Pseudoxanthoma elasticum is a genetic disease from the group of connective tissue dysplasia, in which mineral dystrophy of elastic fibers occurs. Pathology is manifested by multiple yellow plaques on the skin, loss of elasticity of the skin, damage to the eyes and cardiovascular system. The diagnosis requires data from histological analysis of the dermis, molecular genetic testing, ophthalmoscopy. Therapy of pseudoxanthoma elasticum includes medications (bisphosphonates, anti-VEGF), focal laser coagulation of the retina, elimination of skin defects.
ICD 10
L94.8 Other specified localized connective tissue changes
General information
In the medical literature, there are several synonymous names for pseudoxanthoma elasticum — systemic elastorexis, Darier pseudoxanthoma, Grenblad-Strandberg syndrome. The histological features of the disease were first described in 1896 by the scientist J. In 1929, the Swedish ophthalmologist Grenblad and the Norwegian dermatologist Starndberg studied in detail the clinical symptoms of pathology. The frequency of the disease ranges from 1:50,000 to 1:160,000 of the population with a predominance in women (2:1).
Causes
Pseudoxanthoma elasticum is associated with a mutation of the ABCC6 gene localized on the 16th chromosome in the 16p13.1 region. This gene encodes an ATP-dependent carrier protein MRP6, which is one of the factors regulating mineralization processes. In total, about 60 variants of gene defects have been described, and up to 90% of them are inherited by autosomal recessive type, and the remaining 10% are autosomal dominant.
Pseudoxanthomas are characterized by varying degrees of phenotypic traits, but the prerequisites for one or another variant have not yet been established. In 2015, scientists suggested that the severity of symptoms may be regulated by epigenetic factors, dietary peculiarities, and an incorrect lifestyle. Pregnancy is an important trigger for pseudoxanthoma elasticum — during this period, the course of the disease worsens in most patients.
Pathogenesis
Connective tissue disorders are explained by a complex cascade of abnormal biochemical reactions that begin with a lack of MRP6 membrane protein. Normally, it participates in the release of ATP energy molecules in hepatocytes, after which ATP is transformed to form a phosphate ion – an inhibitor of tissue alkaline phosphatase. This substance is an antimineralizing factor.
In those suffering from pseudoxanthoma elasticum, the production of a factor that prevents mineralization is sharply reduced, which results in calcification and fragmentation of connective tissue fibers. There is also an increased accumulation of proteoglycans in the affected areas, which is probably due to a violation of the structure of the extracellular matrix, degradation of elastin fibers.
Genetic pseudoxanthes are characterized by specific pathomorphological changes. The unevenly arranged elastic fibers twisted into bundles are determined, in which an excessive number of calcium salts is detected during special staining. Collagen fibers are placed randomly, and there is also an excessive number of argyrophilic structures. The most pronounced changes occur in the middle layers of the dermis.
Symptoms
The peak manifestation of pathology occurs at the age of 10-13 years. In most cases, the first sign is a skin lesion: multiple rounded nodules (papules) of yellow color with a size of 1-5 mm are formed. As the disease progresses, pseudoxanthomas merge, forming large plaques, as a result of which the skin acquires a bumpy appearance. The typical arrangement of elements on the side surfaces of the neck (“chicken neck”), in the armpits, in the umbilical and inguinal zones.
Occasionally, the mucous membranes of the oral cavity, rectum, and vagina are involved in the pathological process. Characteristic papular elements appear on the mucous membranes. Due to the violation of elasticity, the affected areas of the skin become flabby, covered with excess folds. In addition to the aesthetic disadvantage, patients may experience discomfort when wearing tight clothes, while cycling, sports training.
The second typical symptom of pseudoxanthoma elasticum is eye lesions. First there is an “orange peel” — small pigmented spots on the periphery of the fundus, then there is the formation of angioid bands — ruptures of the thickened Bruch membrane. The third sign of the disease is cardiovascular pathology, which is manifested by intermittent lameness, decreased blood flow in peripheral vessels, mitral valve prolapse.
Complications
The most common consequence of pseudoxanthoma elasticum, eventually detected in 80% of patients, is choroidal neovascularization of the macular zone. There are 3 stages in its development: the first is characterized by an increase in angioid bands, at the second stage vision decreases due to the formation of a subretinal membrane, at the third stage there is a risk of blindness due to scarring of the retina.
Cardiovascular complications include the formation of arterial hypertension and atherosclerosis earlier than in the population, frequent cases of myocardial infarction in young patients. Due to the fragility of calcified vessels, gastrointestinal, pulmonary, uterine bleeding usually begins in patients over the age of 20. There are reports of involvement of cerebral arteries in the process with the occurrence of intracranial hemorrhage.
Diagnostics
The primary examination is most often performed by a dermatovenerologist, to whom patients complain of cosmetic skin defects. If an pseudoxanthoma elasticum is suspected, a geneticist, an ophthalmologist, and a cardiologist are involved in the diagnosis. Since physical data does not provide enough information, an extended examination is mandatory:
- Examination of the heart. Patients need a comprehensive diagnosis, which includes a standard 12-lead ECG, echocardiography, 24-hour monitoring of heart rate and blood pressure indicators. If necessary, duplex scanning of peripheral vessels is performed.
- Ophthalmoscopy. Examination of the fundus reveals multiple foci of increased pigmentation, angioid stripes, areas of neovascularization or scarring. For a comprehensive assessment of the condition of the eyes, biomicroscopy, visometry, and perimetry are performed.
- Histological examination of the skin. When examining skin biopsies under a microscope, signs of progressive fragmentation, mineralization of elastin dermal fibers (elastorexis) are determined. Electron microscopy visualizes small calcium inclusions in the center of the fibers, large peripheral precipitates.
- Genetic testing. Exon sequencing to establish typical ABCC6 defects is the most reliable way to verify the diagnosis, especially with questionable results of histological diagnosis, erased clinical picture. It is believed that the presence of at least 2 mutations is sufficient to confirm the pseudoxanthoma elasticum.
Treatment
Conservative therapy
Effective methods of treatment of hereditary pseudoxanthoma have not yet been developed, treatment is reduced to regular dynamic monitoring of the state of health, prevention of complications. Patients need to visit a cardiologist, ophthalmologist, dermatologist 1-2 times a year. Women are subject to particularly close monitoring during pregnancy. To prevent the negative effects of pseudoxanthoma elasticum, the following groups of drugs are prescribed:
- Bisphosphonates. Drugs introduced before the onset of irreversible calcification processes significantly slow down the mineralization process, reduce the risk of vascular and ophthalmic complications.
- Anti-VEGF. Vascular endothelial growth factor inhibitors are the drugs of choice for the treatment of choroidal neovascularization. They contribute to the restoration of visual acuity, reduce subretinal edema.
- Iron preparations. With frequent bleeding, there is a high probability of developing chronic iron deficiency anemia, therefore, iron-containing drugs, vitamin and mineral complexes are used for preventive and therapeutic purposes.
Lifestyle correction is necessarily carried out: avoiding contact sports, dangerous professions in order to minimize the risk of eye injury, which often becomes a trigger factor of neovascularization. To reduce the likelihood of atherosclerosis and gross vascular lesions, it is recommended to follow a diet with a reduced amount of calcium and fat, and abandon bad habits.
Surgical treatment
With a significant spread of plaques on the skin, the possibility of their minimally invasive or surgical removal is considered. The patient needs long-term work with cosmetologists, aesthetic surgeons to achieve the desired result. In patients with neovascularization of the retina, focal laser coagulation of subretinal membranes gives good results.
Prognosis and prevention
Pseudoxanthoma elasticum is characterized by a benign course, most patients live to an advanced age, may have children. Less favorable prognosis with early onset of retinal neovascularization, severe cardiac complications. The primary prevention of the disease has not been developed, and the secondary one consists in lifelong dispensary supervision, strict adherence to medical recommendations.
