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Pseudoxanthoma elasticum

Pseudoxanthoma elasticum (PXE) is a rare, progressive, heritable multisystem disorder characterized by ectopic mineralization and fragmentation of elastic fibers in the skin, eyes, and cardiovascular and gastrointestinal systems.^[1] Caused by biallelic pathogenic variants in the ABCC6 gene, which encodes a transmembrane transporter protein, PXE disrupts the regulation of extracellular matrix mineralization, leading to dystrophic changes in elastic tissues.^[1] The condition typically manifests in childhood or early adulthood, with an estimated prevalence of 1 in 25,000 to 1 in 100,000 individuals (with a slight female predominance of approximately 2:1), though underdiagnosis may affect these figures.^[2] Clinically, PXE presents with distinctive skin lesions, such as yellowish papules and plaques on the neck, axillae, and flexural areas, often described as having a "plucked chicken" or cobblestone appearance due to progressive laxity and inelasticity.^[3] Ocular involvement is a hallmark feature, including peau d'orange fundus changes, angioid streaks (red-brown lines radiating from the optic disc), and subretinal neovascularization (affecting 70-86% of patients), which can result in central vision loss; visual impairment occurs in approximately 37% and legal blindness in 15% of patients over age 50.^[4]^[5] Cardiovascular manifestations include premature atherosclerosis, intermittent claudication, and renovascular hypertension, while gastrointestinal complications such as bleeding from fragile vessels occur in approximately 10-15% of cases.^[1] PXE follows an autosomal recessive inheritance pattern, with unaffected carrier parents each having a 25% risk of having an affected child; rare autosomal dominant forms have been reported but are exceptional.^[2] Over 300 mutations in ABCC6 have been identified, with the p.R1141X variant predominant in European populations (>25% of cases).^[5]^[6] Pathophysiologically, ABCC6 dysfunction reduces levels of inorganic pyrophosphate (PPi), a key inhibitor of mineralization, leading to calcium deposition in elastic fibers.^[5] Diagnosis relies on clinical findings, supported by skin biopsy showing fragmented and calcified elastic fibers, ophthalmic imaging (e.g., optical coherence tomography for angioid streaks), and genetic testing to confirm ABCC6 variants.^[1] There is no curative treatment, but management focuses on symptom control: cardiovascular risk reduction with antiplatelet therapy and statins, anti-vascular endothelial growth factor injections for ocular neovascularization, and monitoring for complications.^[4] Emerging therapies aim to restore PPi levels, with ongoing clinical trials (e.g., NCT04868578) investigating pyrophosphate analogs.^[5] Prognosis varies, with life expectancy generally normal but reduced by severe vascular events in some cases.^[3]

Clinical Presentation

Dermatological Features

The dermatological manifestations of pseudoxanthoma elasticum (PXE) primarily involve the development of small, asymptomatic papules measuring 1–5 mm in diameter, which are yellowish on lighter skin tones or skin-colored on darker tones, arranged in a linear or reticular pattern.^[7] These papules often coalesce into larger, circumscribed plaques, imparting a characteristic cobblestone-like or "plucked chicken skin" appearance to the affected areas.^[1] The lesions are typically nonpruritic and do not cause pain, though they may lead to cosmetic concerns due to their visibility.^[8] These skin changes predominantly affect flexural and dependent sites, beginning on the lateral and posterior neck before extending to the axillae, antecubital and popliteal fossae, inguinal region, and periumbilical abdomen.^[7] Mucosal involvement can occur less commonly, with similar papular lesions appearing on the inner aspects of the lower lip or genital areas.^[1] The condition usually manifests in adolescence or early adulthood, with papules emerging in the first or second decade of life and progressing slowly and variably over subsequent years.^[8] As the disease advances, the skin in affected regions becomes progressively lax, redundant, and inelastic, with increased wrinkling and furrowing that accentuates the plaque formation.^[7] This evolution results in a parchment-like texture, reflecting underlying dermal alterations.^[1] Histologically, biopsies reveal clumped, fragmented, and mineralized elastic fibers in the mid-dermis—a process termed elastorrhexis—best visualized with stains such as Verhoeff-Van Gieson for elastic tissue and von Kossa or Alizarin Red for calcium deposition.^[8] These changes underscore the dermal elastic fiber pathology central to PXE's cutaneous presentation.^[7]

Ocular Features

Ocular manifestations are a prominent feature of pseudoxanthoma elasticum (PXE), primarily affecting the retina and choroid due to progressive calcification of elastic fibers in Bruch's membrane. These changes typically emerge in the second or third decade of life, with approximately 70-80% of patients developing significant ocular involvement by age 50.^[9]^[10] Early detection through fundus examination is crucial, particularly in individuals with suggestive dermatological findings, to monitor progression.^[1] The earliest retinal abnormality is often the peau d'orange fundus, characterized by a mottled, orange-peel-like appearance in the temporal macular region, resulting from subtle calcification at the periphery of Bruch's membrane. This precedes the development of angioid streaks, which are hallmark lesions appearing as irregular, reddish-brown lines radiating from the optic disc. These streaks arise from fractures in the calcified Bruch's membrane, mimicking the branching pattern of blood vessels but lying beneath the retinal pigment epithelium.^[1]^[9] Angioid streaks are present in nearly all patients by their 20s and can extend across the fundus, sometimes leading to peripapillary atrophy.^[10] Complications from these structural changes frequently include choroidal neovascularization (CNV) and subretinal neovascularization, which promote leakage, hemorrhage, and subsequent macular degeneration. CNV often manifests as classic subretinal membranes along the streaks, evolving into fibrovascular scars that cause geographic atrophy or disciform lesions in the macula. This progression typically accelerates in the third to fifth decades, resulting in central vision impairment.^[9]^[1] Patients commonly experience reduced visual acuity, starting subtly and potentially progressing to legal blindness in advanced cases, with about 15% risk of severe vision loss. Metamorphopsia, or distorted central vision, arises from macular involvement, while peripheral vision may remain relatively preserved unless extensive atrophy occurs. These symptoms underscore the need for regular ophthalmologic surveillance to assess functional impact.^[10]^[9]

Cardiovascular Features

Pseudoxanthoma elasticum (PXE) is associated with progressive arterial calcification primarily affecting the internal elastic lamina of medium-sized arteries, leading to stenosis and reduced vascular compliance. This manifests as peripheral artery disease (PAD), with a prevalence of approximately 45-48% in affected individuals, often involving the femoral-popliteal and subpopliteal arteries.^[11]^[5] Intermittent claudication, a hallmark symptom of lower limb ischemia, occurs in about 7-8% of patients due to these occlusive changes.^[11]^[12] Hypertension is also common, affecting around 25% of PXE patients, independent of traditional risk factors, and contributes to accelerated vascular stiffness as evidenced by elevated carotid-to-femoral pulse wave velocity (mean 8.1 m/s versus 6.3 m/s in controls).^[11]^[13] Fragmentation and calcification of the elastic lamina in coronary and cerebral arteries increase the risk of premature cardiovascular events. Patients face a heightened incidence of early myocardial infarction and angina, with coronary artery disease reported in 3.8-17% of cases, often presenting before age 50.^[11]^[12] Stroke risk is elevated, with ischemic events occurring in 7-15% of patients and a relative risk 3.6 times higher than in the general population under 65 years.^[12]^[5] These complications arise from intimal thickening and plaque formation, mimicking accelerated atherosclerosis, though distinct from typical lipid-driven disease.^[13] Cardiac involvement in PXE includes fibroelastic thickening of valvular structures, leading to mitral valve prolapse in a subset of patients and diastolic dysfunction suggestive of restrictive cardiomyopathy.^[11]^[12] Echocardiographic findings show prolonged left ventricular deceleration time (mean 187 ms versus 142 ms in controls), indicating impaired relaxation.^[11] Cardiovascular symptoms typically emerge in adulthood, often in the third or fourth decade. These vascular changes can overlap with gastrointestinal bleeding risks through shared elastic fiber pathology in visceral arteries.^[13]

Other Systemic Features

Pseudoxanthoma elasticum (PXE) manifests in the gastrointestinal tract through mucosal fragility, leading to recurrent bleeding that affects approximately 10-15% of patients, often presenting as melena or hematemesis.^[14] Telangiectasias in the gastric and colonic mucosa contribute to this fragility, with endoscopic findings revealing angiodysplastic lesions prone to hemorrhage, particularly in the upper and lower GI tracts.^[15] Diverticula formation in the gastrointestinal wall, resulting from elastic fiber degeneration, has been documented in affected individuals, increasing the risk of perforation or bleeding episodes.^[16] Renal involvement in PXE includes nephrocalcinosis, characterized by calcium deposits in the renal cortex and medulla, which can be detected via imaging and is linked to the disorder's ectopic mineralization process.^[17] This calcification may progress to impair renal function, with reports of reduced glomerular filtration rate in symptomatic cases, alongside associations with kidney stone formation due to altered mineral metabolism.^[18] Glomerulonephritis and renovascular issues have also been observed, though renal complications remain less common than dermatological or ocular features.^[19] Rare systemic manifestations encompass dental anomalies, such as impacted teeth and enamel defects attributable to elastic fiber calcification in oral tissues.^[20] Sensorineural hearing loss has been reported in select patients, potentially stemming from mineralization of auditory structures, while central nervous system calcification is infrequent but evident in autopsy findings of intracranial vessels.^[21]^[22] PXE exemplifies a multisystem disorder with ectopic mineralization affecting connective tissues across organs, exhibiting variable expressivity even among family members sharing the same genetic mutation.^[23] This heterogeneity underscores the need for comprehensive evaluation, as non-classic features like gastrointestinal bleeding may be exacerbated by concurrent cardiovascular fragility.^[1]

Genetics and Pathophysiology

Genetic Causes

Pseudoxanthoma elasticum (PXE) is primarily an autosomal recessive disorder caused by biallelic pathogenic variants in the ABCC6 gene located on chromosome 16p13.11.^[1] This inheritance pattern means that affected individuals inherit one mutated allele from each parent, with parents typically being asymptomatic heterozygous carriers.^[12] Although rare instances of pseudodominant inheritance have been reported in some families, where the disorder appears to follow an autosomal dominant pattern due to high penetrance in successive generations, the vast majority of cases conform to the recessive model.^[24] The ABCC6 gene encodes ATP-binding cassette subfamily C member 6 (ABCC6), a transmembrane transporter protein belonging to the ATP-binding cassette (ABC) transporter superfamily, which is predominantly expressed in the liver and kidneys.^[1] This protein is believed to play a role in regulating extracellular matrix homeostasis, potentially by transporting metabolites that inhibit ectopic mineralization.^[25] To date, more than 400 distinct pathogenic variants in ABCC6 have been identified in PXE patients, encompassing a wide spectrum including missense, nonsense, frameshift, splice-site, and deletion mutations.^[25] Common variants include the nonsense mutation c.3421C>T (p.Arg1141*), which accounts for approximately 30% of alleles in European populations, and large deletions such as the exon 23-29 deletion.^[26] These mutations typically lead to loss of transporter function, disrupting systemic regulation of elastic fiber integrity.^[1] Rare autosomal dominant forms of PXE or PXE-like conditions have been associated with mutations in other genes, such as ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1), which can cause generalized arterial calcification of infancy that progresses to PXE-like features, and GGCX (gamma-glutamyl carboxylase), linked to a PXE-like papular dermatosis with ocular and coagulation abnormalities.^[1] The carrier frequency for ABCC6 mutations in the general population is estimated at approximately 1%, reflecting the disorder's prevalence of around 1 in 50,000 to 100,000 individuals.^[27] Genotype-phenotype correlations exist, with complete loss-of-function mutations (e.g., nonsense or large deletions) generally associated with earlier onset and more severe manifestations compared to missense variants that may retain partial function.^[26]

Pathophysiological Mechanisms

Pseudoxanthoma elasticum (PXE) arises from biallelic mutations in the ABCC6 gene, which encodes a transmembrane ATP-binding cassette transporter primarily expressed in the liver and kidneys. This transporter facilitates the efflux of ATP, which is subsequently hydrolyzed extracellularly by ectonucleotidases such as ENPP1 and CD73 to generate inorganic pyrophosphate (PPi), a potent inhibitor of hydroxyapatite crystal formation. Defective ABCC6 function impairs this process, resulting in reduced systemic PPi levels that fail to suppress ectopic mineralization in soft connective tissues.^[28] Consequently, the low PPi environment promotes the nucleation and deposition of calcium phosphate crystals on elastic fibers, initiating pathological calcification.^[29] The hallmark histopathological feature of PXE is the progressive fragmentation and mineralization of elastic fibers, known as elastoidosis, which occurs in a centripetal pattern affecting multiple tissues. In the dermis, elastic fibers undergo clumping, breakage, and coating with basophilic mineral deposits, leading to thickened, brittle structures visible under electron microscopy as electron-dense granules.^[30] Similarly, in the ocular Bruch's membrane, calcification and fragmentation disrupt the elastic lamina, contributing to structural instability, while in the arterial media, mineralization of internal elastic laminae impairs vascular compliance.^[31] These changes reflect a dynamic process where initial crystal seeding on tropoelastin and microfibrils escalates into widespread fiber degradation and tissue stiffening.^[32] Contributing to elastic fiber degradation are interconnected mechanisms involving oxidative stress, matrix metalloproteinases (MMPs), and dysregulation of vitamin K-dependent proteins. Oxidative stress, evidenced by elevated reactive oxygen species and altered antioxidant enzyme profiles in PXE fibroblasts, induces lipid peroxidation and protein modifications that weaken elastic fibers and promote their breakdown.^[33] Upregulated MMP-2 and MMP-9, secreted by dermal fibroblasts, actively degrade elastin and other extracellular matrix components, accelerating fragmentation in calcified regions.^[34] Furthermore, vitamin K-dependent inhibitors like matrix Gla protein (MGP) exhibit reduced carboxylation in PXE due to low serum vitamin K levels, rendering MGP inactive and unable to sequester calcium ions or inhibit osteogenic signaling, thereby exacerbating mineralization and secondary fiber degradation.^[35] Animal models, particularly Abcc6 knockout mice, faithfully recapitulate PXE pathophysiology at the cellular and tissue levels. These mice develop spontaneous ectopic calcification starting at 5-6 weeks of age, with progressive mineralization and elastic fiber fragmentation in the dermis, Bruch's membrane, and vasculature, mirroring human lesions.^[36] Studies in these models demonstrate that the phenotype is systemic, as parabiosis with wild-type mice halts mineralization, underscoring the role of circulating factors like PPi.^[37] This model has been instrumental in validating therapeutic interventions targeting PPi homeostasis.^[38]

Diagnosis

Clinical Evaluation

The clinical evaluation of suspected pseudoxanthoma elasticum (PXE) begins with a detailed medical history to identify patterns suggestive of this autosomal recessive disorder. Inquiry into family history is essential, focusing on relatives with similar skin lesions, ocular abnormalities, or vascular complications, as affected individuals often have unaffected parents who are carriers, though pseudodominant inheritance has been reported in some pedigrees.^[1] Consanguinity among parents should be specifically assessed, given its association with higher risk in recessive conditions like PXE.^[12] The age of onset is typically elicited next, with skin changes often appearing in the first or second decade of life, retinal features between ages 10 and 30, and vascular symptoms emerging from the second decade onward.^[1] Physical examination follows, prioritizing sites of elastic tissue involvement. Skin assessment reveals characteristic yellowish papules coalescing into cobblestone-like plaques on the neck, axillae, and flexural areas, progressing to redundant, lax skin resembling "plucked chicken" texture in advanced cases.^[12] Retinal fundoscopy is critical to detect angioid streaks—linear, reddish-brown lesions radiating from the optic disc—or the peau d'orange fundus pattern, which may precede visual symptoms.^[1] Vascular evaluation includes palpation of peripheral pulses to identify asymmetry or diminution due to arterial calcification and narrowing, often accompanied by history of intermittent claudication.^[12] Differential diagnosis considers other connective tissue disorders with overlapping features, such as Ehlers-Danlos syndrome (distinguished by joint hypermobility and fragility), cutis laxa (featuring more generalized skin laxity without calcification), and beta-thalassemia (which can mimic PXE through secondary angioid streaks from iron overload).^[1] To quantify disease severity during evaluation, the Phenodex score is employed, a composite system assessing skin (stages S0-S3), ocular (E0-E4), and cardiovascular (C0-C4) involvement, as proposed in the 2007 international consensus conference on PXE.^[39] Patients with suspected PXE based on this initial assessment are referred to specialists for further confirmatory evaluation.^[12]

Confirmatory Tests

Confirmatory tests for pseudoxanthoma elasticum (PXE) are essential to verify the diagnosis after initial clinical evaluation reveals suggestive features such as yellow papular skin lesions, angioid streaks on fundoscopy, or premature vascular calcification.^[40] These objective assessments provide histopathological, genetic, and imaging evidence to distinguish PXE from mimicking conditions like other elastic tissue disorders. Skin biopsy remains a cornerstone for histological confirmation, particularly from affected areas such as the flexural regions of the neck, axillae, or groin. Under light microscopy, the mid- and deep dermis exhibits fragmented, clumped, and basophilic elastic fibers due to calcium deposition, which stains positively with von Kossa for calcium salts and Verhoeff-van Gieson for elastin alterations.^[12]^[40] Electron microscopy further reveals granular electron-dense deposits on elastic fibers, confirming the characteristic mineralization.^[10] This procedure is highly specific when correlated with clinical findings, though it may yield normal results in early or atypical cases. Genetic testing targets mutations in the ABCC6 gene on chromosome 16p13.1, which account for the autosomal recessive inheritance of classic PXE. Sequencing identifies biallelic pathogenic variants, including over 300 reported mutations predominantly missense, with a detection rate exceeding 90% in clinically diagnosed cases.^[12]^[40] Common variants like p.R1141X are prevalent in European populations, and negative results may prompt evaluation of modifier genes such as GGCX or ENPP1 in up to 10% of cases.^[10] Ophthalmologic imaging confirms Bruch's membrane involvement, a hallmark of PXE-related ocular pathology. Fundus photography visualizes angioid streaks as irregular, branching lines radiating from the optic disc, often appearing red, brown, or gray, present in approximately 85-90% of patients, typically developing during the second decade of life.^[10]^[41] Optical coherence tomography (OCT) delineates breaks in Bruch's membrane and hyperreflective subretinal lesions associated with peau d'orange or comet lesions.^[12] Fluorescein angiography highlights late hyperfluorescence and leakage from these streaks, aiding in the detection of choroidal neovascularization.^[40] Cardiovascular assessments evaluate systemic elastic fiber calcification to support diagnosis and assess complications. Echocardiography identifies valvular calcifications or mitral insufficiency, which occur in a subset of patients with cardiac symptoms.^[12] Computed tomography (CT) angiography reveals extensive arterial wall calcification, particularly in femoral and popliteal arteries, with peripheral artery disease prevalence up to 45% as measured by ankle-brachial index.^[10]^[40] Emerging non-invasive techniques, such as dynamic optical coherence tomography (D-OCT) for detecting subclinical dermal mineralization and high-resolution OCT for identifying Bruch's membrane calcification in peau d'orange, offer promising alternatives for early diagnosis as of 2025.^[42]^[43]

Treatment and Management

Symptomatic Therapies

Symptomatic therapies for pseudoxanthoma elasticum (PXE) focus on managing complications across affected organ systems, as no curative treatments exist. These interventions aim to alleviate symptoms, prevent progression of secondary issues, and improve quality of life through targeted supportive measures.^[44]^[1] Ophthalmologic interventions primarily address choroidal neovascularization (CNV), a major cause of vision loss in PXE. Intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections, such as bevacizumab, ranibizumab, and aflibercept, are the standard treatment, stabilizing or improving visual acuity in most patients with long-term follow-up showing recurrence rates around 30% annually. These agents inhibit abnormal vessel growth associated with angioid streaks, with studies demonstrating efficacy comparable to treatments for age-related macular degeneration. Laser photocoagulation, once common, is now considered outdated due to limited efficacy and high recurrence rates exceeding 70%, and is rarely used as first-line therapy.^[44]^[10]^[1] Cardiovascular management emphasizes risk factor control to mitigate arterial complications like peripheral artery disease and accelerated atherosclerosis. Antiplatelet therapy, such as low-dose aspirin, is prescribed cautiously to reduce thrombotic events, while statins like atorvastatin are recommended to lower LDL cholesterol below 1.0 mmol/L and stabilize plaques, supported by guidelines for atherosclerotic disease. Lifestyle modifications, including smoking cessation and supervised exercise therapy, significantly improve walking distance in claudication by 120-210 meters. Interventional procedures like percutaneous coronary intervention or bypass grafting are reserved for severe cases, with limited reports indicating variable success due to fragile vessel walls.^[44]^[1] Dermatological options target cosmetic and functional issues from skin laxity, particularly in flexural areas. Surgical excision, such as rhytidectomy or Z-plasty, provides satisfactory aesthetic outcomes for redundant skin folds but carries risks of poor wound healing and keloid formation, as noted in case series. These procedures are elective and performed by plastic surgeons experienced in connective tissue disorders.^[44]^[1] A multidisciplinary approach is essential, involving coordinated care from ophthalmologists for regular retinal monitoring, cardiologists for vascular assessments, dermatologists for skin management, and genetic counselors for family planning. Annual evaluations help tailor interventions and avoid exacerbating factors like contact sports or nonsteroidal anti-inflammatory drugs. Due to the absence of disease-modifying agents, these therapies remain palliative.^[44]^[1]

Emerging and Experimental Treatments

Research into disease-modifying therapies for pseudoxanthoma elasticum (PXE) has focused on inhibiting ectopic mineralization, particularly through modulation of pyrophosphate (PPi) levels and targeting the underlying ABCC6 deficiency. Etidronate, a bisphosphonate and PPi analog, has shown promise in clinical trials by reducing the progression of arterial and ocular calcifications. In a randomized, double-blind, placebo-controlled trial involving 118 PXE patients, cyclical etidronate (20 mg/kg/day for 2 weeks every 3 months) over 24 months halted the progression of femoral artery calcification compared to placebo, with no significant effect on clinical events like claudication.^[45] A 6-year prospective observational study of 20 PXE patients treated with the same cyclical regimen demonstrated a significant reduction in the annualized progression rate of arterial calcification volume (0.52% vs. 1.95% in untreated historical controls).^[46] For ocular involvement, the same trial reported a lower incidence of subretinal neovascularization events in the etidronate group (5% vs. 18% in placebo).^[47] Ongoing trials, such as the TEMP-PREVENT study (NCT05832580), are evaluating etidronate's effects on ectopic calcification in younger PXE patients (aged 18-40), with primary outcomes including changes in arterial pulse wave velocity and skin histology after 36 months.^[48] Magnesium supplementation has been investigated to inhibit hydroxyapatite crystal formation, based on preclinical evidence in Abcc6-/- mice where elevated dietary magnesium prevented connective tissue mineralization.^[49] A randomized, double-blind, placebo-controlled trial of 44 PXE patients administered 800 mg magnesium oxide daily for 12 months, followed by open-label extension, showed a nonsignificant trend toward reduced skin elastic fiber calcification (36% responders vs. 14% in placebo, p=0.17) and improvement in target skin lesion scores (p=0.069 in open-label phase).^[50] However, the open-label phase revealed increased calcification in both groups, indicating mixed overall efficacy and no reversal of established lesions.^[50] These results suggest magnesium may slow early progression but lacks robust clinical benefits in advanced PXE. The PROPHECI trial (NCT04868578) is an ongoing phase II, double-blind, placebo-controlled, randomized clinical trial evaluating the safety and efficacy of daily oral PPi in treating PXE by reducing or stabilizing ectopic calcification. Involving approximately 50 patients, it assesses changes in arterial calcification volume and skin histology over 18 months, with the protocol detailed as of January 2025.^[51] Gene therapy approaches aim to restore ABCC6 expression to normalize PPi transport and prevent mineralization. Preclinical studies in Abcc6-/- mice using adenovirus-mediated delivery of human ABCC6 to the liver increased plasma PPi levels and significantly reduced ectopic mineralization in the skin and arteries without toxicity. Similarly, pyrophosphate analogs like INZ-701 (recombinant ENPP1-Fc fusion protein) are in phase 1/2 trials for ABCC6 deficiency, elevating PPi to inhibit calcification. The ongoing ENERGIZE trial (NCT05030831) in adults with PXE has reported positive interim data, showing INZ-701 was well-tolerated with dose-dependent increases in PPi and reductions in alkaline phosphatase, key markers of mineralization activity. As of January 2025, the adult study demonstrated positive improvements in vascular and retinal pathology after 48 weeks of treatment.^[52] No serious adverse events related to anti-drug antibodies were noted, supporting advancement to phase 3, with initiation planned for early 2025.^[53] Antioxidants and matrix stabilizers remain in preclinical stages, targeting oxidative stress and extracellular matrix integrity implicated in PXE pathogenesis. In Abcc6-/- mouse models, an antioxidant-enriched diet (including vitamins C and E) reduced oxidative parameters in circulation but did not significantly alter mineralization progression.^[54] Case reports of topical tocopherol acetate and ascorbic acid showed transient skin improvements without impacting calcification.^[54] For matrix stabilization, chemical chaperones like 4-phenylbutyrate have demonstrated reduced calcification in preclinical Abcc6-/- models by enhancing ABCC6 folding and trafficking, though human translation is pending.^[54] These approaches highlight the need for combined therapies to address multifactorial aspects of PXE.

Epidemiology

Prevalence and Distribution

Pseudoxanthoma elasticum (PXE) is estimated to affect 1 in 25,000 to 1 in 100,000 individuals worldwide, though the true prevalence may be higher due to underdiagnosis stemming from the disorder's variable clinical expression and the often subtle nature of early symptoms.^[12]^[1]^[55] Geographic patterns show higher reported rates in certain populations, including Europeans, with a Dutch cohort study estimating a minimum prevalence of 1 in 56,000 based on genotyping common ABCC6 mutations.^[56] Founder effects contribute to elevated occurrence in specific communities, such as the South African Afrikaner population, where a shared ancestral mutation has led to increased disease frequency.^[57]^[58] The disorder exhibits an equal sex distribution in some studied cohorts, such as in Finland, although slight female predominance (approximately 2:1) is noted in broader estimates.^[59] Incidence data from population-based registries indicate rates around 0.08 per 100,000 person-years, with ongoing efforts through resources like the PXE International Clinical Data Registry providing further insights into global occurrence.^[60]^[1]

Associated Risk Factors

Pseudoxanthoma elasticum (PXE) is primarily associated with biallelic mutations in the ABCC6 gene, with homozygous mutations representing a key genetic risk factor for disease manifestation due to complete loss of functional ABCC6 protein, which is essential for preventing ectopic mineralization.^[61] Compound heterozygosity, involving two different pathogenic ABCC6 variants, also drives PXE but can lead to increased phenotypic severity and variability in organ involvement compared to homozygous cases, as the combined effects of distinct mutations may disrupt protein function more heterogeneously.^[62] These genetic risks underscore the autosomal recessive inheritance pattern, where carriers of a single mutation typically remain asymptomatic but contribute to familial transmission.^[1] Environmental factors further modify PXE expression by accelerating complications in genetically predisposed individuals. Smoking exacerbates vascular pathology, promoting premature atherosclerosis and increasing the risk of cardiovascular events such as peripheral artery disease in PXE patients.^[63] Similarly, diets high in phosphate, often from excessive dairy consumption or phosphate additives, enhance soft tissue calcification, worsening dermal and ocular manifestations by elevating systemic phosphate levels that interact with ABCC6 deficiency.^[64] Comorbid conditions can amplify PXE severity, particularly through synergistic effects on vascular integrity. Diabetes mellitus worsens cardiovascular outcomes in PXE by promoting additional endothelial dysfunction and calcification, creating a reciprocal aggravation of arterial complications.^[65] Pregnancy poses specific risks, including heightened potential for gastrointestinal bleeding due to hemodynamic stress on fragile, calcified vessels in the gut, though overall maternal and fetal outcomes are often favorable with close monitoring.^[66] Ethnic variations influence PXE risk through differences in ABCC6 mutation prevalence and founder effects. For instance, certain populations, such as those of Northern European descent, exhibit higher frequencies of specific mutations like R1141X, elevating carrier rates and thus disease incidence compared to Asian or mixed-ancestry groups where variant spectra differ.^[67] These disparities highlight the role of population genetics in modulating overall risk profiles.^[68]

History

Early Descriptions

The earliest clinical observations of what is now recognized as pseudoxanthoma elasticum (PXE) focused on distinctive skin lesions resembling xanthomas. In 1881, French dermatologist Dominique Rigal reported a case of diffuse, yellowish, plaque-like skin changes on the neck and trunk, initially interpreted as a form of xanthelasma or cheloid, marking the first documented description of PXE cutaneous manifestations.^[69] Ocular involvement was independently noted shortly thereafter through reports of unusual retinal abnormalities. In 1889, British ophthalmologist Robert Walter Doyne described irregular, vessel-like streaks radiating from the optic disc in a patient with retinal hemorrhages, later termed "angioid streaks" by Hermann Jakob Knapp in 1892 due to their resemblance to blood vessels; these were among the initial recognitions of PXE-related fundus changes, though not yet linked to skin findings.^[70] The condition received its definitive name from French dermatologist Ferdinand-Jean Darier, who in 1896 detailed characteristic yellowish papules and lax skin on the flexural areas, along with histological evidence of fragmented and calcified elastic fibers in the dermis—distinguishing it from true xanthomas and highlighting the elastic tissue pathology.^[7] Darier coined the term "pseudoxanthoma elasticum" in 1896 to reflect the pseudo-xanthomatous appearance and underlying elastic fiber degeneration, a nomenclature solidified by 1898 through further histopathological confirmation.^[69] Early 20th-century reports revealed initial diagnostic confusion with lipid storage disorders like xanthomatosis due to the yellow papules, but by the 1900s, accumulating evidence shifted recognition toward a primary disorder of elastic tissues, with vascular fragility emerging as a key feature.^[7] Case reports from the late 19th and early 20th centuries described individual features of the condition, such as skin changes and ocular abnormalities. A significant advancement came in 1929, when Elsa Grönblad and James Strandberg first linked PXE skin lesions to angioid streaks, establishing the association between dermatological and ocular manifestations. Cardiovascular symptoms, including gastrointestinal bleeding and peripheral arterial disease, were recognized in subsequent reports, solidifying PXE as a multisystem entity by the mid-20th century.^[69] These observations laid the groundwork for later genetic investigations.

Key Developments and Research Milestones

In the 1970s, advancements in electron microscopy provided critical insights into the pathophysiology of pseudoxanthoma elasticum (PXE), identifying calcification of elastic fibers as the central pathological feature. Studies using electron microscopy demonstrated that these calcifications initiated centrally within the elastic fibers and progressively extended to their periphery, confirming the role of mineral deposition in tissue degeneration.^[71] A major breakthrough occurred in 2000 when the International PXE Consortium, in collaboration with researchers, identified mutations in the ABCC6 gene as the primary cause of PXE, facilitating the development of genetic diagnostic tools. This discovery, reported in seminal publications, established ABCC6 as an ATP-binding cassette transporter essential for preventing ectopic mineralization, enabling precise molecular confirmation of the disorder. During the 2010s, clinical research progressed with trials evaluating potential therapies to mitigate mineralization, including etidronate and magnesium supplementation. The Treatment of Ectopic Mineralization in PXE (TEMP) trial demonstrated that cyclical etidronate reduced progression of arterial wall calcification in adults with PXE over 24 months, marking a key step toward disease-modifying interventions. Concurrently, a phase II trial of magnesium oxide supplementation in PXE patients aimed to assess its impact on vascular health, highlighting nutritional strategies as adjunctive options. Additionally, patient registries were expanded during this decade, with PXE International enhancing its biorepository to support longitudinal studies and genotype-phenotype correlations.^[72]^[73]^[74] From 2020 to 2025, ongoing phase I/II trials of INZ-701, an enzyme replacement therapy targeting pyrophosphate levels, showed promising safety and efficacy in reducing ectopic mineralization in adults with ABCC6 deficiency-associated PXE, with positive topline data reported in 2024. Emerging preclinical research on gene editing techniques, including CRISPR-based approaches in animal models, has advanced toward potential liver-directed therapies to restore ABCC6 function. Furthermore, improvements in prenatal counseling have been emphasized, with genetic testing enabling better risk assessment and family planning options such as prenatal diagnosis for at-risk pregnancies.^[75]^[44]^[76]^[77]

References

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Pseudoxanthoma elasticum – Genetics, Pathophysiology, and ...
Apr 17, 2025 · In this review, we summarize the current knowledge on PXE with a focus on ocular alterations and present current treatment approaches under ...<|control11|><|separator|>
[10]
Characterization of Cardiovascular Involvement in Pseudoxanthoma ...
The article focuses on the cardiovascular phenotype of patients with pseudoxanthoma elasticum (PXE), caused by homozygous mutations in the ABCC6 gene, and ...
[11]
Pseudoxanthoma elasticum - Orphanet Journal of Rare Diseases
May 10, 2017 · The current treatment approach for slowing or limiting the cardiovascular manifestations of PXE is based on the reduction of cardiovascular ...<|control11|><|separator|>
[12]
Cardiovascular Manifestations of Pseudoxanthoma Elasticum - PMC
Jul 1, 2025 · Associated manifestations include narrowing of small- to medium-sized arteries, contributing to peripheral vascular disease, hypertension, ...
[13]
Pseudoxanthoma elasticum and angioid streaks: A review of 106 ...
Ten patients with pseudoxanthoma elasticum and two with angioid streaks alone had episodes of gastrointestinal bleeding, some of which were serious. In ...
[14]
Pseudoxanthoma elasticum: A review of 86 cases in China - NIH
Pseudoxanthoma elasticum: A review of 86 cases in China. Yan Li. Yan Li. 1 Key ... gastrointestinal bleeding. Statistical analysis has indicated that the ...
[15]
https://pmc.ncbi.nlm.nih.gov/articles/PMC4214240/
[16]
Pseudoxanthoma elasticum and nephrocalcinosis: Incidental finding ...
Pseudoxanthoma elasticum (PXE) is an inherited disorder characterized by generalized fragmentation and progressive calcification of elastic tissue.
[17]
Pseudoxanthoma Elasticum: An Interesting Model to Evaluate ... - NIH
Jan 10, 2020 · To our knowledge, in patients with PXE, kidney disease mainly presents as nephrocalcinosis, glomerulonephritis, renovascular hypertension, and ...
[18]
Pseudoxanthoma Elasticum and Cardiorenal Disease: A Case Report
Pseudoxanthoma elasticum represents a rare disease that can involve renal problems. ... nephrocalcinosis, glomerulonephritis, renovascular hypertension, ureteral ...
[19]
Dental impactions related to pseudoxanthoma elasticum - PubMed
Pseudoxanthoma elasticum is a rare genetic disorder causing ... Dental impactions related to pseudoxanthoma elasticum. J Oral Maxillofac Surg ...
[20]
Characterization of hearing-impairment in Generalized Arterial ...
Jul 19, 2022 · ... pseudoxanthoma elasticum, and hearing loss (HL) [1, 2]. To date ... Dental and Craniofacial Research, and the National Institute on ...
[21]
https://ojrd.biomedcentral.com/articles/10.1186/s13023-022-02410-w
[22]
Entry - #264800 - PSEUDOXANTHOMA ELASTICUM; PXE - OMIM
Generalized arterial calcification of infancy-2 (GACI2; 614473) is an allelic disorder, also caused by homozygous or compound heterozygous mutation in the ABCC6 ...Missing: dental hearing
[23]
Entry - #264800 - PSEUDOXANTHOMA ELASTICUM; PXE - OMIM
Pseudoxanthoma elasticum is an inherited multisystem disorder that is associated with accumulation of mineralized and fragmented elastic fibers in the skin, ...
[24]
The Purinergic Nature of Pseudoxanthoma Elasticum - MDPI
PXE first appeared to be inherited as both autosomal recessive (AR) and autosomal dominant (AD) forms. The first attempt at defining the mode of transmission ...
[25]
Mutation spectrum in the ABCC6 gene and genotype–phenotype ...
Jan 19, 2017 · Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder caused by variants in the ABCC6 gene. Ectopic mineralization of connective tissues leads to ...
[26]
Pseudoxanthoma Elasticum (PXE) - DermNet
Pseudoxanthoma elasticum (PXE) refers to a group of rare inherited disorders that affect the elastic connective tissue of the skin, eyes, and blood vessels.
[27]
ABCC6, Pyrophosphate and Ectopic Calcification - PubMed Central
Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization disorders.
[28]
https://pmc.ncbi.nlm.nih.gov/articles/PMC8123679/
[29]
https://doi.org/10.1073/pnas.1319582110
[30]
https://doi.org/10.5582/irdr.2015.01014
[31]
https://doi.org/10.1016/j.exer.2012.09.009
[32]
New insights into the pathogenesis of pseudoxanthoma elasticum ...
Many of the alterations observed in PXE could be explained by oxidative stress, for instance ECM remodeling. We found a correlation between genotype and age of ...
[33]
Fibroblasts' secretome from calcified and non-calcified dermis ... - NIH
May 16, 2024 · Pseudoxanthoma elasticum: oxidative stress ... Elevated circulating levels of matrix metalloproteinases MMP-2 and MMP-9 in pseudoxanthoma ...
[34]
Matrix gla protein and alkaline phosphatase are differently ... - PubMed
Mineralization of elastic fibers in pseudoxanthoma elasticum (PXE) has been associated with low levels of carboxylated matrix gla protein (MGP), ...
[35]
Disruption of Abcc6 in the mouse: novel insight in the pathogenesis ...
The phenotype of the Abcc6−/− mouse partly resembles the pathology of PXE patients: Abcc6−/− mice spontaneously developed calcification and elastic fibre ...
[36]
https://academic.oup.com/hmg/article/14/13/1763/621045
[37]
Pseudoxanthoma elasticum: Clinical phenotypes, molecular ...
Pseudoxanthoma elasticum (PXE), a prototype of heritable multi-system disorders, is characterized by pathologic mineralization of connective tissues.
[38]
Mutation spectrum in the ABCC6 gene and genotype–phenotype ...
Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder caused by variants in the ABCC6 gene. Ectopic mineralization of connective tissues leads to ...Missing: physical exam
[39]
Pseudoxanthoma Elasticum Workup - Medscape Reference
Jun 20, 2022 · Skin biopsy can confirm the diagnosis of PXE and is most accurate when obtained from an area of primary skin changes.Missing: confirmatory | Show results with:confirmatory
[40]
Therapy of Pseudoxanthoma Elasticum: Current Knowledge and ...
In this review, we summarize the broad spectrum of treatment options for PXE, focusing on currently available clinical options, the latest research and ...
[41]
Etidronate halts systemic arterial calcification in pseudoxanthoma ...
Etidronate halts systemic arterial calcification in pseudoxanthoma elasticum. •. Further studies must assess the efficacy of etidronate on clinical outcomes.
[42]
Cyclical Etidronate Reduces the Progression of Arterial ... - MDPI
Aug 7, 2024 · Cyclical etidronate administered to patients with PXE in the regimen used here is safe and associated with a reduced progression of arterial ...
[43]
Etidronate for Prevention of Ectopic Mineralization in Patients With ...
Mar 5, 2018 · In patients with PXE, etidronate reduced arterial calcification and subretinal neovascularization events but did not lower femoral 18 fluoride sodium positron ...
[44]
Study Details | NCT05832580 | The Prevention of Systemic Ectopic ...
The goal of this randomized clinical trial is to assess the effect of etidronate on ectopic calcification in relatively young patients with Pseudoxanthoma ...
[45]
Elevated Dietary Magnesium Prevents Connective Tissue ...
In this study, we demonstrate that elevated dietary magnesium prevents connective tissue mineralization in Abcc6−/− mice, a model of PXE. Specifically, although ...
[46]
https://www.mdpi.com/2077-0383/13/16/4612
[47]
https://www.jacc.org/doi/10.1016/j.jacc.2017.12.062
[48]
Inozyme Pharma Announces Positive Interim Data for INZ-701 in ...
Jan 10, 2025 · Positive interim results in infants and young children with ENPP1 Deficiency showed improvements from baseline in multiple measures of disease.
[49]
Therapy of Pseudoxanthoma Elasticum: Current Knowledge ... - MDPI
Gene Therapy and ABCC6 Targeted Therapy ... Premature Termination Codon Read-Through in the ABCC6 Gene: Potential Treatment for Pseudoxanthoma Elasticum.
[50]
Pseudoxanthoma Elasticum - parkwoodskinclinic.com
Mar 2, 2024 · However, the condition may be underdiagnosed due to its variable expression and the subtlety of its early symptoms. ... The differential diagnosis ...
[51]
The prevalence of pseudoxanthoma elasticum - PubMed
Conclusion: The prevalence of PXE is at least 1 per 56,000 meaning that there would be at least 307 affected individuals in the Netherlands that may benefit ...
[52]
Evidence for a founder effect for pseudoxanthoma elasticum in the ...
Whereas PXE has been identified in all ethnic groups studied to date, the prevalence of this disease in various populations is uncertain, although often assumed ...<|separator|>
[53]
ABCC6 and Pseudoxanthoma Elasticum: The Face of a Rare ... - MDPI
The four most frequent PXE mutations in Caucasians are R1141X, exon 23–29 deletion, R1164X, and Q378X. R1141X is in exon 24 and accounts for about 30% of all ...
[54]
Various vascular malformations are prevalent in Finnish ...
May 7, 2022 · Results. The prevalence of PXE in Finland was 1:260,000 with equal sex distribution. Patients with high conventional cardiovascular risk had ...<|separator|>
[55]
Epidemiology of Angioid Streaks and Pseudoxanthoma Elasticum ...
Jul 19, 2023 · The incidence rate of PXE was 0.08 per 100 000 person-years for the total population, which corresponded to 0.05 per 100 000 person-years after ...
[56]
ABCC6 and Pseudoxanthoma Elasticum: The Face of a Rare ...
Jul 11, 2017 · PXE is primarily caused by mutations in the ABCC6 gene. The ABCC6 gene encodes the trans-membrane protein ABCC6, which is highly expressed in ...
[57]
Pseudoxanthoma Elasticum Is a Recessive Disease Characterized ...
Pseudoxanthoma Elasticum Is a Recessive Disease Characterized by Compound Heterozygosity ... severity as well as in the number of organ systems involved.
[58]
The vascular phenotype in Pseudoxanthoma elasticum and related ...
Feb 12, 2013 · Pseudoxanthoma elasticum (PXE) is an inherited disease (OMIM 264800) characterized by elastic fiber fragmentation and calcification in various soft conjunctive ...
[59]
PSEUDOXANTHOMA ELASTICUM: DIAGNOSTIC FEATURES ...
The characteristic eye finding is the angioid streaks present in essentially all patients after 20 years of the disease [1, 12]. However, the earliest ocular ...
[60]
Pseudoxanthoma elasticum: About a case report - Endocrine Abstracts
Conclusion: The association of PXE and diabetes can be harmful because of cardiovascular complications which can be worsening in a reciprocal way. The cause of ...
[61]
Pseudoxantoma elasticum, as a repetitive upper gastrointestinal ...
... hemorrhage during her previous pregnancy in her history. The examination of ... Pseudoxanthoma elasticum 2004. J Am Acad Dermatol. 2004;51:S13–S14. doi ...
[62]
A Streamlined, Ethnicity‐based Mutation Detection Strategy - PMC
To date close to 300 distinct ABCC6 mutations associated with PXE have been disclosed in various populations (for reviews see Refs. 16, 17). The mutations ...
[63]
Evidence for a founder effect for pseudoxanthoma elasticum in the ...
The most common variant accounted for 53% of the PXE alleles, whereas other mutant alleles appeared at lower frequencies ranging from 3% to 12%. Haplotype ...Missing: variations | Show results with:variations
[64]
Pseudoxanthoma elasticum - PMC - PubMed Central
May 10, 2017 · Pseudoxanthoma elasticum (PXE) is a genetic metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene.
[65]
Angioid Streaks - EyeWiki
Sep 18, 2025 · Angioid streaks were first reported in 1889 by Doyne and the term "angioid streaks" was first used by Knapp in 1892. Angioid streaks appear ...
[66]
Light and Electron Microscopic and Element Analysis of ...
Under the electron microscope elastic fibers showed characteristic calcifications, which obviously started in the center and extended to the margin of the fiber ...
[67]
Etidronate for Prevention of Ectopic Mineralization in Patients With ...
Mar 13, 2018 · Here, we report the results of the Treatment of Ectopic Mineralization in Pseudoxanthoma elasticum (TEMP) trial in which we set out to ...
[68]
https://pubmed.ncbi.nlm.nih.gov/12384774/
[69]
About PXE International
PXE International was founded in 1995 to promote research and support individuals affected by pseudoxanthoma elasticum (PXE). We work on behalf of individuals ...
[70]
Inozyme Pharma Announces Positive Topline Data from Ongoing ...
Apr 8, 2024 · Inozyme Pharma Announces Positive Topline Data from Ongoing Phase 1/2 Trials of INZ-701 in Adults with ABCC6 Deficiency (PXE) and ENPP1 ...
[71]
A Single Variant Journey Through Pseudoxanthoma Elasticum's ...
Aug 2, 2025 · There is currently no cure for PXE. Symptomatic treatment focuses on managing specific complications and includes therapies such as vascular ...
[72]
Pseudoxanthoma Elasticum: for professionals - Gene Vision
Jun 3, 2024 · Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic ...Missing: counseling | Show results with:counseling