A case of pseudoxantoma elasticum

Pseudoxanthoma elasticum (PXE) is a genetic multisystem disorder characterized by calcified dystrophic elastic fibres in skin, retina and arteries. Much of the earlier literature on pregnancy in PXE contained reports of severe complications, leading some healthcare providers to advise women with PXE against becoming pregnant and some women with PXE to avoid pregnancy. To evaluate the obstetrical outcomes and the incidence of pregnancy complications in women with PXE and to determine if pregnancy is associated with an adverse effect on the course of the disease. Women with PXE (n = 407) answered detailed questionnaires regarding reproductive history and pregnancy as well as the course of their disease. The frequency of reported pregnancy outcomes and complications was determined. Severity indices for the major clinical manifestations of PXE were developed and correlated with gravidity of affected women aged 40 years or over. Among the 306 respondents with PXE who had ever been pregnant, there were 795 pregnancies. Of these, 83% ended in live births and 1% in stillbirth. The median birth weight was within the normal range and the incidence of low birth weight for gestation was low. Hypertension occurred in 10% of pregnancies, gastric bleeding and retinal complications in < 1%, and 12% of pregnancies were associated with worsening of skin manifestations. There was no effect of gravidity and clinical severity on cutaneous (P = 0.07), ocular (P = 0.59) or cardiac (P = 0.42) manifestations of PXE in women aged 40+ years, nor did ever having been pregnant adversely affect these clinical severity indices. Of the 101 women who had never been pregnant, 17% made the decision because they were advised against becoming pregnant by a healthcare professional and 11% did not become pregnant because they feared an adverse outcome either in their pregnancy or disease. PXE is not associated with markedly increased fetal loss or adverse reproductive outcomes. The incidence of gastric bleeding, although probably higher than in the unaffected population, is much lower than previously reported, and retinal complications are uncommon. Although a few pregnancies were associated with worsening of skin manifestations, there was no correlation of either gravidity or ever having been pregnant with ultimate severity of skin, ocular or cardiovascular manifestations. There is no basis for advising women with PXE to avoid becoming pregnant, and most pregnancies in PXE are uncomplicated.

Angioid streaks are irregular, peripapillary brown to red curvilinear bands that extend in a weblike manner from the optic disc (Fig 1). Often confused with blood vessels, angioid streaks are wider, with tapering ends, lie below the normal retinal vasculature, and are readily discerned by direct ophthalmoscopy. Their importance lies in their association with a host of systemic disorders. Pseudoxanthoma elasticum (PXE), Paget's disease of the bone, and sickle-cell disease account for the majority of diseases linked to angioid streaks. PXE can be demonstrated in more than half the patients with angioid streaks 1,2 ; in one large series, 85% of patients with PXE demonstrated angioid streaks. 3 Additional associated conditions include acromegaly, abetalipoproteinemia, diabetes mellitus, Ehlers-Danlos syndrome, hemochromatosis, facial hemochromatosis, hemolytic anemia, hypercalcinosis, hyperphosphatemia, neurofibromatosis, senile elastosis, Sturge-Weber syndrome, tuberous sclerosis, lead poisoning, and myopia. 1 Additional ocular findings in PXE include a diffuse, yellowish mottling of the retinal pigment

Present the diagnosis and therapeutic approach in a patient with pseudoxanthoma elasticum and ocular involvement. A 46-year-old patient presented for progressive loss of vision and metamorphopsias in the left eye. The ophthalmological examination showed angioid streaks and secondary choroidal neovascularization. The dermatologist performed an incisional biopsy of a skin area in the right axilla that showed white-yellow, discrete streaks. Histopathological examination confirmed the diagnosis of pseudoxanthoma elasticum. It was decided to start intravitreal injections with aflibercept. Three injections were made in the left eye with subsequent visual acuity improvement. Angioid streaks are a rare retinal condition, and pseudoxanthoma elasticum is the most common association. Other systemic conditions are Ehlers-Danlos syndrome, Paget's disease, and hemoglobinopathies. Definite diagnosis requires skin lesions or calcified elastic fibers on pathological examination and angioid streaks of the retina. Choroidal neovascularization is a frequent complication and leads to vision loss. Intravitreal inhibitors of vascular endothelial growth factor are currently the first line of treatment. Pseudoxanthoma elasticum has numerous systemic manifestations and requires a multidisciplinary team to be monitored and treated.

Background and aimsThe contribution of arterial calcification (AC) in peripheral arterial disease (PAD) and arterial wall compressibility is a matter of debate. Pseudoxanthoma elasticum (PXE), an inherited metabolic disease due to ABCC6 gene mutations, combines elastic fiber fragmentation and calcification in various soft tissues including the arterial wall. Since AC is associated with PAD, a frequent complication of PXE, we sought to determine the role of AC in PAD and arterial wall compressibility in this group of patients.Methods and ResultsArterial compressibility and patency were determined by ankle-brachial pressure index (ABI) in a cohort of 71 PXE patients (mean age 48±SD 14 yrs, 45 women) and compared to 30 controls without PAD. Lower limb arterial calcification (LLAC) was determined by non-contrast enhanced helicoidal CT-scan. A calcification score (Ca-score) was computed for the femoral, popliteal and sub-popliteal artery segments of both legs. Forty patients with PXE had an ABI<0.90 and none had an ABI>1.40. LLAC increased with age, significantly more in PXE subjects than controls. A negative association was found between LLAC and ABI (r = −0.363, p = 0.002). The LLAC was independently associated with PXE and age, and ABI was not linked to cardiovascular risk factors.ConclusionsThe presence of AC was associated with PAD and PXE without affecting arterial compressibility. PAD in PXE patients is probably due to proximal obstructive lesions developing independently from cardiovascular risk factors.

The present study reports a case of a patient with choroidal neovascularization (CNV) associated with pseudoxanthoma elasticum (PXE). We observed the functional and anatomical improvement of the patient treated with intravitreal vascular endothelial growth factor (VEGF) inhibitor bevacizumab. The study also systematically searched the database for similar cases to provide a literature review. Data concerning the clinical features, treatment strategies and outcomes were extracted and analyzed. Retrospective interventional case report and systematic literature review. A 56-year-old healthy Chinese woman with CNV secondary to PXE was reported. Examinations included best corrected visual acuity (BCVA), biomicroscopy, optical coherence tomography (OCT), fluorescein and indocyanine green angiography and digital fundus photography. The patient managed with intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections (bevacizumab 1.25 mg/0.05 mL). The Cochrane Library, PubMed, OVID, and UpToDate databases were searched using the term pseudoxanthoma elasticum or Gronblad-Strandberg syndrome with the limits English. Articles that predated the databases were gathered from current references. Fundus examination revealed angioid streaks bilaterally and CNV in left eye (LE). After the patient underwent three intravitreal injections of bevacizumab, the LE showed absorption of the subretinal fluid and shrinkage of the CNV. Visual acuity (VA) was improved in her treated LE. Bevacizumab treatment was well tolerated with no adverse events reported. Approximately ten articles about 45 patients (49 eyes) describing CNV secondary to angioid streaks in PXE treated with anti-VEGF were found in the literature search. In the present case, bevacizumab of an initial three injection loading dose, achieved maintenance of visual function in the treatment of CNV associated with angioid streaks in PXE. Literature articles concluded that the intravitreal application of anti-VEGF is highly efficient for improving and stabilizing the lesion as well as the eyesight. So we believe that anti-VEGF therapy can be a great choice of treatment for CNV secondary to angioid streaks related PXE.

Pseudoxanthoma Elasticum: Genetics, Clinical Manifestations and Therapeutic Approaches

Current literature suggests that the incidence of sudden cardiac arrest (SCA) attributable to mitral valve prolapse (MVP) is more common than historically presumed. Although its true incidence remains unknown, this novel realization suggests that the presence of MVP after resuscitated SCA should prompt exploratory identification of a causative association between MVP and SCA, even in the presence of other plausible explanatory findings. Case Description: A 60-year-old male with a history of hypertension presented with an out-of-hospital cardiac arrest due to ventricular fibrillation (VF). Coronary angiography revealed a 99% occluded 1st diagonal branch which was stented. TTE showed normal biventricular function and coincidentally found a myxomatous mitral valve with bileaflet prolapse. The patient was discharged without further work up under the rationale that the ischemic etiology of his arrest was reversed. 6 months later, he presented with another episode of VF arrest. EKG showed sinus bradycardia and a QTc of 534ms. Troponin was negative. Coronary angiography revealed a patent stent and coronary vessels. A cardiac MRI was obtained to investigate the arrhythmic significance of his MVP and showed late gadolinium enhancement in the basal inferolateral wall and tips of the mitral papillary muscles. A dual chamber implantable cardiac defibrillator was placed with a plan for future mitral valve repair. Discussion: Recent studies suggest that the estimated annual risk of SCA due to MVP is 0.2% to 1.9%, a figure higher than previously reported. Certain EKG, TTE and cardiac MRI findings have been associated with an increased risk of ventricular arrhythmias and SCA. In this patient, this included bileaflet MVP, mitral antral disjunction, and inferobasal wall and papillary muscle fibrosis. Currently, there are no society guidelines to assist in the identification of patients with MVP at high-risk for SCA. Nonetheless, in patients with MVP resuscitated from SCA, further workup to identify high risk features is reasonably justified to guide secondary SCA prophylaxis, even in the presence of other explanatory findings for SCA.

Mitral valve prolapse and sudden cardiac arrest in the community

Pseudoxanthoma elasticum (PXE) is a rare genetic disorder caused by loss-of-function mutations in the ABCC6 gene. While PXE is characterized by ectopic mineralization of connective tissues clinically affecting the skin, eyes, and cardiovascular system, kidney stones were reported in some individuals with PXE. The aim of this study is to determine whether kidney stones are an incidental finding or a frequent manifestation of PXE. We investigated the genetic basis of two siblings diagnosed with PXE. The younger patient presented with recurrent kidney stones since age 8. To address whether kidney stones are associated with PXE, the prevalence of kidney stones in a survey cohort of 563 respondents with PXE was compared to that of a general U.S. population survey, NHANES (National Health and Nutrition Examination Survey), with 28,629 participants. Genetic analysis in both patients identified compound heterozygous mutations in ABCC6, c.2787+1G>T and c.3774_3775insC. The analysis of participants aged 20 and older revealed that 23.4% of PXE patients had previously had a kidney stone, a significant increase compared to 9.2% in the general population. In addition, 17.8% of PXE patients reported their first kidney stone episode before age 18. PXE correlates with an increased risk of developing kidney stones with considerable morbidity and health-care cost.

Retinal autofluorescence imaging in patients with pseudoxanthoma elasticum

Editor, Angioid streaks are irregular, greyish lines that surround the optic disc and extend radially outwards. They are associated with different disorders, the most frequent being pseudoxanthoma elasticum or Grönblad−Strandberg syndrome. In a large proportion of cases, they are associated with choroidal neovascularization (CNV). The treatment most frequently employed for CNV is photodynamic therapy (PDT). However, the current use of antiangiogenic agents for CNV secondary to age-related macular degeneration (AMD) opens a new avenue to treatment for patients affected by CNV secondary to other disorders. Texeira et al. (2006) reported a case of CNV-associated angioid streaks treated with bevacizumab with very good results. We report a case of subfoveal CNV-associated angioid streaks treated with intravitreal pegabtanib sodium. A 41-year-old man presented with a sudden decrease in visual acuity (VA) in the left eye. His best corrected VA was 45 letters (ETDRS). In direct ophthalmoscopy, angioid streaks were observed in both eyes and a lesion suspected of being a neovascular membrane was seen in the foveal area of the left eye (LE). Fluorescein angiography (FA) showed an occult CNV in the LE. Optical coherence tomography (OCT) showed evidence of pigment epithelial detachment (PED) and intraretinal oedema (Fig. 1). Treatment was started with intravitreal injections of sodium pegabtanib (Macugen® 0.3 mg/0.5 ml; ) at regular intervals, with 6 weeks between injections. Four injections of pegabtanib were administered. After 36 weeks, BCVA in the LE was 79 letters. No leakage was seen on FA. Examination by OCT showed a dramatic improvement in the PED and complete disappearance of the intraretinal oedema. No systemic or ocular side-effects were reported. Up figures: fluorescein angiography (FA) and optical coherence tomography (OCT) before treatment; Down figures: FA and OCT post treatment. The most frequent cause of vision loss in patients with angioid streaks is CNV, which occurs in 86% of cases. Photodynamic therapy with verteporfin (Visudyne®) had been the most broadly applied treatment for this type of CNV until the new antiangiogenic therapies emerged. Various authors have found differing results with PDT (Arias et al. 2006; Browning et al. 2002; Karacorlu et al. 2002), but some of the series reported were affected by significant limitations (Arias et al. 2006; Browning et al. 2002; Karacorlu et al. 2002). Antiangiogenic agents are a new therapy for AMD and depend on their inhibitory effect on vascular endothelial growth factor (VEGF). Pegabtanib avoids significant visual loss in patients affected with AMD (Chakravarthy et al. 2006). In addition, bevacizumab and ranibizumab have appeared as alternatives. Texeira et al. (2006) reported a case of CNV associated-angioid streaks treated with two injections of bevacizumab (Avastin®), in which a dramatic visual recovery was seen, along with lack of leakage in OCT and FA. The fundamental difference between this case and the one we present concerns the type of CNV. Texeira et al. (2006) described a classical neovascular membrane; by contrast, our case involved a neovascular membrane of the occult type, which is less frequently associated with angioid streaks. Another difference concerns the number of injections: our case required four injections, whereas Texeira et al. (2006) administered two. Best corrected VA at the end of treatment was very good in both cases. Further research is required, involving detailed studies with extended follow-up to determine the efficacy and safety of intravitreal sodium pegabtanib (Macugen®; pfizer) in the treatment of CNV associated with angioid streaks.

EDITOR-Pseudoxanthoma elasticum (PXE, MIM 264800) is an inherited disorder of connective tissue in which the elastic fibres of the skin, eyes, and cardiovascular system slowly become calcified, causing a spectrum...

To analyze the retinal and choroidal vascular abnormalities in eyes with angioid streaks (AS) associated with pseudoxanthoma elasticum (PXE). Color photographs and fluorescein angiograms of 54 eyes of 27 consecutive patients with AS and PXE were examined retrospectively. Four (7%) of the 54 eyes had a major vascular abnormality at the level of the disc; this took the form of a large vascular loop corresponding to an arteriovenous communication between retina and choroid in 3 eyes (6%) and an anastomosis between 2 retinal arteries in 1 eye (2%). Analysis of the vascular network in these eyes showed several vascular abnormalities, among which chorioretinal arteriovenous communications appear to be the most dramatic.

Congenital haemolytic anaemia may be associated with pseudoxanthoma elasticum (PXE)-like clinical manifestations. The cardiovascular system of 14 homozygous and double heterozygous beta-thalassaemia patients with skin and retinal vessel alterations similar to those in genetic PXE was analysed over a period of 12 years and compared with that of 13 relatives (five sets of parents, one single parent, two thalassaemic brothers), and that of the control group composed of 16, age- and sex-matched, thalassaemic patients. All patients with clinical PXE-like skin lesions exhibited, by light and electron microscopy, dermal alterations and mineralization of elastic fibres identical to those typical of inherited PXE. None of the relatives and none of the control group showed clinical or structural findings of PXE. The follow-up started in 1988. After 12 years of clinical observation, six patients showed dramatic progression of skin involvement, angioid streaks had progressed in two subjects. One patient had recurrent gastrointestinal bleeding and underwent partial stomach removal for gastric artery aneurysm, one underwent colon resection for intestinal infarct, one patient had a transitory ischaemic attack, one died after an intracranial haemorrhage, two patients died from cardiovascular disease and one from neoplasia. Thalassaemic patients with PXE-like skin lesions also manifest PXE-like vessel alterations that progress with time. Considering the severe outcome of these lesions, accurate monitoring should be routinely performed on the cardiovascular system of thalassaemic patients with PXE-like skin manifestations.

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