Ophthalmologic Manifestations of Pseudoxanthoma Elasticum

Pseudoxanthoma elasticum (PXE) is an inherited systemic disease characterized by changes in the elastic tissue of the skin. Pseudoxanthoma elasticum mainly affects the skin, eyes, heart, and gastrointestinal (GI) system.

The cutaneous and ocular findings of pseudoxanthoma elasticum are referred to as Grönblad-Strandberg syndrome. The cutaneous changes in pseudoxanthoma elasticum are distributed in the intertriginous areas of the body, such as the flexural regions of the extremities, in the folds of the skin at the sides of the neck, the cubital and popliteal fossa, the axilla, in the creases of the groin, and periumbilical area. Typical lesions are described as yellow waxy papules associated with loose and thickened skin. Pseudoxanthoma elasticum may be inherited through autosomal-dominant or autosomal-recessive patterns.

Other systemic findings in pseudoxanthoma elasticum include: intracranial aneurysms, claudication, hypertension, cerebrovascular accidents, cerebral ischemia, myocardial infarction, and GI hemorrhage.

The lesions in pseudoxanthoma elasticum are characterized by increased amounts of elastic tissue that have the tendency to become calcified. There has been controversy on the nature of the elastic tissue and whether the elastic tissue is abnormal from the time of synthesis or normal from its production with subsequent degeneration.

The reason elastic fibers become calcified in pseudoxanthoma elasticum remains unknown. Investigators have found polyanions within elastic fibers in both clinically affected and nonaffected dermis by using histochemical and electron microscopy techniques. This polyanionic material may explain the increased affinity of elastic fibers for calcium and may be a factor in the pathogenesis of the disease.

Frequency

United States

The reported prevalence of pseudoxanthoma elasticum is 1 in 160,000 births.

Mortality/Morbidity

Patients with pseudoxanthoma elasticum are at risk for loss of central vision, subarachnoid hemorrhage, severe GI hemorrhage, chronic peripheral occlusive disease, and cerebrovascular insufficiency. Subarachnoid hemorrhage has been a major cause of death.

Sex

Females are affected with pseudoxanthoma elasticum twice as often as males.

Age

Patients with pseudoxanthoma elasticum usually are diagnosed in the third to fourth decades of life.

The syndrome of pseudoxanthoma elasticum is a disorder of connective tissue characterized by multisystem involvement. Clinically, involvement of the eyes, skin, central nervous system, heart, and GI system may be present to variable extents, as well as peripheral arterial disease. The stretchable skin, cardiac changes, and choroidal breaks are signs that pseudoxanthoma elasticum shares with variants of Ehlers-Danlos syndrome (EDS). Under the current 2017 classification system, 13 types of EDS are identified, many of which are linked to mutations in at least 20 different genes.

Eye

It has been reported that 87% of patients with pseudoxanthoma elasticum have associated angioid streaks (AS). Angioid streaks appear as cracks deep to the retinal vascular architecture and originate in a ringlike fashion in the peripapillary area and radiate from the optic nerve head coursing in all directions. Angioid streaks are visible as dark red-to-brown bands and are variable in their pigmentation. These brown bands represent breaks in the thickened and calcified Bruch membrane. The Bruch membrane is the collagen- and elastin-containing membrane between the retina and the choroid.

Angioid streaks may progress slowly or remain stationary for years. Angioid streaks almost always occur bilaterally.

During fluorescein angiography, angioid streaks may show increased fluorescence in the early phase resulting from atrophy of the retinal pigment epithelium overlying an intact choriocapillaris.

Defects in the Bruch membrane may predispose to choroidal neovascular ingrowth, which can result in subretinal hemorrhage and ultimately disciform degeneration.

Macular involvement with loss of vision usually appears after age 40 years and may be due to retinal pigment epithelium atrophy or choroidal neovascular membrane. Some choroidal neovascular membranes are amenable to treatment with laser photocoagulation[1] (however, visual results are disappointing). Visual field loss secondary to optic disk drusen has been reported in patients with pseudoxanthoma elasticum who have angioid streaks.

In addition to angioid streaks, other fundus lesions, including optic disc drusen, macular pattern dystrophy, crystalline bodies, and midperipheral “comet-tail” atrophic spots have been described in pseudoxanthoma elasticum.

Peau d'orange has been described as diffuse mottling of the retinal pigment epithelium in an area temporal to the macula in patients with pseudoxanthoma elasticum. This may occur with or without the presence of angioid streaks.

Choroidal ruptures and retinal hemorrhages have been reported in patients with pseudoxanthoma elasticum as a result of minor ocular trauma.

Irregularly shaped lesions with variable depigmentation have been observed in the periphery of patients with pseudoxanthoma elasticum. This may represent isolated areas of peripheral dehiscences in the Bruch membrane.

Keratoconus is frequently seen in patients with pseudoxanthoma elasticum. This is indistinguishable from other cases of keratoconus. Presenting symptoms include fluctuating or blurred vision that is not correctable by spectacles or hydrophilic contact lenses. Corneal topography reveals irregular astigmatism and inferior corneal steepening that is indistinguishable from cases of keratoconus unassociated with EDS.

Skin

The characteristic skin changes in pseudoxanthoma elasticum consist of yellow plaques or xanthoma-like papules in the flexural areas of the body. This change has been likened to plucked chicken skin. The skin lesions typically are distributed in the intertriginous areas of the body.

The most commonly affected areas of the body are as follows: the folds of the skin at the sides of the neck, the flexural regions of the extremities, the axilla, the popliteal and antecubital fossa, the creases of the groin, and the periumbilical region of the abdominal wall.

The skin changes usually are noted between the second and fourth decades of life. Late in the disease, the skin frequently becomes thickened and hangs in loose redundant folds.

Central nervous system

Neurologic complications in patients with pseudoxanthoma elasticum have been reported in the literature. These include multiple lacunar infarcts, aneurysms, cerebrovascular insufficiency, subarachnoid and intracerebral hemorrhages, progressive intellectual deterioration, and psychic and mental disturbance.

Seizures occur more frequently than in the general population. Subarachnoid hemorrhage is a potential cause of death.

Cardiovascular findings

Cardiovascular involvement in patients with pseudoxanthoma elasticum occurs at an early age, but it is rarely a presenting manifestation.

Angina pectoris is a common finding, but myocardial infarction is rare. Aneurysms may occur in any region of the cardiovascular system.

GI system

Upper GI tract hemorrhage can be a serious complication of pseudoxanthoma elasticum. GI hemorrhage has been reported as early as age 6.5 years.

GI hemorrhage is a fairly common occurrence and usually occurs early in the course of the disease, when the cutaneous and ocular changes are minimal. It may be life threatening and can occur in as many as 15% of patients. The GI hemorrhage may be secondary to the degeneration of the elastic tissue of arteries of the gastric wall.

Peripheral arterial system

Changes in the vascular system are characterized by premature calcification of the peripheral arteries of the extremities and can be detected by x-ray film.

Atherosclerotic changes cause peripheral vascular disease, which results in weak or absent peripheral pulses and claudication of the lower extremities.

Hypertension is 3 times more common in patients with this condition than in the general population and occurs at an early age.

Yellow xanthomalike plaques are present in the flexural areas of the body. The sides of the neck are the most common sites.

Angioid streaks are nearly always bilateral and usually appear in the second decade of life. Angioid streaks are brown streaks forming an incomplete ring around the optic nerve and radiating from the disk toward the equator of the eye. Angioid streaks may lead to macular degeneration, disciform scarring, and hemorrhagic maculopathy via the degenerative process of choroidal neovascularization (ie, abnormal choroidal vessels gaining access to the subretinal space through breaks in the Bruch membrane).[2, 3]

Optic nerve drusen also may occur in patients with pseudoxanthoma elasticum.

Corneal findings in patients with keratoconus include the topographic findings typically associated with keratoconus.

Diffuse mottling of the retinal pigment epithelium in the temporal periphery resembles the appearance of the skin of an orange (peau d'orange).

Peripheral arterial pulsations may be absent in both upper and lower extremities.

Hypertension may result from the involvement of the renal arteries and may occur in the adolescent age group.

Pseudoxanthoma elasticum is an inherited systemic disease characterized by abnormal amounts of elastic tissue that have an unusual propensity to become calcified.

Genetics

Pseudoxanthoma elasticum is primarily inherited in an autosomal-recessive manner, which means both copies of the gene in each cell have mutations. Mutations in the ABCC6 gene cause pseudoxanthoma elasticum. To date, more than 300 distinct mutations have been identified in pseudoxanthoma elasticum. Mutations in the ABCC6 gene lead to an absent or nonfunctional MRP6 protein, an acronym for multidrug resistance-associated protein 6 (MRP6, also known as the ABCC6 protein).[4, 5]

Autosomal-dominant inheritance is less common.

Laboratory tests include the following:

• Complete blood cell (CBC) count

• Serum electrolytes

• Calcium and phosphorus

• Blood glucose

Spectral domain optical coherence tomography (SD-OCT) can identify angioid streaks in the Bruch membrane.[6]

Procedures include skin biopsy.

Histopathologic studies from skin biopsy show characteristic changes consisting of fragmented elastic fibers, which may be calcified in the deeper layers of the dermis.

Evaluation for patients with pseudoxanthoma elasticum usually can be conducted on an outpatient basis. The most visually devastating complication of angioid streaks in the eye is neovascular membrane formation in the macula at the level of the pigment epithelium-Bruch membrane. This is similar to the neovascularization seen in age-related macular degeneration (ARMD).

If choroidal neovascularization (CNV) is found on clinical examination, fluorescein angiography and optical coherence tomography (OCT) may be helpful in delineating and documenting the location and size of a neovascular membrane.[6] Therapy with intravitreal antivascular endothelial growth factor (anti-VEGF) agents should be considered.[7] Neovascular membranes away from the fovea have also been treated via laser. Photodynamic therapy has had limited success in the treatment of CNV. Although repeated intravitreal injection of the fusion protein aflibercept or the monoclonal antibody ranibizumab or the off-label use of bevacizumab seems to maintain visual acuity, CNV frequently recurs or new areas of CNV may develop.[8]

In a small case series of patients with pseudoxanthoma elasticum, 20% of eyes had geographic atrophy independent of choroidal neovascularization. Linear pigmented pattern dystrophy appeared to predate geographic atrophy.[9] Recognition of geographic atrophy is important as therapies to slow or reverse geographic atrophy, including ciliary neurotrophic factor delivered by an encapsulated cell, stem cell therapy, fenretinide, doxycycline, sirolimus, and fluocinolone acetonide intravitreal implants, are under investigation.

If keratoconus is found in association with pseudoxanthoma elasticum, management with contact lenses, riboflavin-assisted cross-linking, or penetrating keratoplasty can be used, similarly to patients without pseudoxanthoma elasticum.

Visual deficits may have variable effects on vision-related quality of life. The extent of each visual deficit varies between patients,  Direct conclusions on the vision-related quality of life based on structural and functional measures may be limited because perceived disease burden may depend on individual coping strategies, age, personal circumstances, and occupation.

Consultations include the following:

• Neurologist

• Pediatrician

• Internist

• Cardiologist

• Gastroenterologist

Dietary restriction of calcium and phosphorus to minimum daily requirement levels has shown arrest in progression of the disease.

Eye protection for contact sports or physical activity is indicated.

Patients with pseudoxanthoma elasticum who are exposed to ocular trauma are predisposed to the development of angioid streaks and subsequent visual loss.

Hypertension should be monitored.

Patients should receive regular eye examinations.

Pregnancy, oral contraceptives, and high calcium and phosphorus intake seem to aggravate all manifestations of pseudoxanthoma elasticum.

See the list below:

• Blindness

• Recurrent GI hemorrhage

• Myocardial infarction

• Subarachnoid hemorrhage

• Cerebrovascular accidents

• Death

The greatest morbidity in patients with pseudoxanthoma elasticum and angioid streaks is the loss of central vision that occurs in a high percentage of patients in the fifth to sixth decade of life.

Inform and educate patients about the multisystem potential complications of pseudoxanthoma elasticum.