Are You Confident of the Diagnosis?
What you should be alert for in the history
Pseudoxanthoma elasticum affects three major organ systems, the skin, cardiovascular system, and eyes. Skin changes at predilection sites develop in childhood or adolescence but often become noticeable only later in life. There may be a personal or sibling history of early onset cardiovascular disease or loss of visual acuity after head trauma.
Characteristic findings on physical examination
Plaques of skin colored to yellow papules are most common on sides of the neck (Figure 1), in axillae (Figure 2), antecubital fossae, inguinal folds, popliteal fossae, and on the wrists. On the neck, the anterior and posterior midline may be spared when skin findings are mild. An aggregate of yellow papules can often be seen on the inner lower mucosal lip (Figure 3) and the skin over the chin may appear loose or form creases. Periumbilical papules may occur in women after multiple pregnancies.
Progression of the disease is signified by formation of very loose skin or redundant skin folds, which are most prominent on the neck and in the axillae and inguinal folds. A spread to convex skin, eg, the upper chest and abdomen, is not uncommon. Peau d’orange or pigment mottling of the retina is the most common eye finding and is usually asymptomatic.
Angioid streaks are the second most common and have been traditionally associated with PXE. While they are not pathognomonic for PXE, they reach an incidence of 100% in those above 40 years of age. (Angiod streaks are also seen in Paget’s disease of the bone, beta thalassemia, sickle cell anemia, Ehlers-Danlos syndrome.) They are fine fractures in Bruch’s membrane along which small new blood vessels form (neovascularization). Leakage from these newly formed vessels after trauma can cause hemorrhage and scarring, which leads to significant impairment of visual acuity and occasionally to legal blindness. Other retinal findings include macular degeneration, optid drusen and “owl’s eyes” (paired hyperpigmented spots).
Cardiovascular symptoms are akin to those that are commonly encountered with advanced age, yet in PXE they occur prematurely. Calcification of midsize arteries can lead to claudication, coronary artery disease, abdominal bleeding after food passage and less likely, stroke. Mitral valve prolapse is a common trait that has been reported to occur with increased frequency in PXE. However, it does not seem to increase morbidity in PXE.
In addition to the aforementioned changes, bleeding diathesis has been noted in individuals and families with PXE with a deficiency in the vitamin K dependant coagulation factor. Most common are epistaxis and spontaneous gingival bleeding but severe vaginal or post partum hemorrhage may be observed. In contrast to classic PXE, skin laxity is more severe and resembles that of cutis laxa and retinal findings are generally asymptomatic.
Expected results of diagnostic studies
Skin biopsy from an affected area or from a scar on the skin is usually diagnostic. It shows fragmented elastic fibers with calcium deposits in the upper and mid dermis on H&E stain (Figure 4). If findings are equivocal, von Kossa stain on the same biopsy specimen can highlight calcium in the upper and mid dermis. DNA analysis may be performed in clinically unaffected siblings. Samples of blood or buccal swabs reveal mutations in the ABCC6 gene (GeneDx, Gaithersburg, MD). Mutation testing is not yet commercially available for GGCX mutations.
Solar elastosis (actinic damage) may mimick PXE on the neck but is otherwise strictly photodistributed. Late-onset focal dermal elastolysis is signified by skin-colored to yellowish papules in flexural areas that occur in the 7th to 9th decade. The histology reveals an increased number of normal elastic fibers in the mid and deep reticular dermis.
Elastoderma is localized lax skin that can affect the neck, arms and trunk and shows an increase of elastic fibers throughout the dermis. Perforating periumbilical calcific elastosis must be distinguished from periumbilcal involvement in multiparous women with PXE. It affects black women after multiple pregnancies, occurs in their 5th to 8th decade and is characterized microscopically by transepidermal elimination of distorted, calcified elastic fibers. PXE-like papilary dermal elastolysis affects predominantly women in their 60s to 90s. In addition to the typical PXE predilection sites in flexural folds, it is also seen across the abdomen and in the inframammary folds. A band-like reduction of elastic fibers in the papillary dermis is the cause of these skin changes.
White fibrous papulosis has been observed on the neck and trunk of Caucasian and Japanese women in their 5th to 9th decade. It differs from PXE histologically through thickening of collagen bundles and a reduction of elastic fibres in the papillary and mid reticular dermis. Amyloid elastosis results in similar skin changes as in PXE but only amyloid deposits without elastic fiber abnormalties are present.
In addition to these differential diagnostic considerations, PXE like skin changes or involvement of all organ systems can be seen with other disorders. D-penicillamine treatment, localized salpetric acid exposure, long standing end-stage renal disease as well as L-tryptophan eosinophilia myalgia syndrome result in clinically and histologicaly identical skin involvement that may resolve with treatment of the causative disease. A subset of patients with beta-thalassemia and sickle cell anemia show changes indistinguishable from classic PXE yet are devoid of PXE pathogenic mutations.
Who is at Risk for Developing this Disease?
PXE develops in those who are deficient in MRP6, a liver-bound transporter protein of unknown function. In a subset of patients with PXE, deficiency of the liver based vitamin K dependent coagulation factor is the underlying abnormality. Disease severity, however, is determined by factors such as life style, diet and co-morbidities.
What is the Cause of the Disease?
This is an autosomal recessive disorder of connective tissue caused by mutations in the ABCC6 gene. Rarely, it is caused by mutations in GGCX or by a combination of deleterious ABCC6 and GGCX mutations..
ABCC6 encodes an ABC cassette protein located in hepatocyte membranes. MRP6 serves as an efflux pump. It has homology to the multidrug resistance associated proteins, hence its name, but does not confer chemotherapy resistance. GGCX encodes gamma glutamyl carboxylase. It is responsible for activation of coagulation factors in the liver as well as for carboxylation of matrix gla proteins in peripheral connective tissue. Carboxylated matrix gla proteins prevent ectopic mineralization.
Low levels of serum vitamin K and the anti-mineralization protein fetuin-A have been measured in patients with PXE. It is speculated that the prospective substrate of MRP6 may be a vitamin K glutathione conjugate or may relate to fetuin-A release, thus allowing progressive mineralization in connective tissue that is rich in elastic fibers.
Systemic Implications and Complications
Classic PXE is a systemic disorder involving multiple organs. The effects on the cardiovascular system are the most serious, as mortality could ensue from myocardial infarction or stroke. Therefore, elimination of co-morbid factors and regular screening are an important part of the management of PXE.
No specific treatment available
Surgical revision of redundant skin is possible
Eyes (symptomatic or progressive angioid streaks):
Intravitreous injection of vascular endothelial growth factor antagonist bevacizumab
Macular translocation (experimental)
Low-dose acetylsalicylic acid 81 mg daily
Pentoxyfyllline 400 mg three times daily or Cilostazol 50-100mg twice daily or Clopidrogel 75mg once daily for claudication
Correction of hyperlipidemia (diet and medication)
Optimal Therapeutic Approach for this Disease
Prevention of ophthalmologic and cardiovascular disease.
Avoidance of head trauma
Diet rich in antioxidants
Semiannual ophthalmologic examination with funduscopic evaluation
Regular use of Amsler grid once a month at home
Balanced, low cholesterol diet
Avoidance of smoking
Moderate calcium intake appropriate for age
Magnesium supplementation (especially magnesium carbonate containing phosphate binders)
Baseline electrocardiogram and echocardiogram
Annual cardiologic examination
Unusual Clinical Scenarios to Consider in Patient Management
PXE-like skin changes or involvement of all organ systems can be seen with other disorders. D-penicillamine treatment, localized salpetric acid exposure, longstanding end-stage renal disease as well as L-tryptophan eosinophilia myalgia syndrome result in clinically and histologically identical skin involvement that may resolve with treatment of the causative disease. A subset of patients with beta-thalassemia and sickle cell anemia show changes indistinguishable from classic PXE yet are devoid of PXE-pathogenic mutations.
What is the Evidence?
Ringpfeil, F, Lebwohl, MG, Christiano, AM, Uitto, J. “Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter”. Proc Natl Acad Sci USA. vol. 97. 2000. pp. 6001-6. (This is the first report of mutations in the ABCC gene responsible for PXE. The distribution of compound heterozygous mutations is delineated in four families with multiple affected individuals.)
Vanakker, OM, Martin, L, Gheduzzi, D, Leroy , BP, Loeys, BL, Guerci, VI. “Pseudoxanthoma elasticum-like phenotype with cutis laxa and multiple coagulation factor deficiency represents a separate genetic entity”. J Invest Dermatol. vol. 127. 2007. pp. 584-7. (This study identified mutations in the GGCX gene in families and individuals with PXE like features, severe cutis-laxa like skin involvement and bleeding tendencies. Due to the impact of these mutations on a similar pathway as ABCC6 mutation, this phenotype is now believed to be a variant of PXE.)
Li, Q, Grange, DK, Armstrong, NL, Whelan, AJ, Hurley, MY, Rishavy, MA. “Mutations in the GGCX and ABCC6 genes in a family with pseudoxanthoma elasticum-like phenotypes”. J Invest Dermatol. vol. 129. 2009. pp. 553-63. (This analysis of one family raises the possibilty that mutations in both the ABCC6 gene and the GGCX gene may work in concert to give rise to PXE-like cliniclal features.)
Hendig, D, Schulz, V, Arndt, M. “Role of serum fetuin-A, a major inhibitor of systemic calcification, in pseudoxanthoma elasticum”. Clin Chem. vol. 52. 2006. pp. 227-34. (In search of the putative substrate of the liver based efflux pump MRP6, serum concentrations of the calcification inhibitor Fetuin A were measured in indiviuals with PXE as well as their unaffected first-degree relatives. The reduced levels of Fetuin-A in both men and women with PXE suggest that Fetuin A regulation is MRP6 dependent.)
LaRusso, J, Li, Q, Uitto, J. “Elevated dietary magnesium prevents connective tissue mineralization in a mouse model of pseudoxanthoma elasticum”. J Invest Dermatol. vol. 129. 2009. pp. 1388-94. (The availabilty of a PXE knockout mouse allowed the study of various minerals on clinical disease severity. It was demonstrated that magnesium may protect connective tissue form calcifying.)
Vanakker, OM, Martin, L, Schurgers, LJ, Quaglino, D, Costrop, L, Vermeer, C. “Low serum vitamin K in PXE results in defective carboxylation of mineralization inhibitors similar to the GGCX mutations in the PXE-like syndrome.”. Lab Invest. vol. 90. 2010. pp. 895-905. (While deficiency of a vitamin K dependent coagulation factor permits ectopic calcification in the PXE-like syndrome with bleeding tendency, low vitamin K levels were found in individuals with classic PXE.)
Jiang, Q, Li, Q, Grand-Pierre, AE, Schurgers, LJ, Uitto, J. “Administration of vitamin K does not counteract the ectopic mineralization of connective tissues in Abcc6 (-/-) mice, a model for pseudoxanthoma elasticum”. Cell Cycle. vol. 10. 2011. pp. 701-7. (The knockout mouse model for PXE provided fundamental understanding of the relevance of vitamin K on reversal of ectopic calcification.)
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