AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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. The nomenclature was first given in 1896 by Darier, differentiating PXE from xanthomas and linking the pathology to elastic tissue fragmentation. 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

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

PXE has an estimated prevalence of 1 case in 25,000-100,000 population. 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 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 all races.

Sex

The female-to-male ratio is 2:1.

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Patients usually present to the dermatologist first with cutaneous manifestations of 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 complain of 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 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, but, occasionally, they first appear in late adulthood.
  • Small, yellow papules of 1-5 mm in diameter are seen in a linear or reticular pattern and may coalesce to form plaques.¹ 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.
  • The lesions are almost perfectly symmetric. Most patients have limited skin surface involvement, but a generalized cutis laxa–like PXE is also reported.
  • 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.
  • Other clinical presentations reported in literature include acneiform lesions, brown reticulate macules, and chronic granulomatous nodules. 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.
  • 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.
• 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. 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.²
  • Gastrointestinal hemorrhage, usually gastric in origin, is the most significant vascular complication of PXE, because of the fragility of calcified submucosal vessels. 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.

Causes

PXE is caused by mutations in the ATP-binding cassette transporter C6 (ABCC6),^{3, 4} 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. To support the hypothesis, recent literature shows that the 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.⁵ Another interesting finding is that the expression of the ABCC6 gene was found to be up-regulated by retinoids through the retinoid X receptor.⁶ The clinical implication of this finding related to PXE is yet to be investigated.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Disseminated dermatofibroma lenticularis (Buschke-Ollendorff syndrome)
Localized acquired cutaneous PXE
Long-term penicillamine therapy
Marfan syndrome
Severe actinic damage to the lateral part of the neck
Papular elastorrhexis
Perforating periumbilical PXE

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Perform a CBC count to screen for iron deficiency anemia from occult blood loss.
• Perform a fecal occult blood test to screen for occult blood loss from the gastrointestinal hemorrhage.
• Perform a urinalysis to screen for urinary tract hemorrhage.
• Obtain serum lipid levels. Elevated serum lipid levels aggravate the disease course and should be treated.
• Obtain calcium and phosphate levels. The serum calcium and phosphate levels are usually in the reference range in PXE, but hypercalcemia and hyperphosphatemia have been reported.

Imaging Studies

• Echocardiography is indicated in patients with a murmur of mitral valve insufficiency, anginal symptoms, or a personal or family history of coronary artery disease.
• CT of the head may be performed if the physical examination shows focal neurologic deficits or other signs of cerebral hemorrhage.
• Radiographs may detect soft-tissue or large artery calcification.

Procedures

• An ophthalmologic examination is essential to detect early signs of retinopathy, angioid streaks, and retinal hemorrhages. Laser treatment may spare vision.
• Upper or lower endoscopy is indicated if the patient has hematemesis, occult blood in the stools, melena, or frank bleeding. Endoscopy allows for treatment as well as diagnosis and is more sensitive than upper gastrointestinal series and barium enema.
• Ankle/brachial blood pressure using Doppler methods is useful in patients experiencing intermittent claudication or in patients with significantly diminished peripheral pulses to ensure adequate tissue perfusion.

Histologic Findings

On cutaneous hematoxylin-eosin stains, elastic fibers are basophilic because of the calcium deposition. The fibers are fragmented, swollen, and clumped in the middle and deep reticular dermis. Collagen fibers are also split and are said to unwind or flower. Similar calcification is noted in the tunic media and intima of the blood vessels. Special stains for calcium deposits (eg, von Kossa) and the elastic fibers (eg, Verhoeff van Gieson, Orcein) can confirm the diagnosis.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Many of the pathologic changes associated with PXE are irreversible, but prophylactic measures can be undertaken to minimize the disease course.

• Cutaneous lesions: The sagging folds of skin that present late in the course of PXE can be easily corrected by surgical excision of redundant skin folds if the patient desires. Collagen⁷ and autologous fat injections may be options for mental crease treatment.
• Cardiovascular lesions
• • Diet and exercise are the main methods to minimize the extent of cardiovascular disease. A diet low in lipids and calcium (600-1200 mg/d) is recommended. Elevated serum lipid levels and hypertension aggravate the disease course. Both of these related conditions should be controlled with diet and exercise first, followed by drug therapy if necessary. Intermittent claudication can be treated by weight reduction and an exercise program to stimulate collateral blood vessel development. Pentoxifylline may be used but with extreme caution of hemorrhage. Excessive dietary calcium consumption should be avoided in childhood and adolescence because a correlation of severity of PXE with high calcium intake has been suggested.
  • Signs and symptoms of gastrointestinal hemorrhage, such as melena or frank blood, must be monitored closely. Aspirin and nonsteroidal anti-inflammatory drugs should be avoided. Gastrointestinal hemorrhage may be managed by hospitalization, iron supplements, blood transfusions, endoscopic treatment, or surgery with partial gastrectomy if necessary.
  • If the murmur of mitral valve insufficiency is present, prophylactic antibiotics against bacterial endocarditis should be used before any dental procedure or surgery. Current recommendations are 2 g of amoxicillin 1 hour before the procedure.
  • Patients are advised to stop tobacco use. Tobacco has been shown to aggravate the disease course.
• Ocular lesions
• • Retinal hemorrhages are preceded by a subretinal membrane formation, which can be detected by an Amsler grid used regularly by the patient. A change can be confirmed by intravenous fluorescein angiography. This early detection allows for the use of laser coagulation to minimize vision loss.
  • Patients should avoid heavy lifting, straining, and head trauma, which increase the risk of retinal hemorrhage.
  • Adolescents should not participate in weight lifting or head-contact sports.
  • Vitamins A, C, and E and zinc supplements may reduce the risk of hemorrhage.
  • Interferon alpha-2a may be a potential treatment.

Consultations

• All patients with PXE should be monitored on a regular basis by an ophthalmologist. Funduscopy is recommended because eye changes may precede cutaneous signs.
• Gastrointestinal hemorrhages should be referred to a gastroenterologist, and cardiovascular manifestations are best managed by a cardiologist.
• If pulmonary, urinary tract, or cerebral involvement is present, appropriate referrals should be made.
• Patients and their families should receive genetic counseling. Current evidence suggests that the inheritance pattern in PXE is usually autosomal recessive. Recurrence risks in sporadic cases are therefore generally low.
• Women with PXE rarely experience gastric or uterine bleeding and are more likely to develop perineal tears and abdominal striae. Pregnancy is otherwise well tolerated, except for an increase in the number of miscarriages in the first trimester. However, multiple pregnancies do aggravate the disease course.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Hemorheologic agents

These agents are used for the symptomatic treatment of peripheral vascular disease.

Drug Category: Antibiotics

Antibiotic prophylaxis is given to patients with murmur of mitral valve insufficiency prior to performing procedures that may cause bacterial endocarditis.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Regular fecal occult blood testing and CBC count should be performed to monitor for gastrointestinal hemorrhaging every 6 months to 1 year.
• An ophthalmologic examination should be performed at least once a year to detect early retinopathy, angioid streaks, or retinal hemorrhage.
• Regular physical examinations, with particular attention to the cardiovascular system, should be performed to detect mitral valve insufficiency, coronary artery disease, or peripheral vascular compromise.
  

Complications

• Ocular involvement with retinal hemorrhages can lead to the progressive loss of central vision. Peripheral vision is always spared.
• Involvement of the elastic media and intima of the arteries can lead to claudication, hypertension, angina, myocardial infarction, and gastrointestinal or cerebral hemorrhage.
• Cerebral and gastrointestinal hemorrhage or coronary occlusion, although uncommon, may be fatal.

Prognosis

• The prognosis of PXE largely depends on the extent of extracutaneous organ involvement. Patients typically have a normal life span, but acute gastrointestinal hemorrhage, myocardial infarction, or cerebral hemorrhage may be fatal.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Special Concerns

• Pregnancy is not contraindicated in these patients; however, the risk of miscarriage is increased in the first trimester.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. McDonald HR, Schatz H, Aaberg TM. Reticular-like pigmentary patterns in pseudoxanthoma elasticum. Ophthalmology. Mar 1988;95(3):306-11. [Medline].
2. 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].
3. 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].
4. Katona E, Aslanidis C, Remenyik E, Csikos M, Karpati 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].
5. 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].
6. 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].
7. 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].
8. Arndt KA, LeBoit PE. Inherited elastic tissue malformation. In: Cutaneous Medicine and Surgery. Vol 1. Philadelphia, Pa: WB Saunders; 1996:1770-74.
9. Bercovitch L, Terry P. Pseudoxanthoma elasticum 2004. J Am Acad Dermatol. Jul 2004;51(1 Suppl):S13-4. [Medline].
10. 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.
11. 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.
12. Hurwitz S. Hereditary skin disorders: the genodermatoses. In: Clinical Pediatric Dermatology. Vol 2. Philadelphia, Pa: WB Saunders; 1993:183-4.
13. Laube S, Moss C. Pseudoxanthoma elasticum. Arch Dis Child. Jul 2005;90(7):754-6. [Medline].
14. 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].
15. 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].
16. Neldner KH. Pseudoxanthoma elasticum. Int J Dermatol. Mar 1988;27(2):98-100. [Medline].
17. 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].

Article Last Updated: Jun 20, 2007