Pseudoxanthoma Elasticum
Summary
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.
Diagnosis
Formal diagnostic criteria for pseudoxanthoma elasticum (PXE) have been established [Uitto et al 2014].
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 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 variants in ABCC6 by molecular genetic testing (see Table 1).
Clinical Diagnosis
The diagnosis of PXE is established in an individual with characteristic skin lesions on the neck, axillae, and/or antecubital fosse and at least one characteristic retinal finding (peau d'orange, angioid streaks, or choroidal vascularization). When eye findings are characteristic but skin findings are equivocal or subtle, identification of calcified dystrophic elastic fibers using a von Kossa or similar stain on a biopsy of potentially lesional skin establishes the diagnosis.
Molecular Diagnosis
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of PXE has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
- Single-gene testing. Sequence analysis of ABCC6 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Sequence analysis is performed first; if only one or no pathogenic variant is found, gene-targeted deletion/duplication analysis is performed to detect intragenic deletions or duplications.Note: (1) Presence of the pseudogenes ABCC6P1 (which has high homology to exons1-9) and ABCC6P2 (high homology to exons 1-4) interferes with both sequence analysis and deletion/duplication analysis. (2) 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).(3) Targeted testing for the most common pathogenic variants may be performed first (see Table 7).
- A multigene panel that includes ABCC6 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
Comprehensive genomic testing. When the diagnosis of PXE has not been considered, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is often an option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Pseudoxanthoma Elasticum (PXE)
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| ABCC6 | Sequence analysis 3 | ~75%-86% 4 |
| Gene-targeted deletion/duplication analysis 5, 6 | ~10%-13% 4, 7 | |
| Unknown 8 | NA | ~4%-12% |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Chassaing et al [2007], Iwanaga et al [2017], Legrand et al [2017]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by Miksch et al [2005] and Kringen et al [2015]) may not be detected by these methods.
- 6.
Note, MLPA analysis using a widely available commercial kit does not include probes for exons 1, 3, 6, 16, 19-20, 29, and 31.
- 7.
A deletion of exons 23-29 is common (~11% of alleles in affected individuals) in European populations [Legrand et al 2017], and a deletion of exons 1-4 is common (~10% of alleles in affected individuals) in the Japanese population [Iwanaga et al 2017].
Clinical Characteristics
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.
Table 2.
Select Features of Pseudoxanthoma Elasticum (PXE)
| Feature | % of Persons with Feature | Comment |
|---|---|---|
| Skin lesions | 100% | In advanced stages, skin can become lax & redundant; sometimes reconstructive surgery is necessary. |
| Retinal involvement | 100% | Subretinal neovascularization w/hemorrhage can cause significant visual impairment. |
| Vascular (arterial arrowing) | 60% | Can cause claudication, small strokes, intestinal angina, renovascular hypertension, angina &/or myocardial infarction |
| GI bleeding | 10% | Most commonly in the upper GI tract |
Based on Uitto et al [2014]
GI = gastrointestinal
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 decent [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.
Differential Diagnosis
Hereditary Disorders
Table 3.
Genes of Interest in the Differential Diagnosis of Pseudoxanthoma Elasticum (PXE)
| Gene(s) | Disorder | MOI | Clinical Features Overlapping w/PXE | Differentiating Features |
|---|---|---|---|---|
| ATP6V0A2 EFEMP2 FBLN5 LTBP4 1 | Cutis laxa (see ATP6V0A2-Related Cutis Laxa, FBLN5-Related Cutis Laxa, EFEMP2-Related Cutis Laxa, LTBP4-Related Cutis Laxa) | AR AD | Loose & sagging skin mimicking PXE; no discrete papules or plaques | Skin lesions appear over the entire body; in PXE they are limited to the flexor areas. |
| ENPP1 | Generalized arterial calcification of infancy (GACI) | AR |
| GACI is very severe in children; PXE is very mild & often not apparent in childhood. |
| FGF23 GALNT3 KL | Hyperphosphatemic familial tumoral calcinosis | AR | Angioid streaks in the retina 3 | Skin lesions are present in PXE. |
| GGCX | PXE-like disorder w/multiple coagulation factor deficiency (OMIM 610842) | AR | Cutis laxa-like skin changes w/histolopathologic changes of PXE & deficiency of vitamin K-dependent clotting factors | No issues w/clotting in PXE |
| HBB | Beta-thalassemia | AR | PXE-like phenotype (skin, eye [angioid streaks in the retina 3], & cardiovascular) | Although similar, the angioid streaks are not concurrent w/skin lesions. |
| HBB | Sickle thalassemia (see Sickle Cell Disease) | AR | Angioid streaks in the retina 3 | Although similar, the angioid streaks are not concurrent w/skin lesions. |
| LEMD3 | Buschke-Ollendorf syndrome (BOS) (OMIM 166700) | AD | Osteopoikilosis assoc w/cutaneous papules w/accumulation of elastin in dermis |
|
| PDB4 SQSTM1 TNFRSF11A TNFRSF11B ZNF687 | Paget disease of bone (OMIM PS167250) | AD AR | Angioid streaks in the retina 3 | No skin lesions in Paget disease of bone |
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
- 1.
Cutis laxa may also be associated with pathogenic variants in ALDH18A1, ATP6V1A, ATP6V1E1, ELN, or PYCR1 (see Phenotypic Series: Cutis laxa).
- 2.
Nitschke et al [2012]
- 3.
PXE is the most common cause of angioid streaks of the retina.
Acquired Disorders and Disorders without a Known Genetic Cause
Skin
The skin lesions of pseudoxanthoma elasticum (PXE) are mimicked by those in the following acquired conditions:
- White fibrous papulosis of the neck and papillary dermal elastolysis, both signs of intrinsic aging, associated with thinning or loss of elastic fibers and focal thickening of the collagen fiber network (collectively known as fibroelastolytic papulosis)
- Solar elastosis, in which yellowish-white papules occur in the skin of the neck and chest as a result of photoaging
- Late-onset focal dermal elastosis
Long-term D-penicillamine treatment (used in the treatment of Wilson disease and prevention of cysteine kidney stones in cystinuria results in skin lesions that clinically resemble PXE but do not exhibit elastic fiber mineralization histologically [Bécuwe et al 2005].
Eyes
In high myopia, lacquer cracks may resemble angioid streaks.
Subretinal neovascularization with hemorrhage can be seen in the absence of angioid streaks in age-related macular degeneration, high myopia, and presumed ocular histoplasmosis. Macular atrophy can also be seen in age-related macular degeneration.
Recurrent Gastrointestinal Bleeding
PXE should be considered in the differential diagnosis of recurrent gastrointestinal bleeding of unknown cause [Dalle & Geboes 2002].
Management
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.
Table 4.
Recommended Evaluations Following Initial Diagnosis in Individuals with Pseudoxanthoma Elasticum (PXE)
| System/Concern | Evaluation | Comment | |
|---|---|---|---|
| Skin | Complete skin exam w/biopsy (if not done previously) by dermatologist | To establish a baseline | |
| Eye | Complete exam by retinal specialist, incl best corrected visual acuity, Amsler grid, OCT, 1 & retinal exam for neovascularization & macular atrophy | Early recognition of choroidal neovascularization assoc w/angioid streaks allows prompt treatment w/anti-angiogenesis drugs & appropriate surveillance. | |
| Reduced vision | Consultation w/agencies for the visually impaired 1 | Use of low vision aids 2 | |
| Gastrointestinal (bleeding, angina) | Obtain past medical history & medical records for findings consistent w/these potential complications | Referral to gastroenterologist | |
| Vascular | Claudication of leg &/or arm muscles | Obtain past medical history & medical records for findings consistent w/these potential vascular complications | Referral to vascular clinic |
| Stroke | Referral to neurologist/stroke clinic | ||
| Renovascular hypertension | Referral to nephrologist | ||
| Cardiovascular assessment | Referral to cardiologist for baseline exam | Cardiovascular issues (if present) may be exacerbated by PXE. | |
| Other | Consultation w/clinical geneticist &/or genetic counselor | ||
OCT = optical coherence tomography
- 1.
In the US, publicly funded agencies at the state level provide services for the blind or those with progressive eye disorders; services include vocational training, mobility training, and skills for independent living.
- 2.
Low vision aids such as magnifiers and closed-circuit television may provide useful reading vision for individuals with reduced central acuity.
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.
Table 5.
Treatment of Manifestations in Individuals with Pseudoxanthoma Elasticum (PXE)
| System/Concern | Treatment | Considerations/Other | |
|---|---|---|---|
| Skin | Reconstructive surgery 1 | Reconstructive surgery may be indicated to improve skin changes of the face, neck, axilla, & groin that are causing infection & inflammation. | |
| Eye | Current treatment for macular neovascularization, including intravitreal injection of anti-angiogenic drugs 2 | A retinal specialist should be consulted immediately for any distortion in vision or ↓ in visual acuity. | |
| Gastrointestinal | Surgical intervention may be indicated for Gl bleeding. 3 | Avoid use of aspirin & NSAIDs to reduce risk of GI bleeding. | |
| Vascular | Claudication of leg &/or arm muscles | Per treating vascular clinic/surgeon 4 | |
| Stroke | Per treating stroke clinic/neurologist | ||
| Renovascular hypertension | Per treating nephrologist 4 | ||
| Cardiovascular complications (angina, MI) | Management of angina &/or prior MI per treating cardiologist/cardiovascular surgeon 5 | ||
GI = gastrointestinal; MI = myocardial infarction; NSAIDs = nonsteroidal anti-inflammatory drugs
- 1.
As directed by a dermatologist or plastic surgeon
- 2.
Mimoun et al [2017], Battaglia Parodi et al [2019]
- 3.
Bleeding may be difficult to control without surgery [Dalle & Geboes 2002].
- 4.
See Anderson et al [2013] for clinical practice guidelines on the management of individuals with peripheral artery disease.
- 5.
See Fihn et al [2012] and Fihn et al [2014] for clinical practice guidelines on the management of individuals with stable ischemic heart disease.
Surveillance
Table 6.
Recommended Surveillance for Individuals with Pseudoxanthoma Elasticum (PXE)
| System/Concern | Evaluation | Frequency | |
|---|---|---|---|
| Skin | Consultation w/cosmetic dermatologist or reconstructive surgeon if redundant skin presents risk of infection | Per patient | |
| Eye | Retinal exam by retinal specialist | Annually, or more frequently as determined by treating ophthalmologist when retinal neovascularization is active &/or treatment is ongoing | |
| Patient use of Amsler grid to monitor for central visual disturbances | Daily | ||
| Gastrointestinal | Per treating gastroenterologist | Per treating gastroenterologist | |
| Vascular | Claudication of leg &/or arm muscles | Per treating vascular clinic/surgeon | Per treating vascular clinic/surgeon |
| Stroke | Per treating stroke clinic/neurologist | Per treating stroke clinic/neurologist | |
| Renovascular hypertension | Per treating nephrologist | Per treating nephrologist | |
| Cardiovascular complications angina, MI) | Per treating cardiologist | Per treating cardiologist | |
MI = myocardial infarction
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.