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 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 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 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.

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