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Introduction: Pseudoxanthoma elasticum (PXE) is an autosomal recessive ectopic calcification disorder clinically affecting the skin, eyes, and vascular system. Most cases of PXE are caused by inactivating pathogenic variants in the ABCC6 gene encoding a hepatic transmembrane efflux transporter, which facilitates the extracellular release of ATP, the precursor of inorganic pyrophosphate (PPi), a potent endogenous inhibitor of calcification. Pathogenic variants in GGCX, encoding γ-glutamyl carboxylase required for activation of vitamin K-dependent coagulation factors as well as matrix Gla protein (MGP) and Gla-rich protein (GRP), two inhibitors of ectopic calcification, have also been reported to cause cutaneous changes like those seen in PXE. While ectopic calcification in ABCC6 deficiency has been associated with reduced plasma levels of PPi due to loss of ABCC6 transport activity in the liver, plasma PPi levels have not been reported in patients with GGCX-associated phenotypes. Methods: We analyzed five patients from three unrelated families on their clinical, laboratory, and molecular findings who carry biallelic variants in GGCX and present with phenotypic characteristics associated with PXE. The variants were identified using a next-generation sequencing panel consisting of 29 genes associated with ectopic calcification. Results and conclusion: This study demonstrates that in addition to ABCC6, GGCX variants can cause the PXE phenotype, expanding PXE and perhaps other heritable ectopic calcification disorders' clinical and genetic heterogeneity. The results also show that the plasma concentrations of PPi in these patients are not reduced compared to healthy control individuals, suggesting that plasma PPi does not govern ectopic calcification in GGCX deficiency. [ABSTRACT FROM AUTHOR]

Germline mosaicism in autosomal recessive disorders is considered a rare disease mechanism with important consequences for diagnosis and patient counseling. In this report, we present two families with PXE in which paternal germline mosaicism for an ABCC6 whole-gene deletion was observed. The first family further illustrates the clinical challenges in PXE, with a typical PXE retinopathy in an apparently heterozygous carrier parent. A systematic review of the literature on gonadal mosaicism in autosomal recessive genodermatoses revealed 16 additional patients. As in most reported families, segregation analysis data are not mentioned, and this may still be an underrepresentation. Though rare, the possibility of germline mosaicism emphasizes the need for variant verification in parents and sibs of a newly diagnosed proband, as it has significant implications for genetic counseling and management.

Background: Pseudoxanthoma elasticum (PXE), a rare genetic disorder presenting with slowly progressing calcification of various tissues, including the arteries, is caused by mutations in the ABCC6 gene that lead to the reduction of pyrophosphate, a natural inhibitor of calcification. We showed that, compared to a placebo, the cyclical administration of etidronate, a stable pyrophosphate analog, significantly reduced arterial calcification assessed by low-dose CT scans after one year. The aim of the present prospective, single center, observational cohort study was the assessment of the efficacy and safety of cyclical etidronate in patients treated for periods longer than one year. Methods: Seventy-three patients were followed for a median of 3.6 years without etidronate and 2.8 years with etidronate, and each patient served as their own control. Results: The median absolute yearly progression of total calcification volume during the period with etidronate (388 [83–838] µL) was significantly lower than that without etidronate (761 [362–1415] µL; p < 0.001). The rates of the relative progression of arterial calcification were 11.7% (95% CI: 9.6–13.9) without etidronate compared to 5.3% (95% CI: 3.7–7.0) with etidronate, after adjustment for confounders. Conclusions: The cyclical administration of etidronate for nearly 3 years significantly reduced the progression rate of arterial calcification in patients with PXE with pre-existing calcifications without any serious adverse effects. [ABSTRACT FROM AUTHOR]

Pseudoxanthoma elasticum (PXE) is an autosomal recessive genetic disorder, charac-terized by calcification and destruction of elastic tissue fibers, which will affect the skin, retina, and cardiovascular system. The current case presentation is a 24-years old female with complete loss of lower teeth. The patient was referred to Oral and Maxillofacial surgery clinic at Taibah university Dental College and hospital. She has been diagnosed with PXE following a medical report from her ophthalmologist and clinical examination. The Prosthetic rehabilitation with two dental Implants with high primary stability were inserted. The patient returned to the clinic after 3 months with excellent soft tissue healing. According to prosthetic protocol, an overdenture was fabricated, and the patient was followed for 2 years. The aim of this study report is to extent our knowledge and strategies of dental management for patients with PXE, in addition, to provides a clear understanding for the doctors involved in the management of such a rare cases. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to report an unusual case of pseudoxanthoma elasticum presenting with an inflammatory phenotype associated with atypical and rapidly progressive subretinal fibrosis. Methods: This was an observational case report. Results: A patient with a history of pseudoxanthoma elasticum presented with rapidly progressive subretinal fibrosis, particularly in the left eye, over the course of one year. The patient was noted at presentation to have intraocular inflammation, outer retinal attenuation, multifocal choroiditis-like lesions, and intraretinal fluid (in the absence of obvious clinical or angiographic signs of exudative choroidal neovascular membranes). An ocular inflammatory phenotype was diagnosed, and the patient was treated with a combination of local steroids and systemic corticosteroids/immunomodulatory agents. After initiation of these agents, the patient demonstrated functional and structural improvement, with partial outer retinal reconstitution, decreased intraretinal fluid, and lack of further progression of subretinal fibrosis. Conclusion: This report describes an inflammatory phenotype of pseudoxanthoma elasticum associated with severe and atypical subretinal fibrosis. This case expands upon the currently known spectrum of inflammatory phenotypes associated with pseudoxanthoma elasticum. Treatment with corticosteroids or immunomodulatory treatment should be considered in similar cases. [ABSTRACT FROM AUTHOR]

Introduction: We report a case of pseudoxanthoma elasticum (PXE) with an atypical phenotype likely related to a hypomorphic variant in ABCC6. Case Presentation: A 66-year-old Caucasian female with a history of a maculopathy interpreted as either age-related macular degeneration or a pattern dystrophy underwent a detailed ophthalmic evaluation. Visual acuities were 20/25, OD, and 20/20, OS. Spectral domain optical coherence and fluorescein angiography demonstrated outer retinal disruptions and breaks in retinal pigment epithelium (RPE)/Bruch’s membrane bilaterally, consistent with angioid streaks. A large area of hypo- and hyperautofluorescence extending from the central retina into the peripapillary retina was documented with short-wavelength excitation autofluorescence. The area of hypoautofluorescence, which was much larger on near-infrared excitation, spared the temporal retina. Two-color dark-adapted perimetries documented severe rod sensitivity losses and less severe cone sensitivity abnormalities co-localizing with the RPE abnormalities. No obvious skin findings were observed, and initial dermatologic biopsy was negative. Gene screening identified a pathogenic ABCC6 gene variant c.1552C>T and a previously reported variant of uncertain significance c.1171A>G. A second dermatologic biopsy demonstrated positive findings consistent with PXE. Conclusion: Although this patient had minimal skin findings, this patient had characteristic structural and functional abnormalities of a pattern dystrophy with angioid streaks and histologic evidence of PXE, suggesting compound heterozygous variants involving the hypomorphic ABCC6 c.1171A>G variant. These findings support the pathogenic role of both variants.

Background/Objectives: To assess the frequency, extent, localization and potential progression of optic disc drusen (ODD) and the correlation with the angioid streak (AS) length and retinal atrophy in patients with pseudoxanthoma elasticum (PXE). Methods: This retrospective study included patient data from a dedicated PXE clinic at the Department of Ophthalmology, University of Bonn, Germany (observation period from February 2008 to July 2023). Two readers evaluated the presence, localization, and the extent of the ODD on fundus autofluorescence (FAF) imaging at baseline and the follow-up assessments. Additionally, we measured the length of the longest AS visible at baseline and follow-up and the area of atrophy at baseline, both on FAF. Results: A total of 150 eyes of 75 PXE patients (median age at baseline 51.8 years, IRQ 46.3; 57.5 years, 49 female) underwent retrospective analysis. At baseline, 23 of 75 patients exhibited ODD in a minimum of one eye, resulting in an ODD prevalence of 30.7% in our cohort of PXE patients. Among these, 14 patients showed monocular and 9 binocular ODD that were localized predominantly nasally (46.9%). During the observational period (mean 97.5 ± 44.7 months), only one patient developed de novo ODD in one eye and one other patient showed a progression in the size of the existing ODD. The group of patients with ODD had significantly longer ASs (median 7020 µm, IQR 4604; 9183, vs. AS length without ODD: median 4404 µm, IQR 3512; 5965, p < 0.001). No association with the size of the atrophy was found at baseline (p = 0.27). Conclusions: This study demonstrates a prevalence of ODD of 30.7%. ODD presence is associated with longer ASs (an indicator of the severity and extent of ocular Bruch's membrane calcification), suggesting that ODD formation is tightly related to ectopic calcification—possibly secondary to calcification of the lamina cribrosa. Prospective studies investigating the impact of ODD (in conjunction with intraocular pressure) on visual function in PXE warrant consideration. [ABSTRACT FROM AUTHOR]

Pseudoxanthoma elasticum (PXE) is a rare inherited disorder characterized by progressive disintegration as well as calcification of elastic tissue, resulting in cutaneous, ophthalmic, cardiovascular and other systemic abnormalities. It is an autosomal recessive condition caused by alterations in the ABCC6 gene. We report two cases of pseudoxanthoma elasticum with varying degrees of cutaneous and systemic manifestations of the disease. Both patients had characteristic histopathological changes on skin biopsies and fulfilled the diagnostic criteria for definite PXE. The goal is to demonstrate diverse clinical facets of the disease and to emphasize clinical clues for prompt diagnosis in order to minimize the associated complications. [ABSTRACT FROM AUTHOR]

Purpose: To report a case of recurrent acute retinopathy associated with pseudoxanthoma elasticum and to propose a reappraisal of this entity based on multimodal imaging analysis. Methods: Retrospective case report. High-resolution optical coherence tomography (high-res OCT), ultra-widefield imaging, and widefield swept-source OCT angiography and en face OCT were performed. Results: A man in his 40s diagnosed with pseudoxanthoma elasticum and angioid streaks presented with two distinct episodes of acute retinopathy in his right eye during a one-year follow-up period. Acute retinopathy was characterized by rapid vision loss. High-res OCT showed multifocal hyperreflective lesions splitting the retinal pigment epithelium/Bruch membrane complex and associated with focal choroidal thickening. After the first episode, OCT angiography confirmed the development of macular neovascularization at the site of a previous inflammatory lesion. During the second episode, multimodal images showed findings consistent with epiphenomenon multiple evanescent white dot syndrome (EpiMEWDS). On en face widefield OCT, acute retinopathy was characterized by multiple hyperreflective spots scattered at the posterior pole. Conclusion: Recurrence of acute retinopathy can be observed in patients with pseudoxanthoma elasticum and angioid streaks. Multimodal imaging shows that some lesions of pseudoxanthoma elasticum-associated acute retinopathy closely resemble those of punctate inner choroidopathy/idiopathic multifocal choroiditis. [ABSTRACT FROM AUTHOR]

Pseudoxanthoma elasticum (PXE) is an autosomal recessive condition caused by mutations in the ABCC6 gene. Ocular features include angioid streaks, peau d'orange fundus, and drusen. We report a novel ABCC6 mutation causing PXE in a patient with a mixed phenotype of PXE and retinitis pigmentosa (RP). A 37-year-old female presented with decreased peripheral vision and nyctalopia. Ocular imaging revealed angioid streaks emanating from the optic nerve as well as peripheral pigmentary changes and bone spicules. Genetic testing revealed two mutations in ABCC6 in trans. No other mutation was identified. We present a rare case with ocular findings of PXE and RP in a patient with a novel ABCC6 mutation. The patient presented both with peripheral pigmentary changes and angioid streaks. Further investigation into this novel mutation would be beneficial to determine if the mutation is involved in the RP phenotype. [ABSTRACT FROM AUTHOR]

Pseudoxanthoma Elasticum (PXE) is a rare genetic disorder caused by an autosomal recessive mutation in the ABCC6 gene. It manifests with distinctive clinical symptoms impacting the skin, eyes, and cardiovascular system, along with an elevated risk of cardiovascular diseases. We present a case of a 34-year-old male patient who was initially referred to the rheumatology clinic for evaluation due to suspected large vessel vasculitis. The patient's primary complaint was severe hemifacial pain radiating to the neck and upper limb. Radiological imaging studies unveiled substantial vascular narrowing and collateral vessel formation, prompting further investigation to exclude systemic vasculitis. Intriguingly, the patient also exhibited cutaneous manifestations, which were later confirmed via skin biopsy as consistent with PXE. An ophthalmological examination further revealed the presence of the classic PXE findings of angioid streaks. Given the rarity of PXE and its multifaceted clinical presentation, it can be particularly challenging to diagnose and manage. As such, cases like the one presented here may necessitate a referral to a rheumatologist for evaluation of potential systemic involvement. To provide a comprehensive perspective on PXE, we conducted a systematic review of case reports published in the past decade in English, collected from PubMed, Scopus, and the Directory of Open Access databases. The analysis of these cases will be discussed to shed light on the diversity of PXE's clinical features and the diagnostic and management dilemmas it poses and to facilitate ongoing exploration and research into this intricate condition, ultimately leading to improved care for individuals affected by PXE. [ABSTRACT FROM AUTHOR]

Introduction: We report a case of pseudoxanthoma elasticum (PXE) with an atypical phenotype likely related to a hypomorphic variant in ABCC6. Case Presentation: A 66-year-old Caucasian female with a history of a maculopathy interpreted as either age-related macular degeneration or a pattern dystrophy underwent a detailed ophthalmic evaluation. Visual acuities were 20/25, OD, and 20/20, OS. Spectral domain optical coherence and fluorescein angiography demonstrated outer retinal disruptions and breaks in retinal pigment epithelium (RPE)/Bruch's membrane bilaterally, consistent with angioid streaks. A large area of hypo- and hyperautofluorescence extending from the central retina into the peripapillary retina was documented with short-wavelength excitation autofluorescence. The area of hypoautofluorescence, which was much larger on near-infrared excitation, spared the temporal retina. Two-color dark-adapted perimetries documented severe rod sensitivity losses and less severe cone sensitivity abnormalities co-localizing with the RPE abnormalities. No obvious skin findings were observed, and initial dermatologic biopsy was negative. Gene screening identified a pathogenic ABCC6 gene variant c.1552C>T and a previously reported variant of uncertain significance c.1171A>G. A second dermatologic biopsy demonstrated positive findings consistent with PXE. Conclusion: Although this patient had minimal skin findings, this patient had characteristic structural and functional abnormalities of a pattern dystrophy with angioid streaks and histologic evidence of PXE, suggesting compound heterozygous variants involving the hypomorphic ABCC6 c.1171A>G variant. These findings support the pathogenic role of both variants. [ABSTRACT FROM AUTHOR]

Generalized arterial calcification of infancy (GACI) is a rare autosomal-recessive disease characterized by extensive arterial calcification in infancy, with clinical manifestations such as arterial stenoses and heart failure. The ENPP1 inactivation mutation has been identified as a potential defect in most of the cases of GACI, while mutations in ABCC6 are demonstrated in patients who are genotyped as pseudoxanthoma elasticum and only limited cases of GACI are reported. Whole-exome sequencing was applied for the detection of pathogenic variants. Copy-number variants of pathogenic genes were also evaluated through a bioinformatic process and were further validated by real-time quantitative PCR. In this report, we described the clinical information and treatment of a patient with extensive arterial calcification. We have identified the underlying cause as biallelic mutations in ABCC6 (NM_00117: exon30, c.4223_4227dupAGCTC p.(Leu1410Serfs*56)) and a unique exonic deletion that spans from the first to the fourth exons of ABCC6 (chr16:16313388-16330869)). This discovery was made by utilizing a combined genetic testing approach. With the review of previously reported GACI patients with ABCC6 mutation, our work contributed to enriching the mutation spectrum of GACI and providing further information on this rare form of inherited disorder. [ABSTRACT FROM AUTHOR]

Background: Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease characterized by diminished inorganic plasma pyrophosphate (PPi), a strong calcification inhibitor. In addition to more typical calcification of skin, retina and arterial wall a diminished plasma PPi could lead to other ectopic calcification, such as formation of kidney stones. Objective: To compare the prevalence of kidney stones between PXE patients and hospital controls on computed tomography (CT). Method: Low-dose CT images of PXE patients and controls were assessed by one radiologist, who was blinded for the diagnosis PXE. The number of kidney stones, and the size of the largest stone was recorded. Odds ratios (ORs) for having kidney stone were calculated using multivariable adjusted logistic regression. Results: Our study comprised 273 PXE patients and 125 controls. The mean age of PXE patients was 51.5 ± 15.9 years compared to 54.9 ± 14.2 in the control group (p = 0.04) and PXE patients more often were women (63 vs. 50%, p = 0.013). The prevalence of kidney stones on CT was similar: 6.9% in PXE patients, compared to 5.6% in controls (p = 0.6). In the multivariate analysis adjusting for age and sex, there was no significantly higher odds for PXE patients on having stones, compared to controls: OR 1.48 (95% CI 0.62–3.96). Conclusion: There is no significant difference in the prevalence of incidental kidney stones on CT in PXE patients versus controls. [ABSTRACT FROM AUTHOR]

Inherited retinal diseases (IRDs) are the most common cause of blindness in working-age adults. Macular neovascularization (MNV) may be a presenting feature or occurs as a late-stage complication in several IRDs. We performed an extensive literature review on MNV associated with IRDs. MNV is a well-known complication of Sorsby fundus dystrophy and pseudoxanthoma elasticum. Those with late-onset Stargardt disease may masquerade as exudative age-related macular degeneration (AMD) when MNV is the presenting feature. Peripherinopathies may develop MNV that responds well to a short course of anti-vascular endothelial growth factor (anti-VEGF) therapy, while bestrophinopathies tend to develop MNV in the early stages of the disease without vision loss. Enhanced S-cone syndrome manifests type 3 MNV that typically regresses into a subfoveal fibrotic nodule. MNV is only a rare complication in choroideraemia and rod-cone dystrophies. Most IRD-related MNVs exhibit a favorable visual prognosis requiring less intensive regimens of anti-vascular endothelial growth factor therapy compared to age-related macular degeneration. We discuss the role of key imaging modalities in the diagnosis of MNV across a wide spectrum of IRDs and highlight the gaps in our knowledge with respect to the natural history and prognosis to pave the way for future directions of research. [ABSTRACT FROM AUTHOR]

Purpose: We report a patient with pseudoxanthoma elasticum (PXE) with angioid streaks near a scleral buckle site. Observations: A 46-year-old male with PXE presented for evaluation of blurry vision and was found to have classic PXE findings in both eyes and angioid streaks adjacent to the site of a scleral buckle in his left eye. He underwent multimodal imaging, genetic testing, and intravitreal aflibercept in the right eye. Conclusions and importance: Bruch's membrane is known to be fragile in PXE, and patients are often counseled about the heightened risk of playing contact sports. This report raises the question of whether tension from a scleral buckle in the setting of a calcified and brittle BM may increase the likelihood of angioid streaks near the buckle site. In the setting of retinal detachment, it may be worthwhile to carefully weigh the pros and cons of vitrectomy versus buckle for PXE patients.

Purpose: To investigate the histology of Bruch’s membrane (BM) calcification in pseudoxanthoma elasticum (PXE) and correlate this to clinical retinal imaging. Design: Experimental study with clinicopathological correlation. Subjects and Controls: Six postmortem eyes from 4 PXE patients and 1 comparison eye from an anonymous donor without PXE. One of the eyes had a multimodal clinical image set for comparison. Methods: Calcification was labeled with OsteSense 680RD, a fluorescent dye specific for hydroxyapatite, and visualized with confocal microscopy. Scanning electron microscopy coupled with energy-dispersive x-ray spectroscopy (SEM-EDX) and time-of-flight secondary ion mass spectrometry (TOF-SIMs) were used to analyze the elemental and ionic composition of different anatomical locations. Findings on cadaver tissues were compared with clinical imaging of 1 PXE patient. Main Outcome Measures: The characteristics and topographical distribution of hydroxyapatite in BM in eyes with PXE were compared with the clinical manifestations of the disease. Results: Analyses of whole-mount and sectioned PXE eyes revealed an extensive, confluent OsteoSense labeling in the central and midperipheral BM, transitioning to a speckled labeling in the midperiphery. These areas corresponded to hyperreflective and isoreflective zones on clinical imaging. Scanning electron microscopy coupled with energy-dispersive x-ray spectroscopy and TOF-SIMs analyses identified these calcifications as hydroxyapatite in BM of PXE eyes. The confluent fluorescent appearance originates from heavily calcified fibrous structures of both the collagen and the elastic layers of BM. Calcification was also detected in an aged comparison eye, but this was markedly different from PXE eyes and presented as small snowflake-like deposits in the posterior pole. Conclusions: Pseudoxanthoma elasticum eyes show extensive hydroxyapatite deposition in the inner and outer collagenous and elastic BM layers in the macula with a gradual change toward the midperiphery, which seems to correlate with the clinical phenotype. The snowflake-like calcification in BM of an aged comparison eye differed markedly from the extensive calcification in PXE. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Purpose: We aimed to describe the epidemiology of angioid streaks (AS) and pseudoxanthoma elasticum (PXE), which are rare diseases, using a national claims database. Design: This was a population-based longitudinal cohort study. Participants: A total of 126 million individuals were covered by the universal health coverage system in Japan. Methods: With permission from the Ministry of Health, Labor and Welfare, we accessed all data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan, which contains the nationwide health insurance claims data for 126 million Japanese. We identified individuals with AS and PXE between January 2011 and December 2020. The incidence rates, prevalence, overlap of AS and PXE, and mean age at death were calculated. Main Outcome Measures: The incidence rates and prevalence of AS and PXE. Results: A total of 6598 cases of AS and 1020 cases of PXE were identified during the 10-year study period. The incidence rates of AS and PXE were 0.52 (95% confidence interval, 0.48–0.56) and 0.08 (95% confidence interval, 0.07–0.10) per 100 000 person-years, respectively. On October 1, 2020, the prevalence of AS and PXE was 6.5 (95% confidence interval, 6.38–6.66) and 0.83 (95% confidence interval, 0.78–0.89) per 100 000 persons, respectively. The overlap of AS and PXE was 363 patients. The mean age at death of individuals with AS and PXE was 79.3 ± 0.51 and 77.1 ± 2.68 years, respectively. Conclusion: This is the first population-based study to elucidate the epidemiology of AS and PXE. The mean age of death of both AS and PXE patients was younger than the mean life expectancy of the general Japanese population, thus, appropriate diagnosis and management are important to avoid preventable death. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Pseudoxanthoma elasticum (PXE) is a heritable multisystem ectopic calcification disorder. The gene responsible for PXE, ABCC6, encodes ABCC6, a hepatic efflux transporter regulating extracellular inorganic pyrophosphate (PPi), a potent endogenous calcification inhibitor. Recent studies demonstrated that in addition to the deficiency of plasma PPi, the activated DDR/PARP signaling in calcified tissues provides an additional possible mechanism of ectopic calcification in PXE. This study examined the effects of etidronate (ETD), a stable PPi analog, and its combination with minocycline (Mino), a potent inhibitor of DDR/PARP, on ectopic calcification in an Abcc6-/- mouse model of PXE. Abcc6-/- mice, at 4 weeks of age, before the development of ectopic calcification, were treated with ETD, Mino, or both for 18 weeks. Micro-computed tomography, histopathologic examination, and quantification of the calcium content in Abcc6-/- mice treated with both ETD and Mino revealed further reduced calcification than either treatment alone. The effects were associated with reduced serum alkaline phosphatase activity without changes in plasma PPi concentrations. These results suggest that ETD and Mino combination therapy might provide an effective therapeutic approach for PXE, a currently intractable disease. [ABSTRACT FROM AUTHOR]

(1) Background: Genodermatoses are a clinically and genetically heterogenous group of inherited skin disorders. Diagnosing inherited skin diseases is a challenging task due to their rarity and diversity. Dermoscopy is a non-invasive, easily accessible, and rapid tool used in dermatology not only for diagnostic processes but also for monitoring therapeutic responses. Standardized terminologies have been published for its proper use, reproducibility, and comparability of dermoscopic terms. (2) Methods: Here, we aimed to investigate dermoscopic features in various genodermatoses by conducting a systematic review and comparing its results to our own findings, data of patients diagnosed with genodermatoses at the Department of Dermatology, Venereology and Dermatooncology, Semmelweis University. (3) Results: Our systematic search provided a total of 471 articles, of which 83 reported both descriptive and metaphoric dermoscopic terminologies of 14 genodermatoses. The literature data were then compared to the data of 119 patients with 14 genodermatoses diagnosed in our department. (4) Conclusion: Dermoscopy is a valuable tool in the diagnosis of genodermatoses, especially when symptoms are mild. To enable the use of dermoscopy as an auxiliary diagnostic method, existing standardized terminologies should be extended to more genodermatoses. [ABSTRACT FROM AUTHOR]

Previous studies revealed a link between inflammation and overactivation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling in syndromes associated with aging. Pseudoxanthoma elasticum (PXE), a rare autosomal-recessive disorder, arises from mutations in ATP-binding cassette subfamily C member 6 (ABCC6). On a molecular level, PXE shares similarities with Hutchinson–Gilford progeria syndrome, such as increased activity of senescence-associated- beta-galactosidase or high expression of inflammatory factors. Thus, this study's aim was the evaluation of activated STAT3 and the influence of JAK1/2-inhibitor baricitinib (BA) on inflammatory processes such as the complement system in PXE. Analysis of activation of STAT3 was performed by immunofluorescence and Western blot, while inflammatory processes and complement system factors were determined based on mRNA expression and protein level. Our results assume overactivation of JAK/STAT3 signaling, increased expression levels of several complement factors and high C3 protein concentration in the sera of PXE patients. Supplementation with BA reduces JAK/STAT3 activation and partly reduces inflammation as well as the gene expression of complement factors belonging to the C1 complex and C3 convertase in PXE fibroblasts. Our results indicate a link between JAK/STAT3 signaling and complement activation contributing to the proinflammatory phenotype in PXE fibroblasts. [ABSTRACT FROM AUTHOR]

Pseudoxanthoma elasticum(PXE) is a rare, genetic, metabolic disease characterized by ectopic calcification of connective tissue that primarily affects the skin, retina and cardiovascular system, which characteristic histopathology is calcification and fragmentation of elastic fibers in dermis.PXE is mainly caused by ABCC6 gene mutation, which is one of the important regulators of the serum inorganic pyrophosphate (PPi) homoeostasis, a main inhibitor of ectopic calcification and the deficiency of PPi can lead to ectopic calcification. The clinical features are highly heterogeneous.Typical skin lesions of PXE are yellowish flat papules and plaques, and the symptoms of skin relaxation and shrinkage can be manifested in the later stage.Retina, cardiovascular and other complications seriously affect the health and quality of life of patients. The current therapy of PXE include symptom improvement, systemic anti-ectopic calcification medicine, gene therapy and so on.We review the pathogenesis, clinical manifestations, diagnosis and treatment of PXE.

Ectopic calcification disorders, including Generalized Arterial Calcification of Infancy (GACI) and Pseudoxanthoma Elasticum are rare but impactful on individuals, healthcare and society, with significant associated morbidity, mortality and healthcare costs. Available therapies are not curative and focus on reducing extracellular calcification to limit progression of the arteriopathy that is responsible for much of the morbidity and, in the case of GACI, significant early mortality (approximately 50% in infancy). In this article, current and emerging medical approaches are reviewed and critiqued, including dietary manipulation, phosphate binders, bisphosphonates, tissue nonspecific alkaline phosphatase inhibitors, ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) enzyme replacement, allele-specific therapies, gene therapies, and antibody targeted treatment. Available therapies may limit further arterial calcification, but in GACI in particular, significant calcification can be present at birth, contributing to high infant mortality. This highlights the need for new approaches that aim to reverse established calcification, rather than merely slow its progression. Recently, a promising new class of antibody-targeted nanoparticle therapeutics has emerged that can reverse established arterial calcification in animals, restoring arterial elasticity. In one realization, nanoparticles carry established chelators, such as ethylenediaminetetraacetic disodium acid, to sites of arterial damage, concentrating the impact of the chelator where it is needed and limiting off-target effects. Such drugs would complement existing and emerging therapies, such as ENPP1 enzyme replacement, that slow or prevent progression of calcification, by offering an opportunity to “reset” arterial health in ectopic calcification disorders. At present, ectopic calcification disorders are challenging to treat effectively and carry a high burden of morbidity and mortality, particularly in GACI. Recent drug developments offer good reason to be hopeful for a new era of effective therapeutics that may reverse established arterial disease as well as halt its progression.

Pseudoxanthoma elasticum (PXE (OMIM 264800)) is an autosomal recessive connective tissue disorder mainly caused by mutations in the ABCC6 gene. PXE results in ectopic calcification primarily in the skin, eye and blood vessels that can lead to blindness, peripheral arterial disease and stroke. Previous studies found correlation between macroscopic skin involvement and severe ophthalmological and cardiovascular complications. This study aimed to investigate correlation between skin calcification and systemic involvement in PXE. Ex vivo nonlinear microscopy (NLM) imaging was performed on formalin fixed, deparaffinized, unstained skin sections to assess the extent of skin calcification. The area affected by calcification (CA) in the dermis and density of calcification (CD) was calculated. From CA and CD, calcification score (CS) was determined. The number of affected typical and nontypical skin sites were counted. Phenodex + scores were determined. The relationship between the ophthalmological, cerebro- and cardiovascular and other systemic complications and CA, CD and CS, respectively, and skin involvement were analyzed. Regression models were built for adjustment to age and sex. We found significant correlation of CA with the number of affected typical skin sites (r = 0.48), the Phenodex + score (r = 0.435), extent of vessel involvement (V-score) (r = 0.434) and disease duration (r = 0.48). CD correlated significantly with V-score (r = 0.539). CA was significantly higher in patients with more severe eye (p = 0.04) and vascular (p = 0.005) complications. We found significantly higher CD in patients with higher V-score (p = 0.018), and with internal carotid artery hypoplasia (p = 0.045). Significant correlation was found between higher CA and the presence of macula atrophy (β = − 0.44, p = 0.032) and acneiform skin changes (β = 0.40, p = 0.047). Based on our results, the assessment of skin calcification pattern with nonlinear microscopy in PXE may be useful for clinicians to identify PXE patients who develop severe systemic complications. [ABSTRACT FROM AUTHOR]

BACKGROUND: Pseudoxanthoma elasticum is a connective tissue metabolic disease of autosomal recessive inheritance due to mutations in the ABCC6 gene in the chromosome 16p13.1 with a prevalence of 1:25,000 to 100,000 inhabitants with a slight predominance in women. This defect causes calcification and progressive fragmentation of elastic fibers in the skin, eyes, gastrointestinal and cardiovascular systems. CLINICAL CASE: A 28-year-old female patient consulted a dermatologist due to a progressive growth dermatosis of 10 years of evolution with onset in the postpartum period at 18 years of age, located on the anterior region of the neck with a rough light brown surface giving a yellowish papule lesion appearance with a 2.5 x 2.5 cm diameter with no current growth evolution. In view of the pseudoxanthoma elasticum suspicion, cardiologic and ophthalmologic evaluation and a skin biopsy were requested. In the histopathological report the Verhoeff-Van Gieson stain evidenced short, curled, and frayed basophilic elastic fibers and the hematoxylin and eosin stain showed calcium deposits in intracellular spaces, twisted collagen fibers and filamentous material. CONCLUSIONS: Early diagnosis of pseudoxanthoma elasticum can modify and reduce its morbidity and mortality. [ABSTRACT FROM AUTHOR]

Pseudoxanthoma elasticum (PXE) is an autosomal recessive genetic disorder characterized by aberrant fragmentation and calcification of elastic fibers, leading to characteristic cutaneous, ophthalmic, and cardiovascular manifestations. PXE demonstrates significant phenotypic variability; involvement of the oral mucosa may be the only clue to the diagnosis. Reports on mucous membrane involvement in PXE are scarce. Here, we present a case of PXE‐like changes in the oral cavity. A 70‐year‐old male patient presented with a painless leukoplakic lesion on the soft palate. Biopsy revealed numerous degenerated fibers in the lamina propria. Verhoeff‐van Gieson and von Kossa staining confirmed their identity as calcified elastic fibers. A histopathological diagnosis of PXE‐like changes was made; the patient was referred to ophthalmology where angioid streaks were visualized fundoscopically. PXE‐like changes in the absence of the characteristic genetic mutation have also been reported with or without systemic manifestations. Furthermore, PXE‐like changes have been reported in up to 10% of oral biopsy specimens undertaken without clinical suspicion for PXE. Therefore, the significance of such changes in isolation is unclear. Clinicians and pathologists should be aware of the potential oral manifestations of PXE to facilitate prompt diagnosis and subspecialist referral. [ABSTRACT FROM AUTHOR]