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Pseudoxanthoma elasticum

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Pseudoxanthoma elasticum

Pseudoxanthoma elasticum
Pseudoxanthoma elasticum of the posterior lateral neck. Note the yellowish slightly raised bumps characteristic of this condition.
Classification and external resources
ICD-10 Q82.8
(ILDS Q82.81)
ICD-9-CM 757.39
OMIM 264800
DiseasesDB

10876 10881

 10885
10894
eMedicine derm/359 oph/475
MeSH D011561

Pseudoxanthoma elasticum (PXE), also known as Grönblad–Strandberg syndrome,[1] is a genetic disease that causes fragmentation and mineralization of elastic fibers in some tissues. The most common problems arise in the skin and eyes, and later in blood vessels in the form of premature atherosclerosis.[2] PXE is caused by autosomal recessive mutations in the ABCC6 gene on the short arm of chromosome 16 (16p13.1).[2][3]

Contents

  • Signs and symptoms 1
  • Classification 2
  • Pathophysiology 3
  • Genetics 4
  • Treatment 5
  • Epidemiology 6
  • History 7
  • Images 8
  • See also 9
  • References 10
  • External links 11

Signs and symptoms

Usually, pseudoxanthoma elasticum affects the skin first, often in childhood but frequently later. Small, yellowish papular lesions form and cutaneous laxity mainly affects the neck, axillae (armpits), groin, and flexural creases (the inside parts of the elbows and knees). Skin may become lax and redundant. Many individuals have "oblique mental creases" (diagonal grooves of the chin).[2]

PXE first affects the retina through a dimpling of the Bruch membrane (a thin membrane separating the blood vessel-rich layer from the pigmented layer of the retina), that is only visible during ophthalmologic examinations. This is called peau d'orange (a French term meaning that the retina resembles the skin of an orange). Eventually the mineralization of the elastic fibers in the Bruch membrane create cracks (angioid streaks) that radiate out from the optic nerve. Angioid streaks themselves do not cause distortion of vision, even if they cross into the foveal area. This symptom is present almost all PXE patients and is usually noticed a few years after the onset of cutaneous lesions. These cracks may allow small blood vessels that were originally held back by Bruch's membrane to penetrate the retina. These blood vessels sometimes leak, and these retinal hemorrhages may lead to the loss of central vision. Vision loss is a major issue in many PXE patients.[2][3]

PXE may affect the gastrointestinal and cardiovascular systems. In the digestive tract, the principal symptom is gastrointestinal bleeding, usually from the stomach. This occurs in very small number of patients. In the circulatory system, intermittent claudication (leg pain during walking which resolves at rest) is a prominent feature, although at later stages coronary artery disease may develop, leading to angina and myocardial infarction (heart attack) may occur.[2]

Classification

The diagnostic criteria for PXE are the typical skin biopsy appearance and the presence of angioid streaks in the retina. Other systems have become somewhat outdated by the discovery of the ABCC6 mutations.[2]

Pathophysiology

In PXE, there is mineralization (accumulation of calcium and other minerals) and fragmentation of the elastin-containing fibers in connective tissue, but primarily in the midlaminar layer of the dermis, Bruch's membrane and the midsized arteries.[4] Recent studies hypothesize that PXE is a metabolic disease, and that its features arise because metabolites of vitamin K cannot reach peripheral tissues.[5]

Genetics

Pseudoxanthoma elasticum has an autosomal recessive pattern of inheritance.

80% of clinical cases of pseudoxanthoma elasticum have detectable mutations in the ABCC6 gene.[6][7][8][9] Mutations in almost all parts of the gene have been described, of all types (missense, nonsense, splice alteration, insertion, small deletion or large deletion). Although there have been reports of autosomal dominant inheritance, the inheritance is typically autosomal recessive (both parents need to be carriers, and there is a 25% chance that a child will inherit both abnormal copies of the gene and therefore develop the condition).[2]

Strong genetic linkage was found with mutations in the liver and kidney. It is unclear in what way this would lead to abnormalities in skin, eyes and blood vessels. It is thought that particular mutations do not cause a more severe or less severe form of the disease. Given the variations in age of onset and severity it is likely that other unknown risk factors (genetic and dietary) may be involved.[2] One study suggested that mutations causing total absence of an MRP6 protein caused a more severe disease,[10] but this could not be confirmed in a subsequent case series.[11]

Premature atherosclerosis is also associated with mutations in the ABCC6 gene, even in those without PXE.[12] A syndrome almost indistinguishable from hereditary PXE has been described in patients with hemoglobinopathies (sickle-cell disease and thalassemia) through a poorly understood mechanism.[2] In addition, there appears to be another PXE-like syndrome with a similar phenotype but as a result of problems with another gene, gamma-glutamyl carboxylase.[13]

Treatment

There is no treatment that directly interferes with the disease process, although dietary restriction of calcium has been tried with limited results.[2] For excessive areas of skin, plastic surgery may be needed. For the growth of abnormal blood vessels in the retina, laser photocoagulation and photodynamic therapy may be used; injections with triamcinolone have shown limited effect. Antiangiogenic drugs such as bevacizumab (Avastin) and ranibizumab (Lucentis) have been effective, similar to its efficacy in age-related macular degeneration.[3] Cardiovascular disease is treated as in individuals without PXE. Some recommend avoidance of nonsteroidal anti-inflammatory drugs (NSAIDS) that increase bleeding risk, such as aspirin, and ibuprofen.[2]

Epidemiology

The reported prevalence of pseudoxanthoma elasticum is about 1:25,000. Females are twice as likely to be affected as males. The disease occurs in all ethnicities, but Afrikaners are more likely to have PXE as a result of a founder effect (i.e. it was relatively prevalent in the small group of people from whom most Afrikaners descend).[2]

History

The first description of PXE that distinguished it from other xanthomatous conditions was by Dr Ferdinand-Jean Darrier in 1896.[14] The eponym "Grönblad-Strandberg syndrome" is used in older literature, after two physicians who made further discoveries in the disease manifestations.[15]

PXE has the distinction of being the only disease for which a layperson is the inventor of the gene, ABCC6. Sharon F. Terry, co-founder of PXE International with her husband, Patrick F. Terry, worked with scientists to discover and patent the gene in 2000.[8] The Terrys' two children have pseudoxanthoma elasticum.[16][17]

Images

See also

References

  1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby.  
  2. ^ a b c d e f g h i j k l Chassaing N, Martin L, Calvas P, Le Bert M, Hovnanian A (2005). "Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations". J. Med. Genet. 42 (12): 881–92.  
  3. ^ a b c Finger RP, Charbel Issa P, Ladewig MS, et al. (2009). "Pseudoxanthoma elasticum: genetics, clinical manifestations and therapeutic approaches". Surv Ophthalmol 54 (2): 272–85.  
  4. ^ Gheduzzi D, Sammarco R, Quaglino D, Bercovitch L, Terry S, Taylor W, Ronchetti I (2003). "Extracutaneous ultrastructural alterations in pseudoxanthoma elasticum". Ultrastructural pathology 27 (6): 375–84.  
  5. ^ Li Q, Jiang Q, Pfendner E, Váradi A, Uitto J (January 2009). "Pseudoxanthoma elasticum: clinical phenotypes, molecular genetics and putative pathomechanisms". Exp. Dermatol. 18 (1): 1–11.  
  6. ^ Ringpfeil F,  
  7. ^ Bergen AA, Plomp AS, Schuurman EJ, et al. (2000). "Mutations in ABCC6 cause pseudoxanthoma elasticum". Nat. Genet. 25 (2): 228–31.  
  8. ^ a b Le Saux O, Urban Z, Tschuch C, et al. (2000). "Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum". Nat. Genet. 25 (2): 223–7.  
  9. ^ Struk B, Cai L, Zäch S, et al. (2000). "Mutations of the gene encoding the transmembrane transporter protein ABC-C6 cause pseudoxanthoma elasticum". J. Mol. Med. 78 (5): 282–6.  
  10. ^ Schulz V, Hendig D, Szliska C, Götting C, Kleesiek K (2005). "Novel mutations in the ABCC6 gene of German patients with pseudoxanthoma elasticum". Hum. Biol. 77 (3): 367–84.  
  11. ^ Pfendner EG, Vanakker OM, Terry SF, et al. (2007). "Mutation detection in the ABCC6 gene and genotype-phenotype analysis in a large international case series affected by pseudoxanthoma elasticum". J. Med. Genet. 44 (10): 621–8.  
  12. ^ Trip MD, Smulders YM, Wegman JJ, et al. (2002). "Frequent mutation in the ABCC6 gene (R1141X) is associated with a strong increase in the prevalence of coronary artery disease". Circulation 106 (7): 773–5.  
  13. ^ Vanakker OM, Martin L, Gheduzzi D, Leroy BP, Loeys BL, Guerci VI, Matthys D, Terry SF, Coucke PJ, Pasquali-Ronchetti I, De Paepe A. (2007). "Pseudoxanthoma elasticum-like phenotype with cutis laxa and multiple coagulation factor deficiency represents a separate genetic entity". J Invest Dermatol. 127 (3): 581–7.  
  14. ^ Darrier FJ (1896). "Pseudoxanthoma elasticum". Monatschr Prakt Dermatol (in German) 23: 609–17. 
  15. ^ synd/1059 at Who Named It?
  16. ^ Terry SF, Terry PF, Rauen KA, Uitto J, Bercovitch LG (2007). "Advocacy groups as research organizations: the PXE International example". Nat. Rev. Genet. 8 (2): 157–64.  
  17. ^ Terry SF (2003). "Learning genetics". Health Aff (Millwood) 22 (5): 166–71.  

External links

  • PXE International
  • pxe at NIH/UW GeneTests
  • Pseudoxanthoma elasticum at NLM Genetics Home Reference
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