Pseudoxanthoma elasticum
Encyclopedia
Pseudoxanthoma elasticum (PXE), also known as Grönblad–Strandberg syndrome, is a genetic disease that causes fragmentation and mineralization of elastic fibers in some tissues. The most common problems arise in the skin
and eye
s, and later in blood vessel
s in the form of premature atherosclerosis
. PXE is caused by autosomal recessive mutations in the ABCC6
gene on the short arm of chromosome 16 (16p13.1).
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 it's these retinal hemorrhages that may lead to the loss of central vision. Vision loss is a major issue in many PXE patients.
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.
in the retina. Other systems have become somewhat outdated by the discovery of the ABCC6 mutations.
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
. Recent studies hypothesize that PXE is a metabolic disease, and that its features arise because metabolites of vitamin K cannot reach peripheral tissues.
80% of clinical cases of pseudoxanthoma elasticum have detectable mutations in the ABCC6 gene. 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).
Strong genetic linkage was found with mutations in the ABCC6
gene, which codes for the MRP6 protein, but the exact mechanism by which this protein (which is a membrane transporter from the large ATP-binding cassette transporter
family) influences the disease course is unknown; the protein is expressed in most organs, but mainly 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. One study suggested that mutations causing total absence of an MRP6 protein caused a more severe disease, but this could not be confirmed in a subsequent case series.
Premature atherosclerosis
is also associated with mutations in the ABCC6
gene, even in those without PXE. A syndrome almost indistinguishable from hereditary PXE has been described in patients with hemoglobinopathies
(sickle-cell disease
and thalassemia
) through a poorly understood mechanism. 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
.
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
. 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
.
s 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).
tous conditions was by Dr Ferdinand-Jean Darrier in 1896. The eponym "Grönblad-Strandberg syndrome" is used in older literature, after two physicians who made further discoveries in the disease manifestations.
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. The Terrys' two children have pseudoxanthoma elasticum.
Human skin
The human skin is the outer covering of the body. In humans, it is the largest organ of the integumentary system. The skin has multiple layers of ectodermal tissue and guards the underlying muscles, bones, ligaments and internal organs. Human skin is similar to that of most other mammals,...
and eye
Human eye
The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...
s, and later in blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
s in the form of premature atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
. PXE is caused by autosomal recessive mutations in the ABCC6
ABCC6
Multidrug resistance-associated protein 6 also known as ATP-binding cassette sub-family C member 6 and multi-specific organic anion transporter E is a protein that in humans is encoded by the ABCC6 gene...
gene on the short arm of chromosome 16 (16p13.1).
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).PXE first affects the retina through a dimpling of the Bruch membrane
Bruch's membrane
Bruch's membrane is the innermost layer of the choroid. It is also called the vitreous lamina, because of its glassy microscopic appearance.It is 2–4 μm thick.-Layers:Bruch's membrane consists of five layers :...
(a thin membrane separating the blood vessel-rich layer from the pigmented layer of the retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
), that is only visible during ophthalmologic examinations. This is called peau d'orange
Peau d'orange
The French term peau d'orange means "orange peel skin", or more literally, "skin of an orange". It is used in medicine to describe anatomy with the appearance and dimpled texture of an orange peel...
(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
Angioid streaks
Angioid streaks, also called Knapp streaks or Knapp striae are small breaks in Bruch's membrane, an elastic tissue containing membrane of the retina that can become calcified and crack....
) 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 it's these retinal hemorrhages that may lead to the loss of central vision. Vision loss is a major issue in many PXE patients.
PXE may affect the gastrointestinal and cardiovascular systems. In the digestive tract, the principal symptom is gastrointestinal bleeding
Gastrointestinal bleeding
Gastrointestinal bleeding or gastrointestinal hemorrhage describes every form of hemorrhage in the gastrointestinal tract, from the pharynx to the rectum. It has diverse causes, and a medical history, as well as physical examination, generally distinguishes between the main forms...
, usually from the stomach
Stomach
The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...
. This occurs in very small number of patients. In the circulatory system, intermittent claudication
Intermittent claudication
Intermittent claudication is a clinical diagnosis given for muscle pain , classically in the calf muscle, which occurs during exercise, such as walking, and is relieved by a short period of rest.Claudication derives from the Latin verb claudicare, "to limp".-Signs:One of the hallmarks of arterial...
(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
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
(heart attack) may occur.
Classification
The diagnostic criteria for PXE are the typical skin biopsy appearance and the presence of angioid streaksAngioid streaks
Angioid streaks, also called Knapp streaks or Knapp striae are small breaks in Bruch's membrane, an elastic tissue containing membrane of the retina that can become calcified and crack....
in the retina. Other systems have become somewhat outdated by the discovery of the ABCC6 mutations.
Pathophysiology
In PXE, there is mineralization (accumulation of calciumCalcium in biology
Calcium plays a pivotal role in the physiology and biochemistry of organisms and the cell. It plays an important role in signal transduction pathways, where it acts as a second messenger, in neurotransmitter release from neurons, contraction of all muscle cell types, and fertilization...
and other minerals) and fragmentation of the elastin
Elastin
Elastin is a protein in connective tissue that is elastic and allows many tissues in the body to resume their shape after stretching or contracting. Elastin helps skin to return to its original position when it is poked or pinched. Elastin is also an important load-bearing tissue in the bodies of...
-containing fibers in connective tissue
Connective tissue
"Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of...
, but primarily in the midlaminar layer of the dermis, Bruch's membrane and the midsized arteries
Artery
Arteries are blood vessels that carry blood away from the heart. This blood is normally oxygenated, exceptions made for the pulmonary and umbilical arteries....
. Recent studies hypothesize that PXE is a metabolic disease, and that its features arise because metabolites of vitamin K cannot reach peripheral tissues.
Genetics
Dominance relationship
Dominance in genetics is a relationship between two variant forms of a single gene, in which one allele masks the effect of the other in influencing some trait. In the simplest case, if a gene exists in two allelic forms , three combinations of alleles are possible: AA, AB, and BB...
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).
Strong genetic linkage was found with mutations in the ABCC6
ABCC6
Multidrug resistance-associated protein 6 also known as ATP-binding cassette sub-family C member 6 and multi-specific organic anion transporter E is a protein that in humans is encoded by the ABCC6 gene...
gene, which codes for the MRP6 protein, but the exact mechanism by which this protein (which is a membrane transporter from the large ATP-binding cassette transporter
ATP-binding cassette transporter genes
ATP-binding cassette transporters are members of a protein superfamily that is one of the largest and most ancient families with representatives in all extant phyla from prokaryotes to humans...
family) influences the disease course is unknown; the protein is expressed in most organs, but mainly in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
and kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
. 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. One study suggested that mutations causing total absence of an MRP6 protein caused a more severe disease, but this could not be confirmed in a subsequent case series.
Premature atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
is also associated with mutations in the ABCC6
ABCC6
Multidrug resistance-associated protein 6 also known as ATP-binding cassette sub-family C member 6 and multi-specific organic anion transporter E is a protein that in humans is encoded by the ABCC6 gene...
gene, even in those without PXE. A syndrome almost indistinguishable from hereditary PXE has been described in patients with hemoglobinopathies
Hemoglobinopathy
Hemoglobinopathy is a kind of genetic defect that results in abnormal structure of one of the globin chains of the hemoglobin molecule. Hemoglobinopathies are inherited single-gene disorders; in most cases, they are inherited as autosomal co-dominant traits. Common hemoglobinopathies include...
(sickle-cell disease
Sickle-cell disease
Sickle-cell disease , or sickle-cell anaemia or drepanocytosis, is an autosomal recessive genetic blood disorder with overdominance, characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickling decreases the cells' flexibility and results in a risk of various...
and thalassemia
Thalassemia
Thalassemia is an inherited autosomal recessive blood disease that originated in the Mediterranean region. In thalassemia the genetic defect, which could be either mutation or deletion, results in reduced rate of synthesis or no synthesis of one of the globin chains that make up hemoglobin...
) through a poorly understood mechanism. 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
Gamma-glutamyl carboxylase
Gamma-glutamyl carboxylase is an enzyme that in humans is encoded by the GGCX gene, located on chromosome 2 at 2p12.-Function:Gamma-glutamyl carboxylase is an enzyme that catalyzes the posttranslational modification of vitamin K-dependent proteins...
.
Treatment
There is no treatment that directly interferes with the disease process, although dietary restriction of calcium has been tried with limited results. For excessive areas of skin, plastic surgeryPlastic surgery
Plastic surgery is a medical specialty concerned with the correction or restoration of form and function. Though cosmetic or aesthetic surgery is the best-known kind of plastic surgery, most plastic surgery is not cosmetic: plastic surgery includes many types of reconstructive surgery, hand...
may be needed. For the growth of abnormal blood vessels in the retina, laser photocoagulation
Laser photocoagulation
Laser coagulation or laser photocoagulation surgery is used to treat a number of eye diseases and has become widely used in recent decades...
and photodynamic therapy
Photodynamic therapy
Photodynamic therapy is used clinically to treat a wide range of medical conditions, including malignant cancers, and is recognised as a treatment strategy which is both minimally invasive and minimally toxic...
may be used; injections with triamcinolone
Triamcinolone
Triamcinolone is a long-acting synthetic corticosteroid given orally, by injection, inhalation, or as a topical ointment or cream....
have shown limited effect. Antiangiogenic drugs such as bevacizumab
Bevacizumab
Bevacizumab is a drug that blocks angiogenesis, the growth of new blood vessels. It is commonly used to treat various cancers, including colorectal, lung, breast, kidney, and glioblastomas....
(Avastin) and ranibizumab
Ranibizumab
Ranibizumab is a monoclonal antibody fragment derived from the same parent mouse antibody as bevacizumab . It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A...
(Lucentis) have been effective, similar to its efficacy in age-related macular degeneration
Macular degeneration
Age-related macular degeneration is a medical condition which usually affects older adults and results in a loss of vision in the center of the visual field because of damage to the retina. It occurs in “dry” and “wet” forms. It is a major cause of blindness and visual impairment in older adults...
. 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
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
, and ibuprofen
Ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....
.
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 AfrikanerAfrikaner
Afrikaners are an ethnic group in Southern Africa descended from almost equal numbers of Dutch, French and German settlers whose native tongue is Afrikaans: a Germanic language which derives primarily from 17th century Dutch, and a variety of other languages.-Related ethno-linguistic groups:The...
s are more likely to have PXE as a result of a founder effect
Founder effect
In population genetics, the founder effect is the loss of genetic variation that occurs when a new population is established by a very small number of individuals from a larger population. It was first fully outlined by Ernst Mayr in 1942, using existing theoretical work by those such as Sewall...
(i.e. it was relatively prevalent in the small group of people from whom most Afrikaners descend).
History
The first description of PXE that distinguished it from other xanthomaXanthoma
A xanthoma , from Greek xanthos, ξανθος, "yellow", is a deposition of yellowish cholesterol-rich material in tendons or other body parts in various disease states...
tous conditions was by Dr Ferdinand-Jean Darrier in 1896. The eponym "Grönblad-Strandberg syndrome" is used in older literature, after two physicians who made further discoveries in the disease manifestations.
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. The Terrys' two children have pseudoxanthoma elasticum.