DISEASE CARD

Disease group connective tissue disorders
DISEASE NAME PSEUDOXANTHOMA ELASTICUM
Synonymous PXE, Grönblad-Strandberg Syndrome
Estimated prevalence 1:25000
OMIM 264800
Inheritance Autosomal recessive
Gene (s) ABCC6 (603234)

Definition

Pseudoxanthoma Elasticum (PXE) is an autosomal recessive systemic disorder, affecting the elastic fibres and characterized by abnormalities of the skin, the ocular and cardiovascular system.

Clinical Description

The mean age of onset of PXE is 13 years. Most often, the cutaneous lesions are the first to be noted. These typically occur in the flexural areas of the body and are characterized by peau d’orange and yellowish papular lesions, often coalescing into plaques (figure 1). An increased laxity of the skin can sometimes be observed. Additionally, mucosal lesions can be seen as yellow reticular patterns, most often at the inner lip.

Figure 1: papular lesions at the lateral side of the neck of a PXE patient

papular lesions

Funduscopical examination can reveal ruptures of the elastin-rich Bruch membrane, called angioid streaks (because of their resemblance with the retinal vessels). These make the fundus prone to subretinal neovascularisation and haemorrhage, often leading to moderate or severe loss of central vision in the fourth or fifth decade of life. Peripheral vision usually remains unaffected. Additionally, a mottled aspect of the fundus, called peau d’orange, and subretinal calcifications (comets and comet tails) are typical characteristics of the PXE retinopathy and often precede angioid streak formation.

Figure 2: PXE fundus with peau d’orange (large circle), angioid streaks (full arrows), opticus drusen (open arrow) and comets (small circle)

PXE   fundus with peau d’orange

The cardiovascular complications of PXE are mainly due to accelerated atherosclerosis, leading to peripheral artery disease (hypertension, intermittent claudication), stroke and, although less frequent, coronary artery disease.
Gastro-intestinal haemorrhages are an infrequent but severe complication due to the fragility of the superficial gastric wall vessels.
PXE patients often tend to have additional sites of ectopic calcifications in abdominal organs and testicles (testicular microlithiasis). While the former do not seem to have major clinical relevance, the latter have been associated in literature with testicular cancer (although this association is not based on prospective data).

Although suggestions have been made in the literature, it is presently unclear whether carriers of one ABCC6 mutation (e.g. parents or offspring of a proband) have a slightly higher cardiovascular risk compared to the general population.

Pathogenesis

The pathogenesis of PXE is still largely unknown. In 2000, the ABCC6 gene (ATP-binding Cassette C6) was identified as the defective gene in PXE. The gene sequence consists of 31 exons, spanning ~ 73 kb of DNA. ABCC6 encodes an ATP-dependent transmembrane transporter, the biological substrate of which is as yet unknown. Similarly, the relationship between aberrant ABCC6 activity and extracellular matrix changes in PXE (fragmentation and mineralization of elastic fibres) remains to be elucidated. ABCC6 is mostly found at the basolateral cell membrane in liver and kidneys and to a lesser extent in the tissues affected by PXE. Its cellular location suggests that ABCC6 transports a substrate important for connective tissue homeostasis into the blood, suggesting that PXE may be considered a metabolic disease.

Diagnosis

The diagnosis of PXE is primarily made on clinical grounds following skin evaluation and funduscopy. A clinical diagnosis of PXE is traditionally confirmed by demonstrating fragmentation and calcification of the elastic fibres in the reticular dermis of a lesional skin biopsy, using van Giesson (elastin) and Von Kossa (calcium) staining methods. Although the elastolysis is characteristic, additional abnormal morphology or distribution of other extracellular matrix components (collagen, fibrillins, and proteoglycans) is also often observed.
Molecular analysis of the ABCC6 gene yields a high mutation detection rate and can therefore be used as an additional test or, in some clinically well defined cases, as alternative for skin biopsy.

Treatment

Currently, there is no causal therapy for PXE. Plastic surgery for skin lesions usually does not yield good results and should be avoided. At an ophthalmological level, management is confined to regular self-testing using the Amsler test and annual follow-up with funduscopy to evaluate progression and possible neovascularisation. At present the latter can be treated, on a research basis, using intra-ocular anti-VEGF (Vascular Endothelial Growth Factor) therapy, which will obliterate the novel vessels and thus minimize the risk for haemorrhage and subsequent vision loss.

Cardiovascular management consists of close follow-up of the traditional cardiovascular risk factors (smoking, weight, blood pressure, cholesterol). Additionally, regular (every 3-5 years) ultrasounds of the heart and carotid/femoral arteries are advised. Because of the possible association with malignancy, control ultrasounds of testicular microlithiasis are regarded as being useful.