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Pseudoxanthoma Elasticum

Groenblad Strandberg Syndrome

Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive connective tissue disease that affects the skin, eyes, and the vasculature. The clinical presentation varies from one individual to another.


Presentation

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease characterized by progressive calcification, mineralization, and thus fragmentation of the elastic fibers present in the skin, arterial wall, and retina [1]. This rare disorder affects the skin, eyes, cardiovascular system, and gastrointestinal (GI) system. It is a clinically heterogeneous disease that manifests in the second or third decade [2].

Skin features are the earliest sign. Lesions appear as small, yellow papules that coalesce to form a papule [3]. It may be described as a rash with "cobblestone" pattern. The skin changes occur on the lateral neck with progression to other sites such as the axillae, inguinal folds, periumbilical region, and the antecubital and popliteal fossa [4]. Hence, loose skin develops in these locations. The inner lower lip and mucosa of the vagina and rectum may be affected as well. Generally, these lesions do not resolve spontaneously [5].

Ocular signs include "peau d’orange" appearance on an ophthalmologic exam [1]. This is followed later by angioid streaks, which reflect the mineralization of Bruch's membrane. As a result, neovascularization and subretinal hemorrhage may develop, which leads to loss of visual acuity [6]. Blindness ensues if the macula is affected.

Cardiovascular manifestations include intermittent claudication, diminished or absent peripheral pulses, hypertension, mitral valve prolapse [7], and complications as described below.

Complications

Although rare, patients are at risk for developing life-threatening sequelae such as myocardial infarction, cerebral aneurysm, ischemic strokes and other cardiovascular complications [8] [9]. Also, GI bleeding is common, as it leads to hematemesis and melena [3].

Coronary Artery Disease
  • Our patient was previously treated for retinal and gastrointestinal hemorrhage and coronary artery disease, and is under surveillance for cerebral aneurysms.[ncbi.nlm.nih.gov]
  • Mutations in the gene cause a rare, recessive genetic disease, pseudoxanthoma elasticum, while the loss of one ABCC6 allele is a genetic risk factor in coronary artery disease.[eurekaselect.com]
  • In the circulatory system, intermittent claudication (leg pain during walking which resolves at rest) is a prominent feature, although at later stages coronary artery disease may develop, leading to angina and myocardial infarction (heart attack) may[en.wikipedia.org]
  • Renal artery disease causes hypertension and coronary artery disease causes angina and myocardial infarction. Mitral valve prolapse often occurs. This prolapse may not be significant unless there is also mitral regurgitation.[patient.info]
  • Coronary artery disease is frequently a symptom. Occlusive disease of the renal arteries can result in hypertension. Malfunction of heart valves, especially the mitral valve, is common.[disorders.eyes.arizona.edu]
Intravenous Administration
  • As anti-vascular endothelial growth factor agents are associated with increased risk of systemic effects, particularly arterial thromboembolic events, following intravenous administration, the absence of serious thromboembolic or cardiovascular adverse[ncbi.nlm.nih.gov]
Easy Bruising
Hematemesis
  • Also, GI bleeding is common, as it leads to hematemesis and melena. The clinical assessment consists of the patient's history, physical exam, and the appropriate studies.[symptoma.com]
  • […] related to the heart and blood vessels include: Angina (chest pain) Myocardial infarction/heart attack Intermittent claudication: Leg pain during walking that resolves at rest Signs and symptoms related to the gastrointestinal (digestive) tract include: Hematemesis[dovemed.com]
Macroglossia
  • A woman in her 50s with a history of AL amyloidosis manifesting as macroglossia and bilateral carpal tunnel syndrome presented with skin-colored to yellow cobblestoned plaques to the neck and bilateral antecubital fossa.[ncbi.nlm.nih.gov]
Mitral Valve Prolapse
  • Mitral valve prolapse often occurs. This prolapse may not be significant unless there is also mitral regurgitation. GI haemorrhage is usually from the stomach and is the most significant vascular complication.[patient.info]
  • Cardiovascular manifestations include intermittent claudication, diminished or absent peripheral pulses, hypertension, mitral valve prolapse, and complications as described below.[symptoma.com]
  • Other areas that can be affected in PXE include the heart which can be affected by atherosclerosis and mitral valve prolapse.[medicinenet.com]
  • Sudden death may occur due to coronary atherosclerosis with acute myocardial ischemia, systemic hypertension, mitral valve prolapse, restrictive cardiomyopathy, gastrointestinal hemorrhage, and cerebral ischemia or hemorrhage. von Kossa stain[histopathology-india.net]
Severe Osteoporosis
  • Osteopenia was disclosed in 46% (17 women) while 23% (9 women) exhibited osteoporosis, 3 with severe osteoporosis. Fractures of an osteoporotic nature were authenticated in 3 patients (1 woman).[ncbi.nlm.nih.gov]
Ankylosis
  • DESIGN AND METHODS: We used RLFP analyses to evaluate the distribution of SNVs in alkaline phosphatase (ALP), ectonucleotide pyrophosphatase 1 (ENPP1) and ankylosis (ANKH) in DNA samples from 190 German PXE patients and 190 age- and sex-matched healthy[ncbi.nlm.nih.gov]
Angioid Streaks of the Retina
  • In the physical examination, typical skin lesions were present and also an angioid streak of the retina. The patient and a control group were evaluated by the CR-2000 Research Cardiovascular Profiling System.[ncbi.nlm.nih.gov]
  • The occurrence of angioid streaks in the retina was described by Grönblad (4) and Strandberg (5) in 1929, FULL TEXT[annals.org]
  • Angioid streaks in the retina, a tendency towards haemorrhage and arterial insufficiency are the most common complications.[dermis.net]
  • Elastic tissues become calcified and fragmented, leading to disruption of the involved organ systems: Ocular system: Angioid streaks of the retina, retinal hemorrhages, and gradual vision loss Cardiovascular system: Premature atherosclerosis with subsequent[msdmanuals.com]
  • The diagnostic criteria for PXE are the typical skin biopsy appearance and the presence of angioid streaks in the retina. Other systems have become somewhat outdated by the discovery of the ABCC6 mutations.[en.wikipedia.org]

Workup

The clinical assessment consists of the patient's history, physical exam, and the appropriate studies. The diagnosis is achieved based on the clinical picture, histopathology, and identification of mutations in the gene responsible for this disease.

Diagnostic criteria

The gold standard for diagnosis is the detection of one or two ABCC6 mutations. Proposed diagnostic criteria include the presence of 1) at least one ophthalmic finding: peau d’orange and/or angioid streaks and 2) at least one skin feature: characteristic lesion (with or without cutaneous laxity) and/or a positive biopsy of the skin [10]. It is imperative that both eye and skin manifestations are present for definitive diagnosis. If either is absent, then two pathogenic ABCC6 mutations must be identified [10].

Laboratory tests

Patients with GI bleeding are evaluated with a complete blood count (CBC) to screen for iron deficiency anemia as well as a fecal occult blood test (FOBT). Additionally, serum lipid levels are obtained since patients are at risk for atherosclerosis. Another component of the workup includes measurement of serum calcium and phosphate, which are usually normal but may be elevated. Also, a urinalysis should be done to test for hematuria.

Diagnostic procedures

Very importantly, echocardiography is performed in patients with cardiac manifestations and risk factors for cardiac disease. Also, GI endoscopy is indicated in individuals with clinical signs of bleeding while a computed tomography (CT) scan of the head is warranted for those with clinical signs suggestive of a cerebrovascular accident. Furthermore, an ankle-brachial index test is beneficial in the assessment of intermittent claudication.

A thorough ophthalmologic exam that includes fundoscopy should be performed. Moreover, biannual surveillance is recommended for patients greater than 40 years old and every 2 years for those less than 40 [11]. Additionally, patients are encouraged to monitor their visual acuity with the use of the Amsler Grid.

Treatment

  • Ranibizumab treatment was well tolerated with no adverse events reported.[ncbi.nlm.nih.gov]
  • Actually, no targeted therapies are available for the treatment; only prevention of complications is possible. Classically, pseudoxanthoma elasticum is a "benign" disease, without cancer association.[ncbi.nlm.nih.gov]
  • The main objectives were to describe patient characteristics, assess changes in best-corrected visual acuity [VA, Early Treatment Diabetic Retinopathy Study (ETDRS) letters] over time, the number and reasons for ranibizumab treatment and overall safety[ncbi.nlm.nih.gov]
  • Treatment with ezetimibe/simvastatin 10/60mg/day, maintained over a 4.5-year period, reduced of LDL-C and the myocardial ischemic area. In PXE patients LDL-lowering treatment might contribute to delay macrovascular complications.[ncbi.nlm.nih.gov]
  • Examination on presentation showed vitreous hemorrhage in his left eye, and vitrectomy was performed for treatment. Intraoperative findings showed fibrovascular membrane around the optic disc and vascular arcade.[ncbi.nlm.nih.gov]

Prognosis

Etiology

  • In middle-aged or young adults with angioid streaks and no obvious systemic disease, the possibility of a hemoglobulinopathy or pseudoxanthoma elasticum (PXE) as etiologic entities should be investigated.[ncbi.nlm.nih.gov]
  • Abstract The molecular etiology of pseudoxanthoma elasticum (PXE), an autosomal recessive connective tissue disorder, has become increasingly complex as not only mutations in ATP-binding cassette family C member 6 (ABCC6) but also ectonucleotide pyrophosphatase[ncbi.nlm.nih.gov]
  • Etiology PXE is caused by homozygous or compound heterozygous mutations in the ABCC6 gene (16p13.1), which encodes a transmembrane protein from the ATP-binding cassette (ABC) transporter superfamily.[orpha.net]
  • (Etiology) Pseudoxanthoma Elasticum is a genetic disorder caused by mutations in the ABCC6 gene and inherited from the parents.[dovemed.com]

Epidemiology

  • Washington University, College Of Arts and Sciences, 125 Michigan Avenue NE, Washington, DC 20017, USA 2 PXE International, 4301 Connecticut Avenue NW, Suite 404, Washington, DC 20008, USA 3 Laboratory of Translational Genomics, The Division of Cancer Epidemiology[mdpi.com]
  • TuranS@trinitydc.edu. 12 PXE International, 4301 Connecticut Avenue NW, Suite 404, Washington, DC 20008, USA. sterry@pxe.org. 13 Laboratory of Translational Genomics, The Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute,[ncbi.nlm.nih.gov]
  • Author information 1 Department of Dermatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan. 2 Department of Healthcare Epidemiology Research, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 3 Department of[ncbi.nlm.nih.gov]
  • Summary Epidemiology Prevalence is estimated at between 1/25,000 and 1/100,000. The female to male ratio is 2:1 but the cause of this female predominance remains poorly understood.[orpha.net]
Sex distribution
Age distribution

Pathophysiology

Prevention

  • Actually, no targeted therapies are available for the treatment; only prevention of complications is possible. Classically, pseudoxanthoma elasticum is a "benign" disease, without cancer association.[ncbi.nlm.nih.gov]
  • Treatment is supportive and is directed at prevention and early detection of adverse ocular and cardiovascular sequelae.[ncbi.nlm.nih.gov]
  • Incisional biopsy of the palatal lesion confirmed the PXE diagnosis, leading to proper management of the disorder to prevent ophthalmologic and cardiovascular complications.[ncbi.nlm.nih.gov]
  • Medical Screening, Gray, Maine, USA 6 Division of Human Genetics, National Health Laboratory Service and the University of Witwatersrand, Johannesburg, South Africa 7 University of Cape Town, Cape Town, South Africa 8 Centers for Disease Control and Prevention[doi.org]
  • […] hypothesis is based on the notion that inorganic pyrophosphate serves as a powerful inhibitor of mineralization, whereas inorganic phosphate is a promineralization factor, and an appropriate inorganic pyrophosphate/inorganic phosphate ratio is critical for prevention[ncbi.nlm.nih.gov]

References

Article

  1. Finger RP, Issa PC, Ladewig MS, et al. Pseudoxanthoma elasticum: genetics, clinical manifestations and therapeutic approaches. Surv. Ophthalmol. 54(2): 272-285, 2009.
  2. Li Q, Jiang Q, Pfendner E, Váradi A, Uitto J. Pseudoxanthoma elasticum: Clinical phenotypes, molecular genetics and putative pathomechanisms. Exp Dermatol. 2009;18(1):1-11.
  3. Marconi B, Bobyr I, Campanati A, et al. Pseudoxanthoma elasticum and skin: Clinical manifestations, histopathology, pathomechanism, perspectives of treatment. Intractable Rare Dis Res. 2015;4(3):113-122.
  4. Varadi A, Szabo Z, Pomozi V, de Boussac H, Fülöp K, Arányi T. ABCC6 as a target in pseudoxanthoma elasticum. Curr Drug Targets. 2011; 12(5):671-682.
  5. Chassaing N, Martin L, Calvas P, Le Bert M, Hovnanian A. Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations. J Med Genet. 2005; 42(12):881-92.
  6. Gliem M, Finger RP, Fimmers R, Brinkmann CK, Holz FG, Charbel Issa P. Treatment of choroidal neovascularization due to angioid streaks: A comprehensive review. Retina. 2013; 33(7):1300-1314.
  7. Hacker SM, Ramos-Caro FA, Beers BB, Flowers FP. Juvenile pseudoxanthoma elasticum: recognition and management. Pediatr Dermatol. 1993;10(1):19-25.
  8. Lefthériotis G, Omarjee L, Saux OL, et al. The vascular phenotype in Pseudoxanthoma elasticum and related disorders: contribution of a genetic disease to the understanding of vascular calcification. Front Genet. 2013;4:4.
  9. van den Berg JSP, Hennekam RCM, Cruysberg JRM, et al. Prevalence of symptomatic intracranial aneurysm and ischaemic stroke in pseudoxanthoma elasticum. Cerebrovasc Dis. 2000;10(4):315–9.
  10. Uitto J, Jiang Q, Váradi A, Bercovitch LG, Terry SF. Pseudoxanthoma Elasticum: Diagnostic Features, Classification, and Treatment Options. Expert Opin Orphan Drugs. 2014;2(6):567-577.
  11. Orssaud C, Roche O, Dufier JL. Visual Impairment in Pseudoxanthoma Elasticum: A Survey of 40 Patients. Ophthalmic Genet. 2015;36(4):327-32.

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Last updated: 2019-07-11 20:34