Pseudoxanthoma elasticum

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayokunle Olubaniyi, M.B,B.S [2]

Pseudoxanthoma elasticum (PXE) is an inherited systemic disorder that affects the elastic tissue of the skin, retina, gastrointestinal tract, and the cardiovascular system.^[1] It is caused by a mutation of the ABCC6 gene on the short arm of chromosome 16 (16p13.1) that encodes an ATP-binding cassette transporter. PXE causes fragmentation and mineralization of elastic fibers in connective tissues and medium-sized arteries.

Pseudoxanthoma elasticum was first described by Dr. Ferdinand-Jean Darrier in 1896. It was also called Grönblad-Strandberg syndrome in older literature.

PXE can be classified into autosomal dominant and autosomal recessive forms. However, some sporadic cases with no family history of the disease have also been reported.

Pseudoxanthoma elasticum involves the accumulation of calcium and fragmentation of elastin-containing fibers in the connective tissue, and in the mid-sized arteries. There is mutation of the ABCC6 gene which encodes for a transmembrane efflux transporter. Premature atherosclerosis is also associated with mutations in the ABCC6 gene. Recently, novel mutations have been found including p.R1141X and g.del23-29, and they account for about 40% of all mutations.

80% of clinical cases of pseudoxanthoma elasticum have detectable mutations in the ABCC6 gene.^[2][3][4][5]

The prevalence of PXE is approximately 1:50,000, with females twice as many as the males. The average age of onset is 13 years.

The ocular involvement including retinal hemorrhages can progressively lead to loss of central vision, sparing the peripheral vision. The involvement of the elastic media and intima of the arteries can lead to claudication, hypertension, angina pectoris, myocardial infarction, and gastrointestinal or cerebral hemorrhage which could be fatal, although relatively uncommon. The prognosis of PXE largely depends on the extracutaneous organ manifestations. The occurence of myocardial infarction, cerebral or GI hemorrhage may have fatal consequences. Spontaneous resolution of skin changes has been reported, but it is exceedingly rare.^[1]

The clinical manifestation of pseudoxanthoma elasticum usually starts with the skin. Patients may present with features of gastrointestinal bleeding such as melena, hematemesis, frank bleeding or hematuria; cardiovascular manifestation such as angina, intermittent claudication, coronary heart disease or ocular symptoms such as loss of central vision.

Cutaneous signs include a small, yellowish papular lesions. Cutaneous laxity mainly affects the neck, axillae (armpits), groin, and flexural creases. Less common cutaneous manifestation include comedones or inflammatory papules, elastosis perforans serpiginosa, and reticulate pigmented rash. Ocular signs include: Peau d’orange, angioid streaks, retinal hemorrhage which may eventually lead to loss of vision. Cardiac involvement may manifest as angina pectoris, intermittent claudication, reduced pulse amplitude. Gastrointestinal bleeding as evident by melena, hematemesis are also experienced by this patients.

Laboratory tests that could be done include: CBC to evaluate iron deficiency anemia; Fecal occult blood and Urinalysis to screen for bleeeding; Serum lipid levels to evaluate possible atherosclerosis; Serum calcium and phosphate levels, and genetic testing to confirm the mutation of the ABCC6 gene.

To make a diagnosis, the patient must have two major criteria from two separate categories or one major criterion plus one or more minor criteria.

Major criteria

• Skin – Yellow papules/plaques on the lateral neck or body, skin biopsy showing increased calcification with clumping of elastic fiber 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 criteria

• 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

There is no specific treatment for PXE. Treatment focuses on prevention, screening and management of complications. The ocular complications can be managed with laser photocoagulation, transpupillary thermotherapy, photodynamic therapy or with anti-VEGF therapy. Pentoxifylline has been used to reduce the blood viscousity. Cardiovascular risk factors can be reduced by diet, exercise, and the avoidance of smoking.

For excessive areas of skin, plastic surgery may be needed. For the growth of abnormal blood vessels in the retina, laser eye surgerymay be needed in forms similar to that used in diabetic retinopathy (eye damage due to diabetes). Collagen and autologous fat injections have been used for the treatment of mental creases.^[6]

Preventive options include: Calcium restriction, reducing the risk for facial trauma by the avoidance of combat sports, avoidance of smoking that may further worsen the cardiovascular pathologies and reduction of hypocoagulable medications that may worsen hemorrhage.

• Magnesium oxide supplements – This is currently being evaluated for its ability to reverse calcium deposits in the skin, and the yellow bumps and folds of skin in patients with pseudoxanthoma elasticum (PXE).

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayokunle Olubaniyi, M.B,B.S [2]

Pseudoxanthoma elasticum was first described by Dr. Ferdinand-Jean Darrier in 1896. It was also called Grönblad-Strandberg syndrome in older literature.

The first to describe the characteristic skin changes for pseudoxanthoma elasticum was the French dermatologist Rigal in 1881, but the first description of PXE that distinguished it from other xanthomatous conditions was by Dr. Ferdinand-Jean Darrier in 1896.^[1] The eponym Grönblad-Strandberg syndrome is named after two physicians who made further discoveries in the disease manifestations.^[2] PXE has the distinction of being the only disease for which a layperson is the inventor of the mutated gene, ABCC6. Sharon F. Terry, co-founder of PXE International with her husband, Patrick F. Terry, worked with scientists to discover and patent the gene in 2000. The Terrys’ two children have pseudoxanthoma elasticum.^[3] PXE was initially thought to be a disorder of the elastic fiber system. However, it has been linked to the mutation of the ABCC6 gene.

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayokunle Olubaniyi, M.B,B.S [2]

PXE can be classified into autosomal dominant and autosomal recessive forms. However, some sporadic cases with no family history of the disease have also been reported.

PXE can be classified into four types:

• Type 1 autosomal dominant – Features include: Thin skin which is delicate and bruises easily, accelerated atherosclerosis, mitral valve disease and severe angioid streaks.
• Type 2 autosomal dominant – Characterised by atypical, yellowish, flatter skin papules than in type 1, skin hyperelasticity, mild angioid streaks and blue sclera.
• Type 1 autosomal recessive – Commonest form. The skin changes are similar to the Type 1 Autosomal Dominant, mild vascular disease but frequent gastrointestinal bleeding and mild angioid streaks.
• Type 2 autosomal recessive – Very rare with severe skin changes but without systemic complications.

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayokunle Olubaniyi, M.B,B.S [2]

Pseudoxanthoma elasticum involves the accumulation of calcium and fragmentation of elastin-containing fibers in the connective tissue, and in the mid-sized arteries. There is mutation of the ABCC6 gene which encodes for a transmembrane efflux transporter. Premature atherosclerosis is also associated with mutations in the ABCC6 gene. Recently, novel mutations have been found including p.R1141X and g.del23-29, and they account for about 40% of all mutations.

In PXE, there is calcification (accumulation of calcium) and fragmentation of the elastin-containing fibers in connective tissue, but primarily in the mid-sized arteries.^[1] Strong genetic linkage was found with mutations in the ABCC6 gene but the exact mechanism by which this protein (which is a transmembrane efflux transporter from the large ATP-binding cassette transporter family) influences the disease course is unknown. The protein is expressed in most organs, but mainly in the liver and kidney. It is unclear in what way this would lead to abnormalities in skin, eyes and blood vessels. It is thought that some particular mutations do not cause a more severe or less severe form of the disease. Given the variations in age of onset and severity it is likely that other unknown risk factors (genetic and dietary) may be involved. Premature atherosclerosis is also associated with mutations in the ABCC6 gene, even in those without PXE.^[2] A syndrome almost indistinguishable from hereditary PXE has been described in patients with hemoglobinopathies(sickle-cell disease and thalassemia) through a poorly understood mechanism. Recently, novel mutations have been found including p.R1141X and g.del23-29, and they account for about 40% of all mutations.^[3] Mutations in the GGCX gene encoding vitamin K–dependent γ-glutamyl carboxylasehave have also been reported.^[4]

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayokunle Olubaniyi, M.B,B.S [2]

80% of clinical cases of pseudoxanthoma elasticum have detectable mutations in the ABCC6 gene.^[1][2][3][4]

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayokunle Olubaniyi, M.B,B.S [2]

Published reports estimate that the prevalence of pseudoxanthoma elasticum, both the recessive and dominant forms, is 1 in 70,000 to 100,000,^[1] with females twice as many as the males.

Pseudoxanthoma elasticum (PXE) is a rare disease but the exact prevalence is unknown. The prevalence has been suggested to be approximately 1:50,000, with an estimate of 150,000 affected in the world assuming the same global prevalence.^[2] Females are twice as likely to be affected as males, and the average age of onset is 13 years. The disease occurs in all ethnicities, and an increased risk for PXE is seen in a few populations including the Afrikaners in South Africa, who display a founder effect.^[3][4]

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayokunle Olubaniyi, M.B,B.S [2]

The ocular involvement including retinal hemorrhages can progressively lead to loss of central vision, sparing the peripheral vision. The involvement of the elastic media and intima of the arteries can lead to claudication, hypertension, angina pectoris, myocardial infarction, and gastrointestinal or cerebral hemorrhage which could be fatal, although relatively uncommon. The prognosis of PXE largely depends on the extracutaneous organ manifestations. The occurence of myocardial infarction, cerebral or GI hemorrhage may have fatal consequences. Spontaneous resolution of skin changes has been reported, but is exceedingly rare.^[1]

Template:WikiDoc Sources