Pseudoxanthoma Elasticum Clinical Presentation

Cutaneous changes are usually the first manifestation of pseudoxanthoma elasticum (PXE), classically arising on the lateral aspect of the neck. They are generally asymptomatic but may be of cosmetic concern.

Extracutaneous presentations include mucosal involvement leading to gastrointestinal hemorrhage with melena, frank bleeding, occult blood in the stool, or hematemesis.

Patients may report fatigue from chronic blood loss or claudication from blood vessel involvement.

Slowly, as the disease progresses, patients note more severe cutaneous and cardiovascular manifestations, such as angina and hypertension.

Hematuria has also been reported.

Retinal hemorrhages with loss of central vision are common after the fourth decade of life.

Physical findings of pseudoxanthoma elasticum can be divided into cutaneous, ocular, and cardiovascular manifestations.

Cutaneous manifestations

The cutaneous manifestations of pseudoxanthoma elasticum are highly characteristic. The lesions usually develop in childhood or early adolescence; however, occasionally, they first appear in late adulthood.^{[9, 11, 12]}

Small, yellow papules of 1-5 mm in diameter are seen in a linear or reticular pattern and may coalesce to form plaques.^[13] The skin takes on a plucked chicken, Moroccan leather, or cobblestone appearance. Typically, these changes are first noted on the lateral part of the neck and later involve the antecubital fossae; the axillae; the popliteal spaces; the inguinal and periumbilical areas; the oral mucosa involving the lower lip, cheek, and palate; and the vaginal and rectal mucosae.^[14]

As the disease progresses, the skin of the neck, the axillae, and the groin may become soft, lax, and wrinkled, hanging in folds. The extent of these changes is usually limited, but generalized cutis laxa–like pseudoxanthoma elasticum has also been reported.^[15]

Horizontal and oblique mental creases before age 30 years is highly specific for pseudoxanthoma elasticum.^[16]

Other clinical presentations reported in literature include acneiform lesions, brown reticulated macules and chronic granulomatous nodules.^{[17, 16]}

Elastosis perforans serpiginosa may coexist with pseudoxanthoma elasticum.

The cutaneous lesions of pseudoxanthoma elasticum usually remain unchanged throughout life, and are generally symmetrically distributed. See the images below.

Ocular manifestations

The characteristic ocular manifestations of pseudoxanthoma elasticum are angioid streaks of the retina, which are slate gray to reddish brown curvilinear bands that radiate from the optic disc.^[18] The streaks represent cracks and fissures in the calcified Bruch’s membrane. This ocular change is generally bilateral and is often noted several years after the onset of cutaneous lesions. Angioid streaks are present in 85% of patients with pseudoxanthoma elasticum.

Although these lesions are highly characteristic of pseudoxanthoma elasticum, they are not pathognomonic because they are also found in various other conditions including sickle cell anemia, thalassemia, Paget disease of the bone, Marfan syndrome, Ehlers-Danlos syndrome, and lead poisoning.

Angioid streaks are often preceded by peau d’orange changes, consisting of fine-yellow drusenlike pigment irregularities. These changes arise on average 1-8 years prior to angioid streaks, and suggest early retinopathy.^[19]

Angioid streaks can serve as a nidus for choroidal neovascularization, which is associated with retinal hemorrhage and a poor prognosis if left untreated. Loss of central vision is progressive with each hemorrhage, but peripheral vision is spared.

Chorioretinal atrophies with a “comet tail” appearance appear to be pathognomonic for pseudoxanthoma elasticum, but their expression widely varies.^[20]

Cardiovascular manifestations

Cardiovascular manifestations, except for intermittent claudication, are usually the last complications to be recognized in pseudoxanthoma elasticum. Calcification of the elastica media and intima of the blood vessels leads to various physical findings. In adults, peripheral pulses are often severely diminished. Renal artery involvement is rare, but can lead to hypertension, and coronary artery disease can result in angina pectoris and subsequent myocardial infarction.^[8] Mitral valve prolapse has a higher prevalence in pseudoxanthoma elasticum. This prolapse may not be significant unless the murmur of mitral valve insufficiency is also present.^[18]

GI hemorrhage, usually gastric in origin, results from the increased fragility of calcified submucosal vessels.^[4] Hemorrhaging may occur early in the disease progression, especially in the second to fourth decade, without warning. Depending on its severity, hospitalization, blood transfusion, and surgery may be necessary. Approximately 10-15% of patients with pseudoxanthoma elasticum experience a GI hemorrhage at some point in their lives. Less commonly, hemorrhaging may occur in the urinary tract or cerebrovascular system. Hematuria or potentially fatal increases in intracranial pressure can be found in these cases, respectively.^{[13, 21]}

Diagnostic criteria

A revised set of criteria has recently been proposed to aid in the diagnosis of pseudoxanthoma elasticum.^[22] In order to make a definitive diagnosis, major criteria from two separate categories must be met; for a probable diagnosis, two major criteria from within the same category (skin or eye) or one major criterion and one or more minor criterion from another category must be present. A possible diagnosis is made when only one major criterion or only minor criteria are found.

Major diagnostic criteria include the following:

• Skin - Yellow papules/plaques on the lateral neck or body, skin biopsy showing increased calcification with clumping of elastic fiber taken from affected skin
• Eye - Peau d’orange changes, angioid streaks (confirmed by angiography)
• Genetics - Presence of a pathogenic mutation of both alleles of ABCC6, a first-degree relative who meets criteria for definitive pseudoxanthoma elasticum.

Minor diagnostic criteria include the following:

• Eye - One angioid streak shorter than one disk diameter, “comets” in the retina, one or more “wing signs” on the retina
• Genetics - A pathogenic mutation in one allele of the ABCC6 gene

Pseudoxanthoma elasticum is caused by mutations in the ABCC6,^{[10, 23]} also known as multidrug resistance–associated protein 6 (MRP6), which has been mapped to 16p13.1. To date, greater than 150 different disease-causing mutations, mainly missense and nonsense mutations, have been identified in the 31 exons coding ABCC6. Because the ABCC6 gene encodes the cellular transport protein ABCC6/MRP6, pseudoxanthoma elasticum may represent a systemic metabolic disorder rather than a purely structural disorder of connective tissue.

In support of this hypothesis, fibroblasts grown in the sera of patients with pseudoxanthoma elasticum interfered with the normal assembly of elastic fibers in vitro.^[23] Most recent studies support the notion that pseudoxanthoma elasticum is primarily a systemic metabolic disorder with secondary mineralization of connective tissues.^[24]

The pathological changes found in pseudoxanthoma elasticum may be due to increased oxidative stress, resulting in elevated levels of intercellular adhesion molecule-1 (ICAM-1) and P-selectin.^{[25, 26, 27]} One hypothesis is that ABCC6 secretes a vitamin-K precursor from the liver, supported by the finding that clinical features simulating pseudoxanthoma elasticum are seen in rats treated with vitamin-K antagonists and in patients with mutations of gamma-glutamyl carboxylase gene. Based on this theory, a precursor of vitamin-K that can be used by peripheral tissues should abate the process of pseudoxanthoma elasticum.^[26] However, this has not been observed, and furthermore, supplementation with antioxidants such as vitamins C and E, selenium, and N -acetylcysteine have not been found to modify the ectopic mineralization process.^[28]