Pseudoxanthoma elasticum is an inherited multisystem disorder that is associated with accumulation of mineralized and fragmented elastic fibers in the skin, vascular walls, and Burch membrane in the eye. Clinically, patients exhibit characteristic lesions of the posterior segment ... Pseudoxanthoma elasticum is an inherited multisystem disorder that is associated with accumulation of mineralized and fragmented elastic fibers in the skin, vascular walls, and Burch membrane in the eye. Clinically, patients exhibit characteristic lesions of the posterior segment of the eye including peau d'orange, angioid streaks, and choroidal neovascularizations, of the skin including soft, ivory colored papules in a reticular pattern that predominantly affect the neck and large flexor surfaces, and of the cardiovascular system with peripheral and coronary arterial occlusive disease as well as gastrointestinal bleedings (summary by Finger et al., 2009). Generalized arterial calcification of infancy-2 (GACI2; 614473) is an allelic disorder, also caused by homozygous or compound heterozygous mutation in the ABCC6 gene; it has been suggested that GACI and PXE represent 2 ends of a clinical spectrum of ectopic calcification and other organ pathologies rather than 2 distinct disorders (Nitschke et al., 2012).
Rigal (1881) is credited with the first description of the skin changes in PXE, and Balzer (1884) provided the first autopsy report. The term 'pseudoxanthoma elasticum' was established by Darier (1896), who histologically demonstrated an abnormality in elastin. ... Rigal (1881) is credited with the first description of the skin changes in PXE, and Balzer (1884) provided the first autopsy report. The term 'pseudoxanthoma elasticum' was established by Darier (1896), who histologically demonstrated an abnormality in elastin. Gronblad (1929), a Swedish ophthalmologist, and Strandberg (1929), a Swedish dermatologist, established the relationship of PXE and angioid streaks in the retina (McKusick, 1972). Goodman et al. (1963) provided a detailed clinical and histopathologic study of 12 patients with PXE. They noted that the condition had been referred to by several different names since it was first described in 1881. Eight of 12 patients noted skin changes since early childhood, usually on the neck and in the axilla. Changes included accentuated fine lines, redundant skin folds, and lesions consisting of yellowish papules or plaques. Skin changes were also present in the inguinal folds, antecubital and popliteal spaces, and oral, rectal, and vaginal mucosa. Ocular involvement included pigmentary changes, angioid streaks, chorioretinal scarring, and some loss of vision. Five of the 12 patients had gastrointestinal bleeding. Arteriography demonstrated narrowing or occlusion of peripheral arteries with marked collateral circulation, particularly in the upper extremities. Histopathologic studies of skin, heart, and vessels showed calcium deposition in elastic fibers. Cartwright et al. (1969) described metachromatic fibroblasts in PXE. By electron microscopy, Ross et al. (1978) demonstrated that the changes in elastic fibers in individuals with PXE involve elastin whereas the microfibrillar component is unchanged. The elastin had a granular appearance, an increased affinity for cations, and often demonstrated increased density presumed to represent foci of calcification. Similar changes were found in clinically unaffected relatives. In 3 families the inheritance was consistent with the autosomal recessive mode and 1 of the presumed heterozygotes showed electron microscopic changes. In 1 kindred (reported also by Altman et al., 1974), the inheritance was apparently more complex than either autosomal dominant or recessive. McKusick (1972) presented autopsy findings of endocardial thickening in PXE with degeneration and calcification of elastic fibers and with collagenosis similar to that seen in the skin. Reviewing some of the same autopsy cases, Mendelsohn et al. (1978) emphasized the severe atherosclerosis present in all, resembling that encountered routinely. Fragmentation and degeneration of the elastic laminae of muscular arteries was followed by vascular calcification which could not be distinguished morphologically from Monckeberg arteriosclerosis. There was striking intimal fibroelastotic thickening, particularly in intrarenal arteries. Like McKusick (1972), Mendelsohn et al. (1978) emphasized the striking endocardial changes, e.g., in the right atrium. Elejalde et al. (1984) described a 30-year-old woman with PXE who was followed during pregnancy with several fetal ultrasonographic examinations; these showed normal development up to week 26, followed by a marked deceleration of fetal growth. The ultrasonographic appearance of the placenta was abnormal at all times. The baby, born after 36 weeks, was small for gestational age due probably to placental abnormality: the cotyledons were small and more numerous than normal; one-third of the placenta was hypoplastic or atrophic with focal calcification; and striking abnormalities of the elastic lamellae were found in the maternal vessels. Fournier (1984) reported a well-studied patient with PXE from an isolate in the Swiss Valais canton and by genealogic research demonstrated relatedness of several affected families in the region. Livedo reticularis and microaneurysms of intrarenal arteries were observed. Challenor et al. (1988) described a 27-year-old man with PXE who presented with pulmonary edema resulting from restrictive left ventricular cardiomyopathy caused by calcified endocardial bands. The bands were resected as far as possible and the involved mitral valve was replaced by a heterograft. A year later calcification of the heterograft forced its replacement by a St. Jude prosthesis. Relief of symptoms was satisfactory. Fukuda et al. (1992) described a 54-year-old woman with PXE who over a year of observation developed tight mitral stenosis without regurgitation after having moderate mitral regurgitation due to mitral valve prolapse. Endocardial changes of characteristic type were demonstrated by myocardial biopsy of the right ventricle. It was thought that the echocardiographic findings differed from those in classic rheumatic mitral stenosis. Lebwohl et al. (1993) described 4 patients who presented with premature cardiovascular disease and had angioid streaks but no clinically discernible skin changes of PXE. Characteristic fragmentation and clumping of elastic fibers in the middle and deep dermis with calcification of elastic tissue was demonstrated in all 4 patients. Two of the patients were sisters, aged 27 and 39 years. The younger sister had 4-vessel coronary artery bypass surgery. Multiple arterial biopsies showed calcification of the internal elastic laminae. A 41-year-old brother was subsequently found to have angioid streaks. The father, who died at the age of 69, had a history of retinal hemorrhage. In a nationwide study in South Africa and Zimbabwe, Viljoen et al. (1987) identified 64 patients with PXE. In the opinion of these workers, 39 of the patients comprised a distinct clinical subgroup of PXE characterized by autosomal recessive inheritance and severe visual impairment out of proportion to the degree of involvement of the skin. In 40% of individuals, severe hypertension and occasionally angina or claudication were also present. The 39 affected individuals were found exclusively among persons of Afrikaner descent. Viljoen et al. (1987) noted that the 'Afrikaner' form and other forms of PXE are indistinguishable on histology, electron microscopy, or biochemistry, and that clinical differences may not be significant. For example, McKusick (1960) had pointed out the occurrence of inconspicuous skin changes despite severe ocular changes. De Paepe et al. (1991) reported on the clinical and genetic characteristics of 26 Belgian and 32 Afrikaner families with PXE. The phenotype in both groups was characterized by severe ophthalmologic manifestations with milder, variable cutaneous and vascular symptoms. The authors reiterated the suggestion that the PXE phenotype in these Belgian and Afrikaner families is distinct from previously described PXE phenotypes. There have been isolated case reports of arterial and skin calcification in mammograms of patients with pseudoxanthoma elasticum, and unpublished anecdotes of many women with PXE undergoing breast biopsy for evaluation of microcalcifications. Bercovitch et al. (2003) systematically evaluated mammography and breast pathology in 51 women with confirmed PXE and compared them with those of a control sample of 109 women without PXE. Breast density, skin thickening, skin microcalcifications, vascular calcification, breast microcalcifications and macrocalcifications, and masses were evaluated specifically. The PXE and control groups were similar in age and indications for mammography. Bercovitch et al. (2003) found a statistically significant increase in skin thickening, vascular calcification, and breast microcalcifications in the PXE group (P less than 0.001 each). Breast density, masses, macrocalcifications, and skin calcification did not differ statistically in the 2 groups, but no control patient had axillary calcification, or both vascular calcification and microcalcifications (p less than 0.001). About 1 in 7 of the patients with PXE demonstrated at least 3 of the following: microcalcifications, skin calcifications, vascular calcification, and skin thickening; however, none of the control group did. Histopathologic findings of breast tissue showed calcification of dermal elastic fibers, subcutaneous arteries, and elastic fibers of the deep fascia and interlobular septae of the fat adjacent to breast parenchyma. Bercovitch et al. (2003) concluded that breast microcalcification and arterial calcification are not rare in the normal population and are not of diagnostic value. However, the presence of both of these findings, especially with skin thickening or axillary skin calcification, should suggest a diagnosis of PXE. The majority of breast calcifications in PXE are benign. - Intrafamilial Phenotypic Variability Le Boulanger et al. (2010) studied a nonconsanguineous French family in which an older brother developed uncomplicated PXE in adolescence, whereas a younger brother died of a condition 'strikingly reminiscent' of generalized arterial calcification of infancy (GACI2; 614473) at 15 months of age. The younger brother had a myocardial infarction complicated by heart failure at 6 months of age, and skin biopsy at 1 year of age for evaluation of a possible connective tissue disorder showed elastic fiber dystrophy, with clumped and fragmented fibers in the mid dermis, as well as calcifications on the elastic fibers and sporadically in vessel walls of the subcutis. At 15 months of age, he had a second, fatal MI, and autopsy showed fibrosis of the coronary arteries with calcifications involving the intima, internal elastic lamina, and media. At 28 years of age, the older brother presented for evaluation of yellowish papules on his neck; he had no cardiovascular symptoms and cardiac examination and echocardiography were normal. Skin samples from the brother with PXE showed heavy staining of mineralized mid-dermal elastic fibers, with active MGP (154870) and fetuin-A (138680) antibodies, and fetuin-A also showed striking staining of the subepidermal area. All arteries in autopsy samples from the brother with GACI showed the same immunohistochemical profile, as well as calcifications.
In several families with PXE, Ringpfeil et al. (2000), Bergen et al. (2000), and Le Saux et al. (2000) identified mutations in the ABCC6 gene. Of 4 families with autosomal recessive inheritance of PXE reported by Ringpfeil et ... In several families with PXE, Ringpfeil et al. (2000), Bergen et al. (2000), and Le Saux et al. (2000) identified mutations in the ABCC6 gene. Of 4 families with autosomal recessive inheritance of PXE reported by Ringpfeil et al. (2000), 1 was compound heterozygous for mutations in the ABCC6 gene (see, e.g., R1141X, 603234.0001), 1 family was hemizygous for the R1141X mutation, and 2 families were homozygous for mutations. Of 4 so-called sporadic cases, 1 was compound heterozygous and 3 appeared heterozygous for mutations in the ABCC6 gene. Bergen et al. (2000) identified mutations in the ABCC6 gene in 2 sporadic patients with PXE (see, e.g., 603234.0009), 4 families with PXE that appeared to be autosomal dominant (see, e.g., 603234.0008), and 1 family with autosomal recessive PXE (603234.0007). Le Saux et al. (2000) identified mutations in the ABCC6 gene in 5 families with autosomal recessive PXE and in 1 sporadic case (see, e.g., 603234.0001 and 603234.0002). The R1141X mutation (603234.0001) was found in families segregating autosomal recessive PXE and in families with expressing heterozygotes. Using multiplex ligation-dependent probe amplification (MLPA) to analyze 35 PXE patients with incomplete ABCC6 genotypes after exonic sequencing, Costrop et al. (2010) identified 6 multiexon deletions and 4 single-exon deletions and were thus able to characterized 25% of the unidentified disease alleles. The findings illustrated the instability of the ABCC6 genomic region and stressed the importance of screening for deletions in the molecular diagnosis of PXE. In a 28-year-old French man with pseudoxanthoma elasticum who had a younger brother who died of generalized arterial calcification of infancy (GACI2; 614473) at age 15 months, Le Boulanger et al. (2010) identified compound heterozygosity for missense mutations in the ABCC6 gene (603234.0025 and 603234.0026), which were also found in heterozygosity in each of his unaffected parents, respectively. No disease-causing mutations were found in the ENPP1 gene (173335), which is known to cause GACI1 (208000). Although no DNA material was available from the deceased younger brother, his disease was presumed to be related to the familial ABCC6 mutations. Le Boulanger et al. (2010) concluded that GACI may represent an atypical and severe end of the vascular phenotypic spectrum of PXE. - PXE-Associated Retinopathy Choroidal neovascularization (CNV) in PXE-associated retinopathy is believed to be mediated by the action of VEGF (192240). Zarbock et al. (2009) evaluated the distribution of 10 SNPs in the promoter and coding region of the VEGFA gene in DNA samples from 163 German patients affected by PXE and in 163 healthy control subjects. Haplotype analysis identified an 8-SNP haplotype CTGGCCCC that was associated with PXE. Furthermore, 5 SNPs showed significant association with severe retinopathy. The most significant single SNP association was -460C-T (dbSNP rs833061, OR = 3.83, 95% CI 2.01-7.31, corrected p = 0.0003). Logistic regression analysis identified the dbSNP rs833061 and 674C-T variant (dbSNP rs1413711; OR = 3.21, 95% CI 1.70-6.02, corrected p = 0.004) as independent risk factors for development of severe retinopathy. Zarbock et al. (2009) suggested an involvement of VEGF in the pathogenesis of ocular PXE manifestations. - Modifier Genes Schon et al. (2006) reported that polymorphisms in the XYLT1 and XYLT2 genes (608124.0001 and 608125.0001, respectively) modify the severity of PXE.
Struk et al. (1997) estimated that the prevalence of PXE, both the recessive and dominant forms, is 1 in 70,000 to 100,000.
In a cohort of 122 unrelated PXE patients from various countries, Le Saux et ... Struk et al. (1997) estimated that the prevalence of PXE, both the recessive and dominant forms, is 1 in 70,000 to 100,000. In a cohort of 122 unrelated PXE patients from various countries, Le Saux et al. (2001) identified a G1321S missense mutation in the ABCC6 gene (603234.0021). The G1321S mutation was detected in heterozygosity in 1 of 74 United States alleles, for an allele frequency of 1.4%, but was not found in the European population. Hu et al. (2003) demonstrated a founder effect for the R1141X mutation (603234.0001) in the Netherlands. They identified the mutation in 19 alleles in 16 Dutch patients with PXE, in heterozygous, homozygous, or compound heterozygous form. Expression of the normal allele in heterozygotes was predominant; no or very low expression was found in homozygotes. The mutation induced instability of the aberrant mRNA. Hu et al. (2003) suggested that the PXE phenotype of the R1141X mutation most likely results from complete loss of function or functional haploinsufficiency of ABCC6.
Current minimal criteria for the clinical diagnosis of pseudoxanthoma elasticum (PXE) are the presence of retinal angioid streaks in combination with characteristic skin lesions showing diagnostic histopathologic findings of calcified dystrophic elastic fibers. The presence of two known PXE-causing mutations with either of the above would establish a diagnosis of PXE; the mutations alone would be presumptive evidence of PXE in an individual too young to demonstrate ocular or skin manifestations. Whether heterozygous carriers of PXE-causing mutations may have mild ocular and cutaneous findings is controversial [Sherer et al 2001, Martin et al 2008]. Molecular genetic studies of known pedigrees have shown no clinical manifestations of PXE in heterozygous carriers [Miksch et al 2005, Christen-Zach et al 2006, Plomp et al 2009, Nitschke et al 2012]. ...
DiagnosisClinical DiagnosisCurrent minimal criteria for the clinical diagnosis of pseudoxanthoma elasticum (PXE) are the presence of retinal angioid streaks in combination with characteristic skin lesions showing diagnostic histopathologic findings of calcified dystrophic elastic fibers. The presence of two known PXE-causing mutations with either of the above would establish a diagnosis of PXE; the mutations alone would be presumptive evidence of PXE in an individual too young to demonstrate ocular or skin manifestations. Whether heterozygous carriers of PXE-causing mutations may have mild ocular and cutaneous findings is controversial [Sherer et al 2001, Martin et al 2008]. Molecular genetic studies of known pedigrees have shown no clinical manifestations of PXE in heterozygous carriers [Miksch et al 2005, Christen-Zach et al 2006, Plomp et al 2009, Nitschke et al 2012]. Angioid streaks are breaks in Bruch's membrane, the elastin-rich tissue layer between the retina and the choriocapillaris. Angioid streaks radiate from the optic disk or peripapillary area in a pattern that resembles blood vessels, hence, the term 'angioid'. Angioid streaks are best observed on examination of the retina with an ophthalmoscope through a dilated pupil. Angioid streaks are readily visualized by fluorescein fundus angiography and indocyanine green (ICG) angiography, although these techniques are rarely needed for diagnosis.Typical skin lesions are yellowish papules, usually seen on the lateral aspect of the neck or the flexural creases, such as the antecubital fossae, axillae, groin, or popliteal fossae. With time, the papules coalesce to form plaques and the skin becomes loose and redundant. TestingSkin biopsy. Calcification of fragmented elastic fibers in a biopsy of lesional skin, confirmed by von Kossa or other calcium stain, is diagnostic.Molecular Genetic TestingGene. Virtually all cases of PXE are caused by mutations in ABCC6, encoding the ATP-binding cassette protein ABCC6 (multidrug resistance-associated protein 6), a putative efflux cellular transport protein. ABCC6 contains 31 exons and spans 75 kb of gene locus 16p13.1. There are two non-functional 5’ pseudogenes, ABCC6P1 and ABCC6P2, almost identical in sequence to the coding gene; gene amplification is designed to eliminate interference from the pseudogenes [Pfendner et al 2007, Li et al 2009b].Clinical testing. Inheritance is autosomal recessive; however, in a small number of cases, only one or no mutation is found. It is possible that some cases of PXE are examples of digenic inheritance, resulting from mutations in both ABCC6 and GGCX [Li et al 2009a] or hypothetically ABCC6 and ENPP1.Table 1. Summary of Molecular Genetic Testing Used in Pseudoxanthoma ElasticumView in own windowGeneTest MethodsMutations DetectedMutation Detection Frequency 1Test AvailabilityABCC6Sequence analysisSequence variants 2~90% 3Clinical Sequence analysis of select exonsSequence variants located in select exons 4UnknownDeletion / duplication analysis 5The recurrent deletion of exons 23-29 6 and other exonic or whole-gene deletions5%-30% depending on population1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Sequence analysis detects missense mutations, the most prevalent mutations in ABCC6 [Le Saux et al 2001, Pfendner et al 2007], as well as nonsense mutations, frameshift mutations, and small deletions and insertions, which have also been described.4. Exons sequenced may vary by laboratory.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.6. A 16.4-kb deletion involving ABCC6 exons 23-29 is a recurrent mutation found in multiple populations with varying frequency. It represents approximately 30% of alleles in the US and about 5% of alleles in Europe [Le Saux et al 2001].Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here. Testing Strategy To confirm/establish the diagnosis in a proband. A commonly used testing strategy is a first-tier screen for the two most common mutations, p.Arg1141X and a deletion of exons 23-29. If only one or neither mutation is found, the next step is to screen all exons, beginning at the 3’ end with direct sequencing [Vanakker et al 2008].Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersThere have been a few individuals with generalized arterial calcification of infancy (GACI) associated with biallelic mutations in ABCC6, in whom no mutations in ENPP1 could be detected [Nitschke et al 2012]. An increased risk for premature coronary artery disease among carriers of the ABCC6 mutation p.Arg1141X has been suggested [Wegman et al 2005] but not confirmed. In a recent study of over 66,000 participants (>13,000 of whom had ischemic vascular disease), heterozygosity for the p.Arg1141X mutation did not correlate with risk forischemic heart or cerebrovascular disease, stroke, or myocardial infarction [Hornstrup et al 2011].
Pseudoxanthoma elasticum (PXE) primarily affects the skin, eye, cardiovascular system, and gastrointestinal system. Individuals with PXE most commonly present with papules in the skin and/or with angioid streaks of the retina found on routine eye examination or associated with retinal hemorrhage. Rarely, individuals may present with vascular signs and symptoms, such as gastrointestinal bleeding, angina, or intermittent claudication. The most frequent cause of morbidity and disability in PXE is reduced vision from macular hemorrhage and disciform scarring. Most affected individuals live a normal life span....
Natural HistoryPseudoxanthoma elasticum (PXE) primarily affects the skin, eye, cardiovascular system, and gastrointestinal system. Individuals with PXE most commonly present with papules in the skin and/or with angioid streaks of the retina found on routine eye examination or associated with retinal hemorrhage. Rarely, individuals may present with vascular signs and symptoms, such as gastrointestinal bleeding, angina, or intermittent claudication. The most frequent cause of morbidity and disability in PXE is reduced vision from macular hemorrhage and disciform scarring. Most affected individuals live a normal life span.Skin. The primary skin lesion is a yellowish papule, usually seen on the lateral aspect of the neck or the flexural creases (e.g., the antecubital fossae, axillae, groin, or popliteal fossae). Occasionally, there is periumbilical involvement, which has also been associated with acquired perforating PXE in multiparous females. The papules gradually coalesce to form plaques, and eventually the skin, especially of the neck, axilla, and groin, becomes loose and redundant. Mucous membranes can show similar lesions, most commonly the inner aspect of the lower lip and the vaginal mucosa.Eye. The earliest ocular finding is a diffuse mottling of the fundus known as peau d'orange, generally appearing between adolescence and the late second decade. In the second and third decades, angioid streaks usually develop. These broad grayish to reddish-brown irregular lines radiate outward from the optic nerve and peripapillary region. They result from dehiscences in a mineralized Bruch's membrane, an elastin-rich layer of the choroid. Neither angioid streaks nor peau d'orange affects visual acuity; however, spontaneous subretinal neovascularization and hemorrhage can occur and lead to visual distortion (metamorphopsia) and loss of visual acuity, resulting in disciform scarring and, when the macula or fovea is involved, permanent loss of central vision.Cardiovascular. Mineralization of the internal elastic lamina of medium-sized arteries resulting in arterial narrowing occurs frequently in PXE. Arterial narrowing can lead to asymmetric or diminished pulses in the limbs, and if severe enough, can cause intermittent claudication of the leg and arm muscles, or angina or myocardial infarction (coronary arteries), small strokes (cerebrovascular arteries), intestinal angina (celiac or mesenteric arteries), and renovascular hypertension (renal arteries). At least one small series suggested an increased incidence of mitral valve prolapse in individuals with PXE [Lebwohl et al 1982]. However, this has yet to be confirmed by larger prospective controlled studies.Gastrointestinal. The most common site of bleeding is the upper gastrointestinal tract, particularly the stomach. The characteristic yellow mucosal lesions of PXE can be seen on gastroscopy. The cause of bleeding is not well understood; one theory is that it may begin with superficial bleeding from erosive gastritis, but becomes massive and uncontrolled due to defective vasoconstriction of affected arteries. Diffuse punctate bleeding and erosions can be seen on gastroscopy but an exact source of the hemorrhage may be difficult to locate. Bleeding may be difficult to control without surgery [Dalle & Geboes 2002].Pregnancy. Most women with PXE have normal pregnancies: PXE is not associated with markedly increased fetal loss or adverse reproductive outcomes. The incidence of gastric bleeding and retinal complications (<1%) is lower than previously thought [Bercovitch et al 2004].
Individuals with beta-thalassemia may present with a phenotype (skin, eye, and cardiovascular) that is similar to pseudoxanthoma elasticum (PXE) but not associated with ABCC6 mutations....
Differential DiagnosisIndividuals with beta-thalassemia may present with a phenotype (skin, eye, and cardiovascular) that is similar to pseudoxanthoma elasticum (PXE) but not associated with ABCC6 mutations.Individuals with mutations in GGCX (gamma-glutamyl carboxylase) may present with a phenotype showing cutis laxa-like skin changes with histolopathologic changes of PXE, and deficiency of vitamin K-dependent clotting factors.Individuals with biallelic mutations in ENPP1 develop a phenotype with severe arteriopathy known as generalized arterial calcification of infancy (GACI). However, there have been cases described of children with GACI and biallelic ENPP1 mutations who also develop the typical cutaneous and ocular phenoptype of PXE [Nitschke et al 2012]. Skin. The skin lesions of PXE are mimicked by those in the following conditions:Buschke-Ollendorf syndrome (osteopoikilosis associated with cutaneous papules with extensive accumulation of elastin in the dermis) White fibrous papulosis of the neck and papillary dermal elastolysis, both signs of intrinsic aging, associated with thinning or loss of elastic fibers and focal thickening of the collagen fiber network (collectively known as fibroelastolytic papulosis) Solar elastosis, in which yellowish-white papules occur in the skin of the neck and chest as a result of photoaging Late-onset focal dermal elastosisCutis laxaD-penicillamine treatment (see Wilson disease) results in skin lesions that clinically resemble PXE but do not exhibit elastic fiber mineralization histologically [Bécuwe et al 2005]. Eyes. PXE is the most common cause of angioid streaks of the retina. Angioid streaks in the retina can also be seen in the following: Sickle thalassemia (see Sickle Cell Disease) Beta-thalassemia Paget's disease High myopia Acromegaly Familial hyperphosphatemia Subretinal neovascularization with hemorrhage can be seen in the absence of angioid streaks in age-related macular degeneration, high myopia, and presumed ocular histoplasmosis. Recurrent gastrointestinal bleeding. PXE should be considered in the differential diagnosis of recurrent gastrointestinal bleeding of unknown cause [Dalle & Geboes 2002]. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with pseudoxanthoma elasticum (PXE), the following assessments are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with pseudoxanthoma elasticum (PXE), the following assessments are recommended:Complete skin examination, including a biopsy of potentially lesional skin from the axilla or neck. A von Kossa or similar histologic stain for calcium should be done on the biopsy to confirm the diagnosis, although PXE can be strongly suspected on skin biopsy even without special stains. Complete dilated eye examination by a retinal specialist, particularly looking for peau d'orange and angioid streaks. A fluorescein angiogram may be necessary to confirm the diagnosis. Baseline cardiovascular examination with periodic follow-up for individuals with pseudoxanthoma elasticum (PXE), including (as clinically indicated based on age, physical findings, and exercise level): Echocardiography Cardiac stress testingDoppler evaluation of peripheral vasculature Treatment of ManifestationsNo specific treatment for PXE exists. Management of PXE requires coordinated input from a multidisciplinary team of specialists including a dermatologist, primary care physician, ophthalmologist, cardiologist, vascular surgeon, plastic surgeon, genetics professional, and nutritionist. Support groups can benefit affected individuals and their families by providing accurate information and education and reducing isolation. Current treatment for macular degeneration, especially the intraocular injection of anti-angiogenic drugs, also appears to be effective in PXE [Finger et al 2011]. A retinal specialist should be consulted immediately when the individual experiences any distortion in vision. Surgical or radiologic intervention may be indicated for gastrointestinal bleeding, severe peripheral vascular disease (if correctable), and the improvement of changes of the skin of the face, neck, axilla, and groin that are of cosmetic concern. Although wound healing seems to be uncomplicated in PXE, cosmetic acceptability of surgery involving the skin is less predictable, although generally good [Viljoen et al 1990]. Prevention of Primary ManifestationsWeight control, avoidance of smoking, and aggressive management of hypertension and lipid disorders may reduce the risk of vascular complications by reducing the risk of comorbidity resulting from atherosclerosis. However, reduction in risk resulting from these measures has not been confirmed in controlled studies.Prevention of Secondary ComplicationsIndividuals with PXE who have coexistent mitral valve prolapse should have antibiotic prophylaxis for dental, gastrointestinal, and genitourinary procedures.SurveillanceThe following are appropriate:Regular examination by an ophthalmologist with expertise in retinal disease. Affected individuals benefit from learning to use the Amsler grid to monitor for central visual disturbances. Regular physical examination with specific attention to the cardiovascular system Monitoring by the affected individual for black tarry stool Periodic monitoring of serum lipid concentrations Agents/Circumstances to AvoidRacquet and contact sports carry an increased risk for ocular and head trauma, both of which have been reported to precipitate retinal hemorrhage in patients with angioid streaks; participation in such activities should be discouraged.Individuals with PXE who participate in sports and physical recreation should wear appropriate protective eyewear such as polycarbonate sports goggles and/or protective helmets with eye shields.Aspirin and nonsteroidal anti-inflammatory medications should be avoided whenever possible to reduce the risk of gastrointestinal bleeding. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. Pregnancy ManagementIn the series of Bercovitch et al [2004], there was no statistically significant effect of gravidity on the severity of skin, eye, cardiac, or peripheral vascular manifestations of PXE in women over 40. In addition, women over 40 with PXE who had been pregnant did not have more severe skin, cardiac, ocular, or vascular manifestations of PXE than those who had never been pregnant. Except for the consequences of severe maternal gastrointestinal hemorrhage, which appears to be uncommon, PXE has no known significant effect on the fetus. Retinal examination during pregnancy and prompt attention to any visual symptoms are advised. Therapies Under InvestigationBased on animal studies [Larusso et al 2009, Li et al 2009c], magnesium supplementation has been proposed as a treatment to prevent progression of elastic tissue mineralization in PXE. A randomized placebo-controlled clinical trial to study the effect of magnesium oxide supplementation is beginning in 2012.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherIt has been reported that high calcium intake in adolescence may correlate with the overall severity of PXE [Renie et al 1984]; however, this has never been confirmed by prospective controlled studies and thus remains unproven and controversial. The AREDS study for macular degeneration suggested that a regimen of antioxidant vitamins could prove beneficial in that disease [Clemons et al 2004]. While it is possible that this could also be the case for PXE, it has not been reported and remains unproven.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Pseudoxanthoma Elasticum: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDABCC616p13.11Multidrug resistance-associated protein 6Retina International Mutations of the Multidrug Resistance-associated Protein 6 (ABCC6/MPR6/MOAT-E) ABCC6 DatabaseABCC6Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Pseudoxanthoma Elasticum (View All in OMIM) View in own window 177850PSEUDOXANTHOMA ELASTICUM, FORME FRUSTE 264800PSEUDOXANTHOMA ELASTICUM; PXE 603234ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 6; ABCC6Normal allelic variants. ABCC6 is approximately 100 kb in length; alternatively spliced transcript variants that encode different proteins have been described for this gene [provided by RefSeq, Jul 2008]. The longer transcript NM_001171.5 has 31 exons. It is a member of the ATP-binding cassette superfamily and shows 45% sequence homology with ABCC1, encoding a multidrug resistant protein, in the same chromosomal region. Normal allelic variants detected to date are missense variants encoded by neutral polymorphic changes in exons at the 3' end. See Table A, Gene Symbol for alternative transcript.Pathologic allelic variants. Mutations in exons 24 and 28 and the 16.4-kb deletion including exons 23-29 account for over 70% of mutations in a large international series [Pfendner et al 2007]. Nonsense, splice junction, missense, insertion and deletion mutations have all been reported. A common mutation is p.Arg1141X (c.3421C>T). Very large partial- and whole-gene deletions causing hemizygosity have been found. The most common is the deletion of exons 23-29.Normal gene product. Multidrug resistance-associated protein 6 (MRP6) (NP_001162.4) or ABCC6, the protein encoded by the transcript NM_001171.5 comprises 1503 amino acids. It is a putative efflux cellular transporter; its physiologic substrate is unknown [Uitto et al 2011]. However, MRP1, the prototypic MRP protein, functions as an efflux pump for amphipathic anionic conjugates. Abnormal gene product. The finding that heterozygous partial- and whole-gene deletions of ABCC6 result in PXE strongly suggests that the phenotype results from haploinsufficiency of the MRP6 protein.