Pseudoxanthoma Elasticum

Synonyms include PXE and Gronblad-Strandberg Syndrome

This is a genetic connective tissue disorder with progressive calcification and fragmentation of elastic fibres in the skin, the retina, and the cardiovascular system. Skin lesions begin in childhood but they are not usually noted until adolescence. In some people skin lesions do not appear until later in life. It is important to recognize the disease early to minimize the problem of retinal or gastrointestinal haemorrhage and cardiovascular complications. It can also involve the urinary tract and lungs.

Incidence

This is between 1 in 70,000 and 1 in 100,000¹ but milder cases occur and are not diagnosed. Presentation can be highly variable and phenotypic penetration may be incomplete.² It affects females twice as often as males. It affects all races. Modes of inheritance are both autosomal dominant and autosomal recessive. 90% of cases are thought to be recessive but some may be new mutations. Both dominant and recessive genes have been mapped to chromosome 13 at 16p13.1.¹

Prevalence

Most new cases present between 10 and 15 years of age but it can vary between infancy and the seventh decade of life or later.

Symptoms

• The first lesions to be noted are on the skin in the lateral part of the neck. The complaint is purely cosmetic.
• Mucosal involvement follows, leading to gastrointestinal haemorrhage with melaena, frank bleeding, occult blood in the stool, or haematemesis.
• Patients may complain of fatigue from chronic blood loss or claudication from blood vessel involvement.
• Slowly, as the disease progresses, patients note more severe skin lesions and there may be cardiovascular disease like angina and hypertension.
• Haematuria has also been reported.
• Retinal haemorrhages with loss of central vision occur after the fourth decade of life.

Signs

On the skin:

• Small, yellow papules are seen in a linear or reticular pattern and may coalesce to form plaques. The skin is variously described as like a plucked chicken, Moroccan leather, or a cobblestone appearance. Usually, these changes are first noted on the lateral part of the neck and later involve the antecubital fossae, the axillae, the popliteal fossae, the inguinal and periumbilical areas and also the oral, vaginal, and rectal mucosa.
• The lesions are symmetrical and may involve the whole body, but this is unusual.
• As the disease progresses, the skin of the neck, the axillae, and the groin may become soft, lax, and wrinkled, hanging in folds. This can be corrected by plastic surgery.
• Acneiform lesions and chronic granulomatous nodules have been reported in the literature. The cutaneous lesions of PXE usually remain unchanged throughout life.
• Elastosis perforans serpiginosa may coexist with PXE. This is a rare disorder of elastic tissue of the skin that affects males more than females. It may be idiopathic, related to other disorders such as Down's syndrome, Ehlers-Danlos syndrome and Marfan's syndrome. It can be a reaction to penicillamine in about 1% of those who receive the drug.

In the eyes:

• The characteristic features are angioid streaks of the retina, which are grey to reddish brown curvilinear bands radiating from the optic disc.
• Angioid streaks result from calcification of the elastic fibres in the Bruch membrane of the retina, with cracking and fissuring. This ocular disease is bilaterally symmetrical and is several years after the onset of cutaneous lesions, in patients aged 20-40 years. Angioid streaks are present in 85% of patients with PXE. Although these lesions are highly characteristic of PXE, they are not pathognomonic. Angioid streaks are found in a variety of other conditions, such as sickle cell disease, thalassaemia,³ Paget's disease of the bone, and Ehlers-Danlos syndrome.
• Fibrovascular ingrowth in the retina may lead to retinal haemorrhages, a serious complication of the disease.
• Loss of central vision progresses with each haemorrhage, but peripheral vision is always spared.
• Before bleeding occurs a subretinal net often forms that can be detected by an Amsler grid and intravenous fluorescein angiography. Before angioid streaks are visible there is often leopard spotting of the posterior pole of the retina, concurrent with the onset of skin lesions. Yellowish speckled mottling is suggestive of early retinopathy.

In the cardiovascular system:

• Cardiovascular disease⁴ is usually the last feature to be recognised although intermittent claudication may occur quite early. Calcification of the elastic media and intima of the blood vessels leads to various physical findings. Peripheral pulses are often much reduced. Renal artery disease causes hypertension, and coronary artery disease causes angina and myocardial infarction. Mitral valve prolapse often occurs. This prolapse may not be significant unless there is also mitral regurgitation.
• Gastrointestinal haemorrhage is usually from the stomach and is the most significant vascular complication. The calcified submucosal vessels are very fragile. Bleeding may occur early in the disease and without warning. 10% of patients have a gastrointestinal haemorrhage at some time in their lives. Less commonly, bleeding may occur in the urinary tract or cerebrovascular system.
• Haematuria or potentially fatal increases in intracranial pressure are found.

• Dermatofibrosis Lenticularis (Buschke-Ollendorf syndrome)
• Ehlers-Danlos syndrome
• Localised acquied cutaneous PXE
• Marfan's syndrome
• Severe actinic damage to the neck
• Long-term penicillamine therapy

Blood tests

• FBC for Fe deficient anaemia from bleeding.
• Occult blood for GI haemorrhage
• Urinalysis for blood
• Ca and PO₄^--- are sometimes elevated but usually normal.

Imaging

• Plain x-rays may show calcified arteries.
• Echocardiogram for mitral valve involvement.
• Coronary angiography if indicated

Other procedures

• Ophthalmic examination is essential to detect early signs of retinopathy, angioid streaks, and retinal haemorrhages. Laser treatment may spare vision.
• Endoscopy is indicated for any form of frank GI bleeding.
• Ankle/brachial blood pressure using Doppler methods is useful in patients with intermittent claudication or significantly diminished peripheral pulses.
• Biopsy can give histological confirmation of the diagnosis.

Non-Drug

• Smoking aggravates the condition.
• Because of the risk of cardiovascular disease advice about diet and exercise should be given as for anyone at high risk. A low calcium diet⁵ may also help, especially in earlier life.
• Avoid contact sports to reduce the risk of damage to the eyes.
• Vitamins A, C, and E and zinc supplements⁶ may reduce the risk of haemorrhage.
• All patients with PXE should be monitored on a regular basis by an ophthalmologist
• Genetic counselling should be offered to assess the risk of having affected children. Is it autosomal dominant or recessive form? Pregnancy is well tolerated,⁷ except for an increase in the number of miscarriages in the first trimester but multiple pregnancies do aggravate the disease course.

Drugs

• Avoid NSAIDs because of the risk of GI haemorrhage.
• With the exception of aspirin, there should be standard management of high risk CHD.
• If there is mitral regurgitation antibiotic prophylaxis should occur for dentistry, etc.
• Pentoxifylline may alter reduces blood viscosity but it can also increase risk of haemorrhage.
• Interferon alpha-2a may be a potential treatment.

Surgical

Plastic surgery can correct the sagging skin.

The problem is mostly cosmetic and there is a normal life expectancy but there can be problems of haemorrhage, especially from the GI tract as well as problems with arteries and prolapsed mitral valve.⁸Ocular involvement with retinal haemorrhages leads to the progressive loss of central vision. Peripheral vision is always spared.
Involvement of the elastic media and intima of the arteries causes claudication, hypertension, angina, myocardial infarction, and gastrointestinal or cerebral haemorrhage.
Cerebral and gastrointestinal haemorrhage or coronary occlusion, although uncommon, may be fatal.

Life expectancy is normal although bleeding and arterial disease can cut it short.

There is no means of prevention. There is no antenatal test for the condition and it would not normally be regarded as an indication for TOP.
First degree relatives should be screened for the disease so that action can be taken at an early stage.⁹