Version May 2024
INTRODUCTION — Pseudoxanthoma elasticum (PXE; MIM #264800) is a rare, late-onset, heritable disorder characterized by ectopic mineralization and fragmentation of elastic fibers in the skin, eye, vascular, and gastrointestinal system [1-3]. PXE is caused by homozygous or compound heterozygous mutations in the ABCC6 gene, which encodes the cellular transmembrane transport protein ABCC6. In this chapter, we will review the etiology and pathogenesis, clinical and histopathologic features, complications, diagnosis, and treatment of PXE. Other inherited disorders of connective tissue are reviewed separately.
●(See "Focal dermal hypoplasia (Goltz syndrome)".)
●(See "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes".)
●(See "Overview of the management of Ehlers-Danlos syndromes".)
●(See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders".)
●(See "Management of Marfan syndrome and related disorders".)
EPIDEMIOLOGY — The exact prevalence of PXE is unknown. It has been estimated to be 1:25,000 to 1:100,000 in the general population [4], but it may be much higher among the Afrikaner population in South Africa due to a founder effect [5]. More precise estimates cannot be made due to the highly variable expressivity of PXE, as some patients have minimal to no skin lesions despite having ocular or cardiovascular manifestations. The carrier rate for pathogenic ABCC6 variants has been estimated to be between 1:80 and 1:150 [6].
GENETICS — PXE is an autosomal recessive disorder with complete penetrance caused by homozygous or compound heterozygous pathogenic variants in the ABCC6 gene on chromosome 16p13.1, encoding the ATP-binding cassette, subfamily C, member 6 (ABCC6) [7]. However, two incompletely penetrant pathogenic variants have been found [8]. Earlier suggestions of autosomal dominant inheritance in families with two affected individuals in subsequent generations have been discounted by genetic analysis and shown to reflect pseudodominance in consanguineous families [9]. The majority (approximately 90 percent) of patients with the classic form of PXE harbor pathogenic inactivating variants in the ABCC6 gene, which is expressed primarily in the liver and, to some extent, in the proximal tubules of the kidneys [10].
However, there is genetic heterogeneity. Rare cases with a PXE phenotype harbor pathogenic variants in the ENPP1 gene (encoding the ectonucleotide pyrophosphatase/phosphodiesterase 1) and genetically overlap with another ectopic mineralization disorder, the generalized arterial calcification of infancy (GACI; MIM #208000), which is inherited in an autosomal recessive mode and is caused by mutations in ENPP1 [11-14].
While patients with PXE characteristically develop the earliest clinical signs at the end of the first decade or during the second decade of life, patients with PXE due to ENPP1 mutations are often diagnosed during the first year of life. In contrast with PXE, classic GACI manifests with extremely severe vascular involvement, often diagnosed prenatally by ultrasound at the 14th to 15th week of gestation. Many of these patients die of cardiovascular complications during the first year of life. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia", section on 'Autosomal recessive hypophosphatemic rickets'.)
In the spectrum of heritable ectopic mineralization disorders, arterial calcification due to deficiency in CD73 (ACDC; MIM#211800) manifests primarily with vascular calcification in the lower extremities and periarticular calcification in older adults [13,15]. This ultrarare autosomal recessive disorder is caused by inactivating mutations in NT5E, encoding the ecto-5-prime-nucleotidase.
PATHOPHYSIOLOGY — Under physiologic conditions, the gene product of ABCC6 (ATP-binding cassette, subfamily C, member 6 [ABCC6]) is an efflux transporter protein expressed primarily in the basolateral surface of hepatocytes and is not present in tissues demonstrating ectopic mineralization or in the principal cells of such tissues (eg, dermal fibroblasts). Physiologically, ABCC6 facilitates transport of ATP from the hepatocytes through the plasma membrane, and ATP is rapidly converted in the extracellular milieu to AMP and inorganic pyrophosphate (PPi) by the ectonucleotide pyrophosphatase/phosphodiesterase (1 ENPP1) [16]. The enzyme protein encoded by NT5E (the ecto-5-prime-nucleotidase CD73) further degrades AMP to adenosine and inorganic phosphate (Pi). Pathogenic variants in the ABCC6, ENPP1, and NT5E genes cause ectopic mineralization for the classic forms of PXE, generalized arterial calcification of infancy (GACI), and arterial calcification due to deficiency in CD73 (ACDC), respectively, which share some metabolic and clinical features (notably, reduced levels of circulating PPi and vascular involvement) [13].
In patients with PXE, the PPi plasma levels are reduced to approximately 30 percent compared with the control levels [17]. However, plasma levels of PPi in PXE do not correlate with either genotype or phenotype [18,19]. By contrast, in patients with GACI due to loss-of-function mutations in the ENPP1 gene, the plasma PPi levels are essentially zero as reflected by its very low levels in urine [20]. Plasma PPi has a relatively short half-life and is physiologically degraded by tissue-nonspecific alkaline phosphatase (TNAP), which is downregulated by adenosine [21]. Thus, in patients with ACDC with deficient conversion of AMP to adenosine and Pi, the plasma adenosine levels are reduced, thus resulting in activation of TNAP and subsequent reduction in plasma PPi levels. In ACDC, the patients' plasma PPi levels have not been reported, but in a mouse model (Nt5e-/-), the serum PPi levels are significantly reduced [22].
Collectively, in the three heritable ectopic mineralization disorders (ie, PXE, GACI, and ACDC), the unifying pathomechanistic feature is the reduced circulating PPi level [13,23]. Since PPi is physiologically a powerful antimineralization factor, reduced PPi levels allow ectopic mineralization to ensue in elastin-rich tissues, including skin, eyes, and the arterial blood vessels.
In general terms, the level of circulating PPi correlates with the severity of the disease:
●In patients with GACI with essentially zero plasma levels of PPi, the ectopic mineralization is extremely severe, resulting in considerable early mortality.
●In PXE (with the residual PPi levels being approximately 30 percent of the controls), the ectopic mineralization is variable and of late onset, the disease is slowly progressive, and the actual lifespan is rarely impacted. However, there is considerable inter- and intra-familial phenotypic heterogeneity, even in individuals with the same mutations. It has been suggested that the influence of modifier genes, epigenetic factors, and lifestyle variables (eg, exercise and diet) might explain such variability in the severity of the disease [24].
●In patients with ACDC, only slightly reduced plasma PPi levels would explain the relatively mild disease manifesting in older adults.
CLINICAL MANIFESTATIONS — The pathologic changes of PXE are found primarily in the dermis, Bruch's membrane of the retina, and internal elastic lamina of medium-sized arteries. Therefore, clinical manifestations occur in the skin, eyes, and cardiovascular system, as well as organs supplied by affected arteries [25].
Age at presentation — Early cutaneous and ocular findings are subtle and are in most cases not noticed until the second or third decades of life, although they have been described in children younger than 10 years [4,25,26]. PXE presents before the age of 15 years in approximately 15 percent of cases, but the diagnosis is often delayed by several years, especially in male patients [26].
Skin — The primary lesion in the skin is a papule that may appear yellowish or darker than the person's natural skin tone, initially located on the side of the neck (picture 1A-B) and later in the axillae (picture 2) and other flexural areas (eg, antecubital fossa, popliteal fossa, groin), chest, and abdomen [25]. The labial, vaginal, anal, and gastric mucosae may show similar lesions. The skin papules eventually coalesce to form plaques, and ultimately the affected skin becomes lax and redundant (picture 3A-B). There is no relationship between the severity of skin manifestations and ocular or cardiovascular manifestations. In some patients, skin findings can be subtle or undetectable [25].
Eye — Angioid streaks, named because of their resemblance to retinal blood vessels, are the most characteristic eye finding in PXE (picture 4) [27]. These are often not seen until late adolescence or the third decade. The earliest ocular manifestation, often seen in childhood, is "peau d'orange" of the retina, a fine, yellowish pebbling of the ocular fundus resulting from dystrophic calcification the Bruch's membrane, the elastic layer that separates the retinal pigmented epithelium from the choroid (picture 5). Progressing calcification results in breaks in Bruch's membrane that form around the optic papilla and radiate peripherally, exposing the choriocapillaris, with a characteristic "angioid" appearance. The color of the streaks may vary from red to black, depending on the amount of pigmentation in the choroid. Although present in most patients with PXE by the third decade, angioid streaks remain asymptomatic until neovascularization occurs and, unless affecting the perifoveal area, do not affect visual acuity [27].
Eventually, in most patients, fragile new vessels grow through the angioid streaks ("neovascularization"). Leakage of serum or blood from these vessels focally detaches the overlying retinal photoreceptors, causing distorted vision (picture 6). This distortion can be documented with an Amsler grid (figure 1), which provides an early diagnostic tool for the patient. Indeed, all patients with angioid streaks should have an Amsler grid and use it on a regular basis to detect early distortions in central vision. Lesions that leak or bleed heal with irreversible scarring (picture 7) which, when involving the macula, can lead to permanent central vision loss and legal blindness.
Cardiovascular system — Cardiovascular manifestations of PXE result from progressive narrowing of small- and medium-sized arteries due to elastorrhexis and calcification of dystrophic elastic fibers in the internal elastic lamina and tunica media of these vessels [4,28]. These changes are associated with peripheral arterial disease independent of other known cardiovascular risk factors [29,30]:
●Diminution or loss of peripheral pulses, including radial pulses, and early onset of intermittent claudication, including in the arms, are the most common peripheral vascular manifestations of PXE. Often there is asymmetry in blood pressure measured in both arms. Studies have shown that low ankle brachial index (ABI) is common in PXE, being found in as many as 44 percent of affected adults [29]. (See "Overview of lower extremity peripheral artery disease" and "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Ankle-brachial index'.)
●Hypertension secondary to renovascular stenosis is also common in PXE and is an additional risk factor for cardiovascular morbidity.
●Premature coronary artery disease, although less common than peripheral arterial disease, is one of the more serious vascular complications of PXE. Rare cases of childhood or adolescent angina and myocardial infarction (separate from those seen with generalized arterial calcification of infancy [GACI]) have been reported [31]. Heterozygous carriers of the ABCC6 variant p.R1141X, most common in the United States and Europe, have been shown to have an increased risk of coronary artery disease [32].
●Cerebrovascular disease, including multi-infarct dementia, minor strokes, or transient ischemic attacks, has been reported in PXE [33,34]. In a French cohort of 239 PXE cases, the prevalence of neurovascular manifestations was 10 percent [35]. In a Dutch cohort of 100 patients with PXE, the estimated risk for ischemic stroke under the age of 65 years was nearly four times higher than in the general population (relative risk 3.6; 95% CI 3.3-4.0) [34].
Gastrointestinal system — Rarely, narrowing of the mesenteric artery or its branches can cause intestinal angina, which presents as postprandial acute, crampy abdominal pain (see "Chronic mesenteric ischemia", section on 'Symptomatic'). Acute upper gastrointestinal bleeding thought to be due to arterial stenosis involving the blood supply to the stomach has also been reported [36].
Clinical presentation in children — The clinical presentation is children is usually limited to typical skin changes in the vast majority of cases. In the PXE International registry (unpublished data), 92 percent of patients diagnosed during childhood reported that skin changes on the neck were the earliest sign of PXE. "Peau d'orange" was the earliest ocular finding, while angioid streaks were not detected until a mean age of 14 years. Children rarely have signs or symptoms of cardiovascular disease other than asymmetric peripheral pulses. However, there are isolated case reports of myocardial infarction, angina, intermittent claudication, and upper gastrointestinal bleeding in children with PXE [37-41].
HISTOPATHOLOGY — Biopsy of lesional skin typically shows calcification of clumped, fragmented elastic fibers in the mid-dermis. Although it may be possible in many instances to make the diagnosis on hematoxylin and eosin-stained sections (picture 8), specific stains for elastic tissue (eg, Weigert or Verhoeff-Van Gieson stains (picture 9)) and for calcium (eg, von Kossa or alizarin red stains (picture 10)) are confirmatory. There are histopathologic mimickers of PXE, including calciphylaxis, occupational exposure to sodium nitrate (saltpeter), and hyperphosphatemia in patients on dialysis, but there is usually no diagnostic confusion in these cases.
IMAGING FINDINGS — In patients with PXE, imaging studies may reveal incidental findings related to elastic fiber calcification. In two studies, diffuse testicular microcalcifications were detected by ultrasonography in nearly all males with PXE, while a significant number of carriers showed focal microcalcifications [42,43]. Microcalcifications in the liver, kidney, or spleen were found in 59 percent of patients and 25 percent of carriers [42,43]. Some of the changes seen on ultrasonography, particularly in the testis, can be found in children with PXE and can even precede the cutaneous signs [42,44,45]. Cutaneous and vascular microcalcifications have also been found in mammograms [46]. Radiologists should be aware of these findings in females with PXE, as they can be misinterpreted as a sign of cancer, leading to unnecessary biopsy.
DIAGNOSIS — The diagnosis of PXE can be challenging, due to its late onset and the subtle and asymptomatic nature of early skin, eye, and vascular manifestations. It is common for diagnosis to be delayed. (See 'Clinical manifestations' above.)
Diagnostic criteria — Clinical diagnostic criteria for PXE were proposed at a consensus conference in 1992, antedating the discovery of the causative gene [47]. An update was suggested in 2010 with criteria including clinical signs as well as molecular testing for definite, probable, and possible diagnosis of PXE [48]:
●Major diagnostic criteria:
•Skin:
-Pseudoxanthomatous papules and plaques on the neck and flexural creases
-Histopathology showing calcification of clumped, pleomorphic elastic fibers in mid- or lower dermis ("elastorrhexis")
•Eye:
-One or more angioid streaks >1 disc diameter in length
-"Peau d'orange"
•Genetic testing – Two allelic pathogenic variants in ABCC6
●Minor diagnostic criteria:
•Definite PXE in a first-degree relative (sibling, parent, or child [especially if there is parental consanguinity in the latter two instances])
•Finding of pathogenic mutation on only one allele on genetic testing
•Histopathologic changes of PXE on nonlesional skin (no visible skin lesions)
A diagnosis of definite PXE is based on major criteria and requires at least two of the following:
●Two major skin criteria
●One major ocular criterion
●Two allelic pathogenic mutations in ABCC6
Minor criteria may be help in diagnosing probable or possible PXE but are insufficient for a definitive diagnosis of PXE if either only two major skin criteria or only one major ocular criterion are present. However, given the late onset of PXE and its virtually 100 percent penetrance, the finding of either a major ocular criterion or two major cutaneous criteria in an individual who has an affected first-degree relative confers a nearly 100 percent probability of definite PXE.
Genetic testing — The finding of homozygosity or compound heterozygosity for two pathogenic variants in ABCC6 is considered the gold standard for the diagnosis of PXE. Several laboratories worldwide perform genetic testing for mutations and deletions in ABCC6 using either Sanger sequencing or next-generation sequencing approaches as part of panels targeting genes associated with retinal diseases or connective tissue disorders [1]. Sensitivity of these tests is up to 97 percent.
In clinical practice, genetic testing is rarely necessary for definitive diagnosis. In many cases, the diagnosis is based on the finding of typical skin lesions with histopathologic demonstration of elastic fiber calcification in the mid-dermis and characteristic retinal lesions. However, genetic testing is useful in select situations:
●Presymptomatic diagnosis in families with history of PXE [49]. As an example, for unaffected children who have a sibling with definite PXE, genetic testing can be of value in early, presymptomatic diagnosis PXE, especially if the causative mutations are already known. However, in the absence of any effective treatment or strategy to slow the progress of the disease in humans, presymptomatic diagnosis may raise ethical concerns. (See "Genetic testing", section on 'Ethical, legal, and psychosocial issues'.)
●Patients with limited clinical manifestations. In patients with isolated angioid streaks, without typical skin lesions and without family history of PXE in a first-degree relative, genetic testing can be of value in confirming or excluding the diagnosis.
In cases in which the diagnosis of PXE has been established clinically but no mutations in ABCC6 have been found on genetic testing, it might be of value to screen for mutations in ENPP1 and GGCX, depending on the phenotype. An uncommon situation arises when PXE is suspected but no causative ABCC6 mutations are found on genetic testing. In these cases, beta-thalassemia or related hemoglobinopathy should be ruled out first. (See 'Differential diagnosis' below.)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of PXE includes heritable and acquired disorders that phenotypically resemble PXE [1,2,6,13,50]:
●Heritable conditions – Heritable conditions that share cutaneous, ocular, and vascular features of PXE but are associated with distinct gene defects and presumably different pathomechanisms include:
•PXE/cutis laxa-like overlapping phenotype with multiple coagulation factor deficiency – PXE-cutis laxa-like phenotype with multiple coagulation factor deficiency presents with overlapping cutaneous and ocular features of PXE and cutis laxa and deficiency in vitamin K-dependent coagulation factors [3]. This disorder is caused by variants in the GGCX gene, encoding gamma-glutamyl-carboxylase, but the precise pathomechanism has not been elucidated [51,52].
•Familial tumoral calcinosis – Familial tumoral calcinosis is a rare, autosomal recessive, ectopic mineralization disorder. The hyperphosphatemic forms are caused by variants in any one of three genes (GALNT3, KL, and FGF23) and are characterized by ectopic calcification of periarticular soft tissue. The normophosphatemic form (MIM #610455) is caused by compound heterozygous mutations in SAMD9 and presents with extensive cutaneous and mucosal calcium deposition [53,54]. (See "Overview of the causes and treatment of hyperphosphatemia", section on 'Familial tumoral calcinosis' and "Calcinosis cutis: Etiology and patient evaluation".)
•Pseudo-PXE related to hemoglobinopathy – Skin manifestations resembling those seen in PXE have been described in some patients with inherited hemoglobinopathies, most often beta-thalassemia and sickle cell disease, in the absence of ABCC6 mutations, hypothetically due to epigenetic factors downregulating the expression of ABCC6 [55]. However, rare variants of ABCC6 and ENPP1 genes have been detected in a few patients with thalassemia and clinical skin and eye findings of PXE, suggesting that in some cases PXE and thalassemia can co-occur [51,56]. (See "Diagnosis of thalassemia (adults and children)" and "Overview of the clinical manifestations of sickle cell disease".)
•Angioid streaks can also occur in Marfan syndrome and Ehlers–Danlos syndromes. (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders" and "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes".)
●Acquired skin disorders – Acquired skin lesions that resemble PXE papules include [57]:
•White fibrous papulosis of the neck [58].
•Papules associated with solar elastosis (picture 11).
•Late-onset focal dermal elastosis [59].
•Papules associated with chronic D-penicillamine therapy [60].
•Perforating calcific elastosis, a rare, acquired skin disease mainly affecting the periumbilical region in multiparous women [61].
•Acquired angioid streak-like retinal lesions can be seen in severe myopia and age-related macular degeneration.
MANAGEMENT — There is no effective treatment to halt or prevent the systemic mineralization in PXE. A multidisciplinary approach is necessary for the management of the major ocular, vascular, and cutaneous manifestations of PXE [1].
Ocular manifestations — Major ocular complication associated with PXE (ie, loss of visual acuity secondary to bleeding or leakage from neovascularization and blindness) can be averted by timely intravitreal injections of vascular endothelial growth factor (VEGF) antagonists (eg, bevacizumab, ranibizumab, aflibercept). In a few small clinical studies, intravitreal anti-VEGFs were associated with stabilization or improvement in the best corrected visual acuity and central macular thickness [62-67].
Patients with PXE need long-term, close follow-up by a specialist in retinal diseases. In-home use of an Amsler grid to self-monitor for distortions in central vision is also recommended. Moreover, as blunt ocular and possibly head trauma can precipitate neovascularization and subretinal hemorrhage, protection from external head and ocular trauma and limited participation in contact and racquet sports are critical for prevention of these complications in patients with PXE.
Cutaneous manifestations — Plastic surgery is sometimes helpful in improving the appearance of lax skin, particularly in the neck, axillae, and groin. However, it does not reverse the development of pseudoxanthomatous skin changes. In addition, laxity may recur and require follow-up surgical correction. Wound healing is thought to be normal in PXE. Due to the depth of the dystrophic changes in elastic tissue, laser treatment is not effective in managing PXE-related skin changes. Similarly, topical treatments, such as corticosteroids and retinoids, are not effective.
Pregnancy — A retrospective study of nearly 800 pregnancies found no evidence for significantly increased fetal loss or adverse reproductive outcomes in PXE. Gastric bleeding, previously thought to be a major risk in pregnant women with PXE, was found to be much lower than previously thought. Although some patients reported worsening of skin manifestations during pregnancy, this was uncommon. There was no correlation between the number of pregnancies or ever having been pregnant with ultimate severity of skin, eye, or cardiovascular manifestations. Most pregnancies in women with PXE appear to be uncomplicated, and there is no basis for advising women with PXE against pregnancy [68]. However, pregnant women with retinal neovascularization may need to consider cesarean section if there is active leakage around the time of delivery and should be closely monitored by retinal specialists. Women with pregnancy-related hypertension may need care by a maternal-fetal specialist.
Prevention of vascular and systemic mineralization — There is no definite therapeutic approach for the prevention of systemic and particularly vascular calcification in PXE. However, considering the vascular involvement in PXE, regular exercise and a cardio-protective diet should be encouraged. The patients should be monitored for their serum lipid profiles, and hyperlipidemia should be treated with cholesterol-lowering drugs. Finally, cigarette smoking should be strongly discouraged as it may worsen intermittent claudication. (See "Overview of primary prevention of cardiovascular disease".)
Research aimed at treatment development has been focusing either on restoration of inorganic pyrophosphate (PPi) levels in plasma or prevention of calcium hydroxyapatite deposition by PPi-independent means [23]:
●Oral PPi – After initial demonstration of PPi deficiency in patients with PXE, it was suggested that PPi plasma levels could be restored by oral administration of PPi.
Although early studies stated that PPi cannot be absorbed by the intestine due to rapid degradation by intestinal phosphatases, subsequent studies have documented that a small percentage of ingested PPi gets absorbed and increases the levels of PPi in patients with PXE [69]. However, a drawback of this approach is that the half-life of PPi is relatively short (ie, approximately 42 minutes). Phase 2 clinical trials are underway to evaluate the efficacy of slow-release PPi compounds (NCT04868578) and drugs inhibiting tissue-nonspecific alkaline phosphatase (TNAP; NCT05569252), thus prolonging the half-life of PPi.
Lansoprazole, a proton pump inhibitor, has partial TNAP inhibitory activity. A double-blind, crossover study showed a small but statistically significant rise in PPi levels after eight weeks of 30 mg lansoprazole daily, but its clinical significance is unknown [70].
●Bisphosphonates – The TEMP trial evaluated the efficacy of etidronate, a first-generation bisphosphonate with relatively high antimineralization activity as compared with antiosteoclastic activity, for the prevention of ectopic mineralization in PXE [71]. In this study that included 74 patients with PXE and leg arterial calcifications treated with etidronate (cyclical 20 mg/kg for 2 weeks every 12 weeks) or placebo for 12 months, etidronate reduced arterial calcification in the lower extremities by 4 percent, while it increased in the placebo group by 8 percent, as measured by computed tomography. Fewer subretinal neovascularization events occurred in the etidronate group compared with the placebo group.
A post-hoc, prespecified analysis of the TEMP trial showed that after one year of treatment, etidronate halted the progression of calcification in multiple vascular beds (carotid siphon, common carotid artery, thoracic and abdominal aorta, iliac arteries, and the femoropopliteal and crural arteries), with the exception of the coronary arteries [72]. However, further research is needed to assess the long-term safety and efficacy of etidronate on clinical outcomes in PXE.
●Dietary magnesium – Previous studies in animal models of PXE demonstrated that increasing magnesium content of the diet of PXE prevented the ectopic mineralization and reduced carotid intima-media thickness [73,74]. Based on these observations, a randomized trial that included 44 patients with PXE evaluated the efficacy of dietary magnesium oxide (MgO) for the treatment of PXE [75]. Treatment consisted of twice-daily 800 mg MgO (500 mg elemental magnesium) or placebo for one year. At one year, a nonstatistically significant decrease in calcification of the skin elastic fibers was noted in the magnesium group, as assessed with a 10-point numeric grading score on skin biopsies stained with Verhoeff-Van Gieson and Von-Kossa stains. Larger studies are needed to confirm the efficacy and safety of magnesium supplementation for PXE. The recommendation of the US Food and Drug Administration (FDA) for daily magnesium intake is 420 mg for an adult male and 320 mg for an adult female.
●Phosphate binders – The potential efficacy of an intestinal phosphate binder, sevelamer hydrochloride, was assessed in a randomized trial that included 40 patients with PXE [76]. Patients received oral sevelamer hydrochloride 800 mg three times daily or placebo for one year. During the first year of treatment, a decrease in the calcium score of the skin elastic fibers was noted. The mean clinical score of skin lesions also improved while no deterioration of eye involvement was noted. Complicating the interpretation of these data was the fact that both the placebo and the active drug preparation contained magnesium stearate, which may have played a confounding role in this study. Larger, better controlled clinical trials are required to assess the role of phosphate binders in treatment of PXE.
Although the results of these studies appear promising, none of these therapies is yet in widely accepted clinical use.
GENETIC COUNSELING — PXE mode of inheritance is autosomal recessive. Genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for an ABCC6 pathogenic variant and to allow reliable assessment of risk for subsequent pregnancies [1]. If parents of an affected child are confirmed heterozygous for an ABCC6 pathogenic variant, each sibling has at conception a 25 percent probability of being affected, a 50 percent probability of being an asymptomatic carrier, and a 25 percent probability of being unaffected and not a carrier [1]. Since siblings of an affected patient are at risk, they should be offered screening by examination and clinical history and, if indicated, genetic testing.
SUMMARY AND RECOMMENDATIONS
●Genetics and pathogenesis – Pseudoxanthoma elasticum (PXE; MIM #264800) is a rare, late-onset, heritable disorder characterized by ectopic mineralization and fragmentation of elastic fibers in the skin, eye, vascular, and gastrointestinal system. PXE is caused by homozygous or compound heterozygous pathogenic variants in the ABCC6 gene, encoding a transporter protein expressed primarily in the liver and involved in the extracellular conversion of ATP to AMP and inorganic pyrophosphate (PPi), a powerful antimineralization factor. (See 'Genetics' above and 'Pathophysiology' above.)
●Cutaneous manifestations – Early cutaneous and ocular findings are subtle and are in most cases not noticed until the second or third decades of life. The primary skin lesions are papules darker than the person's natural skin tone, initially located on the side of the neck (picture 1A-B) and later in the axillae (picture 2) and other flexural areas, chest, and abdomen. Ultimately, the affected skin becomes lax and redundant (picture 3A-B). (See 'Skin' above.)
●Ocular manifestations – Angioid streaks, named because of their resemblance to retinal vessels, are the most characteristic eye finding in PXE (picture 4). As the disease progresses, choroidal neovascularization occurs. Leakage of serum or blood from these vessels results in focal retinal detachments (picture 6) and distorted vision. (See 'Eye' above.)
●Cardiovascular manifestations – Diminution or loss of peripheral pulses and early onset of intermittent claudication are the most common peripheral vascular manifestations of PXE. Additional vascular complications of PXE include renovascular hypertension, premature coronary artery disease, and cerebrovascular disease. Involvement of the mesenteric artery and its branches may be associated with intestinal angina and upper gastrointestinal bleeding. (See 'Cardiovascular system' above.)
●Diagnosis – The finding of homozygosity or compound heterozygosity for two pathogenic mutations in ABCC6 on genetic testing is considered the gold standard for diagnosis of PXE. In most cases, however, the diagnosis of PXE is clinical, based on the finding of typical skin lesions with histopathologic demonstration of elastic fiber calcification in the mid-dermis and angioid streaks in the retina. Due to the late onset and subtle and asymptomatic nature of early skin, eye, and vascular manifestations, the diagnosis is often delayed. (See 'Diagnostic criteria' above and 'Genetic testing' above.)
●Management – There is no effective treatment to halt or prevent the systemic mineralization in PXE. Experimental therapies for the prevention of calcium hydroxyapatite deposition, such as oral PPi, first-generation bisphosphonates, and dietary supplementation of magnesium, have been evaluated in a few clinical studies with varying results. However, none are widely accepted yet for clinical use. (See 'Prevention of vascular and systemic mineralization' above.)
A multidisciplinary approach is necessary for the management of the major ocular, vascular, and cutaneous manifestations of PXE. Intravitreal injections of vascular endothelial growth factor (VEGF) antagonists (eg, bevacizumab, ranibizumab, aflibercept) have been reported as effective for the stabilization or improvement of visual acuity in patients with angioid streaks and choroidal neovascularization. (See 'Cutaneous manifestations' above.)
Plastic surgery may be helpful in improving the appearance of lax skin, particularly in the neck, axillae, and groin. However, laxity may recur and require follow-up surgical corrections. (See 'Cutaneous manifestations' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jouni Uitto, MD, PhD (deceased), who contributed to earlier versions of this topic review.
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