Clinical characteristics.

Pseudoxanthoma elasticum (PXE) is a systemic disorder that affects the elastic tissue of the skin, the eye, and vascular system. Individuals most commonly present with angioid streaks of the retina found on routine eye examination or associated with retinal hemorrhage and/or characteristic papules in the skin. The most frequent cause of morbidity and disability in PXE is reduced vision due to complications of subretinal neovascularizations and macular atrophy. Other manifestations include premature gastrointestinal angina and/or bleeding, intermittent claudication of arm and leg muscles, stroke, renovascular hypertension, and cardiovascular complications (angina/myocardial infarction). Most affected individuals live a normal life span.

Diagnosis/testing.

The clinical diagnosis of PXE is established in a proband with characteristic skin lesions and at least one characteristic retinal finding. When eye findings are characteristic, but skin findings are equivocal, identification of calcified dystrophic elastic fibers using a von Kossa or similar stain on a biopsy of potentially lesional skin establishes the diagnosis.

The molecular diagnosis of PXE is established in a proband by the presence of biallelic ABCC6 pathogenic variants identified on molecular genetic testing.

Management.

Treatment of manifestations: Management requires coordinated input from multidisciplinary specialists; care by a retina specialist including intraocular injection of anti-angiogenic drugs for the treatment of macular neovascularization when indicated; standard-of-care interventions for gastrointestinal bleeding, claudication, stroke, renovascular hypertension, and cardiovascular complications (angina and/or myocardial infarction).

Surveillance: Routine examination by a retina specialist; follow up as recommended by treating physicians for vascular manifestations.

Agents/circumstances to avoid: Contact sports or racquet sports without appropriate eye and head protection; aspirin and nonsteroidal anti-inflammatory medications because of increased risk of gastrointestinal bleeding; smoking because of its vasoconstrictive properties.

Pregnancy management: Vaginal delivery appears safe for the retina of women with PXE if no active choroidal neovascularization (CNV) is present. Women with PXE should have a retinal examination to check for active CNV, as angioid streaks alone are not an indication for medical interventions during delivery.

Genetic counseling.

PXE is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic heterozygote (carrier), and a 25% chance of being unaffected and not a carrier. If both ABCC6 pathogenic variants have been identified in the family, carrier testing for at-risk family members, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

PXE should be suspected in individuals with the following clinical findings and family history.

Clinical findings

• Skin
  • Papules (darker than the skin color), usually seen on the lateral aspect of the neck or the flexural creases, such as the antecubital fossae, axillae, groin, or popliteal fossae
  • Plaques formed by coalescence of papules
  • Loose, slack, or droopy, redundant skin (especially of the neck, axilla, and groin) that occurs with time
• Eye
  • Peau d'orange generally appearing in the first decade and the late second decade, characterized by diffuse mottling of the fundus
  • Retinal angioid streaks often appearing in the second decade, consisting of broad grayish to reddish-brown irregular lines caused by breaks in Bruch's membrane* that appear to radiate outward from the optic disk or peripapillary region in a pattern that resembles blood vessels; hence the term "angioid"
    * Bruch's membrane is the elastin-rich tissue layer of the choroid between the retina and the choriocapillaris.
    Note: Fluorescein angiography may be necessary to confirm this retinal finding.
• Gastrointestinal bleeding, particularly the stomach. The characteristic yellow mucosal lesions of PXE can be seen on gastroscopy.
• Vascular. Beginning in the second decade of life, almost all individuals with PXE develop intermittent claudication.

Family history is consistent with autosomal recessive inheritance. Note: Pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations) has been reported in some families [Bergen 2006, Ringpfeil et al 2006, Legrand et al 2017].

Establishing the Diagnosis

The diagnosis of PXE can be established in a proband based on clinical findings or by identification of biallelic pathogenic (or likely pathogenic) variants in ABCC6 by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic ABCC6 variants of uncertain significance (or of one known ABCC6 pathogenic variant and one ABCC6 variant of uncertain significance) does not establish or rule out the diagnosis.

Clinical Description

Pseudoxanthoma elasticum (PXE) is a systemic disorder that affects the elastic tissue of the skin, the eye, and the cardiovascular and gastrointestinal systems. Individuals can present as early as age five years with papules in the skin and/or between ages ten and 30 years with angioid streaks of the retina found on routine eye examination or associated with retinal hemorrhage. Manifestations of other vascular involvement include gastrointestinal angina and/or bleeding, intermittent claudication of arm and leg muscles, stroke, and renovascular hypertension, especially at an unexpectedly young age.

Skin. Skin lesions are generally the first sign and are present between the first and second decade of life, but are often not recognized as a sign of PXE. The primary skin lesion is a papule that is somewhat darker than the person's natural skin tone, i.e., yellowish on white skin, black on brown skin, usually seen on the lateral aspect of the neck or the flexural creases (e.g., 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, lax, and redundant.

Mucous membranes can show similar yellowish 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 nearly every person with PXE, angioid streaks develop between the first and second decade.

Neither angioid streaks nor peau d'orange affects visual acuity; however, spontaneous subretinal neovascularization and hemorrhage can occur and lead to visual distortion (metamorphopsia) and decreased visual acuity, resulting in disciform scarring and, when the macula or fovea is involved, permanent loss of central vision. In some cases, atrophy similar to geographic atrophy in age-related macular degeneration develops and can be the cause of vision loss [Gliem et al 2016, Risseeuw et al 2019].

Gastrointestinal. The most common site of bleeding is the upper gastrointestinal tract, particularly the stomach. The cause of bleeding is not well understood; one theory is that it may begin with superficial bleeding from erosive gastritis, then becomes massive and uncontrolled due to defective vasoconstriction of affected arteries. Diffuse punctate bleeding and erosions can be seen on gastroscopy, but an exact source of the hemorrhage may be difficult to locate.

Vascular. Mineralization of the internal elastic lamina of medium-sized arteries, predominantly in peripheral arteries (arms, legs) and intracranial internal carotid arteries, resulting in arterial narrowing occurs frequently in PXE. Arterial narrowing can lead to asymmetric or diminished pulses in the limbs and, if severe enough, can cause intermittent claudication of the leg and arm muscles, small strokes (cerebrovascular arteries), intestinal angina (celiac or mesenteric arteries), and renovascular hypertension (renal arteries).

Although one small series suggested an increased incidence of mitral valve prolapse in individuals with PXE [Lebwohl et al 1982], this has never been replicated.

Genotype-Phenotype Correlations

No genotype-phenotype correlations for ABCC6 have been identified.

In addition, the phenotype does not differ between individuals with biallelic ABCC6 pathogenic variants and those who meet clinical diagnostic criteria but who do not have a known genetic cause.

Nomenclature

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

Prevalence

Prevalence data are not available.

Common disease-associated variants have been identified in individuals of European descent [Pfendner et al 2007, Legrand et al 2017] and in Japanese populations [Iwanaga et al 2017]. A founder variant was also identified in the Afrikaner population [Le Saux et al 2002]. See Table 7 for details about notable variants.

Hereditary Disorders

Acquired Disorders and Disorders without a Known Genetic Cause

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with pseudoxanthoma elasticum (PXE), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

No specific treatment for PXE exists.

Management of PXE requires coordinated input from multidisciplinary specialists (see Table 5). Support groups can benefit affected individuals and their families by providing accurate information and education and reducing isolation.

Surveillance

Agents/Circumstances to Avoid

Racquet and contact sports carry an increased risk for ocular and head trauma, both of which have been reported to precipitate retinal hemorrhage in patients with angioid streaks; participation in such activities should be discouraged.

Individuals with PXE who participate in sports and physical recreation should wear appropriate protective eyewear such as polycarbonate sports goggles and/or protective helmets with eye shields.

Aspirin and nonsteroidal anti-inflammatory medications should be avoided whenever possible to reduce the risk of gastrointestinal bleeding.

Smoking is strongly discouraged because of its vasoconstrictive properties.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of medical management and preventive measures. In those without a molecular diagnosis, at-risk sibs should be screened by clinical examination, medical history, and detailed review of cardiovascular systems. Evaluations can include:

• Retinal examination for peau d'orange and angioid streaks, which are usually evident by the first or second decade, and skin examination for characteristic skin lesions if the pathogenic variants in the family are not known;
• Molecular genetic testing if the ABCC6 pathogenic variants in the family are known.

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

Pregnancy Management

Most women with PXE have normal pregnancies; PXE is not associated with markedly increased fetal loss or adverse reproductive outcomes. The incidence of gastrointestinal bleeding and retinal complications (<1%) is lower than previously thought [Bercovitch et al 2004]. Retinal examination during pregnancy and prompt attention to any visual symptoms are advised. Vaginal delivery appears safe for the retina of women with PXE if no active choroidal neovascularization is present. Angioid streaks alone are not an indication for medical interventions during delivery.

In the series of 795 pregnancies examined by Bercovitch et al [2004], a history of pregnancy did not have a statistically significant effect on the severity of manifestations of PXE in women older than age 40 years. This was confirmed in a 2016 review of the literature [Camacho et al 2016].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

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

Note: Pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations) is reported in some families [Bergen 2006, Ringpfeil et al 2006, Legrand et al 2017].

Risk to Family Members

Parents of a proband

• If the parents of a proband are clinically unaffected, they are obligate heterozygotes (i.e., presumed to be carriers of one ABCC6 pathogenic variant based on family history).
• In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that affected children will be born to an affected individual and a carrier (or even to two affected individuals) resulting in pseudodominant inheritance.
• In very rare instances, only one parent is a carrier and the proband has PXE as the result of one inherited ABCC6 pathogenic variant and one de novo ABCC6 pathogenic variant [Legrand et al 2017].
• Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for an ABCC6 pathogenic variant and to allow reliable recurrence risk assessment.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an ABCC6 pathogenic variant, each sib of an affected individual has at conception 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.
• Intrafamilial clinical variability in PXE is observed; thus, sibs who inherit biallelic ABCC6 pathogenic variants may be more or less severely affected than the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

• Unless an affected individual's reproductive partner also has PXE or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in ABCC6.
• In populations with a high carrier rate and/or a high rate of consanguinity, the reproductive partner of the proband may have two ABCC6 pathogenic variants or be heterozygous. Thus, the risk to offspring is most accurately determined after molecular genetic testing of the proband's reproductive partner.

Other family members. If both parents of the proband are known to be heterozygous for an ABCC6 pathogenic variant, each sib of the proband's parents is at a 50% risk of being a carrier of a pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the ABCC6 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for clarification of genetic status, determination of genetic risk, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the ABCC6 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early confirmation or exclusion of the diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

ABCC6 encodes multidrug resistance-associated protein 6 (also known as ATP-binding cassette sub-family C member 6, ABCC6). Although the mechanism of action is not completely understood, there is evidence that disease-associated low levels of inorganic pyrophosphate in the blood cause mineralization in peripheral tissue.

Mechanism of disease causation. Loss of ABCC6 function causes the disease.

ABCC6-specific laboratory technical considerations. The presence of the two following pseudogenes interferes with both sequence analysis and deletion/duplication analysis:

• ABCC6P1, which has high homology to exons 1-9
• ABCC6P2, which has high homology to exons 1-4

Multiplex ligation-dependent probe amplification (MLPA) analysis to detect intragenic deletions or duplications using a widely available commercial kit does not include probes for exons 1, 3, 6, 16, 19-20, 29, and 31. Therefore, deletion or duplications confined to these exons cannot be detected by this assay. This technical challenge likely contributes to the disease alleles not detected in affected individuals (see Table 1).

Author Notes

Sharon F Terry, MA, is the co-founder of PXE International and co-investigator on more than 30 PXE clinical studies. Her publications exceed 170 peer-reviewed papers. She has given more than 500 presentations at national and international meetings. She manages the International PXE Research Consortium. She is the founder of the PXE BioBank and Registry. She is also the president and CEO of Genetic Alliance.

Dr Jouni Uitto is internationally recognized for his research on connective tissue biochemistry and molecular biology in relation to cutaneous diseases. Dr Uitto's publications include 725 original articles in peer-reviewed journals, 352 textbook chapters and review articles, and 1,048 abstracts on presentations at national and international meetings.

Author History

Jouni Uitto, MD (2020-present)
Lionel G Bercovitch, MD; Brown University (2001-2020)
Charles D Boyd, PhD; University of Hawaii (2001-2006)
Sharon F Terry, MA (2001-present)

Revision History

• 4 June 2020 (bp) Comprehensive update posted live
• 14 June 2012 (me) Comprehensive update posted live
• 2 April 2007 (st) Revision: Molecular Genetic Testing – targeted mutation analysis changed to deletion analysis
• 11 December 2006 (me) Comprehensive update posted live
• 5 November 2003 (me) Comprehensive update posted live
• 14 March 2002 (st) Author revision
• 5 June 2001 (me) Review posted live
• September 2000 (st) Original submission

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