Pseudoxanthoma elasticum overview

# Overview
Pseudoxanthoma elasticum (PXE) is an inherited systemic disorder that affects the elastic tissue of the skin, retina, gastrointestinal tract, and the cardiovascular system.  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.

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

# Classification
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.

# Pathophysiology
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.

# Causes
80% of clinical cases of pseudoxanthoma elasticum have detectable mutations in the ABCC6 gene.

# Epidemiology and Demographics
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.

# Natural History, Complications and Prognosis
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.

# Diagnosis

## History and Symptoms
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.

## Physical Examination
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 Findings
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.

## Diagnostic Criteria
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 dorange 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

# Treatment

## Medical Therapy
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.

## Surgery
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.

# Prevention
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.

# Future or Investigational Therapies
- 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).