Figure 1. Rash on neck.
Figure 2. Rash on arm.
A 22-year-old woman presents for evaluation of progressive skin changes on her neck and arms beginning sometime around puberty. She tried various over-the-counter anti-itch, antiaging, and eczema creams that were ineffective. She has no personal or family history of skin conditions and is otherwise healthy. Review of systems is negative for skin laxity, joint hypermobility, or vision changes. Physical examination reveals numerous nontender, noninflammatory, yellow, 2- to 5-mm papules that coalesce into reticulated plaques on the nape of her neck and bilateral antecubital fossa. A punch biopsy demonstrates fragmentation and calcification of elastic fibers.
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Pseudoxanthoma elasticum (PXE), also known as Grönblad-Strandberg syndrome, is a metabolic disorder characterized by progressive dystrophic mineralization of connective tissue of the integumentary, ocular, and cardiovascular systems.1 Achieving the correct diagnosis for this rare disorder requires a constellation of clinical and histological findings and can be confirmed with molecular testing.
Pseudoxanthoma elasticum is an inherited, autosomal recessive disorder most commonly caused by mutations in the adenosine triphosphate (ATP)-binding cassette subfamily C member 6 gene (ABCC6) — also referred to as the multidrug resistance protein 6 gene (MRP6) — located on chromosome 16.1 The ABCC6 gene encodes a cellular transport protein and is expressed in a variety of tissues.2 Missense mutations in ABCC6 are most frequently implicated in the etiology of PXE, with over 300 DNA sequence variants identified to date.3
However, the exact pathophysiological mechanism by which ABCC6 mutations lead to the clinical development of PXE is incompletely understood. It has been proposed that ABCC6 contributes to the transport of ATP, which then serves as a substrate for the production of the inorganic pyrophosphate (PPi), an anticalcifying molecule. Aberrant ABCC6 function is hence postulated to cause downstream deficits in PPi, thereby precipitating unopposed ectopic calcification.4,5 Several studies have corroborated this metabolic hypothesis, reporting significantly reduced tissue and plasma PPi concentrations in patients with clinical PXE.5-7
Therefore, the clinical entity of PXE is currently best conceptualized as a metabolic disorder by which unregulated hydroxyapatite crystal formation precipitates calcification and elastorrhexis of affected tissues.
The prevalence of PXE is estimated to be anywhere between 1:25,000 to 1:100,000, with a female-to-male ratio of approximately 2:1 to 3:1.8 Cutaneous features tend to be the first clinical indicator, with typical onset in childhood to early adolescence, peaking at 10 to 15 years of age.9 The progressive development of predominately asymptomatic, yellow, 2- to 5-mm papules in a symmetrical distribution on the nape and lateral neck and flexural areas, such as the axillae, antecubital, and popliteal fossa, is highly characteristic of PXE. Occasionally, skin changes are found in the periumbilical and anogenital regions; oral findings are not uncommon.3 In patients younger than 30 years, the finding of an exaggerated horizontal or oblique mental crease is highly specific.10 While papules may begin as isolated lesions, they typically coalesce over time, forming plaques that resemble cobblestones or plucked chicken skin. As the disease progresses, the skin subsequently becomes laxer and more wrinkled.1
Ocular changes attributed to PXE can cause significant morbidity, as they can lead to hemorrhage and irreversible vision loss. Calcification of Bruch membrane of the retina initiates a “peau d’orange” change in the peripheral retina, which can evolve into breaks in the membrane, called angioid streaks, and neovascularization over an average of 1 to 8 years.11 Although angioid streaks are seen in up to 96% of patients with PXE, they are not pathognomonic and can be observed in other conditions such as sickle cell anemia, beta-thalassemia, Ehlers-Danlos syndrome, and Paget disease of bone.3 These streaks, also called comet lesions, are the only ocular finding specific to PXE and represent areas of chorioretinal atrophy.12
Cardiovascular manifestations are typically the last to develop in PXE owing to the gradual but stead-fast calcification of elastic fibers in the tunica media and intima of small- and medium-sized blood vessels. This primarily presents as intermittent claudication of the upper and lower extremities with diminished peripheral pulses, hypertension, and a low ankle-brachial index.3 Potentially life-threatening complications include myocardial and cerebral vascular infarctions, ruptured aneurysms, and gastrointestinal hemorrhage.1
Histologically, the primary feature of PXE is fragmentation of the elastic tissue called elastorrhexis with subsequent calcification. Collagen fibrils, arranged in a flower-like distribution, numerous fibroblasts, and macrophage-laden calcium deposits have also been observed in some cases.8 These features are described only in clinically affected skin. Calcification can also be observed on histopathologic assessment of Bruch membrane as can elastic fiber fragmentation of the myocardium, pericardium, and arterial vessels. These histopathologic findings are strongly suggestive of PXE but are not pathognomonic for this condition.3
Although the diagnosis of PXE can technically be established by clinical features alone, molecular analysis is recommended for confirmation and to avoid confusion with other genetic conditions that may clinically and histologically masquerade as PXE such as GGXC-mediated coagulation factor deficiency and ENPP1-mediated premature arterial calcification.13,14 Furthermore, identifying the causal mutation permits adequate genetic counseling for PXE-affected patients and their relatives who may have subclinical disease or be heterozygous carriers and, therefore, benefit from early intervention.3
Because PXE is an intractable and progressive condition, management is typically multidisciplinary and geared towards minimizing and controlling the complications that arise as the condition evolves. While no specific treatment for the skin changes is available, surgical excision of redundant, lax skin, and mandibular collagen injections have been utilized for cosmetic purposes.15 Ophthalmologic care may include antioxidant supplementation, treatment with medications such as intravitreal bevacizumab (which may attenuate choroidal neovascularization) as well as laser photocoagulation or photodynamic therapy.8 A low-calcium diet and modification of other cardiovascular risk factors such as smoking cessation, exercise, and lipid and blood pressure management are the mainstays in reducing the risk of cardiovascular disease, an important cause of mortality in PXE.
Of note, aspirin is principally contraindicated as its use may lead to an increased risk of retinal and gastrointestinal hemorrhage.3 Novel, targeted gene therapy may be on the distant horizon for treatment; however, this treatment is still in development with many challenges to overcome.16
The overall prognosis for PXE is dependent on the extent of ocular and vascular disease. Premature atherosclerosis with resultant myocardial and cerebral infarctions can occur, but many patients have a normal lifespan, especially when they receive prompt diagnosis and appropriate monitoring and management.
The patient in this case was referred to genetics and then to the appropriate subspecialties for long-term management.
Sarah Shapiro is a 4th-year medical student at Virginia Commonwealth University and a research fellow at Wake Forest School of Medicine Department of Dermatology. Julia R. Nunley, MD, is a professor in the Department of Dermatology at Virginia Commonwealth University in Richmond.
- Bhutani N, Kamlesh, Nadesan A. Pseudoxanthoma elasticum as a diagnostic challenge for pathologists: a rare case report. Ann Med Surg (Lond). 2022;77:103571. doi:10.1016/j.amsu.2022.103571
- Zheng A, Thibodeau PH. Commentary on variants in the ABCC6 gene implicated in pseudoxanthoma elasticum, a heritable ectopic mineralization disorder. J Invest Dermatol. 2022;142(4):1002-1003. doi:10.1016/j.jid.2022.02.008
- Germain DP. Pseudoxanthoma elasticum. Orphanet J Rare Dis. 2017;12(1):85. doi:10.1186/s13023-017-0639-8
- Kauffenstein G, Yegutkin GG, Khiati S, et al. Alteration of extracellular nucleotide metabolism in pseudoxanthoma elasticum. J Invest Dermatol. 2018;138(8):1862-1870. doi:10.1016/j.jid.2018.02.023
- Zhao J, Kingman J, Sundberg JP, Uitto J, Li Q. Plasma PPi deficiency is the major, but not the exclusive, cause of ectopic mineralization in an Abcc6–/– mouse model of PXE. J Invest Dermatol. 2017;137(11):2336-2343. doi:10.1016/j.jid.2017.06.006
- Jansen RS, Duijst S, Mahakena S, et al. ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report. Arterioscler Thromb Vasc Biol. 2014;34(9):1985-1989. doi:10.1161/ATVBAHA.114.304017
- Jansen RS, Küçükosmanoglu A, de Haas M, et al. ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release. Proc Natl Acad Sci U S A. 2013;110(50):20206-20211. doi:10.1073/pnas.1319582110
- Marconi B, Bobyr I, Campanati A, et al. Pseudoxanthoma elasticum and skin: clinical manifestations, histopathology, pathomechanism, perspectives of treatment. Intractable Rare Dis Res. 2015;4(3):113-122. doi:10.5582/irdr.2015.01014
- Lucas C, Aranha J, da Rocha I, Sousa D. Case report: pseudoxanthoma elasticum. F1000Res. 2020;9:9. doi:10.12688/f1000research.21431.1
- Lebwohl M, Lebwohl E, Bercovitch L. Prominent mental (chin) crease: a new sign of pseudoxanthoma elasticum. J Am Acad Dermatol. 2003;48(4):620-2. doi:10.1067/mjd.2003.195.
- Gliem M, Zaeytijd JD, Finger RP, Holz FG, Leroy BP, Issa PC. An update on the ocular phenotype in patients with pseudoxanthoma elasticum. Front Genet. 2013;4:14. doi:10.3389/fgene.2013.00014
- Tatlıpınar S, Şahan B, Altunsoy M. Comet lesions in patients with pseudoxanthoma elasticum. Turk J Ophthalmol. 2015;45(6):268-270. doi:10.4274/tjo.84756.
- Li Q, Grange DK, Armstrong NL, et al. Mutations in the GGCX and ABCC6 genes in a family with pseudoxanthoma elasticum-like phenotypes. J Invest Dermatol. 2009;129(3):553-563. doi:10.1038/jid.2008.271
- Nitschke Y, Baujat G, Botschen U, et al. Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am J Hum Genet. 2012;90(1):25-39. doi:10.1016/j.ajhg.2011.11.020
- Galadari H, Lebwohl M. Pseudoxanthoma elasticum: temporary treatment of chin folds and lines with injectable collagen. J Am Acad Dermatol. 2003;49(5 Suppl):S265-266. doi:10.1016/s0190-9622(03)00468-7
- Brampton C, Aherrahrou Z, Chen LH, et al. The level of hepatic ABCC6 expression determines the severity of calcification after cardiac injury. Am J Pathol. 2014;184(1):159-170. doi:10.1016/j.ajpath.2013.09.015