COMPREHENSIVE REVIEW OF PSEUDOXANTHOMA ELASTICUM: PATHOGENESIS, CLINICAL MANIFESTATIONS, AND THERAPEUTIC STRATEGIES

International Journal of Pharmaceutical Science and Health Care Volume 15, Number 5, 2025 Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738 DOI: 10.5281/zenodo.17349683 Original Article ©2025 RS Publicaon, rspublica[email protected] 132 COMPREHENSIVE REVIEW OF PSEUDOXANTHOMA ELASTICUM: PATHOGENESIS, CLINICAL MANIFESTATIONS, AND THERAPEUTIC STRATEGIES Palnati Poojasri*,Syeda Nishat Fathima Department of Pharmacology, Jayamukhi College of Pharmacy, Narsampet, Warangal506332, Telangana, India Corresponding Author: Palnati Poojasri, Email: [email protected] ARTICLE INFO ABSTRACT ©2025 RS Publicaon Paper ID: IJPHC68ED1543D2532 Received: 2025-09-14 Published: 2025-10-14 DOI: https://dx.doi.org /10.5281/zenodo.17 349683 Page No: 132-145 Pseudoxanthoma elasticum is a rare, autosomal recessive metabolic disorder marked by progressive ectopic mineralization and fragmentation of elastic fibers, primarily affecting the skin, eyes, and vasculature. Pathogenic ABCC6 mutations reduce ATP release from hepatocytes, causing systemic inorganic pyrophosphate deficiency and promoting soft tissue calcification. Clinically, PXE presents with yellowish, lax skin papules, retinal angioid streaks, choroidal neovascularization, and vascular complications including peripheral artery disease and gastrointestinal haemorrhage. Diagnosis combines dermatologic, ophthalmologic, histopathologic, and molecular assessments, with genetic testing confirming ABCC6 variants. Management is largely preventive and supportive, with intravitreal anti-VEGF therapy improving ocular outcomes, cosmetic and surgical interventions addressing skin lesions, and lifestyle modification minimizing cardiovascular risk. Emerging systemic therapies targeting mineralization pathways and genetic counselling offer promise for disease modification, underscoring the importance of multidisciplinary care. Keywords: Pseudoxanthoma elasticum; ABCC6; Ectopic mineralization; Genetic counselling; Rare disease INTRODUCTION: The term pseudoxanthoma elasticum (PXE) was first coined by the French dermatologist Ferdinand-Jean Darier in 1896, inspired by the yellowish discoloration of the skin resembling true xanthomas and the lax, redundant skin folds observed at flexural surfaces. Darier also noted abnormal histological features in affected skin, describing degeneration and fragmentation of elastic fibers. However, earlier in 1881, Rigal had already documented similar skin plaques that were later recognized as characteristic of PXE. The association between the Internaonal Journal of Pharmaceucal Science and Health Care Available online on h p://www.rspublicaon.com/ijphc/index.html ISSN 2249 – 5738 Cite This Paper: Palnati Poojasri and Syeda Nishat Fathima (2025). "Comprehensive review of pseudoxanthoma elasticum, pathogenesis, clinical manifestations and therapeutic strategies ". INTERNATIONAL JOURNAL PHARMACEUTICAL SCIENCE AND HEALTH CARE (IJPHC), vol. 15, no. 5, 2025, pp. 132-145. DOI: https://dx.doi.org/10.5281/zenodo.17349683 International Journal of Pharmaceutical Science and Health Care Volume 15, Number 5, 2025 Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738 DOI: 10.5281/zenodo.17349683 Original Article ©2025 RS Publicaon, rspublica[email protected] 133 cutaneous manifestations and ocular abnormalities—particularly retinal angioid streaks—was established in 1929 by Grönblad and Strandberg, leading to the alternate designation of Grönblad-Strandberg syndrome. [1] PXE is a hereditary, autosomal recessive connective tissue disorder characterized by dystrophic calcification—an abnormal accumulation of calcium and phosphate complexes— within elastic fibers of the skin, eyes, and cardiovascular system. The disease is classified under Online Mendelian Inheritance in Man (OMIM) entry #264800. The condition arises primarily from mutations in the ABCC6 gene located on chromosome 16p13.1, which encodes an ATPbinding cassette transporter protein. This transporter plays a crucial role in maintaining systemic levels of inorganic pyrophosphate (PPi)—a potent inhibitor of soft tissue calcification. Reduced plasma PPi levels are now recognized as a central pathogenic factor in PXE, contributing to ectopic mineral deposition and elastic fiber degeneration. This review, summarize the current understanding of pseudoxanthoma elasticum, emphasizing its clinical spectrum, molecular pathogenesis, diagnostic approaches, and emerging therapeutic developments, with particular focus on the ocular alterations that define the disease’s clinical course. [2] EPIDEMIOLOGY: Pseudoxanthoma elasticum is a rare autosomal recessive disorder with an estimated prevalence of 1 in 25,000 to 1 in 100,000 individuals worldwide. It affects all ethnicities, though South African Afrikaners show higher prevalence due to a founder effect (i.e., higher prevalence in the small group of people from whom Afrikaners descend). PXE exhibits a female predominance, with a female-to-male ratio of approximately 2:1. The average age of onset is 13 years, but manifestations may appear from infancy to late adulthood, peaking between 10 and 15 years. Limited data on allelic frequencies suggest variable expressivity, emphasizing the need for early recognition and diagnosis. [3-4] CLINICAL MANIFESTATIONS: Pseudoxanthoma elasticum is a multisystem disorder primarily affecting the skin, eyes, and cardiovascular system, though other organs may occasionally be involved. [5]  Cutaneous Manifestations: Cutaneous changes are usually the first clinical sign, typically appearing in childhood or early adolescence. These initial lesions consist of small yellowish papules that may coalesce into plaques, resulting in skin laxity and redundancy, particularly in the neck, axillae, antecubital and popliteal fossae, groin, and periumbilical regions. Lesions may also involve oral, vaginal, and rectal mucosae. Over International Journal of Pharmaceutical Science and Health Care Volume 15, Number 5, 2025 Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738 DOI: 10.5281/zenodo.17349683 Original Article ©2025 RS Publicaon, rspublica[email protected] 134 time, the skin develops a characteristic cobblestone, plucked chicken, or Moroccan leather appearance. Some patients exhibit horizontal or oblique mental creases, considered highly specific for PXE. While cutaneous lesions are generally asymptomatic, they may cause cosmetic concerns. Histological examination reveals fragmented and thickened elastic fibers with mineral deposits, which may be present even in clinically normal skin. [6]  Ocular Manifestations: Ocular involvement is a hallmark of PXE and often develops several years after the appearance of skin lesions. The earliest retinal change is peau d’orange, a mottled, orange-peel appearance of the macula caused by dimpling of Bruch’s membrane. Progressive calcification of elastic fibers in this membrane results in angioid streaks, radiating from the optic disc. These streaks can serve as a nidus for choroidal neovascularization, leading to retinal hemorrhages and central vision loss, while peripheral vision typically remains intact. Other ocular findings include optic nerve head drusen and distinctive “comet tail” lesions, which may be pathognomonic. Although highly characteristic, angioid streaks are not exclusive to PXE, also occurring in conditions such as sickle cell disease, thalassemia, and Ehlers-Danlos syndrome. [7]  Cardiovascular Manifestations: Cardiovascular manifestations usually appear later in the disease course and result from calcification of the arterial media and intima, particularly in small and medium-sized arteries. Patients may experience intermittent claudication and peripheral artery disease, while more severe vascular involvement can lead to stroke, transient ischemic attacks, aneurysms, or stenosis of major arteries. Cardiac complications, including angina, myocardial infarction, and mitral valve prolapse, are less frequent but clinically significant. Notably, heterozygous carriers of ABCC6 mutations may also show premature vascular calcification and increased cardiovascular risk. [8]  Gastrointestinal Manifestations: Gastrointestinal (GI) involvement is one of the bettercharacterized extracutaneous manifestations. Calcification and fragility of submucosal vessels, particularly in the stomach and duodenum, may lead to gastrointestinal haemorrhage, presenting as melena, hematemesis, or occult blood in stool. Approximately 10–15% of PXE patients experience significant GI bleeding during their lifetime, which may require hospitalization, blood transfusions, or surgical intervention in severe cases. Rarely, haemorrhage may also occur in the urinary tract, leading to haematuria. International Journal of Pharmaceutical Science and Health Care Volume 15, Number 5, 2025 Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738 DOI: 10.5281/zenodo.17349683 Original Article ©2025 RS Publicaon, rspublica[email protected] 135  Renal Manifestations: Renal involvement is uncommon but has been reported, including vascular calcification within the kidneys. Although most cases do not result in clinically significant renal impairment, careful monitoring is advised in patients with additional risk factors for renal disease. PXE may also cause calcification in other organs, such as the testes, liver, spleen, pancreas, and breasts, although these findings are typically incidental and rarely have functional consequences.  Neurological Manifestations: Neurological complications are rare but serious. PXErelated vascular mineralization can lead to intracranial aneurysms, subarachnoid haemorrhage, and intracerebral haemorrhage. Ischemic cerebrovascular events, including stroke and transient ischemic attacks, have been reported, with some studies suggesting an increased risk compared to the general population. Microangiopathy may also contribute to complications in diabetic patients, further affecting the small cerebral and retinal vessels. [9]  Pulmonary Manifestations: Pulmonary involvement in PXE is not well established but has been documented in some functional studies. Reduced carbon monoxide diffusing capacity has been observed in a subset of patients, suggesting a possible preclinical interstitial lung disease. However, clinically significant lung disease remains rare. PATHOPHYSIOLOGY: Pseudoxanthoma Elasticum is a systemic metabolic disorder characterized by progressive mineralization and fragmentation of elastic fibers within connective tissues, predominantly affecting the mid-reticular dermis, Bruch’s membrane of the eye, and mediumsized arteries. The central pathogenic mechanism involves a deficiency of inorganic pyrophosphate (PPi), a key inhibitor of ectopic calcium phosphate deposition. Under physiological conditions, ABCC6, an ATP-binding cassette transporter expressed primarily in hepatocytes and kidneys, mediates the extracellular release of ATP. Extracellular ATP is hydrolysed by ENPP1 into AMP and PPi. Mutations in ABCC6 reduce ATP efflux, resulting in low circulating PPi levels, which favor hydroxyapatite deposition in elastic fiber–rich tissues. Elastic fibers, composed of elastin and microfibrillar proteins such as fibrillin, undergo fragmentation, clumping, and calcification in PXE. Histologically, these changes are first noted in the mid-dermis, where basophilic, fragmented fibers can be visualized with calcium-specific stains such as von Kossa or alizarin red. International Journal of Pharmaceutical Science and Health Care Volume 15, Number 5, 2025 Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738 DOI: 10.5281/zenodo.17349683 Original Article ©2025 RS Publicaon, rspublica[email protected] 136 In the ocular system, mineralization of Bruch’s membrane leads to angioid streaks, which increase susceptibility to choroidal neovascularization and progressive vision loss. Vascular involvement manifests as calcification of medium-sized arteries, reduced compliance, hypertension, and intermittent claudication, reflecting early-onset arteriosclerosis. PXE is now recognized as a metabolic disease, rather than a purely connective tissue disorder. The predominant expression of ABCC6 in the liver, contrasted with peripheral manifestations, supports a “metabolic hypothesis” in which systemic factors—primarily PPi deficiency—mediate tissue damage. Variants in ENPP1 and GGCX may produce overlapping PXE-like phenotypes, further emphasizing the metabolic contribution. [10] Genotype-phenotype correlations indicate that individuals with mixed ABCC6 genotypes exhibit lower arterial calcification and reduced prevalence of choroidal neovascularization compared to those with truncating mutations. Recent studies also highlight dermal myofibroblast dysregulation and abnormal extracellular matrix organization as potential contributors to PXE pathology, linking cellular matrix remodelling to systemic mineralization. [11] AETIOLOGY AND GENETICS: Pseudoxanthoma elasticum (PXE) is a heritable disorder characterized by progressive mineralization of elastic fibers in the skin, eyes, and cardiovascular system. Approximately 80% of PXE cases are associated with mutations in the ABCC6 gene, located on chromosome 16p13.1, which encodes a transmembrane transporter protein primarily expressed in the liver and, to a lesser extent, in the kidneys. Although mutations have been reported throughout the gene—including missense, nonsense, splice site alterations, and small or large deletions—the inheritance is typically autosomal recessive, with both parents carrying one mutant allele conferring a 25% risk to offspring. Rare autosomal dominant cases have also been described. [12] ABCC6 is a member of the ATP-binding cassette (ABC) transporter family and mediates ATP release from the liver, the main source of circulating pyrophosphate (PPi). Reduced plasma PPi in affected individuals contributes to pathological mineralization in peripheral tissues. While some studies suggested that complete loss of ABCC6 function leads to more severe disease, clinical variability indicates that additional genetic, environmental, and lifestyle factors modify the phenotype. ABCC6 mutations are also linked to premature atherosclerosis, generalized arterial calcification of infancy, and PXE-like manifestations in International Journal of Pharmaceutical Science and Health Care Volume 15, Number 5, 2025 Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738 DOI: 10.5281/zenodo.17349683 Original Article ©2025 RS Publicaon, rspublica[email protected] 137 patients with hemoglobinopathies. In rare cases, PXE phenotypes arise from mutations in other genes, such as ENPP1 or GGCX (encoding γ-glutamyl carboxylase). Initial studies focused on genes involved in elastic fiber synthesis (ELN, FBN1, FBN2, LOX), but linkage analyses excluded these loci. Positional cloning identified ABCC6 as the causative gene. The gene spans 31 exons (~75 kb), producing a 165 kDa protein with three transmembrane domains and two intracellular nucleotide-binding folds. Over 200 distinct mutations have been reported, with two recurrent mutations, p.R1141X and del23-29, accounting for a significant proportion of cases in European and American populations. Mutation analysis allows for clinical confirmation, carrier detection, and presymptomatic diagnosis, though clinical onset is usually between 8 and 12 years of age. [13] Two main hypotheses explain PXE pathogenesis. The metabolic hypothesis proposes that loss of ABCC6 in the liver leads to deficiency of circulating factors that normally inhibit ectopic mineralization, supported by grafting studies in Abcc6-/- mice. The PXE cell hypothesis suggests that ABCC6 deficiency in local cells (fibroblasts or smooth muscle cells) alters extracellular matrix composition and cell-matrix interactions, promoting calcification. Related PXE-like conditions have been observed in patients with vitamin K-dependent coagulation defects. Mutations in GGCX reduce γ-glutamyl carboxylation of matrix Gla protein (MGP), an inhibitor of tissue mineralization, resulting in cutaneous PXE-like lesions. ABCC6 may also influence vitamin K transport, affecting MGP activation and contributing to tissue mineralization. Phenotypic expression of PXE is further modified by genetic polymorphisms (e.g., in SPP1), diet (high calcium and phosphate intake), and oxidative stress. [14] DIAGNOSIS: Diagnosis of PXE requires an integrated approach encompassing clinical, histopathological, and molecular assessments, as universally accepted international guidelines are lacking. Clinically, PXE was identified based on three major criteria—yellowish cobblestone lesions in flexural regions, characteristic histopathologic features in affected skin, and ocular manifestations such as angioid streaks, peau d’orange, or maculopathy in adults over 20 years of age—alongside two minor criteria, including histopathological changes in non-lesional skin and a positive family history. While informative, this framework did not always align with molecular findings, particularly mutations in the ABCC6 gene. In response, a revised semistandardized classification was proposed in 2010, emphasizing a multi-step evaluation comprising dermatologic examination, skin biopsy from affected or lateral neck sites with International Journal of Pharmaceutical Science and Health Care Volume 15, Number 5, 2025 Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738 DOI: 10.5281/zenodo.17349683 Original Article ©2025 RS Publicaon, rspublica[email protected] 138 hematoxylin–eosin, Verhoeff–van Gieson, and von Kossa staining, and detailed ophthalmologic assessment including fundoscopy and, where indicated, fluorescein or indocyanine green angiography and fundus autofluorescence. The presence of characteristic skin lesions typically prompts ABCC6 genetic testing, as approximately 90% of clinically diagnosed PXE patients harbor pathogenic mutations in both alleles. Notably, the mutational spectrum varies across populations, with p.Arg1141* prevalent in Europeans, del23-29 in Northern Europe and the Mediterranean, p.Gly1321Ser in North America, and 2542delG predominantly in Japanese patients, while certain polymorphisms such as p.Arg1268Gln are non-pathogenic, underscoring the need for correlation with clinical findings. [15-16] Table 1. Major and Minor Diagnostic Criteria for PXE Category Major Criteria Minor Criteria Skin Yellowish papules/plaques on lateral neck or flexural areas; OR morphologically altered elastic fibers with fragmentation, clumping, and calcification in a biopsy from affected skin — Eye Peau d’orange of the retina; OR ≥1 angioid streak ≥1 disk diameter (confirmation with angiography if needed) Angioid streak <1 disk diameter; comets; wing signs Genetics Pathogenic mutation in both alleles of ABCC6; OR firstdegree relative meeting definitive PXE criteria Pathogenic mutation in one ABCC6 allele Diagnostic thresholds: i. Definitive PXE: Two or more major criteria from distinct categories ii. Probable PXE: Two major criteria from the same category, or one major plus ≥1 minor criterion from a different category iii. Possible PXE: Single major criterion or ≥1 minor criteria Histopathologically, PXE is defined by fragmented, clumped, and calcified mid-dermal elastic fibers, which are highlighted by Verhoeff–van Gieson and von Kossa stains. Collagen fibers may exhibit splitting, thickening, coiling, or flower-like deformation, although these features are inconsistent. Similar mineralization occurs in Bruch’s membrane of the retina and in arterial, myocardial, and pericardial elastic fibers. Laboratory investigations primarily serve to exclude mimicking conditions, including sickle cell disease, beta-thalassemia, and multiple coagulation factor deficiencies, using International Journal of Pharmaceutical Science and Health Care Volume 15, Number 5, 2025 Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738 DOI: 10.5281/zenodo.17349683 Original Article ©2025 RS Publicaon, rspublica[email protected] 139 haemoglobin profiling and vitamin K–dependent coagulation factor assays. Routine evaluations may include complete blood counts, faecal occult blood testing, urinalysis, and serum lipid, calcium, and phosphate measurements, given the association of PXE with premature atherosclerosis and vascular calcification. Imaging modalities such as echocardiography, computed tomography, and radiography can detect cardiovascular and soft tissue involvement, while ophthalmologic examinations remain pivotal for early detection of retinal abnormalities. In cases where biopsy-confirmed PXE reveals only one or no ABCC6 mutation, additional screening for genes such as GGCX or ENPP1 may be warranted due to possible digenic inheritance. Definitive diagnosis requires two major criteria from distinct categories, whereas probable or possible diagnoses rely on combinations of major and minor criteria. Given the progressive nature of PXE, serial dermatologic and ophthalmologic evaluations are recommended, particularly in younger patients. DIFFERENTIAL DIAGNOSIS: PXE can be differentiated from various dermatologic, hematologic, pyrophosphate pathway, and Bruch’s membrane disorders by combining clinical features, systemic involvement, and targeted genetic testing. [17] Table 2: Differential Diagnosis of PXE by Category Category Condition Key Features: PXE-like Manifestations Distinguishing Features Dermatologic / Connective Tissue Solar elastosis Skin laxity, neck wrinkles Age-related, sunexposed skin; no ABCC6 mutation Late-onset focal dermal elastosis PXE-like papules Rare; localized, no systemic involvement Papillary dermal elastolysis Skin atrophy, papules Histology distinct from PXE Mid-dermal elastolysis Skin wrinkling No systemic involvement International Journal of Pharmaceutical Science and Health Care Volume 15, Number 5, 2025 Available online on http://www.rspublication.com/ijphc/index.html ISSN 2249 – 5738 DOI: 10.5281/zenodo.17349683 Original Article ©2025 RS Publicaon, rspublica[email protected] 140 Acquired PXE (perforating calcific elastosis) Peri-umbilical PXE-like lesions Multiparous women; non-genetic Cutis laxa (GGCX/VKORC1 deficiency) Skin hyperlaxity, PXE-like folds Coagulopathy; leathery lesions D-penicillamine induced PXE-like skin changes Drug history crucial Hematologic Disorders β-thalassemia PXE-like skin, vessels, angioid streaks ABCC6 wild-type; severity varies by thalassemia type Sickle cell disease Retinal PXE-like changes, mild dermal/vascular involvement Prevalence 1–20%; mainly ocular Sickle-thalassemia Combination of above features Rare; requires genetic/hematologic confirmation Pyrophosphate Pathway Disorders General arterial calcification of infancy (GACI) Severe vascular calcification, angioid streaks ENPP1 mutations; infantile onset Arterial calcification due to CD73 deficiency (ACDC) Peripheral arterial calcification NT5E mutations; adults; limited ocular/skin data Vitamin K-dependent protein deficiency PXE-like skin, coagulation defects GGCX/VKORC1 mutations; distinct progression Conditions with Angioid Streaks PXE Skin papules, angioid streaks ABCC6 mutation; systemic features Paget’s disease AS in 6–8% of cases Bone remodeling; lateonset