Pseudoxanthoma elasticum | |
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Other names | Grönblad–Strandberg syndrome; [1] Groenblad-Strandberg syndrome |
Pseudoxanthoma elasticum of the posterior lateral neck. Note the yellowish slightly raised bumps characteristic of this condition. | |
Specialty | Medical genetics |
Pseudoxanthoma elasticum (PXE) is a genetic disease that causes mineralization of elastic fibers in some tissues. The most common problems arise in the skin and eyes, and later in blood vessels in the form of premature atherosclerosis. [2] [3] [4] PXE is caused by autosomal recessive mutations in the ABCC6 gene on the short arm of chromosome 16 (16p13.1). [3] [5] [6]
Usually, pseudoxanthoma elasticum affects the skin first, often in childhood or early adolescence. [7] Small, yellowish papular lesions form and cutaneous laxity mainly affect the neck, axillae (armpits), groin, and flexural creases (the inside parts of the elbows and knees). [3] [8] Skin may become lax and redundant. Many individuals have "oblique mental creases" (horizontal grooves of the chin). [9] The lesions are asymptomatic and have a stochastic pattern of growth and spread. [10]
PXE first affects the retina through a dimpling of the Bruch membrane (a thin membrane separating the blood vessel-rich layer from the pigmented layer of the retina), that is only visible during ophthalmologic examinations. [11] This is called peau d'orange (a French term meaning "skin of the orange"). Eventually the mineralization of the elastic fibers in the Bruch membrane create cracks called angioid streaks that radiate out from the optic nerve. Angioid streaks themselves do not cause distortion of vision, even if they cross into the foveal area. This symptom is present in almost all PXE patients and is usually noticed a few years after the onset of cutaneous lesions. These cracks may allow small blood vessels that were originally held back by Bruch's membrane to penetrate the retina. These blood vessels sometimes leak, and these retinal hemorrhages may lead to the loss of central vision. Vision loss is a major issue in many PXE patients. [12] [3] [4]
Additionally, patients with PXE are at a greater risk of developing optic nerve head (ONH) drusen, which are calcified lesions within the optic nerve. Careful monitoring should be considered to prevent further complication, such as retinal artery occlusion and optic neuropathy. [13]
PXE is caused by mineralization in connective tissues in mainly the skin, eyes, and blood vessels. [14] As a result of mineralized buildup in the vascular wall, patients may be at a greater risk for intermittent claudication, a condition in which cramping pain in the leg is induced by exercise, [15] and peripheral artery disease. [14] Occlusions in cerebral arteries can lead to reduced or blocked blood flow, resulting in serious complications including transient ischemic attack (TIA) and stroke. Similarly, blockages in the coronary circulatory system, also called coronary artery disease may develop, leading to angina and myocardial infarction (heart attack). [16] Cerebral ischemia in PXE is caused by small vessel occlusive disease.[ citation needed ]
Although not much is known about potential gastroenterological manifestations, gastrointestinal bleeding is a rare symptom and usually involved bleeding from the stomach.[ citation needed ]
Other rare neurological complications may include intracranial aneurysms, subarachnoid and intracerebral hemorrhages. [17]
80% of clinical cases of pseudoxanthoma elasticum have detectable mutations in the ABCC6 gene. [18] [19] [20] [21] Mutations in almost all parts of the gene have been described, of all types (missense, nonsense, splice alteration, insertion, small deletion or large deletion). Although there have been reports of autosomal dominant inheritance, the inheritance is typically autosomal recessive (both parents need to be carriers, and there is a 25% chance that a child will inherit both abnormal copies of the gene and therefore develop the condition). [3]
Strong genetic linkage was found with mutations in the ABCC6 gene, which codes for the ABCC6 protein, which is a membrane transporter from the large ATP-binding cassette transporter family. The protein is expressed in most organs, but mainly in the liver and kidney. ABCC6 mediates ATP release in the liver. This is the main source of circulating pyrophosphate (PPi), and individuals affected by PXE have strongly reduced plasma PPi levels, explaining their mineralization disorder. [22] One study suggested that mutations causing total absence of an ABCC6 protein caused a more severe disease, [23] but this could not be confirmed in a subsequent case series. [24] Given the variations in age of onset and severity it is likely that other unknown risk factors (genetic, environmental, and lifestyle) may be involved. [3]
Premature atherosclerosis is also associated with mutations in the ABCC6 gene, even in those without PXE. [25] A syndrome almost indistinguishable from hereditary PXE has been described in patients with hemoglobinopathies (sickle-cell disease and thalassemia) through a poorly understood mechanism. [3] In addition, there appears to be another PXE-like syndrome with a similar phenotype but as a result of problems with another gene, gamma-glutamyl carboxylase. [26] Mutations in ABCC6 can also cause generalized arterial calcification of infancy. [27] In some cases of PXE, mutations in ABCC6 cannot be found, and other genes such as ENPP1 may be implicated. [28]
In PXE, there is mineralization (accumulation of calcium and other minerals) and fragmentation of the elastin-containing fibers in connective tissue, but primarily in the midlaminar layer of the dermis, Bruch's membrane and the midsized arteries. [29] Recent studies have confirmed that PXE is a metabolic disease, and that its features arise because metabolites of vitamin K cannot reach peripheral tissues. [30] Low levels of PPi cause mineralization in peripheral tissues. [22]
The diagnostic criteria for PXE are the typical skin biopsy appearance and the presence of angioid streaks in the retina. Criteria were established by consensus of clinicians and researchers at the 2010 biennial research meeting of the PXE Research Consortium. [32] and confirmed at the 2014 meeting [33] These consensus criteria state that definitive PXE is characterized by two pathogenic mutations in the ABCC6 or ocular findings – angioid streaks > 1 DD or peau d'orange in an individual <20 years of age together with skin findings:
Pseudoxanthoma elasticum | LM: Mid-dermal calcification and fragmentation of elastic fibers EM: Mineralization in elastic fiber core |
PXE-like disease with coagulation deficiency | LM: Middermal calcification and fragmentation of elastic fibers EM: Mineralization in elastic fiber periphery |
Hemoglobinopathies | LM: Middermal calcification and fragmentation of elastic fibers EM: Mineralization in elastic fiber core |
PXE-like papillary dermal elastolysis | LM: Selective elastic tissue elimination in the papillary dermis and presence of melanophages |
White fibrous papulosis of the neck | LM: Dermal fibrosis in papillary and mid-reticular dermis |
Late-onset focal dermal elastosis | EM: Decrease of elastic fibers; fragmentation of remaining fibers LM: Accumulation of elastic fibers in mid- and reticular dermis without fragmentation or calcification |
Perforating calcific elastosis | LM: Middermal calcification and degeneration of elastic fibers with transepidermal elimination |
Buschke–Ollendorff syndrome | LM: Increased amount of hypertrophic elastic fibers in dermis EM: Altered translucent elastic fibers |
Elastosis perforans serpiginosa | LM: Transepidermal or perifollicular perforating canals |
Papular elastorrhexis | LM: Thickening of collagen bundles next to loss and fragmentation of elastic fibers |
Upper dermal elastolysis | LM: Complete loss of elastic fibers in the upper dermis |
Middermal elastolysis | LM: Complete absence of elastic fibers in the middermis |
Linear focal elastosis | LM: Massive basophilic fibers; clumping of elastic fibers in papillary dermis |
Elastoderma | LM: Increased, intertwining thin elastic fibers in papillary and upper reticular dermis |
Calcinosis cutis | LM: Deposits of calcium in the dermis |
There is no confirmed treatment that directly interferes with the disease process. [5] [6]
Cosmetic surgery to remove excessive skin has been used to improve aesthetic appearance in PXE patients [5] but because of the non-life-threatening nature of these symptoms, should be used with caution. [6]
One of the most critical symptom of PXE is choroidal neovascularization which can lead to deterioration of central vision. Photodynamic therapy has been used as a treatment, but this has been replaced with endothelial growth factor (VEGF) inhibitors (such as bevacizumab, ranibizumab, and aflibercept) [6] with efficacy similar to their use in treatment of age-related macular degeneration. [4]
To limit cardiovascular symptoms, reduction of cardiovascular risk factors through lifestyle changes is recommended. [6] Generally clinicians recommend avoidance of non-steroidal anti-inflammatory drugs (NSAIDS) that increase bleeding risk, such as aspirin, and ibuprofen to prevent eye and gastrointestinal bleeding. [6]
Formerly, dietary restriction of calcium was tried with no benefit, and in fact accelerated mineralization in mice. [34] There are a number of potential treatments that are currently being tested or have just undergone testing including magnesium, [35] etidronate, [36] PPi, [37] and tissue-nonspecific alkaline phosphatase inhibitors. [38]
Given that ABCC6 heterozygous mutations result in few symptoms of PXE, this disease is a candidate for gene therapy. Some initial proof-of-principle experiments have been done in mice that have relieved some of symptoms of PXE, but as with all gene therapy treatments, there are many hurdles that must be overcome including insuring that the treatment will be long-lasting and reducing the risk of insertional mutagenesis and severe immune reactions. [6]
The reported prevalence of pseudoxanthoma elasticum is about 1:25,000. Females are twice as likely to be affected as males. The disease occurs in all ethnicities, but Afrikaners are more likely to have PXE as a result of a founder effect (i.e., higher prevalence in the small group of people from whom Afrikaners descend). [39]
The first description of PXE that distinguished it from other xanthoma conditions was by Dr Ferdinand-Jean Darrier in 1896. [40] The eponym "Grönblad-Strandberg syndrome" is used in older literature, after two physicians who made further discoveries in the disease manifestations. [41]
PXE has the distinction of being the only disease for which a layperson is the discover of the mutated gene. The ABCC6 gene mutation was discovered simultaneously by four research teams, all of which published at the same time. The principal investigators were (in order of the date of publication): Jouni Uitto, [18] Arthur Bergen, [19] Charles Boyd, [20] and Klaus Lindpainter. [21] The gene was patented by Charles D. Boyd, Katalin Csiszar, Olivier LeSaux, Zsolt Urban, Sharon Terry, and assigned to PXE International by these co-inventors. Between the filing and 2013, when the Supreme Court of the United States declared that genes may not be patented. [42] PXE International freely licensed the gene to any lab for clinical testing and research. PXE International continues to hold and maintain other patents (diagnosis and treatment patents). [43] [44]
PXE International, a support organization, was founded in 1995, by Patrick and Sharon Terry, [45] [46] [47] [48] following the diagnosis of their two children. It has a registry of 4,600 affected individuals.
Ehlers–Danlos syndromes (EDS) are a group of 13 genetic connective-tissue disorders. Symptoms often include loose joints, joint pain, stretchy velvety skin, and abnormal scar formation. These may be noticed at birth or in early childhood. Complications may include aortic dissection, joint dislocations, scoliosis, chronic pain, or early osteoarthritis. The current classification was last updated in 2017, when a number of rarer forms of EDS were added.
Epidermolysis bullosa (EB) is a group of rare medical conditions that result in easy blistering of the skin and mucous membranes. Blisters occur with minor trauma or friction and are painful. Its severity can range from mild to fatal. Inherited EB is a rare disease with a prevalence in the United States of 8.2 per million live births. Those with mild cases may not develop symptoms until they start to crawl or walk. Complications may include esophageal narrowing, squamous cell skin cancer, and the need for amputations.
Elastin is a protein encoded by the ELN gene in humans. Elastin is a key component in the extracellular matrix of gnathostomes. It is highly elastic and present in connective tissue of the body to resume its shape after stretching or contracting. Elastin helps skin return to its original position whence poked or pinched. Elastin is also in important load-bearing tissue of vertebrates and used in places where storage of mechanical energy is required.
Elastic fibers are an essential component of the extracellular matrix composed of bundles of proteins (elastin) which are produced by a number of different cell types including fibroblasts, endothelial, smooth muscle, and airway epithelial cells. These fibers are able to stretch many times their length, and snap back to their original length when relaxed without loss of energy. Elastic fibers include elastin, elaunin and oxytalan.
Connective tissue disease, also known as connective tissue disorder, or collagen vascular diseases, refers to any disorder that affects the connective tissue. The body's structures are held together by connective tissues, consisting of two distinct proteins: elastin and collagen. Tendons, ligaments, skin, cartilage, bone, and blood vessels are all made of collagen. Skin and ligaments contain elastin. The proteins and the body's surrounding tissues may suffer damage when these connective tissues become inflamed.
Multidrug resistance-associated protein 6 (MRP6) also known as ATP-binding cassette sub-family C member 6 (ABCC6) and multi-specific organic anion transporter E (MOAT-E) is a protein that in humans is encoded by the ABCC6 gene. The protein encoded by the ABCC6 gene is a member of the superfamily of ATP-binding cassette (ABC) transporters.
Kindler syndrome is a rare congenital disease of the skin caused by a mutation in the KIND1 gene.
Genetic Alliance is a nonprofit organization, founded in 1986 by Joan O. Weiss, working with Victor A. McKusick, to advocate for health benefits in the accelerating field of genomic research. This organization is a network of over 1,000 disease advocacy organizations, universities, government organizations, private companies, and public policy organizations. They aim to advance genetic research agendas toward health benefit by engaging a broad range of stakeholders, including healthcare providers, researchers, industry professionals, public policy leaders, as well as individuals, families and communities. They create programs using a collaborative approach, and aim to increase efficiency and reduce obstacles in genetic research, while ensuring that voices from the involved disease communities are heard. They also promote public policies to advance healthcare. Genetic Alliance provides technical support and informational resources to guide disease-specific advocacy organizations in being their own research advocates. They also maintain a biobank as a central storage facility for several organizations who otherwise would not have the infrastructure to maintain their own repository.
Keratin 5, also known as KRT5, K5, or CK5, is a protein that is encoded in humans by the KRT5 gene. It dimerizes with keratin 14 and forms the intermediate filaments (IF) that make up the cytoskeleton of basal epithelial cells. This protein is involved in several diseases including epidermolysis bullosa simplex and breast and lung cancers.
Collagen XVII, previously called BP180, is a transmembrane protein which plays a critical role in maintaining the linkage between the intracellular and the extracellular structural elements involved in epidermal adhesion, identified by Diaz and colleagues in 1990.
Fibroblast growth factor receptor 3 (FGFR-3) is a protein that in humans is encoded by the FGFR3 gene. FGFR3 has also been designated as CD333. The gene, which is located on chromosome 4, location p16.3, is expressed in tissues such as the cartilage, brain, intestine, and kidneys.
Epidermolysis bullosa dystrophica or dystrophic EB (DEB) is an inherited disease affecting the skin and other organs.
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Collagen alpha-1(VII) chain is a protein that in humans is encoded by the COL7A1 gene. It is composed of a triple helical, collagenous domain flanked by two non-collagenous domains, and functions as an anchoring fibril between the dermal-epidermal junction in the basement membrane. Mutations in COL7A1 cause all types of dystrophic epidermolysis bullosa, and the exact mutations vary based on the specific type or subtype. It has been shown that interactions between the NC-1 domain of collagen VII and several other proteins, including laminin-5 and collagen IV, contribute greatly to the overall stability of the basement membrane.
Xylosyltransferase 1 is an enzyme that in humans is encoded by the XYLT1 gene.
Nodal modulator 1 is a protein that in humans is encoded by the NOMO1 gene.
Urbach–Wiethe disease is a very rare recessive genetic disorder, with approximately 400 reported cases since its discovery. It was first officially reported in 1929 by Erich Urbach and Camillo Wiethe, although cases may be recognized dating back as early as 1908.
Generalized arterial calcification of infancy (GACI) is an extremely rare genetic disorder. It is caused by mutations in the ENPP1 gene in 75% of the subjects or in mutations in the ABCC6 genes in 10% of patients. However, sometimes individuals affected with GACI do not have mutations in the ENPP1 or ABCC6 gene and in those cases the cause of the disorder is unknown.
Arterial calcification due to deficiency of CD73 (ACDC) is a rare genetic disorder that causes calcium buildup in the arteries and joints of the hands and feet, and other areas below the waist. Although patients exhibiting these symptoms have been identified as early as 1914, this disorder had not been studied extensively until recently. The identification of the specific ACDC gene and mutations occurred in 2011. ACDC is caused by a mutation in the NT5E gene, which prevents calcium-removing agents from functioning,. Patients with this mutation experience chronic pain, difficulty moving, and increased risk of cardiovascular problems. In experiments at the molecular level, treatment with adenosine or a phosphatase inhibitor reversed and prevented calcification, suggesting they could be used as possible treatment methods. There is currently no cure for ACDC, and patients have limited treatment options which focus primarily on removal of blood calcium and improving mobility.
INZ-701 is a recombinant ENPP1 enzyme developed to treat some genetic disorders that prevent normal production of ENPP1. It is developed by Inozyme Pharma.