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Pseudoxanthoma Elasticum: for professionals


Overview

PrevalenceEstimated at 1 in 25,000 to 100,000 individuals
InheritanceAutosomal recessive
Genes Involved (OMIM No.)ABCC6 (#264800)
SymptomsProgressive vision loss, Metamorphopsia, Scotomas, Nyctalopia, Photopsia, Skin lesions (yellowish papules), Gastrointestinal haemorrhage, Loss of skin elasticity
Ocular FeaturesPeau d’orange Appearance
Angioid Streaks
Pattern Dystrophy-like Changes
Comet-like Lesions
Optic Nerve Head Drusen
Systemic FeaturesIncreased risk of cerebrovascular incidents, Peripheral artery disease, Organ asymptomatic calcification (e.g., breast, kidney, liver, spleen)
Key InvestigationsOphthalmic: Ophthalmic examination including fundoscopy, Optical coherence tomography (OCT), Fundus autofluorescence (FAF), Electroretinogram (ERG), Electro-oculogram (EOG), Fluorescein angiography (FA)

Systemic: Cardiovascular assessments (Echocardiography, Carotid Doppler ultrasound), Ankle-brachial index (ABI) testing, Dermatological examination, Imaging studies (Ultrasound, CT, MRI)
Molecular DiagnosisWhole genome sequencing with retinal panel, or targeted sequencing of ABCC6
ManagementOcular: Regular ophthalmic monitoring, Anti-VEGF therapy, Patient education on self-monitoring for symptoms of CNV

Systemic: Cardiovascular monitoring, Lifestyle modifications (smoking cessation, diet and exercise), Pharmacological management (antihypertensives, statins, antiplatelet agents), Dermatological care, Nutritional support

Genetic counselling, advice on family planning, emotional and practical support
Therapies under ResearchDS-1211b (NCT05569252), Magnesium supplements (NCT01525875), Bisphosphonates (NCT05030831), Etidronate (NCT05832580)

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Clinical phenotype

Pseudoxanthoma elasticum (PXE) is a rare genetic disorder characterised by progressive calcification and fragmentation of elastic fibres in various tissues throughout the body, particularly in the skin, eyes, and cardiovascular system.1,2

Presenting features

Ocular

  • Visual Disturbances: Patients may experience distortion or blurring of central vision, which can progress to significant vision loss.3
  • Metamorphopsia: A condition where straight lines appear wavy or distorted, often due to the development of choroidal neovascularisation (CNV).4
  • Scotomas: Blind spots in the visual field, particularly central scotomas, can develop due to retinal changes and CNV.
  • Nyctalopia: Difficulty seeing in low light or at night, although this is less common.
  • Photopsia: Flashes of light in the vision, particularly in the presence of retinal changes or CNV.

Systemic

  • Skin: Yellowish papules (xanthoma-like lesions) predominantly in the neck and axillae, with loss of skin elasticity leading to increased skin laxity.1,5
  • Cardiovascular: Accelerated atherosclerosis, increased risk of cerebrovascular incidents, peripheral artery disease, and possible gastrointestinal haemorrhage.
  • Other: Organ asymptomatic calcification (e.g., breast, kidney, liver, spleen) observed on ultrasound.

Fundus

  • Peau d’orange appearance: The earliest ophthalmic feature, presenting as a speckled appearance of the fundus due to calcification in Bruch’s membrane.1,2,6
  • Angioid streaks: Breaks in the calcified Bruch’s membrane appearing as jagged, irregular lines radiating from the optic disc. These streaks can lead to choroidal neovascularisation and central visual loss if untreated.
  • Pattern dystrophy-like changes: These changes may progress to chorioretinal atrophy independently of CNV development.
  • Comet-like lesions: Solitary, nodular yellow-white changes in the mid-peripheral fundus, often accompanied by a ‘comet tail’ of chorioretinal atrophy pointing towards the posterior pole.
  • Optic nerve head drusen: More common in PXE patients than in the general population.

Genetics

Gene: ABCC6 (ATP-binding cassette subfamily C member 6).

  • OMIM No.: #264800
  • Inheritance Pattern: Autosomal Recessive (note pseudodominant inheritance i.e., an autosomal recessive condition present in individuals in two or more generations, is reported in some families)
  • Function: ABCC6 encodes a transmembrane transporter protein involved in the transport of molecules such as ATP and glutathione. Dysfunction of ABCC6 disrupts calcium and phosphate homeostasis, leading to ectopic mineralisation in various tissues.7,8

Even with genetic testing it can be difficult to identify variants in ABCC6 because of its similar structure to two other genes. If the clinical index of suspicion is high and but genetic testing is negative, it is worth requesting specific sequencing of ABCC6. In the UK, a facility in Exeter is able to do this with specialised testing.

Further information about each gene can be found on OMIM and Medline Plus.

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Key investigations

Early detection and diagnosis of PXE rely on comprehensive clinical assessments and specialised investigations.

Ocular

  1. Optical Coherence Tomography (OCT)
    • Detection of subretinal fluid, often presenting as shallow serous detachments.
    • Hyper-reflective Bruch’s membrane, indicating calcification.
    • Areas of RPE atrophy and disruptions in the outer retinal layers.9
  2. Fundus Autofluorescence (FAF)
    • Patterns of hyper- and hypo-autofluorescence, highlighting areas of calcification and atrophy.
    • Enhanced visualisation of pattern dystrophy-like changes and comet-like lesions.10
  3. Electrophysiological Testing
    • Electroretinogram (ERG): Typically within normal limits, as PXE primarily affects the RPE and Bruch’s membrane rather than the retinal neurons.
    • Electro-oculogram (EOG): May show a reduced light peak to dark trough ratio, indicating RPE dysfunction.2
  4. Fluorescein Angiography (FA)
    • Highlights CNV and areas of subretinal leakage.11
  5. Genetic Testing
    • Whole genome sequencing with retinal panel, or targeted sequencing of ABCC6.

Systemic

  1. Cardiovascular Assessments
    • Echocardiography and carotid Doppler ultrasound to detect vascular calcifications and assess the risk of cerebrovascular incidents and peripheral artery disease.
    • Ankle-brachial index (ABI) testing to evaluate peripheral artery disease.12
  2. Dermatological Examination
    • Physical examination for yellowish papules and lax skin, primarily in the neck and axillary regions.
    • Skin biopsy showing clumping and fragmentation of elastic fibres with calcification.2
  3. Imaging Studies
    • Ultrasound, CT, or MRI scans to detect calcification in various organs such as the kidneys, liver, spleen, and breasts.Top of Form

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Diagnosis

A definitive diagnosis of PXE involves integrating clinical features, genetic testing results, and histopathological findings from skin biopsies. Consider PXE in young patients with macular atrophy and secondary neovascularisation. Angioid streaks can be subtle and not identified unless specifically looking for this.

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Differential Diagnoses

Differential diagnoses include other conditions presenting with similar cutaneous, ocular, or cardiovascular manifestations, such as Ehlers-Danlos syndrome, Marfan syndrome, and systemic sclerosis.

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Management

The management of PXE aims to address the multisystem manifestations of the disease and mitigate complications.

Ocular

  1. Regular Ophthalmic Monitoring
    • To monitor disease progression and detect early signs of CNV.
  2. Anti-VEGF Therapy
    • For the treatment of CNV, which can lead to severe vision loss.
    • Intravitreal injections of anti-VEGF agents such as bevacizumab, ranibizumab, or aflibercept.13,14
  3. Patient Education
    • To educate patients on self-monitoring for symptoms of CNV, such as sudden vision loss, scotomata, or metamorphopsia.
    • Use of Amsler grid for home monitoring.
    • Patients should be advised to wear goggles during contact spots as retinal detachments can occur at angioid streaks.

Systemic

  1. Cardiovascular Monitoring (by cardiology team)
    • To assess and manage the risk of atherosclerosis and related complications.
    • Regular cardiovascular assessments, including echocardiography, carotid Doppler ultrasound, and ankle-brachial index (ABI) testing.
  2. Lifestyle Modifications
    • Smoking Cessation: Strongly advised due to the negative impact of smoking on vascular health and overall disease progression.
    • Diet and Exercise: Adoption of a heart-healthy diet and regular physical activity to manage weight, blood pressure, and cholesterol levels.
  3. Pharmacological Management (by appropriate system specialists)
    • Use of antihypertensives, statins, and antiplatelet agents to manage hypertension, hyperlipidaemia, and reduce the risk of cardiovascular events.
    • Avoidance of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) due to the risk of gastrointestinal haemorrhage.
  4. Dermatological Care
    • Regular dermatological assessments to monitor skin changes and manage symptoms.15
    • Avoidance of excessive sun exposure and the use of sunscreens to prevent exacerbation of cutaneous lesions.
    • Options such as laser therapy or surgical excision may be considered for significant cosmetic or functional issues.
  5. Nutritional Support
  6. To ensure adequate nutrition and address any deficiencies that may arise due to gastrointestinal issues or dietary restrictions.

Family management and counselling

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Emotional and social support

Genetic counsellors and Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

Referral to a specialist centre

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive comprehensive management of their condition (genetic testing and genetic counselling) and to have the opportunity to participate in clinical research.

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Current research

  1. DS-1211b
    • NCT05569252: This Phase 2, 12-week, randomised, double-blind, placebo-controlled study evaluates the safety, tolerability, and pharmacodynamics of DS-1211b, a potent small-molecule inhibitor of tissue-nonspecific alkaline phosphatase. It aims to reduce ectopic calcification in individuals with PXE. Primary outcomes include treatment-emergent adverse events and changes in alkaline phosphatase levels.
  2. Magnesium Supplements
    • NCT01525875: This trial investigates the efficacy of magnesium supplements in treating PXE. The rationale is based on the hypothesis that magnesium may inhibit ectopic calcification processes.
  3. Bisphosphonates
    • NCT05030831: Phase 1/2, open-label, dose-finding study assessing the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple ascending doses of INZ-701, a recombinant ENPP1 fusion protein, in adults with ABCC6 deficiency causing Pseudoxanthoma elasticum (PXE). The study aims to identify an optimal dosing regimen for further clinical development, with exploratory endpoints including evaluations of arterial and organ calcification, ophthalmologic, cardiac, and renal parameters, as well as patient-reported outcomes.
  4. Etidronate
    • NCT05832580: A double-blind, placebo-controlled study evaluating the effect of etidronate on arterial calcification and vascular health in PXE patients aged 18-50. The primary endpoint is the difference in arterial calcification scores as measured by low-dose CT scans. Secondary endpoints include ophthalmological and dermatological assessments, vascular measurements, and quality of life evaluations. The trial aims to determine if early intervention with etidronate can prevent calcium deposit formation and improve vascular health in PXE patients.

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Further information and support

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References

  1. Uitto J, Jiang Q, Varadi A, Bercovitch LG, Terry SF. Pseudoxanthoma elasticum: diagnostic features, classification, and treatment options. Expert Opin Orphan Drugs. 2014;2:567-77.
  2. Terry SF, Uitto J. Pseudoxanthoma Elasticum. 2001 Jun 5 [Updated 2020 Jun 4]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1113/
  3. Gliem M, Müller PL, Birtel J, Hendig D, Holz FG, Charbel Issa P. Frequency, phenotypic characteristics and progression of atrophy associated with a diseased Bruch’s membrane in pseudoxanthoma elasticum. Invest Ophthalmol Vis Sci. 2016;57:3323-30.
  4. Risseeuw S, Ossewaarde-van Norel J, Klaver CCW, Colijn JM, Imhof SM, van Leeuwen R. Visual acuity in pseudoxanthoma elasticum. Retina. 2019;39:1580-7.
  5. Li Q, van de Wetering K, Uitto J. Pseudoxanthoma Elasticum as a Paradigm of Heritable Ectopic Mineralization Disorders: Pathomechanisms and Treatment Development. Am J Pathol. 2019;189(2):216-25. doi:10.1016/j.ajpath.2018.09.014.
  6. 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. 2005;42(12):881-92. doi:10.1136/jmg.2004.030171.
  7. Bergen AA. Pseudoxanthoma elasticum: the end of the autosomal dominant segregation myth. J Invest Dermatol. 2006;126:704-5.
  8. Legrand A, Cornez L, Samkari W, Mazzella JM, Venisse A, Boccio V, Auribault K, Keren B, Benistan K, Germain DP, Frank M, Jeunemaitre X, Albuisson J. Mutation spectrum in the ABCC6 gene and genotype-phenotype correlations in a French cohort with pseudoxanthoma elasticum. Genet Med. 2017;19:909-17.
  9. Gliem M, Müller PL, Birtel J, Hendig D, Holz FG, Charbel Issa P. Frequency, phenotypic characteristics and progression of atrophy associated with a diseased Bruch’s membrane in pseudoxanthoma elasticum. Invest Ophthalmol Vis Sci. 2016;57:3323-30.
  10. Charbel Issa P, Hess K. The complexity of visual dysfunction in patients with pseudoxanthoma elasticum. Eye (Lond). 2022;36(3):492-4. doi:10.1038/s41433-021-01858-7.
  11. Marques JP, Bernardes J, Geada S, Soares M, Teixeira D, Farinha C, et al. Non-exudative macular neovascularization in pseudoxanthoma elasticum. Graefes Arch Clin Exp Ophthalmol. 2021;259:873-82. doi:10.1007/s00417-020-04979-z.
  12. Lefthériotis G, Abraham P, Le Corre Y, Le Saux O, Henrion D, Ducluzeau PH, et al. Relationship between ankle brachial index and arterial remodeling in pseudoxanthoma elasticum. J Vasc Surg. 2011;54(5):1390-4.
  13. Mimoun G, Ebran JM, Grenet T, Donati A, Cohen SY, Ponthieux A. Ranibizumab for choroidal neovascularization secondary to pseudoxanthoma elasticum: 4-year results from the PIXEL study in France. Graefes Arch Clin Exp Ophthalmol. 2017;255:1651-60.
  14. Battaglia Parodi M, Romano F, Marchese A, Arrigo A, Llorenç V, Cicinelli MV, Bandello F, Adán A. Anti-VEGF treatment for choroidal neovascularization complicating pattern dystrophy-like deposit associated with pseudoxanthoma elasticum. Graefes Arch Clin Exp Ophthalmol. 2019;257:273-8.
  15. Marconi B, Bobyr I, Campanati A, Molinelli E, Consales V, Brisigotti V, et al. Pseudoxanthoma elasticum and skin: Clinical manifestations, histopathology, pathomechanism, perspectives of treatment. Intractable Rare Dis Res. 2015;4(3):113-22.

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Updated on June 3, 2024
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