Pseudoxanthoma Elasticum: Causes, Symptoms, Treatment, Diagnosis, Prognosis

Pseudoxanthoma elasticum (PXE) is an extremely uncommon genetic disorder; so uncommon that about 97% of people worldwide have never heard of this disease; and it comprises of symptoms, such as elastorrhexia or progressive fragmentation and calcification of the elastic fibers, mainly targeting the skin, the retina and the cardiovascular system.⁽⁹⁾

Pseudoxanthoma elasticum was first described by Dr. Rigal, the French dermatologist in the year 1881 and was later named by Dr. Darier in 1896,⁽¹⁾ who tried to differentiate Pseudoxanthoma elasticum from other common xanthomas.⁽¹⁰⁾

The cause of Pseudoxanthoma Elasticum seems to be genetic abnormalities on chromosome 16p13.1 that also comprises of genes ABCC6 or MRP6 in at least few affected families.^{(1, 11)} There is abnormality of the collagen and ground substance in patients suffering from Pseudoxanthoma Elasticum. This leads to accumulation of calcium in the abnormal elastic fibers in the skin, eyes, blood vessels and heart.

• The estimated prevalence of Pseudoxanthoma elasticum is about 1 case per 25,000-100,000.⁽¹²⁾
• Pseudoxanthoma Elasticum affects women more than men.⁽¹⁾
• Pseudoxanthoma elasticum is seen to develop in people of all races. However, there is a somewhat higher prevalence seen in South African Afrikaners, probably because of the founder effect.⁽¹³⁾
• The average age of onset of pseudoxanthoma elasticum is 13 years; but there can be variations in the ages.⁽¹⁴⁾

• The initial manifestations of pseudoxanthoma elasticum are the cutaneous or the skin changes arising on the lateral side and the posterior part of the neck.⁽¹⁾ These changes are usually harmless, but can be a concern to the patient, appearance wise.
• The extra-cutaneous growths comprise of mucosal involvement, which leads to gastrointestinal hemorrhage with occult blood in the stool, frank bleeding, melena or hematemesis.⁽¹⁵⁾
• Due to chronic blood loss, patient may feel tired and fatigued. The fatigue can also be experienced due to claudication from involvement of blood vessels.
• Gradually, as pseudoxanthoma elasticum progresses, there is development of severe cutaneous and cardiovascular symptoms, such as hypertension and angina.
• Hematuria can also be present in patients suffering from pseudoxanthoma elasticum.
• Patients in fourth decade of life who are suffering from pseudoxanthoma elasticum commonly suffer from retinal hemorrhages along with loss of central vision.
• In-Depth Study of Symptoms of Pseudoxanthoma Elasticum

Physical findings are categorized into cutaneous, ocular and cardiovascular symptoms.

• The cutaneous symptoms of pseudoxanthoma elasticum are highly characteristic in their appearance in that they often form during childhood or early teens;⁽¹⁾ however, sometimes these symptoms can also appear in late adulthood.
• A patient suffering from pseudoxanthoma elasticum initially develops yellow colored, small papules of 1 to 5 mm in width that can be seen in a reticular or linear pattern.⁽¹⁾ These papules can coalesce leading to development of plaques.^{(1, 23)}
• The skin of the patient suffering from pseudoxanthoma elasticum has the appearance of Moroccan leather, cobblestone appearance or like a plucked chicken.^{(16, 17)}
• Usually, these skin changes are initially observed on the lateral side or the posterior area of the neck and go onto involve the axillae, the antecubital fossa; the popliteal spaces; the periumbilical and inguinal areas; the oral mucosa along with the lower lip, the palate and cheek; and the rectal and vaginal mucosa.^{(1, 23)}
• As the pseudoxanthoma elasticum worsens, the skin of the neck, the axillae, and the groin tends to become lax, soft, wrinkled and starts to hang in folds.⁽¹⁾ The degree of the skin changes in pseudoxanthoma elasticum is often limited, but sometimes these changes can be seen all over the body.
• The presence of oblique and horizontal mental creases before the age of 30 is highly distinctive for pseudoxanthoma elasticum.^{(9, 18)}
• Other clinical cutaneous symptoms seen in patients include: brown reticulated macules, acneiform lesions and chronic granulomatous nodules.⁽¹⁹⁾
• Another skin condition known as Elastosis Perforans Serpiginosa can also coexist with pseudoxanthoma elasticum.^{(20, 21)}
• The cutaneous lesions of pseudoxanthoma elasticum often remain the same throughout the patient’s life, and are usually distributed symmetrically.

The ocular symptoms of Pseudoxanthoma Elasticum (PXE) consist of slate gray to reddish brown angioid streaks on the retina, appearing as curvilinear bands radiating from the optic disc.^{(1, 2)} These streaks represent the fissures and cracks in the calcified Bruch membrane. The ocular symptoms of Pseudoxanthoma Elasticum are usually bilateral and are commonly observed many years after the development of the cutaneous lesions. The angioid streaks can be seen in about 80% of the patients suffering with pseudoxanthoma elasticum.

Although these ocular lesions are highly specific for pseudoxanthoma elasticum, these type of ocular lesions are also seen in other diseases, such as sickle cell anemia, Paget disease of the bone, thalassemia, syndrome, Ehlers-Danlos syndrome, Marfan syndrome and lead poisoning.^{(1, 3)}

• Peau d’orange changes usually precede the angioid streaks and these comprise of fine-yellow drusen like pigment irregularities.^{(1, 4)} These skin changes develop on average of about one to eight years before the angioid streaks and are indicative of early retinopathy.
• The presence of chorioretinal atrophy with a “comet tail” like appearance seems to be specific only to pseudoxanthoma elasticum; however, their expression differs greatly.⁽⁵⁾

Cardiovascular symptoms other than intermittent claudication are often the last complications or symptoms to be seen in patients with pseudoxanthoma elasticum.⁽⁶⁾ There is calcification of the elastica media and intima of the blood vessels resulting in various health problems.^{(1, 6)} The peripheral pulses are greatly reduced in adults. The involvement of the renal artery is rare; however, can cause hypertension. Coronary artery disease can cause angina pectoris and further on cause myocardial infarction.

There is a higher incidence of Mitral Valve Prolapse in pseudoxanthoma elasticum (PXE.⁽²²⁾ Mitral valve prolapse need not be a cause for alarm until there is murmur heard, which indicates mitral valve insufficiency.

Patients suffering from pseudoxanthoma elasticum also experience GI hemorrhage that is gastric in origin, caused due to the increased fragility of the calcified vessels.⁽²⁴⁾ As the disease progresses, hemorrhage can develop without any warning early on; especially in the second to fourth decade of the life of the patient. Treatment of hemorrhage depends on its severity and consists of blood transfusion with hospitalization; and surgery may also be needed.

About 10-15% patients suffering with pseudoxanthoma elasticum suffer from GI hemorrhage at some point or the other in their lives.⁽⁷⁾ Hemorrhaging can also occur in the cerebrovascular system or the urinary tract, but it is less common.⁽⁷⁾

The characteristic Cutaneous Lesions in Pseudoxanthoma elasticum usually develop in childhood or early teens; however, because of their asymptomatic nature, the diagnosis is delayed by an average of 8 to 9 years. Patients with pseudoxanthoma elasticum are usually diagnosed only after the development of vascular and ocular complications.⁽²³⁾

It is difficult to diagnose Pseudoxanthoma Elasticum, as this condition exhibits a late onset of symptoms, which are very subtle and can also overlap with other medical conditions.⁽²³⁾ The first and primary diagnostic sign of pseudoxanthoma elasticum are the cutaneous findings or the skin changes that develop on the lateral side and back of the neck. These skin growths are usually asymptomatic and not easily identified until the patient is in 20s or 30s of his life.

It is extremely important to diagnose and instill the right prophylactic measures when suffering from pseudoxanthoma elasticum.

To make a definitive diagnosis for pseudoxanthoma elasticum, you need major criteria from two different classifications; for a probable diagnosis of pseudoxanthoma elasticum, two major criteria from within the same classification (eye or skin) is needed OR one or more minor criterion and one major criterion from another classification should be present.⁽²⁵⁾

A possible diagnosis for pseudoxanthoma elasticum is made only when minor criteria and one major criterion are found.

Skin: The presence of yellow plaques/ papules on the lateral or posterior side of the neck or body. A biopsy of the skin from the affected region shows increased calcification with aggregation of elastic fiber and this is the best and accurate way to diagnose pseudoxanthoma elasticum; especially if the biopsy sample is taken from the affected region.

Eyes: Development of angioid streaks and Peau d’orange changes are seen in pseudoxanthoma elasticum.

Eyes: Presence of one angioid streak that is shorter than one disc width; one or more “wing signs” on the retina; and “comets” in the retina.

• Fecal occult blood test should be done to assess GI bleeding.
• CBC count needs to be done to check for iron deficiency anemia.
• Urinalysis needs to be done to look for urinary tract hemorrhage.
• Serum lipid levels need to be obtained, as Pseudoxanthoma elasticum is linked with early atherosclerosis and increased lipid levels and this needs medical attention.⁽²⁵⁾
• Serum calcium and phosphate levels also need to be obtained as in some patients, hyperphosphatemia and hypercalcemia has been observed.
• Patients having pseudoxanthoma elasticum confirmed with biopsy and having zero or only one ABCC6 mutation need screening for ectonucleotide
• pyrophosphatase/phosphodiesterase 1 (ENPP1) and gamma-glutamyl carboxylase (GGCX) mutations, as there could be an indication of digenic inheritance.

• Echocardiography: Patients having a heart murmur, which is indicative of mitral valve insufficiency, need Echocardiography. This test is also done if the patient is having anginal symptoms or has family history of heart or coronary artery disease.
• Radiography: This imaging test helps in identifying the large artery or soft tissue calcification.
• Head CT Scan: This test is needed if upon physical exam of the patient, there are signs of cerebral hemorrhage or findings of focal neurologic deficits.

Funduscopy: Ophthalmologic examination consisting of funduscopy is mandatory for detection of early signs of retinopathy, retinal hemorrhages and angioid streaks.
Self-monitoring the visual acuity by the patient diagnosed with pseudoxanthoma elasticum is highly recommended, as the risk for macular choroidal neo-vascularization increases with age. This can be done with Amsler grid.⁽²⁷⁾ Other than this, patient should also go for fundus examinations every 2 years if the patient is aged under 40 years; and two times a year if the patient is over 40 years of age.

Ankle/Brachial Blood Pressure utilizing the Doppler method is beneficial in patients with severely diminished peripheral pulses and patients suffering from intermittent claudication to ensure adequate tissue perfusion.

Endoscopy: Upper and/or lower endoscopy is needed if the patient has melena, occult blood in the stools, hematemesis or frank GI bleeding. Endoscopy works as a treatment, as well as diagnosis and is better than barium enema and upper GI series.

Skin biopsy when obtained from an area of primary skin changes is the best and accurate way to confirm the diagnosis of pseudoxanthoma elasticum.

For diagnosis, according to studies, the presence of one or two major eye findings along with one or two skin symptoms with or without cutaneous laxity and with a positive skin biopsy is a definitive diagnosis for pseudoxanthoma elasticum. This condition cannot be definitively diagnosed if either eye or skin findings are absent; except if there are two ABCC6 mutations seen with molecular genetic testing.

Loss of Vision: The ocular involvement in pseudoxanthoma elasticum with retinal hemorrhages cause complications, such as progressive loss of central vision.⁽²⁶⁾ Peripheral vision is not affected though.

Claudication: As there is calcification of blood vessels in pseudoxanthoma elasticum, patient suffers from claudication as a complication of this disease.

Cardiac Complications and Bleeding: Other complications of pseudoxanthoma elasticum include: angina, hypertension, myocardial infarction and GI or cerebral hemorrhage.

Fatal Complications: The gastrointestinal and cerebral hemorrhage or coronary occlusion can be life threatening; however, these complications are rare.

Most of the pathologic changes occurring as a result of pseudoxanthoma elasticum are irreversible;⁽²⁷⁾ however, prophylactic measures can be undertaken to cut down and minimize the severity of the disease course.⁽²⁷⁾

Unfortunately, there is no cure for Pseudoxanthoma Elasticum. Treatment primarily focuses on halting the progression of this disease and management of symptoms of Pseudoxanthoma Elasticum.

Treatment consists of managing and slowing the disease, which is pseudoxanthoma elasticum, by incorporating lifestyle modifications, such as quitting smoking, daily exercise, and a healthy diet with supplemented magnesium, pyrophosphate analog and phosphate binders. It is important to note that smoking worsens the disease progression.

The main aim of pharmacotherapy in treatment of pseudoxanthoma elasticum is to increase the life span of the patient and to prevent complications. However, the primary treatment for pseudoxanthoma elasticum remains lifestyle modifications such as better diet, exercise and smoking cessation along with avoiding heavy physical exertion.^{(1, 27)}

Surgical excision can be done to correct the sagging, redundant folds of skin that are characteristic of pseudoxanthoma elasticum.^{(8, 27)} However, there can be delayed healing and scarring.⁽²⁷⁾

Autologous fat and collagen injections are other treatment options for mental creases.

Laser Treatment with Fractional Carbon Dioxide also helps in improving the skin’s appearance, especially the skin texture, dispensability, volume and the irregularity of skin lesions seen in pseudoxanthoma elasticum.

To minimize the severity of cardiovascular disease associated with pseudoxanthoma elasticum, exercise and diet are the primary and best treatment options. If these do not work and the patient also has increased levels of serum lipid and hypertension, which worsens pseudoxanthoma elasticum, then in such cases, medications are prescribed to control the symptoms.

Intermittent claudication is treated with weight reduction and exercise. This helps in stimulating the development of collateral blood vessels.

Pentoxifylline is a medicine which can be effective, but carries increased risk of hemorrhage; hence should be used with extreme caution.

If the patient is having melena or frank blood, then he/she should be closely monitored. Medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs), anti-platelet agents and aspirin, should be strictly avoided.⁽²⁷⁾ Gastrointestinal hemorrhage can also be managed by iron supplements, hospitalization, endoscopic treatment, blood transfusions or surgery with partial gastrectomy if needed.

Sub-retinal membrane formation precedes the retinal hemorrhages and these can be identified by Amsler grid. Intravenous fluorescein angiography can confirm these eye changes so that prompt treatment can be started to minimize the vision loss.

Intravitreal triamcinolone and photodynamic therapy are also helpful in treating ocular complications seen in pseudoxanthoma elasticum.

The risk of retinal hemorrhage can be reduced with zinc supplements and vitamins A, C, and E.

According to research, treatment for choroidal neo-vascularization of the epithelium of retinal pigment seen in pseudoxanthoma elasticum can consist of transpupillary thermotherapy; laser photocoagulation, photodynamic therapy; anti-vascular endothelial growth factor intravitreal injections and macular translocation surgery.

Patients suffering from pseudoxanthoma elasticum (PXE) need to be monitored on a regular basis by an ophthalmologist.

Gastroenterologist and a cardiologist should be referred to if the patient is also having gastrointestinal hemorrhages and cardiovascular symptoms.

If the patient suffering from pseudoxanthoma elasticum also has cerebral, pulmonary, urinary tract involvement; then it is imperative to consult with the appropriate physicians with the right referrals being made.

Genetic counseling is highly recommended and is beneficial for patients having pseudoxanthoma elasticum and their families.^{(1, 27)}

It is important to avoid excessive dietary calcium consumption in childhood and in adolescence because there has been observed a link between high calcium intake and the severity of pseudoxanthoma elasticum (PXE).⁽²⁷⁾

Activities, such as straining, heavy lifting, activities, which increases the risk of head trauma, which in turn increases the risk of retinal hemorrhage, should be absolutely avoided by patients with pseudoxanthoma elasticum (PXE). Contact sports and strenuous weight lifting should also be strictly avoided when suffering from pseudoxanthoma elasticum.⁽¹⁾

An ophthalmologic examination is mandatory for pseudoxanthoma elasticum patients, once a year at least, to detect angioid streaks, early retinopathy or retinal hemorrhage.⁽²⁷⁾

It is important to perform CBC count and fecal occult blood testing every 6 months to 1 year to assess for GI hemorrhaging.

Patients with Pseudoxanthoma Elasticum have to undergo regular physical exams with specific attention to the cardiovascular system, in order to detect mitral valve insufficiency, peripheral vascular compromise or coronary artery disease.⁽²⁷⁾

It is also of extreme importance to adequately and appropriately manage co-morbid conditions, such as hyperlipidemia, diabetes and hypertension due to early atherosclerosis and the increased risk of cardiovascular disease present in pseudoxanthoma elasticum.

The patient should be made to understand the importance of quitting smoking, avoiding contact sports, aspirin, NSAIDs and anticoagulants due to the risk of hemorrhage.^{(1, 27)}

NOTE: Patient Should Be Reiterated Again And Again On All The Above Points.

The degree of the extra-cutaneous organ involvement determines the prognosis of pseudoxanthoma elasticum (PXE).⁽²⁷⁾ Patients suffering from pseudoxanthoma elasticum usually lead a normal life span;⁽²⁷⁾ however, suffer from GI hemorrhage, cerebral hemorrhage and myocardial infarction; and all these can be life threatening. Rarely, it is seen that there is spontaneous resolution of the changes of the skin.

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