|Disease group||connective tissue disorders|
|DISEASE NAME||PSEUDOXANTHOMA ELASTICUM|
|Synonymous||PXE, Grönblad-Strandberg Syndrome|
|Gene (s)||ABCC6 (603234)|
Pseudoxanthoma Elasticum (PXE) is an autosomal recessive systemic disorder, affecting the elastic fibres and leading to abnormalities of the skin, ocular and cardiovascular system.1 Pathogenic variants in the gene ABCC6 are disease causing.
Skin. With a mean age of disease-onset of 13 years, cutaneous lesions are the first to occur. These typically arise in the flexural areas of the body (e.g. lateral neck, antecubital fossae, axillae) and are called peau d’orange due to their color (darker than the skin) and yellowish papular configuration, often coalescing into plaques. An increased laxity/redundancy of the skin is occasionally present, occurring with time. In addition, mucosal lesions may develop, showing a yellow reticular pattern, most often at the inner part of the lip.2-4
Eye. Funduscopical examination frequently reveals 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 features of the PXE retinopathy and often precede angioid streak formation.3, 5, 6
Vascular. The cardiovascular complications of PXE are mainly due to early atherosclerosis (mineralization of the internal elastic lamina of medium-sized arteries), leading to peripheral artery disease, intermittent claudication and hypertension (renovascular) as well as stroke, intestinal angina and also (less frequent) coronary artery disease.3, 4, 7
Gastro-intestinal haemorrhages are an infrequent but severe complication due to an increased fragility of the gastric wall vessels.8
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).4
Individuals with PXE show a progressive deterioration of their quality-of-life, particular because of the loss of vision and vascular disease.9
In 2000, the ABCC6 gene (ATP-binding Cassette C6) was identified as the defective gene in PXE.10 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 still unknown. ABCC6 is involved in the homoeostasis of serum pyrophosphate (PPi), a main inhibitor of ectopic calcification. A lack in ABCC6 leads to low serum PPi and consequently ectopic calcification, especially of soft connective tissue.11
The diagnosis of PXE is primarily made on clinical grounds following skin evaluation and funduscopy (showing one characteristic finding: peau d’orange, angioid streaks, choroidal vascularization). A clinical diagnosis of PXE can be 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 to confirm clinically not clear cases.
Currently, there is no causal therapy for PXE. Adequate management requires a multidisciplinary team.
Plastic, reconstructive surgery for skin lesions (e.g. subcutaneous rhytidectomy and neck skin lifting) may be an option for improving skin changes at sensitive areas, however poor wound healing, friable skin and keloid formation limit this treatment option. Further possible interventions include injectable collagen and fractional CO2 laser. As controlled studies are lacking, those therapies should be considered with caution.
Regular ophthalmologic evaluation is necessary including retinal exam and Amsler grid test (self-test) to early identify PXE associated ocular patholgoies and evaluate progression. Therapies against neovascularisation include intraviteal injection of anti-angiogenic drugs or surgical approaches.12
Cardiovascular management consists of close follow-up including monitoring and education about cardiovascular risk factors (smoking, weight, blood pressure, cholesterol). Vascular pathologies should be treated according the clinical practice guidelines for the specific pathology (peripheral artery disease, coronary artery disease, ischemic stroke) by e.g. nephrologists (renal hypertension), angiologists (peripheral artery disease), gastroenterologists (intestinal involvement) or cardiologists.13, 14
Gene therapy (e.g .directed gene transfer) or PTC-124 (premature stop codon readthrough therapy) are promising therapeutic options that are currently being evaluated in pre- and clinical trials. PPi supplementation or pyrophosphate administration hold great potential to reduce calcifications.11
2. Marconi B, Bobyr I, Campanati A, et al. Pseudoxanthoma elasticum and skin: Clinical manifestations, histopathology, pathomechanism, perspectives of treatment. Intractable Rare Dis Res. 2015;4(3):113-122.
5. Gliem M, Müller PL, Birtel J, Hendig D, Holz FG, Charbel Issa P. Frequency, Phenotypic Characteristics and Progression of Atrophy Associated With a Diseased Bruch's Membrane in Pseudoxanthoma Elasticum. Invest Ophthalmol Vis Sci. 2016;57(7):3323-3330.
9. Finger RP, Fenwick E, Marella M, et al. The relative impact of vision impairment and cardiovascular disease on quality of life: the example of pseudoxanthoma elasticum. Health Qual Life Outcomes. 2011;9:113.
12. Battaglia Parodi M, Romano F, Marchese A. Anti-VEGF treatment for choroidal neovascularization complicating pattern dystrophy-like deposit associated with pseudoxanthoma elasticum. 2019;257(2):273-278.
13. Anderson JL, Halperin JL, Albert NM, et al. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(13):1425-1443.
14. Fihn SD, Blankenship JC, Alexander KP, et al. 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2014;64(18):1929-1949.