Pseudoxanthoma Elasticum (PXE) is an autosomal recessive genetic disorder caused by mutations in the ABCC6 gene located on chromosome 16p13.1. It is also known as Grönblad-Strandberg syndrome. Ectopic calcification and fragmentation of elastic fibers lead to multi-organ damage in the skin, eyes, and cardiovascular system, making it a progressive systemic disease.
The prevalence is estimated to be 1/25,000 to 1/100,000 8). In Japan, it was designated as a specified intractable disease (intractable disease number 335) in 2015.
ABCC6 protein is an ATPase-dependent transporter mainly expressed in the liver and kidneys. Deficiency of this protein reduces the production of inorganic pyrophosphate (PPi) in the blood. PPi is an inhibitor of calcification, and its deficiency causes ectopic deposition of Ca/Pi in elastic fibers. Lower PPi production than in healthy individuals is the core of PXE pathology 8).
Because it is an autosomal recessive disorder, a child develops the disease only when both parents are carriers of ABCC6 gene mutations. Since the phenotype of heterozygous carriers is not uniform 8), genetic counseling should be considered if there is a family history.
Ocular symptoms usually begin in the 20s to 30s and progress slowly.
Characteristic fundus findings are observed depending on the disease stage.
Early Findings
Peau d’orange changes: Changes at the level of the RPE (retinal pigment epithelium). An irregular texture resembling orange peel appears in the fundus.
Angioid streaks (AS): Dark red to brown streaks radiating from the optic disc. They result from calcification and breaks in Bruch’s membrane.
Advanced Findings
Choroidal neovascularization (CNV): New blood vessels invade through breaks in Bruch’s membrane. It occurs in 72–86% of patients3).
Comet tail lesion: Characteristic subretinal pigmentation associated with angioid streaks. Reported in a 46-year-old male case1, 8).
Acute retinopathy: Acute onset triggered by ocular trauma. Occurs in about 5% of all patients3).
In a rare subtype called the inflammatory phenotype, cases presenting with rapidly progressive subretinal fibrosis have been reported3).
Skin findings also include a subtype called periumbilical perforating PXE (Perforating PXE; PPPXE), which is more common in elderly multiparous obese women, such as an 85-year-old female4).
Angioid streaks are findings in which calcium deposits in Bruch’s membrane (the thin membrane separating the retina from the underlying choroid) cause cracks, appearing as linear shadows resembling blood vessels on the fundus. This is one of the most specific fundus findings in PXE, extending radially from the optic disc.
PXE is caused by biallelic mutations in the ABCC6 gene (16p13.1). It is an autosomal recessive disorder, and heterozygotes or modifier genes may also influence the phenotype 6,8).
Do not start or stop medications that affect bleeding risk, such as NSAIDs, or those that may influence calcification, such as calcium, vitamin D, or osteoporosis treatments, without consulting your doctor. PXE-like changes have also been reported with abaloparatide 5). Always consult your doctor before changing any medication.
PXE is diagnosed based on a combination of major and minor findings.
| Judgment | Criteria |
|---|---|
| Definitive diagnosis | 2 or more major findings |
| Suspected diagnosis | 1 major finding + 1 or more minor findings |
Major findings:
Minor findings:
Genetic analysis of ABCC6 identifies mutations 1, 3, 5). In addition to common variants (e.g., c.3490C>T), various mutations have been reported. It is essential for definitive diagnosis, family screening, and genetic counseling.
Von Kossa or Alizarin Red staining confirms calcification of elastic fibers 8). Differential diagnoses include age-related macular degeneration (AMD), Paget disease, Marfan syndrome, and Ehlers-Danlos syndrome (EDS).
There is no established curative treatment for PXE; symptomatic treatment for CNV is the mainstay.
Anti-VEGF therapy (first-line for CNV):
Intravitreal injection of anti-VEGF agents is the first-line treatment for PXE complicated by CNV.
Treatment for inflammatory phenotype (refractory CNV):
If response to anti-VEGF therapy is poor and rapid progressive subretinal fibrosis occurs, consider inflammatory mechanisms and coordinate between retinal specialist and internal medicine3). Immunosuppressive therapy is not standard treatment and should be carefully considered on a case-by-case basis.
Cardiovascular disease is a major complication that determines the prognosis of PXE.
| Complication | Management Strategy |
|---|---|
| Ischemic heart disease | DOAC recommended, avoid warfarin6) |
| Acute coronary syndrome | Stentless PCI (drug-coated balloon)7) |
| Peripheral artery disease | Collaboration with vascular surgery |
| Celiac artery compression syndrome (MALS) | Consider surgical intervention6) |
In a 72-year-old female with acute coronary syndrome (ACS), OCT-guided PCI with a drug-coated balloon was performed for complete occlusion of the left circumflex artery, confirming plaque erosion. DAPT was switched to prasugrel monotherapy after one week7).
ABCC6 is involved in the transport of substances that produce PPi using ATP as a substrate. ABCC6 dysfunction leads to decreased blood PPi (a calcification inhibitor)8).
Ca and Pi deposit as hydroxyapatite (Ca10(PO4)6(OH)2) on collagen and elastic fibers, causing fiber rupture 8). Mineral composition analysis has confirmed a mixture of hydroxyapatite and calcium phosphate 8).
Mushtaq et al. (2024) reported a mechanism in which VEGF production by RPE is promoted by choroidal ischemia through Bruch’s membrane rupture, leading to CNV formation. It is reported that 59–87% of patients with angioid streaks are attributed to PXE 2).
Calcification and rupture of Bruch’s membrane → choroidal ischemia → increased VEGF production → CNV formation: this chain is the main mechanism of visual impairment.
Fragmentation of elastic laminae in the tunica media of blood vessels has been confirmed at autopsy 6) (Mendelsohn sign). Structural disruption of the elastic laminae leads to weakening and calcification of the vessel wall, resulting in occlusive lesions of the coronary and peripheral arteries.
In the case by Willett et al. (2025), multi-organ cardiovascular disorders such as median arcuate ligament syndrome (MALS) and left ventricular diastolic dysfunction were confirmed, and skin scores showed a significant difference between the severe group (5.7) and the control group (1.8)6).
In acute coronary syndrome, plaque erosion is the main mechanism7). A characteristic of cardiovascular lesions in PXE is that erosion is more common than atheromatous rupture.
Liver-directed gene therapy for the ABCC6 gene is being studied. PPi analogs (such as etidronate) supplements have been reported to inhibit calcification in mouse models, and combination with magnesium supplementation is also being investigated 8).
Modifier genes such as CSF1R and NLRP1 are becoming clear to influence the severity of cardiovascular symptoms 6). They are attracting attention as a key to explaining the highly variable PXE phenotype.
Reports of PXE induction by abaloparatide (an osteoporosis drug) 5) provide new insights that the PPi metabolic pathway is directly linked to the onset and exacerbation of PXE. Development of a PXE activity assessment method using T50 (calcification propensity biomarker) is also progressing.
A case report by Oyeniran et al. (2024) demonstrated the existence of a PXE subtype presenting with rapidly progressive inflammation in addition to CNV 3). The finding that immunosuppressive therapy (MMF + tacrolimus) was effective for this inflammatory phenotype suggests that inflammatory mechanisms may be involved in the pathogenesis of PXE.
