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A rare, genetic, metabolic disease with connective tissue and eye involvement, characterized by progressive ectopic mineralization and fragmented elastic fibers in the skin, retina and vascular walls.
ORPHA:758Classification level: Disorder
Prevalence is estimated at between 1/40,000 and 1/100,000 in the general population, with, for unknown reason, female predominance (female to male ratio 4:1).
Disease onset is typically in adolescence or young adulthood but may appear at any age. The first clinical sign is almost always small yellow papules on the nape and sides of the neck and in flexural areas. The papules subsequently coalesce, and the skin becomes loose and wrinkled. Dystrophic calcification of Bruch's membrane of the retina, revealed by angioid streaks at fundus examination, may trigger choroidal neovascularization and, ultimately, loss of central vision and blindness in late-stage disease. Lesions in small and medium-sized artery walls may result in intermittent claudication and peripheral artery disease. The disease may be limited to one organ (skin, eye, or blood vessels) in some patients or affect two or all three organs. Cardiac complications (angina pectoris, myocardial infarction) are relatively rare but, when present, deserve thorough investigation. Transient ischemic attacks and, more rarely, ischemic strokes have been reported. Gastrointestinal hemorrhage occurs in about 5% of cases. Calcification of other organs, such as the kidneys, breasts, pancreas, testicles, liver and spleen may be observed.
The vast majority of cases are caused by biallelic pathogenic variants in the ABCC6 gene (16p13.11). Rarely, patients with pseudoxanthoma elasticum (PXE)-like clinical features harbor pathogenic variants in the ENPP1 gene (6q23.2), which is usually associated with generalized arterial calcification of infancy (GACI). Both genes are presumably part of one metabolic way, and the pathogenic variants are thought to lead to decreased circulating pyrophosphate (PPi), a major anti-mineralization factor.
Diagnosis is suspected on clinical presentation of characteristic yellow cobblestone skin lesions at the predilection sites. Biopsy of the affected skin using elastin and calcium-specific staining reveals abundant morphological alterations with fragmented, clustered and calcified elastin fibers in the middle and lower dermis. Fundus examination reveals characteristic retinopathy with angioid streaks, drusen or maculopathy. Genetic testing for ABCC6 can confirm diagnosis or rule it out in clinically ambiguous cases.
Differential diagnosis of angioid streaks includes hemoglobinopathies (sickle cell disease, Beta-thalassemia, spherocytosis), dermal elastic tissue disorders (solar elastosis, perforating calcific elastosis, PXE-like late-onset focal dermal elastosis, PXE-like papillary dermal elastolysis) and other multisystem disorders (cutis laxa) as well as combined vitamin K-dependent clotting factors deficiency.
The pattern of transmission is autosomal recessive, with a 25% risk of recurrence in siblings. Pseudo-dominant pattern of inheritance due to high frequency of ABCC6 heterozygotes (around 1/200), has been occasionally observed. Genetic counseling for affected families is recommended.
Management and treatment
There is no specific therapy; the main symptomatic treatments include direct injection of vascular endothelial growth factor inhibitor in the eyes (for choroidal neovascularization), lifestyle, lipid-lowering and dietary measures (for reducing vascular risk factors), vascular surgery (for severe arteriosclerosis), and plastic surgery (for excess skin folds).
It is a life-long progressive disease with high debilitating potential, but the life-span is normal in most patients.
A summary on this disease is available in Español (2020) Français (2020) Nederlands (2020) Italiano (2006)
- Article for general public
- Svenska (2020) - Socialstyrelsen
- Clinical practice guidelines
- Français (2021) - PNDS
- English (2022) - J Dermatol
Disease review articles
- Review article
- English (2017) - Orphanet J Rare Dis
- Clinical genetics review
- English (2020) - GeneReviews
- Guidance for genetic testing
- English (2018, pdf) - Eur J Hum Genet
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