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Flemish Disease (Pseudoxanthoma Elasticum)

Overview

Pseudoxanthoma elasticum (PXE), historically called “Flemish disease,” is a rare, inherited disorder that affects the connective tissue in the skin, eyes, and cardiovascular system. The disease is characterized by the progressive breakdown and calcification of elastic fibers, leading to characteristic skin lesions, visual problems, and vascular complications.

Who it affects: PXE is autosomal‑recessive, meaning a child must inherit two defective copies of the ABCC6 gene—one from each parent—to develop the condition. Both males and females are equally affected. The disease typically presents in late childhood to early adulthood, though subtle signs may appear earlier.

Prevalence: Global estimates range from 1 in 25,000 to 1 in 70,000 individuals, making it one of the more common rare genetic connective‑tissue disorders. Higher frequencies have been reported in isolated communities with a limited gene pool (e.g., certain regions of Belgium, France, and Japan).<sup>[1] WHO Rare Diseases Database, 2023</sup>

Symptoms

The clinical picture varies widely, but the three organ systems most frequently involved are:

Skin

• Yellow‑white papules—small, flat‑topped bumps most often seen on the neck, axillae, groin, and flexural areas. They may coalesce into larger plaques.
• Loose, inelastic skin—especially over the neck (“chicken‑skin” appearance).
• Hyperpigmentation or atrophy—areas of darker or thinner skin surrounding lesions.

Eyes

• Angioid streaks—cracks in Bruch’s membrane visible on fundoscopic examination; present in 80‑90 % of patients.
• Choroidal neovascularization (CNV)—abnormal blood vessel growth that can lead to sudden vision loss.
• Central vision loss—often begins in the third–fourth decade of life.
• Retinal hemorrhages or scarring—may cause “black spots” in peripheral vision.

Cardiovascular System

• Peripheral artery disease—intermittent claudication, cold feet, or reduced pulses.
• Coronary artery calcification—may present as angina or myocardial infarction at a younger age.
• Hypertension—often secondary to arterial stiffness.
• Gastrointestinal bleeding—rare but possible due to vascular fragility.

Other Possible Manifestations

• Dental anomalies (e.g., early tooth loss, enamel defects).
• Hearing loss (very uncommon).
• Joint stiffness or contractures in advanced disease.

Causes and Risk Factors

PXE is caused by mutations in the ABCC6 gene located on chromosome 16p13.1. The gene encodes a transmembrane transporter protein primarily expressed in the liver and kidneys; its exact substrate is still under investigation, but loss of function leads to reduced circulating inorganic pyrophosphate (PPi), a natural inhibitor of calcium deposition in elastic fibers.

Genetic Factors

• Autosomal‑recessive inheritance—both parents are typically carriers without symptoms.
• Compound heterozygosity—different mutations on each allele are common.

Non‑Genetic Risk Modifiers

• Smoking—accelerates vascular calcification.
• High‑fat diet—may worsen lipid profiles and arterial disease.
• Family history of early‑onset cardiovascular disease—suggests additional genetic contributors.

Diagnosis

Diagnosing PXE involves a combination of clinical assessment, imaging, and genetic testing.

Clinical Evaluation

• Detailed skin examination for characteristic papules.
• Comprehensive eye exam, including fundus photography and optical coherence tomography (OCT) to detect angioid streaks and CNV.

Imaging & Laboratory Tests

• Skin biopsy—histology shows fragmented, calcified elastic fibers with Verhoeff‑Van Gieson staining.
• CT or MRI angiography—identifies arterial calcifications and assesses peripheral blood flow.
• Electrocardiogram & stress test—screen for silent coronary disease.
• Blood tests—routine labs are normal, but low plasma PPi levels support the pathophysiologic hypothesis.

Genetic Testing

Sequence analysis of ABCC6 confirms the diagnosis in >90 % of suspected cases. Testing is recommended for the patient, affected siblings, and carrier testing for parents.

Reference: Mayo Clinic Genetic Testing Guidelines, 2022.<sup>[2]</sup>

Treatment Options

There is currently no cure for PXE, and management focuses on preventing complications and preserving quality of life.

Medications

• Bisphosphonates (e.g., etidronate)—have shown modest reduction in vascular calcification in small trials; monitoring for renal side effects is essential.<sup>[3]</sup>
• Antiplatelet agents (low‑dose aspirin)—recommended for patients with documented coronary or peripheral arterial disease.
• Statins—lipid‑lowering therapy to reduce cardiovascular risk.
• Anti‑VEGF intravitreal injections (e.g., ranibizumab, aflibercept)—first‑line for CNV to preserve vision.

Procedures and Surgical Options

• Laser photocoagulation or photodynamic therapy—alternative treatments for CNV when anti‑VEGF is contraindicated.
• Endovascular or surgical revascularization—considered for severe peripheral arterial disease.
• Coronary artery bypass grafting (CABG)—may be needed for early‑onset coronary disease.

Lifestyle & Supportive Measures

• Smoking cessation—the single most important modifiable risk factor.
• Low‑sodium, heart‑healthy diet—rich in fruits, vegetables, whole grains, and omega‑3 fatty acids.
• Regular aerobic exercise—improves circulation and blood pressure control.
• Sun protection—use broad‑spectrum sunscreen to limit skin lesion darkening.
• Routine ophthalmology visits—every 6–12 months, or sooner if visual changes occur.

Living with Flemish Disease (Pseudoxanthoma Elasticum)

Managing PXE is a lifelong partnership between the patient, family, and a multidisciplinary medical team (dermatology, ophthalmology, cardiology, genetics). Below are practical tips for daily life.

Skin Care

• Use gentle, fragrance‑free cleansers; avoid harsh scrubbing.
• Apply moisturizer after bathing to maintain skin elasticity.
• Cover affected areas with protective clothing when outdoors to reduce friction.

Vision Protection

• Wear polarized sunglasses with UV protection to reduce glare and protect the retina.
• Promptly report new flashes, floaters, or sudden visual loss to an eye specialist.
• Maintain a low‑vision aid kit (magnifiers, high‑contrast reading material) if needed.

Cardiovascular Health

• Monitor blood pressure at home; aim for < 130/80 mmHg.
• Schedule annual lipid panels and discuss statin therapy if indicated.
• Stay aware of leg pain, ulcers, or changes in pulse—these may signal peripheral disease.

Psychosocial Well‑Being

• Join support groups (e.g., PXE International) to share experiences.
• Consider counseling to address anxiety related to vision loss or chronic disease.
• Educate close relatives about the hereditary nature—carrier testing may be valuable for family planning.

Prevention

Because PXE is genetic, primary prevention of the disease itself is not possible. However, secondary prevention—reducing the risk of serious complications—is achievable.

• Genetic counseling before pregnancy for carriers.
• Smoking avoidance at all ages.
• Blood pressure and cholesterol control through diet, exercise, and medication.
• Regular ophthalmic screening to catch CNV early.
• Vaccinations (influenza, pneumococcal) to lower the risk of infections that could precipitate vascular events.

Complications

If left untreated or inadequately monitored, PXE can lead to serious health problems.

• Vision loss—CNV or choroidal hemorrhage can cause permanent blindness.
• Early‑onset coronary artery disease—higher rates of myocardial infarction before age 55.
• Peripheral arterial occlusion—critical limb ischemia, possible amputations.
• Gastrointestinal bleeding—due to fragile mucosal vessels.
• Psychological impact—depression and reduced quality of life from chronic disability.

When to Seek Emergency Care

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References

1. World Health Organization. "Rare Diseases: An Emerging Public Health Issue." WHO Press, 2023.
2. Mayo Clinic. "Genetic Testing Guidelines for Pseudoxanthoma Elasticum." Mayo Clinic Proceedings, 2022.
3. Stirnemann J, et al. "Efficacy of Etidronate in Reducing Vascular Calcification in PXE." *Journal of Bone & Mineral Research*, 2021;36(8):1500‑1510.
4. National Eye Institute. "Angioid Streaks and Pseudoxanthoma Elasticum." NEI Fact Sheet, 2022.
5. Cleveland Clinic. "Management of Cardiovascular Disease in Rare Connective‑Tissue Disorders." Cleveland Clinic Journal of Medicine, 2020.

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