Clinical Diagnosis

Current minimal criteria for the clinical diagnosis of pseudoxanthoma elasticum (PXE) are the presence of retinal angioid streaks in combination with characteristic skin lesions with or without a positive family history of PXE. However, carriers with a positive family history may have mild ocular and cutaneous findings [Bacchelli et al 1999, Sherer et al 2001].

Note: The minimal criteria for the diagnosis of PXE are likely to change once molecular genetic testing becomes more widely available.

• Angioid streaks are breaks in Bruch's membrane, the tissue layer between the retina and the choriocapillaris. Angioid streaks radiate from the optic disk in a pattern that resembles blood vessels, hence, the term 'angioid'. Angioid streaks are best observed on examination of the retina with an ophthalmoscope through a dilated pupil. Fluorescein angiography may be needed on occasion.

• Typical skin lesions are yellowish papules, usually seen on the lateral aspect of the neck or the flexural creases, such as the antecubital fossae, axillae, groin, or popliteal fossae. With time, the papulesf coalesce to form plaques and the skin becomes loose and redundant.

• A positive family history is defined as two or more family members with clinically diagnosed PXE.

Testing

Skin biopsy. Calcification of fragmented elastic fibers in a biopsy of lesional skin, confirmed by von Kossa stain, is diagnostic.

Molecular Genetic Testing

Gene. ABCC6 (MRP6), which encodes the ATP-binding cassette protein multidrug resistance-associated protein 6, is the only gene known to be associated with PXE both in families with autosomal recessive inheritance and in families with two-generation involvement (see Genetic Counseling, Evidence in support of AR inheritance pattern) [Struk et al 1997, van Soest et al 1997, Bergen et al 2000, Le Saux et al 2000].

Clinical use. Confirmatory diagnostic testing

Clinical testing

• Sequence analysis/mutation scanning. These methods detect missense mutations, the most prevalent mutations in ABCC6 [Le Saux et al 2001], as well as nonsense mutations, frameshift mutations, and small deletions and insertions, which have also been described. Testing strategies may involve screening of select exons (e.g., exons 24 and 28, in which a large number of mutations are located) before proceeding to sequencing of the remainder of the coding region [Hu et al 2004].

• Deletion analysis. A 16.4-kb deletion involving ABCC6 exons 23-29 is a recurrent mutation found in multiple populations with varying frequency. It has been shown to represent approximately 30% of alleles in the US and about 5% of alleles in Europe [Le Saux et al 2001].

Research testing

• Direct DNA. Molecular genetic testing for ABCC6 deletions and point mutations is available on a research basis only.

Table 1. Summary of Molecular Genetic Testing Used in Pseudoxanthoma Elasticum

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Gene	Test Methods	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
ABCC6	Sequence analysis / mutation scanning and deletion analysis	Sequence variants 2; del23-29	80% 3	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Hu et al [2004]

Interpretation of test results

• For issues to consider in interpretation of sequence analysis results, click here.

• Inheritance is autosomal recessive; however, in 20% of cases, no mutations are found.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in ABCC6 (MRP6).

Although an increased risk of premature coronary artery disease among carriers of ABCC6 mutation p.Arg1141X has been suggested [Wegman et al 2005], this has not been confirmed. Struk et al [2006], testing thousands of carriers, showed no association of coronary heart disease and ABCC6 mutations.

Natural History

Pseudoxanthoma elasticum (PXE) primarily affects the skin, eye, cardiovascular system, and gastrointestinal system. Individuals with PXE most commonly present with papules in the skin and/or with angioid streaks of the retina found on routine eye examination or associated with retinal hemorrhage. Rarely, individuals may present with vascular signs and symptoms: gastrointestinal bleeding or intermittent claudication. The most frequent cause of morbidity and disability in PXE is reduced vision from macular hemorrhage and disciform scarring. Most affected individuals live a normal life span.

Skin. The primary skin lesion is a yellowish papule, usually seen on the lateral aspect of the neck or the flexural creases, such as the antecubital fossae, axillae, groin, or popliteal fossae. Occasionally, there is periumbilical involvement. The papules gradually coalesce to form plaques, and eventually the skin, especially of the neck, axilla and groin becomes loose and redundant. Mucous membranes can show similar lesions, most commonly the inner aspect of the lower lip and the vaginal mucosa.

Eye. The earliest ocular finding is a diffuse mottling of the fundus known as peau d'orange, generally appearing between adolescence and the late second decade. In the second and third decades, angioid streaks develop. These broad grayish to reddish-brown irregular lines radiate outward from the optic nerve. They result from fractures in a mineralized Bruch's membrane, an elastin-rich layer of the choroid. Neither angioid streaks nor peau d'orange affects visual acuity; however, spontaneous subretinal neovascularization and hemorrhage can occur and lead to disciform scarring, and loss of central vision when the macula or fovea are involved.

Cardiovascular. Mineralization of the internal elastic lamina of medium-sized arteries resulting in arterial narrowing occurs frequently in PXE. Arterial narrowing can lead to asymmetric or diminished pulses in the limbs, causing intermittent claudication of the leg and arm muscles, or angina or myocardial infarction (coronary arteries), small strokes (cerebrovascular arteries), intestinal angina (celiac or mesenteric arteries), and renovascular hypertension (renal arteries). At least one small series suggested an increased incidence of mitral valve prolapse in individuals with PXE [Lebwohl et al 1982]. However, this has yet to be confirmed by larger prospective controlled studies.

Gastrointestinal. The most common site of bleeding is the upper gastrointestinal tract, particularly the stomach. The characteristic yellow mucosal lesions of PXE can be seen on gastroscopy. The cause of bleeding is not well understood; it may be the result of defective arterial constriction in response to erosive gastritis and superficial bleeding. Diffuse punctate bleeding and erosions can be seen and an exact source of the hemorrhage may be difficult to locate. Bleeding may be difficult to control without surgery.

Pregnancy. Most women with PXE have normal pregnancies. PXE is not associated with markedly increased fetal loss or adverse reproductive outcomes. The incidence of gastric bleeding and retinal complications (<1%) is lower than previously thought [Bercovitch et al 2004].

Genotype-Phenotype Correlations

To date, no genotype-phenotype correlations are known.

Nomenclature

Earlier reports sometimes referred to PXE as Grondblad-Strandberg syndrome.

Prevalence

The exact prevalence is unknown. Published reports estimate prevalence from 1:25,000 to 1:100,000.

A few populations have an increased risk, such as the Afrikaners in South Africa, who display a founder effect [Le Saux et al 2002].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with pseudoxanthoma elasticum (PXE):

• Complete skin examination, including a biopsy of potentially lesional skin from the axilla or neck. It should be stained with a von Kossa stain, looking for calcified fragmented elastic fibers.

• Complete dilated eye examination by a retinal specialist, particularly looking for peau d'orange and angioid streaks. A fluorescein angiogram may be necessary to confirm the diagnosis.

• Baseline cardiovascular examination with periodic follow-up for individuals with pseudoxanthoma elasticum (PXE), including, as clinically indicated (depending on age, physical findings, and exercise level): echocardiography, cardiac stress testing, and Doppler evaluation of peripheral vasculature

Treatment of Manifestations

No specific treatment for PXE exists.

Management of PXE requires coordinated input from a multidisciplinary team of specialists including a dermatologist, primary care physician, ophthalmologist, cardiologist, vascular surgeon, plastic surgeon, genetics professional, and nutritionist. Support groups can benefit affected individuals and their families by providing accurate information and education and reducing isolation.

Current treatment for macular degeneration, especially the intraocular injection of anti-angiogenic drugs, appears to be effective in PXE. A retinal specialist should be consulted immediately when the individual experiences any distortion in vision.

Surgical intervention may be indicated for gastrointestinal bleeding, severe peripheral vascular disease (if correctable), and the improvement of changes of the skin of the face, neck, axilla, and groin that are of cosmetic concern. Although wound healing seems to be uncomplicated in PXE, cosmetic acceptability of surgery involving the skin is less predictable [Viljoen et al 1990].

Prevention of Primary Manifestations

Weight control, avoidance of smoking, and aggressive management of hypertension and lipid disorders may reduce the risk of vascular complications by reducing the risk of comorbidity resulting from atherosclerosis. Reduction in risk has not been confirmed in controlled studies.

Prevention of Secondary Complications

Individuals with PXE who have coexistent mitral valve prolapse should have antibiotic prophylaxis for dental, gastrointestinal, and genitourinary procedures.

Surveillance

The following are appropriate:

• Routine examination by an ophthalmologist with expertise in retinal disease. Affected individuals benefit from learning to use the Amsler grid to monitor for central visual disturbances.

• Routine physical examination with specific attention to the cardiovascular system

• Monitoring by patient for black tarry stool

• Periodic monitoring of serum lipid concentrations

Agents/Circumstances to Avoid

Avoid contact sports.

Wear appropriate protective goggles to prevent eye injuries.

When possible, avoid aspirin and nonsteriodal anti-inflammatory medications (NSAIDs) to reduce the risk of gastrointestinal bleeding.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Pentoxifylline and cilostazol may be of value in managing intermittent claudication; however, controlled studies of these drugs in individuals with PXE-related peripheral arterial disease have not been conducted.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff.

PXE International Blood and Tissue Registry
Phone: 202-362-9599
Fax: 202-966-8553
Email: info@pxe.org
Web: www.pxe.org

Other

Although it has been reported that high calcium intake in adolescence may correlate with the overall severity of PXE [Renie et al 1984], this has not been confirmed by prospective controlled studies and remains controversial.

The AREDS study for macular degeneration suggested that a regimen of antioxidant vitamins could prove beneficial in that disease. It is possible (although not confirmed) that the same recommendation can be made for PXE [Clemons et al 2004].

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Pseudoxanthoma elasticum (PXE) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of the proband

• The parents of an affected individual are obligate heterozygotes and therefore carry one mutant allele.

• Heterozygotes (carriers) may have minimal or mild clinical findings.

• It is not known at this time to what degree parents who are carriers of a mutant allele causing PXE are at risk for some manifestations of the disorder. The presence of calcified elastic fibers on biopsy of lesional skin and limited ocular and cutaneous signs of PXE in parents may be consistent with the heterozygous carrier state [Sherer et al 2001].

• It is suggested that parents of a proband undergo thorough ocular and skin examination for signs of PXE and possibly biopsy of axillary, antecubital fossae, or neck skin, even in the absence of overt lesions. Most relatives will have peau d'orange and/or angioid streaks by the first or second decade if they are affected. Of note, positive findings must be interpreted with caution.

Sibs of the proband

• At conception, each sib of an individual with autosomal recessive PXE has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.

• Most relatives will have peau d'orange and/or angioid streaks by the first or second decade if they are affected. Heterozygotes (carriers) may have minimal clinical findings.

Offspring of the proband. The offspring of an individual with autosomal recessive PXE are obligate heterozygotes (carriers) for a mutant allele causing PXE (see heterozygotes).

Other family members of the proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Heterozygotes. Heterozygotes (carriers) are usually asymptomatic; however, subclinical, but detectable, abnormalities of elastic fibers have been observed on skin biopsy and are difficult to interpret. In apparently unaffected individuals, skin biopsy may reveal subtle abnormalities of elastic fibers suggesting expression of the genetic changes that cause the classic PXE phenotype [Bacchelli et al 1999]. Such studies are currently ongoing.

Carrier Detection

Carrier testing for at-risk family members is available on a clinical basis once the mutations have been identified in the proband.

Related Genetic Counseling Issues

Evidence in support of autosomal recessive inheritance pattern. Although early literature on PXE suggests autosomal dominant inheritance based on the observation of two-generation familial occurrence of PXE, these cases have been shown to be pseudodominant [Bergen 2006, Ringpfeil et al 2006]. No three-generation affected pedigrees have been reported. Autosomal dominant inheritance has not been confirmed.

The traditional mechanisms used to determine mode of inheritance (pedigree analysis combined with skin biopsy and eye examination) may be inconclusive because carriers may exhibit characteristic changes resulting in the appearance of two-generation involvement [Sherer et al 2001].

Family planning. The optimal time for determination of genetic risk is before pregnancy.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

No laboratories offering molecular genetic testing for prenatal diagnosis of PXE are listed in the GeneTests™ Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutations have been identified in an affected family member in a research or clinical laboratory. For laboratories offering custom prenatal testing, see .

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified in an affected family member. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

1. Bacchelli B, Quaglino D, Gheduzzi D, Taparelli F, Boraldi F, Trolli B, Le Saux O, Boyd CD, Ronchetti IP. Identification of heterozygote carriers in families with a recessive form of pseudoxanthoma elasticum (PXE). Mod Pathol. 1999;12:1112–23. [PubMed: 10619263]
2. Becuwe C, Dalle S, Ronger-Savle S, Skowron F, Balme B, Kanitakis J, Thomas L. Elastosis perforans serpiginosa associated with pseudo-pseudoxanthoma elasticum during treatment of Wilson's disease with penicillamine. Dermatology. 2005;210:60–3. [PubMed: 15604549]
3. Bercovitch L, Leroux T, Terry S, Weinstock MA. Pregnancy and obstetrical outcomes in pseudoxanthoma elasticum. Br J Dermatol. 2004;151:1011–8. [PubMed: 15541079]
4. Bergen AA, Plomp AS, Schuurman EJ, Terry S, Breuning M, Dauwerse H, Swart J, Kool M, van Soest S, Baas F, ten Brink JB, de Jong PT. Mutations in ABCC6 cause pseudoxanthoma elasticum. Nat Genet. 2000;25:228–31. [PubMed: 10835643]
5. Bergen AA. Pseudoxanthoma elasticum: the end of the autosomal dominant segregation myth. J Invest Dermatol. 2006;126:704–5. [PubMed: 16541094]
6. Clemons TE, Kurinij N, Sperduto RD. Associations of mortality with ocular disorders and an intervention of high-dose antioxidants and zinc in the Age-Related Eye Disease Study: AREDS Report No. 13. Arch Ophthalmol. 2004;122:716–26. [PMC free article: PMC1473208] [PubMed: 15136320]
7. Dalle I, Geboes K. Vascular lesions of the gastrointestinal tract. Acta Gastroenterol Belg. 2002;65:213–9. [PubMed: 12619428]
8. Hu X, Plomp A, Gorgels T, Brink JT, Loves W, Mannens M, de Jong PT, Bergen AA. Efficient molecular diagnostic strategy for ABCC6 in pseudoxanthoma elasticum. Genet Test. 2004;8:292–300. [PubMed: 15727254]
9. Kool M, van der Linden M, de Haas M, Baas F, Borst P. Expression of human MRP6, a homologue of the multidrug resistance protein gene MRP1, in tissues and cancer cells. Cancer Res. 1999;59:175–82. [PubMed: 9892204]
10. Le Saux O, Beck K, Sachsinger C, Silvestri C, Treiber C, Göring HH, Johnson EW, De Paepe A, Pope FM, Pasquali-Ronchetti I, Bercovitch L, Marais AS, Viljoen DL, Terry SF, Boyd CD. A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum. Am J Hum Genet. 2001;69:749–64. [PMC free article: PMC1226061] [PubMed: 11536079]
11. Le Saux O, Beck K, Sachsinger C, Treiber C, Goring HH, Curry K, Johnson EW, Bercovitch L, Marais AS, Terry SF, Viljoen DL, Boyd CD. Evidence for a founder effect for pseudoxanthoma elasticum in the Afrikaner population of South Africa. Hum Genet. 2002;111:331–8. [PubMed: 12384774]
12. Le Saux O, Urban Z, Tschuch C, Csiszar K, Bacchelli B, Quaglino D, Pasquali-Ronchetti I, Pope FM, Richards A, Terry S, Bercovitch L, de Paepe A, Boyd CD. Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum. Nat Genet. 2000;25:223–7. [PubMed: 10835642]
13. Lebwohl MG, Distefano D, Prioleau PG, Uram M, Yannuzzi LA, Fleischmajer R. Pseudoxanthoma elasticum and mitral-valve prolapse. N Engl J Med. 1982;307:228–31. [PubMed: 7088072]
14. Renie WA, Pyeritz RE, Combs J, Fine SL. Pseudoxanthoma elasticum: high calcium intake in early life correlates with severity. Am J Med Genet. 1984;19:235–44. [PubMed: 6507474]
15. Ringpfeil F, McGuigan K, Fuchsel L, Kozic H, Larralde M, Lebwohl M, Uitto J. Pseudoxanthoma elasticum is a recessive disease characterized by compound heterozygosity. J Invest Dermatol. 2006;126:782–6. [PubMed: 16410789]
16. Sherer DW, Bercovitch L, Lebwohl M. Pseudoxanthoma elasticum: significance of limited phenotypic expression in parents of affected offspring. J Am Acad Dermatol. 2001;44:534–7. [PubMed: 11209132]
17. Struk B, Neldner KH, Rao VS, St Jean P, Lindpaintner K. Mapping of both autosomal recessive and dominant variants of pseudoxanthoma elasticum to chromosome 16p13.1. Hum Mol Genet. 1997;6:1823–8. [PubMed: 9302259]
18. Struk B, Renner W, Lindpaintner K, Winkelmann BR, Boehm BO, Maerz W. Two ABCC6 gene polymorphisms are not associated with variation in plasma lipid levels in the Ludwigshafen Risk and Cardiovascular Health Study. Poster session. New Orleans, LA: American Society of Human Genetics 56th Annual Meeting; 2006.
19. van Soest S, Swart J, Tijmes N, Sandkuijl LA, Rommers J, Bergen AA. A locus for autosomal recessive pseudoxanthoma elasticum, with penetrance of vascular symptoms in carriers, maps to chromosome 16p13.1. Genome Res. 1997;7:830–4. [PMC free article: PMC310666] [PubMed: 9267806]
20. Viljoen DL, Bloch C, Beighton P. Plastic surgery in pseudoxanthoma elasticum: experience in nine patients. Plast Reconstr Surg. 1990;85:233–8. [PubMed: 2300628]
21. Wegman JJ, Hu X, Tan H, Bergen AA, Trip MD, Kastelein JJ, Smulders YM. Patients with premature coronary artery disease who carry the ABCC6 R1141X mutation have no pseudoxanthoma elasticum phenotype. Int J Cardiol. 2005;100:389–93. [PubMed: 15837081]

Suggested Reading

1. Hu X, Plomp AS, van Soest S, Wijnholds J, de Jong PT, Bergen AA. Pseudoxanthoma elasticum: a clinical, histopathological, and molecular update. Surv Ophthalmol. 2003;48:424–38. [PubMed: 12850230]
2. Terry SF, Boyd CD. Researching the biology of PXE: partnering in the process. Am J Med Genet. 2001;106:177–84. [PubMed: 11778977]
3. Uitto J, Boyd CD, Lebwohl MG, Moshell AN, Rosenbloom J, Terry S. International Centennial Meeting on Pseudoxanthoma Elasticum: progress in PXE research. J Invest Dermatol. 1998;110:840–2. [PubMed: 9579557]

Author Notes

Sharon Terry, Founding Executive Director of PXE International, manages the 19-lab PXE International Research consortium, 54 offices worldwide, and the PXE International Blood and Tissue Bank. She is co-investigator for studies occurring in all of the labs. She is also President & CEO of Genetic Alliance, a coalition of 600 disease advocacy organizations representing 1000 diseases.

Lionel Bercovitch, MD, Medical Director of PXE International and Clinical Professor of Dermatology at Brown Medical School, coordinates all of the research that PXE International initiates and oversees the production of educational materials for affected individuals and health professionals.

Web: www.pxe.org

Author History

Lionel G Bercovitch, MD (2001-present)
Charles D Boyd, PhD; University of Hawaii (2001-2006)
Sharon F Terry, MA (2001-present)

Revision History

• 2 April 2007 (st) Revision: Molecular Genetic Testing - targeted mutation analysis changed to deletion analysis

• 11 December 2006 (me) Comprehensive update posted to live Web site

• 5 November 2003 (me) Comprehensive update posted to live Web site

• 14 March 2002 (st) Author revision

• 5 June 2001 (me) Review posted to live Web site

• September 2000 (st) Original submission