Hypermobility Types of HMS Pseudoxanthoma Elasticum Pseudoxanthoma Elasticum Pseudoxanthoma elasticum (PXE) can present with joint hypermobility; laxity of the skin is also a feature shared with other HDCT's. The HMSA provides support and information to members who have PXE, many of whom were previously misdiagnosed as having Ehlers-Danlos syndrome. We would like to thank our colleagues at PXE International for allowing us to publish this ‘PXE in Primary Care article’. Further information on PXE, and PXE International, can be found at: www.pxe.org Introduction Pseudoxanthoma elasticum (PXE) is a genetic systemic disorder, the hallmark of which is dystrophic mineralization of elastic tissue of the skin, retina, and arteries. PXE is caused by mutations in the gene that codes for the membrane transport protein ABCC6 (MRP6). Recent experiments on a PXE knockout mouse suggest that a circulating metabolite is important to this mineralization. The primary care physician may be the first to suspect and diagnose PXE because of the varied clinical manifestations involving several body systems. He or she may coordinate the lifelong specialty care of the affected patient, and most importantly, may be expected to be an authoritative resource as well as source of support for the patient and family. Incidence PXE is a rare disease. Published reports estimate incidence at 1/25,000-100,000. The true incidence is unknown, as it is likely that affected individuals with mild involvement and/or atypical presentation escape diagnosis. It affects all races and ethnicities, and is reported twice as frequently in women than in men. The reason for this gender discrepancy is not clear. Skin manifestations The primary lesion of PXE is a small 2-5 mm yellowish or flesh coloured papule, irregular or rhomboid in shape (hence the term pseudoxanthoma), which may form groups or coalesce into larger plaques. The lesions are asymptomatic and tend to be distributed symmetrically on flexural areas progressing downward from the neck to the axillae and antecubital fossae, and later to the groin and popliteal fossa. Less common areas of involvement include the periumbilical area, oral, and anogenital mucosa. Oral lesions, seen on the inner aspect of the lower lip, resemble Fordyce spots. The lesions may give the affected skin a "plucked chicken" or "cobblestone" appearance. The lesions may cause the skin of the neck to appear unwashed. Differential diagnosis includes the common entity solar elastosis as well as fibroelastolytic papulosis (PXE-like papillary dermal elastolysis), which can appear clinically identical to PXE. The skin lesions develop during childhood or adolescence, and progress slowly and unpredictably with age, progressing to other flexural areas. The neck, axillae, groin, or face may sometimes manifest lax, redundant folds of skin in late stage PXE. Prominent horizontal mental (chin) creases may develop at an early age in adults with PXE. Skin biopsy of lesional (and sometimes nonlesional) skin confirms the diagnosis if it shows calcification of fragmented, clumped elastic fibres in the mid and lower dermis on von Kossa staining. The highest yield is from biopsy of a primary lesion (papule). In the absence of primary lesions, punch biopsy of neck, axillary and/or antecubital fossa is recommended. The skin lesions are asymptomatic. However, affected individuals with unsightly redundant folds can undergo cosmetic surgical correction, in most cases with satisfactory wound healing. Although skin manifestations are most characteristic of PXE, the ocular and cardiovascular manifestations are responsible for the morbidity of the disease. Indeed, in some cases the skin lesions are barely visible. Retinal Disease The earliest, and often subtle, manifestation of PXE in the retina is peau d'orange, a diffuse yellowish mottling of the fundus usually seen in the first two decades of life. The characteristic retinal lesion is the angioid streak, seen in most affected adults, and sometimes seen in childhood or adolescence. Angioid streaks are grey to brown or dark red, spoke-like bands radiating out from the optic disc or encircling the disc with peripapillary streaks. Angioid streaks correspond to breaks in Bruch's membrane, an elastin rich layer of the choroid. Neither angioid streaks nor peau d’orange affect visual acuity; however subretinal neovascular capillary nets can grow through these breaks, leading to haemorrhage and central visual loss (not true blindness) if they occur in the macula or fovea. Current treatments for age-related macular degeneration (AMD), the intra-ocular injection of the anti-angiogenic drugs Lucentis, Avastin, and Eylea, are now widely used in PXE and appear to be as effective as in AMD. Eylea and Lucentis are FDA approved drugs for wet AMD, and Avastin is FDA approved for colon cancer, and all are used off-label for PXE. No longer first line treatments, laser photocoagulation and photodynamic therapy were used in PXE to seal bleeding or leaking blood vessels, with disappointing results. Laser treatment might stabilize vision and stop bleeding, but often causes scarring and loss of vision in the target area, and there is a high recurrence rate of new vessels. Photodynamic therapy results with PXE have also been disappointing, although a few patients have had good results. However, there is also a high rate of recurrent neovascularization. Vascular Disease The basic vascular pathology in PXE is dystrophic calcification of the abnormal elastic fibers in the internal elastic lamina and media of middle sized arteries. These lead to changes resembling atherosclerosis leading to vascular stenosis or fragility. The most common manifestations of arterial disease in PXE are diminished peripheral pulses (including the upper extremities) and intermittent claudication. Angina and symptoms of intestinal ischemia may occur relatively early in life. Hypertension may be more common among affected individuals with PXE. If present, this increases the risk of vascular complication in the individuals affected by PXE, and needs to be well controlled. Uncommonly, dramatic GI bleeding, usually gastric, may be an early manifestation and even the presenting sign of PXE. The mechanism is unknown, but gastroscopy shows gastric mucosal changes resembling mucosal PXE elsewhere (yellowish papules), and the histology of the gastric vessels resembles that of other arteries affected by PXE. Genetics of PXE PXE is an autosomal recessive disorder. There are no confirmed autosomal dominant cases. However, the carrier frequency may be higher than previously thought and some recessive carriers may have mild subclinical manifestations on biopsy. Clinical expression is not helpful in predicting the severity in family members as there is no evidence of correlation between genotype and phenotype. PXE has variable expressivity and environmental influences may modify the clinical expression. The gene is on the short arm of chromosome 16 (16p13.1) and codes for the membrane transport protein, ABCC6/MRP6. The substrate and exact function of this transport protein remain unknown. Genetic testing is available through PXE International, and can be useful for confirmation of an uncertain clinical diagnosis, identification of at-risk family members, prenatal diagnosis or genetic counselling. Please contact the PXE International office at 202.362.9599 for details. Workup of the Affected Individual General workup of the individual affected by PXE should include: A clinical history detailing onset of signs or symptoms, detailed cardiovascular and ocular history, as well as family history. Examination of the skin, with special attention to neck and flexural creases. Examination of lip mucosa and cardiovascular system, including peripheral pulses. Confirmation of diagnosis by skin biopsy with appropriate special stains for elastic tissue and calcium. Laboratory evaluation of lipids. Examination of first-degree relatives when feasible. Ophthalmologic consultation should include: Recording visual acuity. Dilated direct and indirect ophthalmoscopic exam. Fluorescein angiography and optical coherence tomography if clinically indicated. Amsler grid monitoring of central visual fields by patient. Cardiovascular consultation should include: Non-invasive studies of the peripheral vasculature - Ankle brachial indices (ABIs) and Doppler ultrasound studies if clinically indicated. Baseline stress test and sonogram of heart valves. EKGs (if symptoms or clinical findings warrant). Management of Affected Individuals As are most genetic diseases, PXE is incurable. Management should focus on education of the affected individual, genetic counselling, monitoring and treatment of complications, and dietary and lifestyle modifications to delay or possibly prevent complications. This may involve a team approach including dermatologist, primary care physician, ophthalmologist, cardiologist, vascular surgeon, plastic surgeon, genetic counselor, nutritionist, physical therapist, low vision specialist and support groups. Support groups are of tremendous benefit in helping affected individuals cope with the disorder. The affected individual (or parent) needs to be educated in understandable terms regarding the various manifestations of the disease and the prognosis (which is not as dire as some affected individuals are led to believe). Genetic testing is available and is most useful when a young person is diagnosed and his or her siblings may be too young to exhibit clinical manifestations. Not all mutations are found through genetic testing, so it is not 100% reliable. Genetic testing is costly, is not predictive of severity, and may not be conclusive. Genetic counselling is recommended prior to genetic testing, and is available at no charge through PXE International. Regular ophthalmologic examination by a physician with expertise in retinal disease is essential, and affected individuals should learn to use the Amsler grid to monitor for central visual disturbances. Avoidance of contact sports and wearing of appropriate protective goggles for sports is suggested to prevent eye trauma that could cause retinal haemorrhage. Regular physical examinations with specific attention to the cardiovascular system are essential. Lipid levels should be monitored periodically. Surgical intervention may be indicated for gastrointestinal bleeding, severe peripheral vascular disease (if correctable), and improvement of cosmetic deformities of the face, neck, axilla, and groin. Weight control, avoidance of smoking, and aggressive management of hypertension and lipid disorders is essential in delaying or reducing the severity of vascular complications. Pentoxifylline and cilostazol (Pletal) may be of value in managing claudication. Aspirin and other non-steroidal anti-inflammatory medications should be avoided due to the risk of gastrointestinal haemorrhage unless the benefits are felt to outweigh the risk and no safer alternative is available. Women’s Health and PXE Most women with PXE have normal pregnancies. PXE is not associated with markedly increased fetal loss or an increased risk of adverse reproductive outcomes. Mineralization of the placenta is more common in women with PXE, but does not appear to affect placental function or fetal well-being, and fetal complications due to impaired uteroplacental blood flow do not appear to be a problem. The incidence of gastric bleeding and retinal complications is lower than previously thought (<1%). There is no basis for women affected by PXE to avoid becoming pregnant. A study of mammography in PXE showed that there is an increased incidence of microcalcifications, vascular calcification and skin thickening but no increase in breast cancer due to PXE. The pattern of breast microcalcification in PXE is benign and does not suggest cancer. The finding in mammography of three of the following: skin thickening, skin calcification, breast microcalcifications, or vascular calcification, should suggest a diagnosis of PXE. Men’s Health and PXE Testicular microlithiasis has been observed in males with PXE, and a study suggests an association between PXE and testicular microlithiasis. In all males examined in one study, testicular microlithiasis was not associated with cancer. Supplements It was reported in an early retrospective case study that high calcium intake early in life may correlate with the overall severity of PXE, but this has not been confirmed by studies, and calcium restriction remains unproven in the management of PXE. Calcium restriction can also lead to development of osteoporosis. Calcium intake should be at the RDA levels and supplementation avoided unless dietary intake is known to be inadequate, or there is evidence of osteopenia or osteoporosis. Phosphate binding, which reduces calcium/phosphorus product in serum, was thought to reduce mineralization, and perhaps improve the symptoms and course of PXE. However, a controlled clinical trial of the safety and efficacy of treatment with Renagel, an oral phosphate binder, showed no difference in skin calcifications and eye findings between PXE patients taking Renagel and placebo. Magnesium oxide as a treatment for PXE is currently being examined in a two-year clinical trial being conducted at Mt. Sinai Medical Center in New York City. Lionel G. Bercovitch, MD Medical Director of PXE International PXE International 4301 Connecticut Avenue, NW Suite 404 Washington, DC 20008-2369 For more information on Pseudoxanthoma Elasticum, please visit the PXE International website at www.PXE.org.