Pseudoxanthoma elasticum (PXE) is a rare progressive genetic disorder that causes the fragmentation and calcification of elastic fibers due to the accumulation of minerals in the connective tissue. The organs mainly affected are the skin, the eye, the cardiovascular and gastrointestinal systems. The onset is usually after puberty. The most characteristic clinical manifestations include small yellowish papular lesions of the skin, lesions of the posterior segment of the eye, a tendency to gastrointestinal bleeding and arterial insufficiency. Diagnosis is mainly clinical.
Detailed clinical description
Pseudoxanthoma elasticum (PXE) is a multisystemic genetic disorder that affects the connective tissue of various organs, including the skin, the retina, the gastrointestinal system and the cardiovascular system.
One of the typical skin manifestations of PXE is the appearance of small yellowish papules mainly in the flexion regions of the neck, elbows, groin, armpits, associated with skin laxity in that area. These lesions often appear at onset, between the first and second decade of life, and as the disease progresses, they can flow into larger plaques.
In the eye, one of the first signs is the formation of lesions in the posterior segment of the eye which include the so-called "peau d'orange" and angioid streaks of the retina. These lesions do not alter the patient's visual acuity, unlike retinal hemorrhages which can cause blindness due to bleeding and for this reason are one of the most frequent causes of morbidity and disability PXE-related.
PXE causes narrowing and calcification of blood vessels, particularly medium-sized arteries. This can cause early-onset atherosclerosis resulting in intermittent claudication (due to decreased blood flow in the limbs), hypertension, angina and in some cases myocardial infarction.
Although more rarely, in about 10% of patients, PXE can also affect the gastrointestinal system causing gastrointestinal bleeding and small vessel bleeding, resulting in anemia.
It is important to underline that patients with PXE show a high degree of inter and intra-familial phenotypic variability: in some patients only one tissue is affected, in others all 4, and it is not possible to predict the progression of the disease.
The diagnosis is mainly clinical, based on the patient's phenotypic characteristics and can be confirmed by histological examination on a skin biopsy. Finally, it is possible to confirm the clinical diagnosis through molecular analysis to find bi-allelic pathogenic mutations in the ABCC6 gene.
The exact prevalence of the disease is not known, although it is estimated that PXE may have an incidence of 1/25,000- 1/100,000. The estimate is complicated by the fact that the disease is probably not diagnosed in many people, especially those with a very mild phenotype. The disease occurs mainly in females, with a ratio of 2: 1 compared to males. However, the reason for this difference is not known.
PXE is an autosomal recessive inherited disease due to mutations in the ABCC6 gene, which encodes a transmembrane transport protein involved in cell detoxification. About 75-86% of patients have a sequence analysis mutation, while 10-13% of patients have large exonic or multiexonic intragenic deletions/duplications. In particular, a deletion of exons 23-29 is frequently identified in the European population, while in the Japanese population the deletion of exons 1-4 of the ABCC6 gene is frequent. The pathogenic mechanism is loss of function.
In some cases, patients with dominant transmission of the disease have been reported. However, it is still unclear whether in these cases, the transmission is really dominant or whether there may be underlying mechanisms such as pseudodominance, incomplete penetrance or inability to identify the second mutated allele.
It is also important to underline the presence of two peseudogenes, which have a high sequence homology with the ABCC6 gene. ABCC6P1 has a very similar sequence to ABCC6 exons 1-9, while ABCC6P2 overlaps with exons 1-4. The presence of these pseudogenes complicates the identification of both sequence mutations and structure mutations (large deletions and duplications): just think that the commercial kits for MLPA do not include exons 1, 3, 6, 16, 19-20, 29, and 31 of the ABCC6 gene.
Although ABCC6 is the only gene associated with the phenotype of PXE, bi-allelic mutations in the ABCC6 gene have been identified in some patients with suspicion of generalized arterial calcification of infancy-1, but without mutations in the ENPP1 gene.
Finally, it should be noted that in approximately 4% -12% of patients with a clinical diagnosis of PXE no mutation in the ABCC6 gene is identified.
Pseudoxanthoma elasticum-like disorder with multiple coagulation factor deficiency It is an autosomal recessive disease characterized by a phenotype similar to that of PXE in association with cutis laxa and coagulation problems, due to bi-allelic mutations in the GGCX gene.
Cutis laxa A group of diseases characterized by loose redundant and inelastic skin, in which however the typical papules of PXE are absent and in which skin lesions occur throughout the body and are not localized. The genes involved are ATP6V0A2, EFEMP2, FBLN5 and LTBP4.
Hyperphosphatemic familial tumoral calcinosis It is an autosomal recessive disorder characterized by the deposition of calcium phosphate crystals in various tissues, including the arteries and the retina. This disorder is associated with mutations in the FGF23, GALNT3 and KL genes.
Other disorders that can cause angioid streaks of the retina such as beta-thalassemia (HBB gene) and some forms of Paget's disease of the bones (due to mutations in the PDB4, SQSTM1, TNFRSF11A, TNFRSF11B, ZNF687 genes).
Genetic testing strategy
The sequencing of a next-generation sequencing panel that includes the ABCC6, ENNP1, GGCX genes is the most suitable choice for pursuing the genetic confirmation of PXE. Panel analysis can be performed successfully on the basis of exome or genome sequencing, which can pave the way for the identification of mutations in genes not yet associated with the disease. Solutions based on whole genome sequencing also allow for the screening of copy number variations (CNVs), i.e. large deletions and large duplications on the entire genome. In the event of a negative result, it is advisable to carry out the test for large deletions/duplications by techniques such as MLPA and qPCR.
Panel testing recommended at Breda Genetics for this condition:
OMIM # 264800
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