eMedicine Specialties > Dermatology > Diseases of the Dermis
Pseudoxanthoma Elasticum
Updated: Nov 21, 2008
Introduction
Background
Pseudoxanthoma elasticum (PXE) is a rare, genetic disorder characterized by progressive calcification and fragmentation of elastic fibers in the skin, the retina, and the cardiovascular system, which is termed as elastorrhexia.1,2,3,4,5 The nomenclature was first given in 1896 by Darier, differentiating PXE from xanthomas and linking the pathology to elastic tissue fragmentation.6 Typically, cutaneous lesions begin in childhood, but, because of their asymptomatic nature, they are not noted until adolescence. In some individuals, skin lesions do not develop until later in life. This disease is important to recognize early to minimize the occurrence of retinal or gastrointestinal hemorrhage and cardiovascular complications.
Pathophysiology
Pseudoxanthoma elasticum (PXE) commonly involves the elastic fibers present in the mid and deep reticular dermis of skin, the Bruch membrane of the eye, and the blood vessels. Cases of involvement of the endocardium and the pericardium of the heart, the urinary tract, and pulmonary tissue have also been reported.
Frequency
United States
Pseudoxanthoma elasticum (PXE) has an estimated prevalence of 1 case in 25,000-100,000 population.7 Although autosomal dominant and autosomal recessive inheritance patterns have been reported, no molecular evidence for autosomal dominant inheritance has been established to date. Current research supports a common (probably exclusive) autosomal recessive inheritance of PXE.
Mortality/Morbidity
The cutaneous manifestations of pseudoxanthoma elasticum (PXE) are of cosmetic concern. Patients typically have a normal life span. The mortality and morbidity of PXE vary based on the extent of extracutaneous involvement (see Complications). Many of the pathological changes are irreversible. Prophylactic measures and lifestyle modifications can be used to minimize the risk of complications. Early detection of PXE is, therefore, of paramount importance.
Race
PXE has been reported in persons of all races.
Sex
The female-to-male ratio is 2:1.7
Age
The average age of onset is 13 years; however, ages can vary between infancy and the seventh decade of life or older, with a peak in the number of new cases from ages 10-15 years.
Clinical
History
Patients usually present to the dermatologist first with cutaneous manifestations of pseudoxanthoma elasticum (PXE) on the lateral part of the neck. The lesions are asymptomatic but of cosmetic concern.
- Extracutaneous presentations include mucosal involvement leading to gastrointestinal hemorrhage with melena, frank bleeding, occult blood in the stool, or hematemesis as the presenting sign.
- Patients may report fatigue from chronic blood loss or claudication from blood vessel involvement.
- Slowly, as the disease progresses, patients note more severe cutaneous and cardiovascular manifestations, such as angina and hypertension.
- Hematuria has also been reported.
- Retinal hemorrhages with loss of central vision occur after the fourth decade of life.
Physical
Physical findings of pseudoxanthoma elasticum (PXE) can be divided into cutaneous, ocular, and cardiovascular manifestations.
- Cutaneous manifestations
- The cutaneous manifestations of PXE are highly characteristic. The lesions usually develop in early childhood and are noted in adolescence; however, occasionally, they first appear in late adulthood.8,9,10
- Small, yellow papules of 1-5 mm in diameter are seen in a linear or reticular pattern and may coalesce to form plaques.11 The skin takes on a plucked chicken, Moroccan leather, or cobblestone appearance. Typically, these changes are first noted on the lateral part of the neck and later involve the antecubital fossae; the axillae; the popliteal spaces; the inguinal and periumbilical areas; the oral mucosa involving the lower lip, cheek, and palate; and the vaginal and rectal mucosae.12
- The lesions are almost perfectly symmetric. Most patients have limited skin surface involvement, but a generalized cutis laxa–like PXE is also reported.13
- As the disease progresses, the skin of the neck, the axillae, and the groin may become soft, lax, and wrinkled, hanging in folds. These folds can be easily corrected through plastic surgery.
- Horizontal and oblique mental creases before age 30 years is highly specific for PXE.14
- Other clinical presentations reported in literature include acneiform lesions, brown reticulate macules, and chronic granulomatous nodules.15,10 The cutaneous lesions of PXE usually remain unchanged throughout life.
- Elastosis perforans serpiginosa may coexist with PXE.
- Ocular manifestations
- The characteristic ocular manifestations of PXE are angioid streaks of the retina, which are slate gray to reddish brown curvilinear bands radiating from the optic disc.16
- Angioid streaks result from calcification of the elastic fibers in the Bruch membrane of the retina, with cracking and fissuring. This ocular change is symmetric bilaterally and is noted several years after the onset of cutaneous lesions, in patients aged 20-40 years. Angioid streaks are present in 85% of patients with PXE. Although these lesions are highly characteristic of PXE, they are not pathognomonic. Angioid streaks are found in a variety of other conditions, such as sickle cell anemia, thalassanemia, Paget disease of the bone, Marfan syndrome, Ehlers-Danlos syndrome, and lead poisoning.
- Fibrovascular ingrowth in the retina may lead to retinal hemorrhages, the most feared complication of the disease.
- Loss of central vision is progressive with each hemorrhage, but peripheral vision is always spared. Before hemorrhaging occurs, often, a subretinal net forms that can be detected by an Amsler grid and intravenous fluorescein angiography. Before angioid streaks are visible, patients often have leopard spotting of the posterior pole of the retina, concurrent with the onset of skin lesions. Yellowish speckled mottling described as peau d' orange is seen and is suggestive of early retinopathy.8
- Cardiovascular manifestations
- Cardiovascular manifestations, except for intermittent claudication, are usually the last lesions to be recognized in PXE. Calcification of the elastica media and intima of the blood vessels leads to a variety of physical findings. In adults, peripheral pulses are often severely diminished. Renal artery involvement leads to hypertension, and coronary artery disease causes angina pectoris and subsequent myocardial infarction.8 Mitral valve prolapse has a higher prevalence in PXE. This prolapse may not be significant unless the murmur of mitral valve insufficiency is also present.17
- Gastrointestinal hemorrhage, usually gastric in origin, is the most significant vascular complication of PXE, because of the fragility of calcified submucosal vessels.4 Hemorrhaging may occur early in the disease progression, especially in the second to fourth decade, without warning. Depending on its severity, hospitalization, blood transfusion, and surgery may be necessary. Ten percent of patients with PXE experience a gastrointestinal hemorrhage at some point in their lives. Less commonly, hemorrhaging may occur in the urinary tract or cerebrovascular system. Hematuria or potentially fatal increases in intracranial pressure are found in these cases, respectively.9,18
Causes
Pseudoxanthoma elasticum (PXE) is caused by mutations in the ATP-binding cassette transporter C6 (ABCC6),19,20 also known as multidrug resistance–associated protein 6 (MRP6) gene, which has been mapped to 16p13.1. To date, genetic studies have identified 90 different disease-causing mutations, mainly missense and nonsense mutations. The ABCC6 gene encodes for the cellular transport protein ABCC6/MRP6, giving rise to the concept of PXE as a systemic metabolic disorder rather than a purely structural disorder of connective tissue.
ABCC6 expression occurs in several types of affected tissues, including the skin, eyes, and arterial walls. However, it is most abundant in kidney and liver cells, suggesting that PXE could be a generalized metabolic disorder of cellular transport that results in an accumulation of metabolites, leading to the pathologic changes in the elastic fibers over time.21 To support the hypothesis, studies with fibroblasts grown in the sera of PXE patients, when compared with that in normal sera, interfered with the normal assembly of elastic fibers in vitro.22 Most recent studies strongly support the fact that PXE is primarily a systemic metabolic disorder with secondary mineralization of connective tissues.23
The notion also exists that lack of ABCC6 (-/-) leads to chronic oxidative stress.24 Elevated levels of intercellular adhesion molecule-1 (ICAM-1) and P- selectin were also found in patients with PXE, and oxidative stress was thought to be the contributing factor.25,26 One hypothesis is that ABCC6 secretes vitamin-K precursor from the liver and that clinical features simulating PXE are seen in rats treated with vitamin-K antagonists and in patients with mutations of gamma-glutamyl carboxylase gene. Based on this hypothesis, a precursor of vitamin-K that can be used by peripheral tissues may likely abate the process of PXE.27 However, supplementation with antioxidants such as vitamins C and E, selenium, and N -acetylcysteine have not been found to modify the ectopic mineralization process.24
From prior studies, the clinical implication of the up-regulation of ABCC6 gene expression through the retinoid X receptor by retinoids28 for PXE is yet to be investigated.
The Medscape Genomic Medicine Resource Center may be of interest.
More on Pseudoxanthoma Elasticum |
 Overview: Pseudoxanthoma Elasticum |
| Differential Diagnoses & Workup: Pseudoxanthoma Elasticum |
| Treatment & Medication: Pseudoxanthoma Elasticum |
| Follow-up: Pseudoxanthoma Elasticum |
| References |
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References
Neldner KH. Pseudoxanthoma elasticum. Int J Dermatol. Mar 1988;27(2):98-100. [Medline].
Connor PJ Jr, Juergens JL, Perry HO, Hollenhorst RW, Edwards JE. Pseudoxanthoma elasticum and angioid streaks. A review of 106 cases. Am J Med. Apr 1961;30:537-43. [Medline].
Pope FM. Historical evidence for the genetic heterogeneity of pseudoxanthoma elasticum. Br J Dermatol. May 1975;92(5):493-509. [Medline].
Goodman RM, Smith EW, Paton D, Bergman RA, Siegel CL, Ottesen OE, et al. Pseudoxanthoma elasticum: A clinical and histopathological study. Medicine (Baltimore). Sep 1963;42:297-334. [Medline].
Eddy D. Pseudoxanthoma elasticum. Internal manifestations. A report of cases and a statistical review of the literature. Arch Dermatol. 1962;86:729–40.
Darier J. Pseudoxanthoma elasticum. Monatshefte Praktische. 1896;23:609–17.
Bercovitch L, Terry P. Pseudoxanthoma elasticum 2004. J Am Acad Dermatol. Jul 2004;51(1 Suppl):S13-4. [Medline].
Hacker SM, Ramos-Caro FA, Beers BB, Flowers FP. Juvenile pseudoxanthoma elasticum: recognition and management. Pediatr Dermatol. Mar 1993;10(1):19-25. [Medline].
Sherer DW, Bercovitch L, Lebwohl M. Pseudoxanthoma elasticum: significance of limited phenotypic expression in parents of affected offspring. J Am Acad Dermatol. Mar 2001;44(3):534-7. [Medline].
Li TH, Tseng CR, Hsiao GH, Chiu HC. An unusual cutaneous manifestation of pseudoxanthoma elasticum mimicking reticulate pigmentary disorders. Br J Dermatol. Jun 1996;134(6):1157-9. [Medline].
McDonald HR, Schatz H, Aaberg TM. Reticular-like pigmentary patterns in pseudoxanthoma elasticum. Ophthalmology. Mar 1988;95(3):306-11. [Medline].
Spinzi G, Strocchi E, Imperiali G, Sangiovanni A, Terruzzi V, Minoli G. Pseudoxanthoma elasticum: a rare cause of gastrointestinal bleeding. Am J Gastroenterol. Aug 1996;91(8):1631-4. [Medline].
Uenishi T, Uchiyama M, Sugiura H, Danno K. Pseudoxanthoma elasticum with generalized cutaneous laxity. Arch Dermatol. May 1997;133(5):664-6. [Medline].
Lebwohl M, Lebwohl E, Bercovitch L. Prominent mental (chin) crease: a new sign of pseudoxanthoma elasticum. J Am Acad Dermatol. Apr 2003;48(4):620-2. [Medline].
Li TH, Tseng CR, Hsiao GH, Chiu HC. An unusual cutaneous manifestation of pseudoxanthoma elasticum mimicking reticulate pigmentary disorders. Br J Dermatol. Jun 1996;134(6):1157-9. [Medline].
Hu X, Plomp AS, van Soest S, Wijnholds J, de Jong PT, Bergen AA. Pseudoxanthoma elasticum: a clinical, histopathological, and molecular update. Surv Ophthalmol. Jul-Aug 2003;48(4):424-38. [Medline].
Lebwohl MG, Distefano D, Prioleau PG, Uram M, Yannuzzi LA, Fleischmajer R. Pseudoxanthoma elasticum and mitral-valve prolapse. N Engl J Med. Jul 22 1982;307(4):228-31. [Medline].
Heaton JP, Wilson JW. Pseudoxanthoma elasticum and its urological implications. J Urol. Apr 1986;135(4):776-7. [Medline].
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. Dec 2005;42(12):881-92. [Medline].
Katona E, Aslanidis C, Remenyik E, Csikós M, Kárpáti S, Paragh G, et al. Identification of a novel deletion in the ABCC6 gene leading to Pseudoxanthoma elasticum. J Dermatol Sci. Nov 2005;40(2):115-21. [Medline].
Ringpfeil F, Pulkkinen L, Uitto J. Molecular genetics of pseudoxanthoma elasticum. Exp Dermatol. Aug 2001;10(4):221-8. [Medline].
Le Saux O, Bunda S, VanWart CM, Douet V, Got L, Martin L, et al. Serum factors from pseudoxanthoma elasticum patients alter elastic fiber formation in vitro. J Invest Dermatol. Jul 2006;126(7):1497-505. [Medline].
Jiang Q, Endo M, Dibra F, Wang K, Uitto J. Pseudoxanthoma Elasticum Is a Metabolic Disease. J Invest Dermatol. Aug 7 2008;[Medline].
Li Q, Jiang Q, Uitto J. Pseudoxanthoma elasticum: oxidative stress and antioxidant diet in a mouse model (Abcc6-/-). J Invest Dermatol. May 2008;128(5):1160-4. [Medline].
Hendig D, Adam A, Zarbock R, Szliska C, Kleesiek K, Götting C. Elevated serum levels of intercellular adhesion molecule ICAM-1 in Pseudoxanthoma elasticum. Clin Chim Acta. Aug 2008;394(1-2):54-8. [Medline].
Götting C, Adam A, Szliska C, Kleesiek K. Circulating P-, L- and E-selectins in pseudoxanthoma elasticum patients. Clin Biochem. Apr 2008;41(6):368-74. [Medline].
Borst P, van de Wetering K, Schlingemann R. Does the absence of ABCC6 (multidrug resistance protein 6) in patients with Pseudoxanthoma elasticum prevent the liver from providing sufficient vitamin K to the periphery?. Cell Cycle. Jun 1 2008;7(11):1575-9. [Medline].
Ratajewski M, Bartosz G, Pulaski L. Expression of the human ABCC6 gene is induced by retinoids through the retinoid X receptor. Biochem Biophys Res Commun. Dec 1 2006;350(4):1082-7. [Medline].
Tsuji T. Three-dimensional architecture of altered dermal elastic fibers in pseudoxanthoma elasticum: scanning electron microscopic studies. J Invest Dermatol. May 1984;82(5):518-21. [Medline].
Galadari H, Lebwohl M. Pseudoxanthoma elasticum: Temporary treatment of chin folds and lines with injectable collagen. J Am Acad Dermatol. Nov 2003;49(5 Suppl):S265-6. [Medline].
Arndt KA, LeBoit PE. Inherited elastic tissue malformation. In: Cutaneous Medicine and Surgery. Vol 1. Philadelphia, Pa: WB Saunders; 1996:1770-74.
Bercovitch L, Terry P. Pseudoxanthoma elasticum 2004. J Am Acad Dermatol. Jul 2004;51(1 Suppl):S13-4. [Medline].
Champion RH, Burton JL. Disorders of Connective Tissue. In: Champion H, Burton JL, Burns DA, Breathnach SM, eds. Rook/Wilkinson/Ebling Textbook of Dermatology. Vol 6. Boston, Mass: Blackwell Science; 1998:2022-6.
Freedberg IM, Eisen AZ. Heritable disorders of connective tissue with skin changes. In: Fitzpatrick's Dermatology In General Medicine. Vol 5. New York, NY: McGraw-Hill; 1999:1843-44.
Hurwitz S. Hereditary skin disorders: the genodermatoses. In: Clinical Pediatric Dermatology. Vol 2. Philadelphia, Pa: WB Saunders; 1993:183-4.
Laube S, Moss C. Pseudoxanthoma elasticum. Arch Dis Child. Jul 2005;90(7):754-6. [Medline].
Lebwohl M, Phelps RG, Yannuzzi L, Chang S, Schwartz I, Fuchs W. Diagnosis of pseudoxanthoma elasticum by scar biopsy in patients without characteristic skin lesions. N Engl J Med. Aug 6 1987;317(6):347-50. [Medline].
Further Reading
Keywords
pseudoxanthoma elasticum, PXE, Grönbald-Strandberg syndrome, OMIM# 177850, OMIM# 264800, connective tissue disorder, calcification and fragmentation of elastic fibers, connective-tissue disorders
