Pseudoxanthoma elascticum (PXE) is an inherited connective tissue disorder in which the elastic fibers present in the skin, eyes, and cardiovascular system gradually become calcified and inelastic.
Description
PXE was first reported in 1881 by Rigal, but the problem with elastic fibers was described in 1986 by Darier who gave the condition its name. PXE is also known as Grönblad-Strandberg-Touraine syndrome and systemic elastorrhexis.
The course of PXE varies greatly between individuals. Typically, it is first noticed during adolescence as yellow-orange bumps on the side of the neck. Similar bumps may appear at other places where the skin bends a lot, like the backs of the knees and the insides of the elbows. The skin in these areas tends to get thick, leathery, inelastic, and acquire extra folds. These skin problems have no serious consequences, and for some people, the disease progresses no further.
Bruch's membrane, a layer of elastic fibers in front of the retina, becomes calcified in some people with PXE. Calcification causes cracks in Bruch's membrane, which can be seen through an ophthalmoscope as red, brown, or gray streaks called angioid streaks. The cracks can eventually (e.g., in 10–20 years) cause bleeding, and the usual resultant scarring leads to central vision deterioration. However, peripheral vision is unaffected.
Arterial walls and heart valves contain elastic fibers that can become calcified. This leads to a greater susceptibility to the conditions that are associated with hardening of the arteries in the normal aging population—high blood pressure, heart attack, stroke, and arterial obstruction—and, similarly, mitral valve prolapse. Heart disease and hypertension associated with PXE have been reported in children as young as four to 13 years of age. Although often appearing at a younger age, the overall incidence of these conditions is only slightly higher for people with PXE than it is in the general population.
PXE is caused by changes in the genetic material, called mutations, that are inherited in either a dominant or recessive mode. A person with the recessive form of the disease (which is most common) must possess two copies of the PXE gene to be affected, and, therefore, must have received one from each parent. In the dominant form, one copy of the abnormal gene is sufficient to cause the disease. In some cases, a person with the dominant form inherits the abnormal gene from a parent with PXE. More commonly, the mutation arises as a spontaneous change in the genetic material of the affected person. These cases are called "sporadic" and do not affect parents or siblings, although each child of a person with sporadic PXE has a 50% risk to inherit the condition.
Both males and females can develop PXE, although the skin findings seem to be somewhat more common in females.
The actual genetic causes of this condition were not discovered until 2000. The recessive, dominant, and sporadic forms of PXE all appear to be caused by different mutations or deletions in a single gene called ABCC6 (also known as MRP6), located on chromosome 16. Although the responsible gene has been identified, how it causes PXE is still unknown.
Genetic researchers have since identified mutations in a number of persons with PXE, most of whom have been found to have the recessive type. Affected individuals in these families had mutations in both copies of the gene and parents, who are obligate carriers, had a mutation in only one copy. Contrary to the usual lack of symptoms in carriers of recessive genes, some carriers of recessive PXE have been found to have cardiovascular symptoms typical of PXE.
Although the recessive type is the most common, there are also familial and sporadic cases that have been found to be caused by dominant mutations in the ABCC6 gene.
Demographics
PXE is rare and occurs in about one in every 160,000 people in the general population. It is likely, though, that PXE is underdiagnosed because of the presence of mild symptoms in some affected persons and the lack of awareness of the condition among primary care physicians.
Signs and symptoms
A wide range in the type and severity of symptoms exists between people with PXE. The age of onset also varies, although most people notice initial symptoms during adolescence or early adulthood. Often, the first symptoms to appear are thickened skin with yellow bumps in localized areas such as the folds of the groin, arms, knees, and armpits. These changes can also occur in the mucous membranes, most often in the inner portion of the lower lip. The appearance of the skin in PXE has been likened to a plucked chicken or Moroccan leather.
Angioid streaks in front of the retina are present in most people with PXE and an ophthalmologic examination can be used as an initial screen for the condition. Persons with PXE often complain of sensitivity to light. Because of the progressive breakdown of Bruch's membrane, affected persons are at increased risk for bleeding and scarring of the retina, which can lead to decreased central vision but does not usually cause complete blindness.
Calcium deposits in the artery walls contribute to early-onset atherosclerosis, and another condition called claudication, inadequate blood flow that results in pain in the legs after exertion. Abnormal bleeding, caused by calcification of the inner layer of the arteries, can occur in the brain, retina, uterus, bladder, and joints but is most common in the gastrointestinal tract.
Diagnosis
The presence of calcium in elastic fibers, as revealed by microscopic examination of biopsied skin, unequivocally establishes the diagnosis of PXE.
Measures should be taken to prevent or lessen cardiovascular complications. People with PXE should control their cholesterol and blood pressure, and maintain normal weight. They should exercise for cardiovascular health and to prevent or reduce claudication later in life. They should also avoid the use of tobacco, thiazide anti-hypertensive drugs, blood thinners like coumadin, and non-steroidal anti-inflammatory drugs like aspirin and ibuprofen. In addition, they should avoid strain, heavy lifting, and contact sports, since these activities could trigger retinal and gastrointestinal bleeding.
People with PXE should have regular eye examinations by an ophthalmologist and report any eye problems immediately. Regular check-ups with a physician are also recommended, including periodic blood pressure readings.
Some people have advocated a calcium-restricted diet, but it is not yet known whether this aids the problems brought about by PXE. It is known, however, that calcium-restriction can lead to bone disorders.
Prognosis
The prognosis is for a normal life span with an increased chance of cardiovascular and circulatory problems, hypertension, gastrointestinal bleeding, and impaired vision. However, now that the gene for PXE has been identified, the groundwork for research to provide effective treatment has been laid. Studying the role of the ABCC6 protein in elastic fibers may lead to drugs that will improve or prevent the problems caused by PXE.
Genetic tests are now available that can provide knowledge needed to both diagnose PXE in symptomatic persons and predict it prior to the onset of symptoms in persons at risk. Prenatal diagnosis of PXE, by testing fetal cells for mutations in the ABCC6 gene, can be done in early pregnancy by procedures such as amniocentesisor chorionic villus sampling. For most people, PXE is compatible with a reasonably normal life, and prenatal diagnosis is not likely to be highly desired.
Genetic testing to predict whether an at-risk child will develop PXE may be helpful for medical management. A child who is found to carry a mutation can be monitored more closely for eye problems and bleeding, and can begin the appropriate lifestyle changes to prevent cardiovascular problems.
BOOKS
Pope, F. Michael. "Pseudoxanthoma Elasticum, Cutis Laxa, and Other Disorders of Elastic Tissue." In Emery and Rimoin's Principles and Practice of Medical Genetics. 3rd ed. Ed. David L. Rimoin, J. Michael Connor, and Reed E. Pyeritz. New York: Churchill Livingstone, 1997.
PERIODICALS
Ringpfeil, F., et al. "Pseudoxanthoma Elasticum: Mutations in the MRP6 Gene Encoding a Transmembrane AFP-binding Cassette (ABC) Transporter." Proceedings of the National Academy of Sciences 97 (May 2000): 6001–6.
Sherer, D.W., et al. "Pseudoxanthoma Elasticum: An Update."
Dermatology 199 (1999):3–7.
ORGANIZATIONS
National Association for Pseudoxanthoma Elasticum. 3500 East 12th Avenue, Denver, CO 80206. (303) 355-3866. Fax: (303) 355-3859. Pxenape@estreet.com. <http://www.napxe.org>.
PXE International, Inc. 23 Mountain Street, Sharon, MA 02067. (781) 784-3817. Fax: (781) 784-6672. PXEInter @aol.com. <http://www.pxe.org/>.
