Increased Intracranial Arterial Pulsatility and Microvascular Brain Damage in Pseudoxanthoma Elasticum.

BACKGROUND AND PURPOSE: Carotid siphon calcification might contribute to the high prevalence of cerebrovascular disease in pseudoxanthoma elasticum through increased arterial flow pulsatility. This study aimed to compare intracranial artery flow pulsatility, brain volumes, and small-vessel disease markers between patients with pseudoxanthoma elasticum and controls and the association between arterial calcification and pulsatility in pseudoxanthoma elasticum. MATERIALS AND METHODS: Fifty patients with pseudoxanthoma elasticum and 40 age- and sex-matched controls underwent 3T MR imaging, including 2D phase-contrast acquisitions for flow pulsatility in the assessment of ICA and MCA and FLAIR acquisitions for brain volumes, white matter lesions, and infarctions. All patients with pseudoxanthoma elasticum underwent CT scanning to measure siphon calcification. Flow pulsatility (2D phase-contrast), brain volumes, white matter lesions, and infarctions (3D T1 and 3D T2 FLAIR) were compared between patients and controls. The association between siphon calcification and pulsatility in pseudoxanthoma elasticum was tested with linear regression models. RESULTS: Patients with pseudoxanthoma elasticum (mean age, 57 [SD, 12] years; 24 men) had significantly higher pulsatility indexes (1.05; range, 0.94-1.21 versus 0.94; range, 0.82-1.04; P = .02), lower mean GM volumes (597 [SD, 53] mL versus 632 [SD, 53] mL; P < .01), more white matter lesions (2.6; range, 0.5-7.5 versus 1.1; range, 0.5-2.4) mL; P = .05), and more lacunar infarctions (64 versus 8, P = .04) than controls (mean age, 58 [SD, 11] years; 20 men). Carotid siphon calcification was associated with higher pulsatility indexes in patients with pseudoxanthoma elasticum (ß = 0.10; 95% CI, 0.01-0.18). CONCLUSIONS: Patients with pseudoxanthoma elasticum have increased intracranial artery flow pulsatility and measures of small-vessel disease. Carotid siphon calcification might underlie the high prevalence of cerebrovascular disease in pseudoxanthoma elasticum.

Do pseudoxanthoma elasticum patients have higher prevalence of kidney stones on computed tomography compared to hospital controls?

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.

Minocycline Counteracts Ectopic Calcification in a Murine Model of Pseudoxanthoma Elasticum: A Proof-of-Concept Study.

Pseudoxanthoma elasticum (PXE) is an intractable Mendelian disease characterized by ectopic calcification in skin, eyes and blood vessels. Recently, increased activation of the DNA damage response (DDR) was shown to be involved in PXE pathogenesis, while the DDR/PARP1 inhibitor minocycline was found to attenuate aberrant mineralization in PXE cells and zebrafish. In this proof-of-concept study, we evaluated the anticalcifying properties of minocycline in Abcc6-/- mice, an established mammalian PXE model. Abcc6-/- mice received oral minocycline supplementation (40 mg/kg/day) from 12 to 36 weeks of age and were compared to untreated Abcc6-/- and Abcc6+/+ siblings. Ectopic calcification was evaluated using X-ray microtomography with three-dimensional reconstruction of calcium deposits in muzzle skin and Yasue's calcium staining. Immunohistochemistry for the key DDR marker H2AX was also performed. Following minocycline treatment, ectopic calcification in Abcc6-/- mice was significantly reduced (-43.4%, p < 0.0001) compared to untreated Abcc6-/- littermates. H2AX immunostaining revealed activation of the DDR at sites of aberrant mineralization in untreated Abcc6-/- animals. In conclusion, we validated the anticalcifying effect of minocycline in Abcc6-/- mice for the first time. Considering its favorable safety profile in humans and low cost as a generic drug, minocycline may be a promising therapeutic compound for PXE patients.

Pulsatility Attenuation along the Carotid Siphon in Pseudoxanthoma Elasticum.

We compared velocity pulsatility, distensibility, and pulsatility attenuation along the intracranial ICA and MCA between 50 patients with pseudoxanthoma elasticum and 40 controls. Patients with pseudoxanthoma elasticum had higher pulsatility and lower distensibility at all measured locations, except for a similar distensibility at C4. The pulsatility attenuation over the siphon was similar between patients with pseudoxanthoma elasticum and controls. This finding suggests that other disease mechanisms are the main contributors to increased intracranial pulsatility in pseudoxanthoma elasticum.

Adaptive Optics Imaging in Patients Affected by Pseudoxanthoma Elasticum.

PURPOSE: To describe the retinal findings of patients affected by pseudoxanthoma elasticum (PXE) using a multimodal imaging approach including flood-illumination adaptive optics ophthalmoscopy (AO). DESIGN: Retrospective case series. MATERIALS AND METHODS: Patients affected by PXE were retrospectively studied. Clinical data, color, infrared and autofluorescence fundus imaging, optical coherence tomographic scans, and AO examinations were collected. Furthermore, the photoreceptor count was assessed. PXE diagnosis was confirmed by a positive skin biopsy and/or genetic testing. RESULTS: Twenty-one eyes of 18 patients (11 females and 7 males) were included in the study. In 3 patients, both eyes were studied. The mean age at examination was 37.7 ± 16.4 years (range 14-66) and the mean best-corrected visual acuity (BCVA) was 0.1 ± 0.2 logMAR (range 0-1). We identified 3 types of angioid streaks (AS) using AO: "crack," "band," and "hypopigmented." The first 2 were very similar and they differed in size; the third type showed specific clinical features. Comet lesions appeared as hyper-reflective round lesions on AO imaging. In all eyes, the cone mosaic appeared reduced inside the streaks compared to the neighboring areas (13,532.8 ± 1,366.5 cones/mm2 vs 16,817.1 ± 1,263.0 cones/mm2 respectively). CONCLUSION: Using AO imaging in PXE-related retinopathy, we were able to observe the presence of the photoreceptors within the angioid streaks, differentiate 3 types of angioid streaks, based on size and reflective features, and identify the very small crystalline bodies not identifiable using other retinal imaging techniques.

Pseudoxantoma elástico infantil en paciente con beta-talasemia / Pseudoxanthoma elasticum in childhood in patient with Beta-thalassaemia

El pseudoxantoma elástico (PXE) es una enfermedad hereditaria rara, que cursa con alteraciones del tejido conectivo, debido a una alteración en el cromosoma 16p del gen ABCC6. Desde una perspectiva clínica, da lugar a manifestaciones predominantemente cutáneas, cardiacas y oftalmológicas. La asociación de β-talasemia y cuadros clínicos compatibles con PXE (síndromes PXE-like) ha sido descrita en la literatura en pacientes con β-talasemia mayor e intermedia, que es indistinguible clínicamente del PXE clásico. Presentamos el caso de un niño de 10 años con beta-talasemia minor y lesiones características de PXE. Cabe destacar el beneficio de la imagen multimodal para el diagnóstico y seguimiento de las lesiones

Pseudoxanthoma elasticum (PXE) is a rare genetic disorder characterised by elastic tissue alterations and caused by mutations in a single gene, ABCC6, on chromosome 16p that includes manifestations that are predominantly cutaneous, ocular and cardiovascular. PXE-like lesions in association with β-thalassemia have previously been reported in the literature in patients with Beta-thalassaemia intermediate and major, being clinically indistinguishable from classic PXE. The case is presented of a 10-year-old boy with β-thalassaemia minor and characteristic lesions of PXE. It is worth noting the benefit of multimodal imaging in the diagnosis and monitoring of the lesions

The effect of etidronate on choroidal neovascular activity in patients with pseudoxanthoma elasticum.

AIM: To assess the effect of the bisphosphonate etidronate on choroidal neovascular (CNV) activity in patients with pseudoxanthoma elasticum (PXE). METHODS: This is an ancillary study in a single center, randomized, double-blind placebo-controlled trial (RCT) in which 74 patients with PXE were assigned to either one-year etidronate or placebo treatment. Spectral domain optical coherence tomography (SD-OCT) imaging and color fundus photography were performed every three months for one year and were systematically assessed on signs of CNV activity. RESULTS: In the etidronate group, 11 (30%) of the patients had CNV activity at baseline, compared to 25 (67%) of the patients in the placebo group (P = 0.005). The proportion of eyes with CNV activity during the study ranged from 18-33% in the etidronate group and 42-56% in the placebo group and no significant difference in improvement or worsening of CNV activity was found (P = 0.168). Using a generalized mixed model for repeated measures, there was a protective effect of etidronate in crude analysis (RR 0.86, 95% CI 0.75-0.98) that disappeared when adjusting for baseline CNV activity (RR 0.97, 95% CI 0.84-1.13). CONCLUSION: In this post-hoc RCT analysis we did not observe a protecting or deteriorating effect of etidronate on CNV activity in patients with PXE after adjustment for baseline CNV.

NOVEL METHOD FOR IMAGE AVERAGING OF OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IMAGES.

PURPOSE: To develop a method of averaging optical coherence tomography (OCT) angiography to improve visualization of choriocapillaris structure. METHODS: A stack of OCT angiographic data from vascular layers were placed into the red-green-blue channels of a conventional digital color image. The superficial plexus was placed in the blue channel, choriocapillaris in the green, and deep vascular plexus in the red channel. The red-green-blue images derived from nine separate OCT angiographic scans were registered using an automatic registration sequence and the images were averaged. The averaged red-green-blue image was then split into the three averaged component layers. The technique is flexible and any vascular layer, such as macular neovascularization, can be used as well. RESULTS: The utility of the imaging method was demonstrated by showing the imaging of two different diseases. A patient with a history of familial amyloidosis, hypertension, kidney failure, kidney transplantation, and prednisone use, followed by central serous chorioretinopathy treated by photodynamic therapy. She had alterations in retinal pigment epithelial pigmentation and widespread abnormalities of autofluorescence. She showed remarkably decreased vascular density and vessel configuration of her choriocapillaris. A patient with pseudoxanthoma elasticum with subretinal drusenoid deposits at an early age also showed marked decreased choriocapillaris density and vascular configuration. These findings were compared with healthy controls of similar age with no abnormalities. CONCLUSION: The detailed method is capable of averaging choriocapillaris OCT angiographic images using a simple automatic method. Image averaging offers opportunity to improve the noisy OCT angiographic images such that actual vascular structure is visible.

Nonlinear optical microscopy is a novel tool for the analysis of cutaneous alterations in pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE, OMIM 264800) is a rare autosomal recessive disorder with ectopic mineralization and fragmentation of elastin fibers. It is caused by mutations of the ABCC6 gene that leads to decreased serum levels of inorganic pyrophosphate (PPi) anti-mineralization factor. The occurrence of severe complications among PXE patients highlights the importance of early diagnosis so that prompt multidisciplinary care can be provided to patients. We aimed to examine dermal connective tissue with nonlinear optical (NLO) techniques, as collagen emits second-harmonic generation (SHG) signal, while elastin can be excited by two-photon excitation fluorescence (TPF). We performed molecular genetic analysis, ophthalmological and cardiovascular assessment, plasma PPi measurement, conventional histopathological examination, and ex vivo SHG and TPF imaging in five patients with PXE and five age- and gender-matched healthy controls. Pathological mutations including one new variant were found in the ABCC6 gene in all PXE patients and their plasma PPi level was significantly lower compared with controls. Degradation and mineralization of elastin fibers and extensive calcium deposition in the mid-dermis was visualized and quantified together with the alterations of the collagen structure in PXE. Our data suggests that NLO provides high-resolution imaging of the specific histopathological features of PXE-affected skin. In vivo NLO may be a promising tool in the assessment of PXE, promoting early diagnosis and follow-up.

Bidimensional Multiscale Fuzzy Entropy and Its Application to Pseudoxanthoma Elasticum.

OBJECTIVE: We propose a new bidimensional entropy measure and its multiscale form and evaluate their behavior using various synthetic and real images. The bidimensional multiscale measure finds application in helping clinicians for pseudoxanthoma elasticum (PXE) detection in dermoscopic images. METHOD: We developed bidimensional fuzzy entropy ( FuzEn2D) and its multiscale extension ( MSF2D) and then evaluated them on a set of synthetic images and texture datasets. Afterwards, we applied MSF2D to dermoscopic PXE images and compared the results to those obtained by bidimensional multiscale sample entropy ( MSE2D). RESULTS: The results for the synthetic images illustrate that FuzEn2D has the ability to quantify images irregularity. Moreover, FuzEn2D, compared with bidimensional sample entropy ( SampEn2D), leads to more stable results. The tests with the multiscale version show that MSF2D is a proper image complexity measure. When applied to the dermoscopic PXE images, the paired t-test illustrates a significant statistical difference between MSF2D of neck images with papules and normal skin images at a couple of scale factors. CONCLUSION: The results for the synthetic data illustrate that FuzEn2D is an image irregularity measure that overcomes SampEn2D in terms of reliability, especially for small-sized images, and stability of results. The results for the PXE dermoscopic images demonstrate the ability of MSF2D to recognize dermoscopic images of normal zones from PXE papules zones with a large effect size. SIGNIFICANCE: This work introduces new image irregularity and complexity measures and shows the potential for MSF2D to serve as a possible tool helping medical doctors in PXE diagnosis.

Evaluation of lamina cribrosa in angioid streaks using spectral-domain optical coherence tomography enhanced depth imaging.

PURPOSE: To investigate retinal nerve fiber layer (RNFL) thickness, anterior lamina cribrosa depth (ALD) and laminar thickness (LT) in eyes with angioid streaks (AS) in comparison with healthy eyes. METHODS: Patients with AS (n=32 eyes) and age-matched healthy subjects (n=42 eyes) underwent enhanced depth imaging with spectral domain optical coherence tomography of the optic nerve head. RNFL thickness was obtained automatically by using the Heidelberg software. The ALD was defined as the vertical distance between the Bruch's membrane openings as reference plane and the anterior border of the lamina cribrosa. The LT was measured as the distance between the anterior and posterior borders of the lamina cribrosa. RNFL thickness, ALD and LT were compared between the AS and healthy eyes adjusting for axial length. RESULTS: The mean age was 51.7±8.0 years for AS patients and 53.8±10.2 years for control subjects (P=0.34). The mean RNFL thickness was 88.6±17.6µm in AS eyes and 102.1±8.3µm in control eyes; the difference between the groups was significantly significant. ALD was 350.9±70.8µm in AS eyes and 432.5±82.1µm in control eyes, while LT was 166.3±41.0µm in AS eyes and 241.3±43.2µm in control eyes. ALD and LT were also significantly thinner in AS eyes than control eyes (P=0.003, P<0.001; respectively). CONCLUSION: Enhanced depth imaging revealed that eyes with AS demonstrate thinner RNFL, ALD and LT compared with normal eyes. Further studies with a larger sample size are needed to understand the relationship between these findings and the morphologic changes and pathogenesis of AS.

Dermatoscopy of Common Lesions in Pediatric Dermatology.

The use of dermatoscopy to assist in the diagnosis of a variety of proliferative, pigmentary, inflammatory, infectious, congenital, and genetic cutaneous and skin appendage disorders is constantly increasing, as it is effective, affordable, noninvasive, and quick to perform.

ABCC6 Deficiency Promotes Development of Randall Plaque.

BACKGROUND: Pseudoxanthoma elasticum (PXE) is a genetic disease caused by mutations in the ABCC6 gene that result in low pyrophosphate levels and subsequent progressive soft tissue calcifications. PXE mainly affects the skin, retina, and arteries. However, many patients with PXE experience kidney stones. We determined the prevalence of this pathology in patients with PXE and examined the possible underlying mechanisms in murine models. METHODS: We conducted a retrospective study in a large cohort of patients with PXE and analyzed urine samples and kidneys from Abcc6-/- mice at various ages. We used Yasue staining, scanning electron microscopy, electron microscopy coupled to electron energy loss spectroscopy, and Fourier transform infrared microspectroscopy to characterize kidney calcifications. RESULTS: Among 113 patients with PXE, 45 (40%) had a past medical history of kidney stones. Five of six computed tomography scans performed showed evidence of massive papillary calcifications (Randall plaques). Abcc6-/- mice spontaneously developed kidney interstitial apatite calcifications with aging. These calcifications appeared specifically at the tip of the papilla and formed Randall plaques similar to those observed in human kidneys. Compared with controls, Abcc6-/- mice had low urinary excretion of pyrophosphate. CONCLUSIONS: The frequency of kidney stones and probably, Randall plaque is extremely high in patients with PXE, and Abcc6-/- mice provide a new and useful model in which to study Randall plaque formation. Our findings also suggest that pyrophosphate administration should be evaluated for the prevention of Randall plaque and kidney stones.

Mujer de 60 años con problemas de visión y lesiones cutáneas / A 60-year-old woman with visual impairment and cutaneous lesions

No disponible