempts with vitamin E or chelating agents (EDTA) are described in the same way as low-calcium diets, but are without lasting success.

Interdisciplinary cooperation with internists and ophthalmologists.

The diagnosis is probably:

• Existence of 2 main criteria from the category skin or eye
• Presence of a main criterion and (at least) one secondary criterion that does not belong to the same category as the main criterion.

A presentation in a specialised centre for the diagnosis and therapy of the ophthalmological aspect of the disease is highly recommended. A molecular biological confirmation of the diagnosis is necessary. Human genetic counselling should be offered. The connection of patients to a self-help group is recommended.

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