Pseudoxanthoma Elasticum

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Disease Entity

Disease

Pseudoxanthoma elasticum (PXE) is a rare genetic disease characterized by elastorrhexia, or progressive calcification and fragmentation, of elastic fibers primarily affecting the skin, retina, and the cardiovascular system. [1] [2] [3]

Epidemiology

The reported prevalence of pseudoxanthoma elasticum is about 1:25,000 to 1:100,000.[4][5] The female-to-male ratio is 2:1. 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). The average age of onset is 13 years. However, ages can vary between infancy and the seventh decade of life or older, with a peak in the number of new cases from ages 10-15 years. [1] [2] [3]

Genetics

80% of clinical cases of pseudoxanthoma elasticum have detectable mutations in the ABCC6 gene, on the short arm of chromosome 16 (16p13.1). This condition is usually inherited in autosomal recessive pattern.

There are two other genetic disorders that result in abnormal mineralization that are thought to be on the same phenotypic spectrum as PXE, called Generalized Arterial Calcification of Infancy (GACI) and Arterial Calcification due to Deficiency of CD73 (ADCD). These are the result of mutations in the ENPPI and NT5E genes, respectively. They may have some overlapping features with PXE. [5][6]

Pathophysiology

PXE is associated with mutations in the ABCC6 gene, which encodes an ATP-binding cassette transporter protein localized to the mitochondria-associated membrane (MAM).[7] The gene is expressed predominantly in the liver and kidney. However, in PXE most commonly there is mineralization (accumulation of calcium and other minerals) and fragmentation of the elastic fibers of the mid and deep reticular dermis of skin, Bruch's membrane of the eye, and the blood vessels. The disease’s manifestations are primarily due to an underlying metabolic disorder.[7][8] Studies have found that levels of inorganic pyrophosphate (PPi), which has a role in anti-mineralization, are very low in PXE and therefore allows for the abnormal mineralization to occur in various tissues. [1] [5]

Recent studies have also suggested a microvascular component to the disease. Although there is vascular damage of large blood vessels due to abnormal calcification, studies of capillaries have shown a dilated and distorted structure with overall reduced density in patients with PXE. There may be a correlation to restrictive lung disease as well. [4]

Diagnosis

Clinical findings

Systemic

  • Skin: Pseudoxanthoma elasticum affects the skin first, often in childhood or early adolescence. Small, yellowish papular lesions form and eventually coalesce into larger plaques, and eventually cutaneous laxity develops. The most commonly affected areas are the neck, axillae (armpits), groin, and flexural creases.[3] Skin may become lax and redundant.
  • Gastrointestinal system: Gastrointestinal bleeding is a rare symptom and usually involves bleeding from the stomach.
  • Cardiovascular system: Premature atherosclerosis and calcification can occur in blood vessels. Intermittent claudication induced by exercise is a prominent feature.[9] At later stages, coronary artery disease may develop, leading to angina and myocardial infarction.[10]
  • Neurological system: Cerebral ischemia in PXE is caused by small vessel occlusive disease. Other rare neurological complications may include intracranial aneurysms, subarachnoid and intracerebral hemorrhages.

Ocular

Ocular signs eventually develop in most patients with PXE and are bilateral.

  • Peau d'orange: Eye abnormalities start with this finding that correspond to diffuse mottling of the retinal pigment epithelium in the temporal midperiphery and are not associated with loss of vision
  • Figure 1. Angioid streaks
    Angioid streaks (Figure 1): PXE affects the retina through a dimpling of the Bruch's membrane. Eventually the mineralization of the elastic fibers, loss of elasticity, and enhanced calcification lead to cracks in Bruch's membrane called angioid streaks that radiate out from the optic nerve and surround it concentrically as brownish‐grey irregular lines. The color of the angioid streaks depends on the degree of atrophy of the overlying RPE. Thus, in light‐colored individuals, angioid streaks are red, while in patients who have darker background pigmentation, are usually medium to dark brown. Angioid streaks become progressively darker and at the same time discoloration of RPE occurs. Sometimes angioid streaks are extremely dark and have several bonds between them, giving the appearance of a ‘spider's web’ in the retina. At other times a fibrous connective tissue develops around the angioid streaks, which appears to be vague and light‐colored. Angioid streaks themselves do not cause distortion of vision, even if they cross into the foveal area.[11] [12] [13] [14]
  • Choroidal neovascularization (CNV): The major complication of angioid streaks that can lead to fibrosis and atrophy, resulting in vision loss. The risk of neovascular complications increases with age. [11] [12] [13] [14]
  • Other retinal lesions: pattern dystrophy, drusen of the optic nerve, peripheral “comet tails” lesions, and subretinal fibrosis. A recent series describes an acute retinopathy in which there are features reminiscent of multiple evanescent white dot syndrome (MEWDS) and a uveitic reaction, usually resulting in transient visual decline, although permanent vision loss as been reported. The pathophysiology is yet unknown. [15]
  • Other ocular findings: blue sclera

Classification

  • Dominant type 1, which contains cutaneous changes and the skin becomes thin, delicate and bruises easily. Also, accelerated atherosclerosis mitral valve disease and severe angioid streaks occur (Gröenblad–Strandberg syndrome) with choroidal neovascularization.
  • Dominant type 2, which is characterized by atypical, yellowish, flatter skin papules than in dominant type 1, skin hyperelasticity, mild angioid streaks and blue sclera.
  • Recessive type 1, which is the most common form with intermediate severity. The skin changes are similar to dominant type 1, with mild vascular disease but frequent gastrointestinal bleeding and mild angioid streaks.
  • Recessive type 2 is excessively rare with severe and generalized skin changes, laxity with angioid streaks but without systemic complications.

Differential Diagnosis

Other diseases associated to angioid streaks:

  • Systemic diseases: Pseudoxanthoma elasticum, Paget disease, Acromegaly, Marfan syndrome, Ehlers‐Danlos syndrome, tuberous sclerosis
  • Hemoglobinopathies: Sickle cell anemia, Thalassemia, Spherocytosis
  • A‐Beta‐Lipoproteinemia, hyperphosphatemia, hypercalcinosis, hemochromatosis, homocysteinuria
  • Trauma, Cutaneous calcinosis, Hypertensive coronary disease, Sturge‐Weber syndrome, Neurofibromatosis, Diabetes, Diffuse lipomatosis, Microsomia, Epilepsy, Senile elastosis
  • Lead poisoning, myopia
  • Idiopathic


Other diseases associated to blue sclera:

  • Osteogenesis imperfecta
  • Ehlers-Danlos syndrome (type VI)
  • Cornea plana, peripheral sclerocornea, buphthalmos, keratoconus, keratoglobus, high myopia, ciliary/ equatorial staphyloma, oculodermal melanocytosis, and microcornea, brittle corneas
  • Hallermann-Streiff syndrome, Marfan syndrome, Turner syndrome, Cheney syndrome, Menkes syndrome, Marshall-Smith-Weaver Syndrome (Marshall-Smith Syndrome), Bd syndrome, pyknodysostosis, or ectodermal dysplasia
  • Alkaptonuria
  • Hypophosphatasia
  • Diamond-Blackfan anemia
  • Juvenile Paget disease
  • Recurrent hereditary polyserositis (familial Mediterranean fever)
  • Loey-Dietz Syndrome


Differential diagnosis of angioid streaks:

  • Lacquer cracks (pathologic myopia)
  • Choroidal rupture
  • Toxoplasmosis
  • Histoplasmosis
  • Metastatic choroidal tumor
  • Central serous chorioretinopathy

Diagnosic criteria[5][6]

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 and state that definitive PXE is characterized by:

  • two pathogenic mutations in the ABCC6 gene or
  • ocular findings (angioid streaks > 1 DD or peau d’orange in an individual <20 years of age) together with skin findings
    • characteristic pseudoxanthomatous papules and plaques on the neck or flexural creases
    • diagnostic histopathological changes in lesional skin: calcified elastic fibers in the mid and lower dermis, confirmed by positive calcium stain


Diagnostic procedures

Ocular diagnostic complementary exams:

  • OCT: The areas of chorioretinal atrophy may show a halo of pigment hypertrophy, usually located in the mid‐periphery and show a localized atrophy of the RPE pointing from the lesion towards the posterior pole of the retina like a comet's tail. Examining these lesions by optical coherence tomography (OCT), small intraretinal cysts are observed with a defect of the RPE underneath. Contrary to angioid streaks, these chorioretinal lesions appear to be pathognomonic for pseudoxanthoma elasticum. As these atrophic areas are usually small (average diameter of approximately 125 µm) and located in the mid‐ to outer‐periphery, they do not affect visual function. [1] [2] [3] [7] [8] [16] [9] [10] [11] [12] [13] [14]
  • Fluorescein angiography: Typically, angioid streaks have a ‘window defect’ in fluorescein angiography due to atrophy of RPE adjacent to them. When choroidal neovascularization is present, leakage of fluorescein is evident.
  • Indocyanine green (ICG) angiography is a useful diagnostic tool for angioid streaks in the rare case that fundoscopy and fluorescein angiography cannot confirm the diagnosis. Such occasions involve severe lesions of the RPE, which cause hyperfluorescent lines that are vague or the development of macular CNV. [1] [2] [3] [7] [8] [16] [9] [10] [11] [12] [13] [14]
  • Fundus autofluorescence (FAF): Angioid streaks can show areas of increased, as well as areas of decreased fundus autofluorescence. Focal spots of increased autofluorescence next to angioid streaks, consisting of pigmentations visible on fundus photography, constitute the ‘parastreak phenomenon’. Patterns of fundus autofluorescence in the macular area in patients with pseudoxanthoma elasticum are often similar to those observed in pattern dystrophies. The small chorioretinal atrophies in the mid‐periphery typically show an increased fundus autofluorescence signal and appear hyperfluorescent on fluorescein angiography. Whether this is caused by a drusen‐like substance deposited within the atrophic area combined with a window defect or some similar cause remains to be clarified. Fundus autofluorescence depicts RPE atrophic lesions, which are often more extensive than fundoscopy or fluorescein angiography would suggest. Thus, fundus autofluorescence has been suggested as a good non‐invasive tool to monitor progression of RPE changes secondary to angioid streaks, CNV or alterations of Bruch's membrane in general and predict possible therapeutic outcomes. [1] [2] [3] [7] [8] [16] [9] [10] [11] [12] [13] [14]

Management

General treatment

There is no confirmed treatment that directly interferes with the disease process. Most management relies on treating the specific system that is affected.

Ocular

  • Initially, patients are asymptomatic and no indication for prophylactic treatment is present. People who have PXE can use an Amsler grid to monitor their central vision.
  • The only stage of the disease where therapy for ocular complications is indicated is when choroidal neovascularization has developed. In the early stages, most symptomatic patients complain of a decrease in visual acuity and some develop metamorphopsias, sometimes more disturbing than the associated central scotoma. Usually, central scotoma tend to increase in size if untreated, and subsequently, scarring of the macula occurs. Treatment options for secondary CNV include laser photocoagulation, transpupillary thermotherapy and photodynamic therapy, macular translocation surgery and most commonly, anti‐vascular endothelial growth factor (anti‐VEGF) treatment.

Systemic

  • Cosmetic surgery to remove excessive skin has been used to improve aesthetic appearance in PXE patients but because of the non-life-threatening nature of these changes, should be used with caution.[17] [5]
  • To limit cardiovascular symptoms, reduction of cardiovascular risk factors through lifestyle changes is recommended. 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. [5]
  • Formerly, dietary restriction of calcium was tried with no benefit, and in fact accelerated mineralization in mice. There are a number of potential treatments that are currently being tested or have just undergone testing including magnesium, etidronate, and tissue-nonspecific alkaline phosphatase inhibitors. [1] [2] [3] [7] [8] [16] [9] [10] [11] [12] [13] [14] [17] [5]
  • 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 over come including insuring that the treatment will be long-lasting and reducing the risk of insertional mutagenesis and severe immune reactions.[5]

Prognosis

The prognosis of PXE largely depends on the extent of extracutaneous organ involvement. Patients typically have a normal life span, but acute gastrointestinal hemorrhage, myocardial infarction, or cerebral hemorrhage may be fatal. Spontaneous resolution of skin changes has been reported, but is exceedingly rare.[18]

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Li Q, van de Wetering K, Uitto J (February 2019). "Pseudoxanthoma Elasticum as a Paradigm of Heritable Ectopic Mineralization Disorders: Pathomechanisms and Treatment Development". review. The American Journal of Pathology. 189 (2): 216–225. doi:10.1016/j.ajpath.2018.09.014. PMC 6412714. PMID 30414410.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 Chassaing N, Martin L, Calvas P, Le Bert M, Hovnanian A (December 2005). "Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations". review. Journal of Medical Genetics. 42 (12): 881–92. doi:10.1136/jmg.2004.030171. PMC 1735972. PMID 15894595.
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  4. 4.0 4.1 Stumpf MJ, Mahn T, Steinmetz M, Fimmers R, Pizarro C, Nickenig G, et al. Pseudoxanthoma elasticum- also a microvascular disease. Vasa. 2020;49(1):57-62.
  5. 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 Germain DP (May 2017). "Pseudoxanthoma elasticum". review. Orphanet Journal of Rare Diseases. 12(1): 85.
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  7. 7.0 7.1 7.2 7.3 7.4 7.5 Martin LJ, Lau E, Singh H, Vergnes L, Tarling EJ, Mehrabian M. ABCC6 localizes to the mitochondria-associated membrane. Circ Res. 2012 Aug 17. 111(5):516-20.
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  17. 17.0 17.1 Marconi B, Bobyr I, Campanati A, Molinelli E, Consales V, Brisigotti V, et al. (August 2015). "Pseudoxanthoma elasticum and skin: Clinical manifestations, histopathology, pathomechanism, perspectives of treatment". review. Intractable & Rare Diseases Research. 4 (3): 113–22
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