弾性線維性仮性黄色腫

Pseudoxanthoma elasticum (PXE) is a rare genetic disease characterized by ectopic calcification in the eyes, skin, and arteries. It is caused by pathogenic variants in the ABCC6 gene and leads to reduced plasma levels of inorganic pyrophosphate. Etidronate, a stable analogue of pyrophosphate, has been shown to reduce arterial calcification. However, the long-term skeletal safety of high-dose cyclical etidronate treatment remains unclear. This study aimed to evaluate the skeletal effects of cyclical etidronate administration in adults aged ≥50 years with PXE. This prospective study included patients treated with etidronate (20 mg/kg/day for 14 days every 12 weeks) for ≥1 year and untreated control patients from the Dutch Expertise Center for PXE. Bone density (BD) was measured on whole-body low-dose CT scans in Hounsfield units at the spine and femoral necks. Safety was assessed using bone turnover markers and fracture data. BD changes were compared within treated patients and between the treated and control groups using scanner-adjusted linear mixed models. In total, 71 treated patients (mean age 57.0 ± 7.6 years; 56% female) and 72 untreated patients (mean age 54.2 ± 11.0 years; 69% female) were included. Median etidronate follow-up duration was 5.2 years (IQR 5.1-7.5). Of the 71 treated patients, 66 (93%) completed 5 years of follow-up, and all treated patients completed at least 2.5 years of treatment. In the treated group, BD remained stable during treatment, whereas in the untreated group it declined substantially, resulting in a greater overall loss in the untreated group compared to the treated group. Non-vertebral fracture incidence was low and comparable to controls, and no atypical femur fractures, excessive suppression of bone turnover markers, or medication-related osteonecrosis of the jaw were observed. This study demonstrates that cyclical administration of high-dose etidronate to patients aged ≥50 years with PXE for 5 years did not negatively affect skeletal integrity and metabolism and prevented bone loss at both the spine and the hip.

ABCC6 (ATP-binding cassette subfamily C member 6) was initially identified as the disease gene for pseudoxanthoma elasticum, a disorder marked by ectopic mineralization. Beyond this classical role, emerging evidence supports ABCC6 as a liver-enriched transporter with broader metabolic relevance. ABCC6 promotes hepatocyte ATP (adenosine triphosphate)/ADP (adenosine diphosphate) release and supports ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1)-dependent PPi (inorganic pyrophosphate) generation, thereby maintaining circulating anti-mineralization buffering; downstream AMP (adenosine monophosphate) metabolism may also influence adenosine-related signaling. Although its subcellular localization remains debated, evidence supports predominant basolateral plasma membrane localization, whereas one fractionation study reported enrichment at MAM (mitochondria-associated membranes) that has not been independently validated. ABCC6 deficiency has been associated with altered lipoprotein metabolism, mitochondrial bioenergetic impairment, oxidative stress, senescence-like phenotypes, and context-dependent metabolic susceptibility. These mitochondrial findings are interpreted as ABCC6 deficiency-associated downstream phenotypes rather than as evidence for stable mitochondrial or MAM residence. This review integrates established mineralization biology with emerging metabolic evidence, focusing on the extracellular nucleotide-PPi pathway, downstream adenosine-related signaling, mitochondrial stress, lipid and cholesterol handling, and vascular complications. We also discuss therapeutic strategies aimed at restoring PPi availability, limiting calcification, or recovering ABCC6 expression and function.

We report a clinical case of pseudoxanthoma elasticum-like papillary dermal elastolysis. A 36-year-old female presented to our institution with a 30-year history of spontaneously erupting papules on her anterior neck. These lesions had gradually increased in both number and size without any identifiable trigger. Physical examination revealed numerous densely distributed, firm, pale-yellow subcutaneous papules localized to the anterior neck, right supraclavicular region, right shoulder, and right posterior neck. Dermoscopy demonstrated pale or milky-white structureless areas with globular or irregular morphologies. Some lesions exhibited slight confluence. Focal linear or atypical vessels were observed between the lesions, but no classic frog-spawn appearance or typical vascular structures were present. Histopathologic examination of serial sections showed mild acanthosis and papillomatosis. The superficial dermis exhibited mild vascular dilatation accompanied by a sparse perivascular inflammatory infiltrate. Crucially, elastic tissue staining revealed fragmented and markedly reduced elastic fibers within the papillary dermis. Consequently, the diagnosis of pseudoxanthoma elasticum-like papillary dermal elastolysis was established.

Pseudoxanthoma elasticum (PXE) is a rare inherited disorder characterized by progressive ectopic calcification of soft connective tissues, including skin, arteries, and eyes, leading to significant morbidity. PXE results from loss of functional ABCC6, a liver specific ATP efflux conduit. Reduced ATP release into the circulation limits its conversion into AMP and the mineralization inhibitor pyrophosphate (PPi). Consequently, low plasma PPi levels drive ectopic calcification in PXE. Although oral PPi supplementation can inhibit ectopic calcification in Abcc6-/- mice, impractically high doses are needed, due to its rapid hydrolysis in the gastrointestinal tract. Here, we evaluated phosphocitrate, an exceedingly more potent mineralization inhibitor, in vitro and in Abcc6-/- mice. In ATDC5 cells, 1 μM phosphocitrate significantly inhibited mineralization following induction, comparable to approximately tenfold higher concentrations of PPi. In vivo, daily intraperitoneal administration of phosphocitrate (4.7 μmol/kg bw) markedly reduced calcification in muzzle skin and kidneys, whereas an at least fivefold higher dose of PPi was needed to achieve a similar effect. Oral administration required substantially higher doses of both compounds (~2.4 mmol/kg bw), but PC remained more effective than PPi at inhibiting soft tissue calcification in Abcc6-/- mice. Importantly, unlike PPi, oral phosphocitrate did not adversely affect skeletal strength or stiffness, even at supraphysiological doses. In summary, phosphocitrate is a more potent inhibitor of ectopic calcification than PPi in Abcc6-/- mice. While optimization of oral delivery remains necessary, its increased potency supports the potential of alternative administration routes, including subcutaneous delivery, as a practical therapeutic strategy for PXE.