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Background
This is an inherited disorder of connective tissue involving the elastic tissue fibers. There are at least four variants. The classic skin changes usually arise by the second decade and are closely set yellowship papules occurring in the flexural creases especially in the neck and axillae, with decreasing involvement in the groins, periumbilical area, cubital and popliteal fossae, and oral cavity. These skin lesions are wrinkled and thickened and evolve into lax and redundant skin. The characteristic eye changes consist of angioid streaks and choroidoretinitis which may progress to blindness. In tissue sections, the calcium content is greatly increased leading to calcification of the elastic fibers and arteries of the eyes. Other vascular changes may lead to hypertension, cerebrovascular accidents, and gastrointestinal hemorrhage.
The cause is unknown. Cultured fibroblasts from afflicted patients release a proteolytic substance which may damage the elastin in the elastic fibers leading to calcificaiton.
An acquired variant may be several diseases and has been associated with exposure to calcium salts and obese patients, usually multiparous black women. These latter patients may also develop perforation. Unlike the inherited form, there is an absence of extra-cutaneous disease.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS PXE INCIDENCE Rare
PATHOGENESIS CHARACTERIZATION ABCC6 GENE
- Identification of a novel deletion in the ABCC6 gene leading to Pseudoxanthoma elasticum.
Katona E, Aslanidis C, Remenyik E, Csikos M, Karpati S, Paragh G, Schmitz G.
Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93053 Regensburg, Germany; 1st Department of Medicine, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
J Dermatol Sci. 2005 Nov;40(2):115-21. Epub 2005 Sep 23. Abstract quote
BACKGROUND:: Pseudoxanthoma elasticum (PXE) is an inherited systemic disorder, characterized by dermal, ocular and cardiovascular lesions. Genetic defects of the ABCC6 (MRP6) transporter are known to cause PXE.
OBJECTIVES:: The purpose of this study was to identify the genetic background of a PXE patient with a very early onset of the disease and severe systemic involvement.
METHODS:: Direct sequencing of genomic DNA obtained from peripheral whole blood.
RESULTS:: Our patient was found to be compound heterozygous with both ABCC6 alleles having genomic deletions. A novel exon 24-25 deletion was identified on one allele, while the frequently observed exon 23-29 deletion was found on the other allele. The novel deletion is 4.68kb long and was shown to extend from intron 23 to 25. DNA-sequencing of a 2.03kb fusion fragment revealed the deletion breakpoints within introns 23 and 25 originating in the middle of two Alu-repeats.
CONCLUSION:: In a patient with severe clinical symptoms, we found two genomic deletions in regions that might be important for function of the ABCC6 transporter. Genomic deletions in ABCC6 may occur more frequently in PXE patients than previously expected and future genetic analysis should focus on these mutations as well.Neutrophil elastase in patients with homozygous beta-thalassemia and pseudoxanthoma elasticum-like syndrome.
Samarkos M, Aessopos A, Fragodimitri C, Karagiorga M, Kalotychou V, Voskaridou E, Kavouklis E, Loukopoulos D.
1st Department of Internal Medicine, University of Athens School of Medicine, Athens, Greece.
Am J Hematol 2000 Feb;63(2):63-7 Abstract quote
In this study we investigated the possible role of neutrophil (PMN) elastase and its natural inhibitor, alpha1-proteinase inhibitor (alpha1-PI) in the pathogenesis of the pseudoxanthoma elasticum (PXE)-like syndrome which is found in patients with homozygous beta-thalassemia.
We studied 30 beta-thalassemia homozygotes with the PXE-like syndrome [PXE(+) group], 20 beta-thalassemia homozygotes without this syndrome [PXE(-) group] and 15 healthy controls.
Plasma PMN elastase concentration in the PXE(+) and in the PXE(-) group was 136.4 +/- 89 and 163.8 +/- 126 microg/L, respectively (P > 0.05). In the control group, the concentration was 42.9 +/- 16.8 microg/L (P < 0.01 for the comparison with both patients' groups). The plasma alpha1-PI concentration in the PXE(+) and in the PXE(-) group was 2.28 +/- 0.75 and 2.6 +/- 0.96 g/L, respectively (P > 0.05). Using logistic regression, we studied the prognostic value for PXE of the following independent variables: number of transfusions, chelation therapy, mean hemoglobin concentration, PMN elastase concentration, alpha1-PI concentration, chronic transaminase elevation, and positivity for anti-HCV. None of the above variables was found to have significant prognostic value for the PXE.
Plasma PMN elastase concentration is elevated in all beta-thalassemia homozygotes; its role in the pathogenesis of the PXE-like syndrome in beta-thalassemia can not be established, but our findings suggest that neutrophils of beta-thalassemia patients are activated, since PMN elastase is a marker of neutrophil activation.
Molecular genetics of pseudoxanthoma elasticum.
Ringpfeil F, Pulkkinen L, Uitto J.
Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107.
Exp Dermatol 2001 Aug;10(4):221-8 Abstract quote
Pseudoxanthoma elasticum (PXE), a systemic heritable connective tissue disorder, is characterized by progressive calcification of elastic structures in the skin, the eyes and the cardiovascular system, with considerable intra- and interfamilial phenotypic variability.
Recently, underlying genetic defects have been identified in the ABCC6 gene, which resides on the chromosomal locus 16p13.1 and encodes the MRP6 protein, a member of the ATP-binding cassette (ABC) family of proteins.
The affected individuals are homozygous or compound heterozygous for a spectrum of genetic lesions, including nonsense and missense mutations, or deletions and splice-site alterations, confirming the autosomal recessive nature of this condition. Analysis of the deduced primary sequence suggests that MRP6 is a transmembrane transporter, but its function has not been delineated yet. Surprisingly, however, MRP6 is expressed primarily, if not exclusively, in the liver and the kidneys, suggesting that PXE may be a primary metabolic disorder with secondary involvement of elastic fibers.
Identification of mutations in the ABCC6 gene in PXE provides a means for prenatal and presymptomatic testing in families at risk for recurrence. DNA-based analyses will also identify heterozygous carriers who may be at risk for development of limited manifestations of the disease as a result of compounding genetic factors and/or environmental modifiers.
A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum.
Le Saux O, Beck K, Sachsinger C, Silvestri C, Treiber C, Goring HH, Johnson EW, De Paepe A, Pope FM, Pasquali-Ronchetti I, Bercovitch L, Terry S, Boyd CD.
Pacific Biomedical Research Center, University of Hawai'i, Honolulu, HI 96822, USA.
Am J Hum Genet 2001 Oct;69(4):749-64 Abstract quote
To better understand the pathogenetics of pseudoxanthoma elasticum (PXE), we performed a mutational analysis of ATP-binding cassette subfamily C member 6 (ABCC6) in 122 unrelated patients with PXE, the largest cohort of patients yet studied.
Thirty-six mutations were characterized, and, among these, 28 were novel variants (for a total of 43 PXE mutations known to date). Twenty-one alleles were missense variants, six were small insertions or deletions, five were nonsense, two were alleles likely to result in aberrant mRNA splicing, and two were large deletions involving ABCC6. Although most mutations appeared to be unique variants, two disease-causing alleles occurred frequently in apparently unrelated individuals. R1141X was found in our patient cohort at a frequency of 18.8% and was preponderant in European patients. ABCC6del23-29 occurred at a frequency of 12.9% and was prevalent in patients from the United States. These results suggested that R1141X and ABCC6del23-29 might have been derived regionally from founder alleles. Putative disease-causing mutations were identified in approximately 64% of the 244 chromosomes studied, and 85.2% of the 122 patients were found to have at least one disease-causing allele.
Our results suggest that a fraction of the undetected mutant alleles could be either genomic rearrangements or mutations occurring in noncoding regions of the ABCC6 gene. The distribution pattern of ABCC6 mutations revealed a cluster of disease-causing variants within exons encoding a large C-terminal cytoplasmic loop and in the C-terminal nucleotide-binding domain (NBD2).
We discuss the potential structural and functional significance of this mutation pattern within the context of the complex relationship between the PXE phenotype and the function of ABCC6.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES INFLAMED SKIN
Department of Dermatology, University of Utah, Salt Lake City, UT, USA.
Background: Pseudoxanthoma elasticum (PXE) is an inherited disorder leading to characteristic calcified elastic fibers in skin, eyes and vasculature. PXE-like fibers have not been described in inflammatory skin disease in the absence of other signs of PXE.
Methods: The histopathology of inflamed skin from 13 patients that contained PXE-like fibers but lacked clinical evidence of PXE were studied. Six of these and six comparison specimens from known patients with PXE were subjected to polymerase chain reaction amplification and sequencing of exons 24 and 28 of the PXE-associated gene ABCC6. This genetic analysis employed a novel assay utilizing paraffin-embedded tissue.
Results: Incidental PXE-like fibers were found in patients without clinical suspicion of PXE in lesional tissue showing lipodermatosclerosis, granuloma annulare, lichen sclerosus, morphea profunda, erythema nodosum, septal panniculitis, basal cell carcinoma and fibrosing dermatitis. Two patients with PXE-like fibers but without clinical findings of PXE were heterozygous for a PXE-associated ABCC6 sequence alteration.
Conclusions: This pilot study shows elastic fibers similar to those of PXE in the lesional skin of patients with a variety of inflammatory skin diseases in the absence of clinical evidence of PXE; and some of these patients harbor changes in ABCC6.PAPILLARY DERMAL ELASTOLYSIS Pseudoxanthoma elasticum-like papillary dermal elastolysis (PDE). This group of patients are usually women aged 60-80 yrs with lesions clinically resembling PXE of the skin but without the associated systemic involvement.
Under the microscope, there is total loss of the elastic fibers within the papillary dermis, unlike the changes in PXE. Because of the inherited nature of PXE, it is important to distinguish PDE from PXE.
Pseudoxanthoma elasticum-like papillary dermal elastolysis: a report of two cases.
el-Charif MA, Mousawi AM, Rubeiz NG, Kibbi AG.
Department of Dermatology, American University of Beirut Medical Center, Lebanon.
J Cutan Pathol 1994 Jun;21(3):252-5 Abstract quote
We report 2 women, aged 83 and 63 years, who presented with multiple asymptomatic, slowly progressive, coalescing, skin-colored papules affecting the sides of the neck and lower abdomen. Incisional biopsies obtained from both patients revealed elastolysis in the papillary dermis. T
hese 2 cases represent pseudoxanthoma elasticum-like papillary dermal elastolysis, a recently described entity, the etiology of which remains unclear.
Pseudoxanthoma elasticum-like papillary dermal elastolysis: report of four Japanese cases and an immunohistochemical study of elastin and fibrillin-1.
Ohnishi Y, Tajima S, Ishibashi A, Inazumi T, Sasaki T, Sakamoto H.
Department of Dermatology, National Defense Medical College, Saitama, Japan.
Br J Dermatol 1998 Jul;139(1):141-4 Abstract quote
We report four patients with pseudoxanthoma elasticum-like papillary dermal elastolysis (PDE).
Multiple small papules on the neck, clinically resembling pseudoxanthoma elasticum, and loss of the elastic fibre network in the papillary dermis were found in each case. Immunohistochemical staining for elastin and fibrillin-1 in one patient demonstrated the disappearance of elastin and fibrillin-1 in the papillary dermis. Site-matched normal skins of the elderly showed intact elastin but a lack of fibrillin-1 in the papillary dermis. The younger normal skins revealed intact elastin and fibrillin-1. T
he results suggest that fibrillin-1 is absent from the papillary dermis of the normal-appearing neck skin of the elderly and that the primary defect in PDE may be in elastin rather than in fibrillin-1.
Coexistence of pseudoxanthoma elasticum-like papillary dermal elastolysis and linear focal dermal elastosis.Akagi A, Tajima S, Kawada A, Ishibashi A.
Departments of Dermatology, National Defense Medical College, Saitama, and Kinki University School of Medicine, Osaka.
J Am Acad Dermatol 2002 Aug;47(2 Pt 2):S189-92 Abstract quote An 89-year-old Japanese woman had pseudoxanthoma elasticum-like papillary dermal elastolysis on the neck and linear focal elastosis on the flexor aspects of the legs and thighs.
The lesions of both diseases had similar histologic patterns-loss of elastic fibers in the papillary dermis and accumulation of normal-appearing elastic fibers in the subpapillary or mid dermis. Immunohistochemical analysis showed elastin, and microfibril-associated proteins (fibrillin 1 and 2 and microfibril associated glycoprotein 1 and 4) were absent or decreased in the papillary dermis and present in the accumulated elastic fibers in both lesions.
The association of 2 diseases on different areas of the same patient and histologic and immunohistologic similarities between the diseases suggest that, despite the clinical differences, both diseases are closely related.
CALCIPHYLAXIS Calciphylaxis with histologic changes of pseudoxanthoma elasticum.
Nikko AP, Dunningan M, Cockerell CJ
Division of Dermatopathology, University of Texas Southwestern Medical Center, Dallas, USA.
Am J Dermatopathol 1996 Aug;18(4):396-9 Abstract quote
Calciphylaxis is a rare condition of widespread calcification of tissues and blood vessels with accompanying vascular thrombosis and ischemic necrosis. Most cases develop in association with hyperparathyroidism in patients with chronic renal failure.
Pseudoxanthoma elasticum (PXE) is a hereditary condition of abnormal elastic tissue structure that leads to widespread abnormalities of the skin, retina, and visceral organs. Histologic changes of PXE have been observed as coincidental findings in several conditions such as following trauma to the skin manifest as isolated plaques often in scars.
We observed histologic findings of PXE in a patient with chronic renal failure who developed fatal calciphylaxis. Complete evaluation failed to reveal evidence of systemic findings of PXE. Histologic changes of PXE may be seen in patients with calciphylaxis as a coincidental finding. Rapidly developing soft tissue calcification may lead to the expression of the characteristic histopathologic findings of PXE without evidence of classic clinical manifestations of PXE.
Calciphylaxis should be added to the list of disorders that may lead to microscopic PXE-like changes.
MOYA MOYA DISEASE
- Elastosis perforans serpiginosa-like pseudoxanthoma elasticum in a child with severe Moya Moya disease.
Meyer S, Zanardo L, Kaminski WE, Horn P, Schmitz G, Hohenleutner U, Herrmann WA, Landthaler M, Vogt T.
Department of Dermatology, University of Regensburg, D-93042 Regensburg, Germany.
Br J Dermatol. 2005 Aug;153(2):431-4. Abstract quote
A 2-year-old girl with Moya Moya disease who had relapsing cerebrovascular strokes presented with loose skin folds, 'chicken' skin appearance and perforating elastosis serpiginosa-like lesions in the genitocrural region.
Histologically, calcified material perforating the epidermis and adjacent short curled and mineralized elastic fibres suggested a variant of pseudoxanthoma elasticum (PXE). As PXE is known to be caused by various mutations in the transmembrane transporter ABCC6 gene, we hypothesized that a novel ABCC6 mutation may underlie this unique combination of PXE and elastopathic vascular damage. Therefore, the complete ABCC6 coding region of the patient and her parents was screened for genetic alterations.
No bona fide disease-causing mutation of ABCC6 could be found in the child and in her parents. However, two novel allelic amino acid substitutions (Arg1273Lys and Glu1293Lys; exon 27) were found in the girl and her father, localized in close proximity to the region that codes for the functionally critical second nucleotide-binding fold of ABCC6. Although a causal involvement of these amino acid substitutions could not be proven based on this study, both heterozygote substitutions may possibly have interacted with other undetected recessive maternal ABCC6 changes in the child.
To the best of our knowledge, this is the first report of an association between early-onset PXE and severe Moya Moya syndrome possibly related to ABCC6 changes.TUMEFACTIVE LIPEDEMA
Tumefactive lipedema with pseudoxanthoma elasticum-like microscopic changes.
Taylor NE, Foster WC, Wick MR, Patterson JW.
Department of Pathology, Department of Orthopedic Surgery, and Department of Dermatology, University of Virginia Health System, Charlottesville, VA, USA.
J Cutan Pathol. 2004 Feb;31(2):205-9 Abstract quote.
BACKGROUND: Lipedema is a condition characterized by diffuse, bilaterally symmetrical, painful swelling of the legs and buttocks. Microscopically, there are dermal and septal edema, adipocyte degeneration, and numerous mast cells, features held in common with lipedematous alopecia.
CASE REPORT: We present the case of a 60-year-old woman with a long history of bilateral leg masses with microscopic features of lipedema. In addition, elastic-fiber changes typical of pseudoxanthoma elasticum (PXE) were discovered within the subcutaneous septa in three separate specimens obtained from an affected extremity. The patient did not have other clinical findings of PXE, although there was a history of both hypertension and congestive heart failure.
CONCLUSION: This tumefactive presentation of lipedema has not been previously described. Regarding the elastic-tissue abnormalities, the patient could have either a subclinical form of PXE, perhaps predisposing to lipedema, or secondary elastic-tissue changes resulting from the massive edema. If the latter is the case, then this could represent an unusual manifestation of localized acquired cutaneous PXE (calcific elastosis).
TREATMENT AND PROGNOSIS CHARACTERIZATION PROGNOSIS PREGNANCY
- Pseudoxanthoma elasticum and pregnancy.
Xiromeritis P, Valembois B.
Department of Obstetrics and Gynecology, Catholic University of Louvain (U.C.L.), Brussels, Belgium,
Arch Gynecol Obstet. 2005 Sep 30;:1-2 [Epub ahead of print] Abstract quote
A 29-year-old woman affected by pseudoxanthoma elasticum gave birth to her second child in our department, thirteen months after the delivery of her first boy. Her care illustrates many of the potential risks of this rare autosomal systemic disorder.
In order to detect any changes due to pregnancy, ophthalmologic and cardiologic screening examinations should be performed in the beginning of the pregnancy and repeated several weeks after the delivery.
During labor, epidural anesthesia seems to be more advantageous.TREATMENT SURGERY Management of upper gastrointestinal hemorrhage in patients with pseudoxanthoma elasticum.
McCreedy CA, Zimmerman TJ, Webster SF.
Department of Surgery, Kaiser Permanente Medical Center, Oakland, Calif.
Surgery 1989 Feb;105(2 Pt 1):170-4 Abstract quote
Pseudoxanthoma elasticum is a rare inherited connective tissue disorder, which exhibits genetic heterogeneity. It is characterized by elastic tissue degeneration involving many organ systems, with typical cutaneous, ocular, arterial, and gastrointestinal manifestations. Upper gastrointestinal tract hemorrhage occurs in 13% of patients with pseudoxanthoma elasticum and is often resistant to conventional methods of treatment.
A case report involving gastric hemorrhage in a patient with pseudoxanthoma elasticum is presented. The characteristics of pseudoxanthoma elasticum are reviewed, and the management of upper gastrointestinal tract hemorrhage in these patients is discussed.
PHOSPHATE BINDERS
- Oral phosphate binders in the treatment of pseudoxanthoma elasticum.
Sherer DW, Singer G, Uribarri J, Phelps RG, Sapadin AN, Freund KB, Yanuzzi L, Fuchs W, Lebwohl M.
Mount Sinai School of Medicine, New York, New York, USA.
J Am Acad Dermatol. 2005 Oct;53(4):610-5. Abstract quote
BACKGROUND: Pseudoxanthoma elasticum (PXE) is a systemic connective tissue disorder involving elastic fiber calcification and fragmentation with major clinical manifestations occurring in the cutaneous, ocular, and cardiovascular systems. Normalization of the serum calcium-phosphate product through hemodialysis in a previous patient with perforating periumbilical PXE and elevated serum phosphate resulted in regression of skin lesions.
OBJECTIVE: We sought to study the effect of pharmacologically limiting the intestinal absorption of phosphate in patients with PXE.
METHODS: Patients received baseline skin examinations, target skin lesion evaluation, and photography; renal function tests and serum calcium and phosphate levels; urine calcium, phosphate, and creatinine levels; skin biopsy; and eye examinations and indocyanine-green angiography. Patients were treated with aluminium hydroxide tablets or liquid and returned every 2 to 4 months for skin photography and lesion evaluation. Repeated skin biopsies were performed on clinically improved target sites. Ophthalmologic evaluation was obtained at yearly intervals.
RESULTS: Of 6 patients, 3 showed significant clinical improvement of skin lesions and all 3 of these patients showed histopathologic regression of disease in their target lesions. No deterioration of eye disease was seen in any of the 6 patients at 1-year follow-up.
CONCLUSION: Our results demonstrate that the calcification seen in PXE may be reversible in some patients. This could hold true for eye and vascular lesions and for skin. Further studies supporting these results could reveal the first real treatment option for PXE.J Cutan Pathol 1994;21:252-255.
J Am Acad Dermatol 1992;26:649-650.
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