Cutis laxa is a disorder of connective tissue, which is the tissue that provides structure and strength to the muscles, joints, organs, and skin. Most cases are inherited, but some are acquired, which means they do not appear to be caused by genetic variations. While signs and symptoms of inherited cutis laxa are often noticeable in infancy or childhood, acquired cutis laxa typically appears later in life. This summary primarily describes inherited forms of cutis laxa.

The term "cutis laxa" is Latin for loose or lax skin, and this condition is characterized by skin that is sagging and not stretchy (inelastic). The skin often hangs in loose folds, causing the face and other parts of the body to have a droopy or wrinkled appearance. Extremely wrinkled skin may be particularly noticeable on the neck and in the armpits and groin.

Cutis laxa can also affect connective tissue in other parts of the body, including the heart, blood vessels, intestines, and lungs. The disorder can cause heart problems and abnormal narrowing, bulging, or tearing of critical blood vessels. Affected individuals may have soft out-pouchings in the lower abdomen (inguinal hernia) or around the belly button (umbilical hernia). Sacs called diverticula can also develop in the walls of certain organs, such as the bladder and intestines. During childhood, some people with cutis laxa develop a life-long lung disease called emphysema, which can make it difficult to breathe. Depending on which organs and tissues are affected, the signs and symptoms of cutis laxa can range from mild to life-threatening.

Researchers have described several different forms of cutis laxa. The forms are often distinguished by their pattern of inheritance: autosomal dominant, autosomal recessive, or X-linked. In general, the autosomal recessive forms of cutis laxa tend to be more severe than the autosomal dominant forms, although some people with autosomal dominant cutis laxa are severely affected. In addition to the features described above, people with autosomal recessive cutis laxa can have delayed development, intellectual disability, seizures, problems with movement, or eye or bone abnormalities.

The X-linked form of cutis laxa is often called occipital horn syndrome. This form of the disorder is considered a mild type of Menkes syndrome, which is a condition that affects copper levels in the body. In addition to sagging and inelastic skin, occipital horn syndrome is characterized by wedge-shaped calcium deposits in a bone at the base of the skull (the occipital bone), coarse hair, and loose joints.

Other rare conditions, including arterial tortuosity syndrome, geroderma osteodysplastica, and RIN2 syndrome, are sometimes classified as cutis laxa-related conditions, because affected individuals can have loose, sagging skin. These conditions each have a particular pattern of signs and symptoms affecting different tissues and body systems.

Cutis laxa can be caused by variants (also known as mutations) in several genes. Autosomal dominant cutis laxa (ADCL), the most common form of the disorder, is primarily caused by variants in the ELN gene. Very rarely, FBLN5 and ALDH18A1 gene variants are associated with autosomal dominant forms of the disorder. Autosomal recessive cutis laxa (ARCL) can be caused by variants in the FBLN5, EFEMP2, LTBP4, ATP6V0A2, PYCR1, or ALDH18A1 gene.

Many of the genes associated with autosomal dominant and autosomal recessive forms of cutis laxa are involved in the formation and function of elastic fibers, which are slender bundles of proteins that provide strength and flexibility to connective tissue throughout the body. Elastic fibers allow the skin to stretch, the lungs to expand and contract, and arteries to handle blood flowing through them at high pressure.

The major component of elastic fibers, a protein called elastin, is produced from the ELN gene. Other proteins involved in cutis laxa that have critical roles in the assembly of elastic fibers are produced from the EFEMP2, FBLN5, LTBP4, and ATP6V0A2 genes. Variants in any of these genes disrupt the formation, assembly, or function of elastic fibers. A shortage of these fibers weakens connective tissue in the skin, arteries, lungs, and other organs. These defects in connective tissue underlie the major features of cutis laxa.

Two other genes involved in cutis laxa, ALDH18A1 and PYCR1, provide instructions for making proteins that have important roles in cells. The proteins are critical in the formation of the protein building block (amino acid) proline, which is a key component of elastic fiber proteins. The proteins produced from the ALDH18A1 and PYCR1 genes are also important for the function of cell structures called mitochondria, which are the energy-producing centers of cells. Alterations in these genes appear to disrupt mitochondrial function, which could lead to the death of cells in the connective tissue that supports the skin. It is unclear if disruption of proline formation plays a role in the development of cutis laxa.

The X-linked form of cutis laxa, occipital horn syndrome, is caused by variants in the ATP7A gene. This gene provides instructions for making a protein that is important for regulating copper levels in the body. Variants in the ATP7A gene result in poor distribution of copper to the body's cells. A reduced supply of copper can decrease the activity of numerous copper-containing enzymes that are necessary for the structure and function of bone, skin, hair, blood vessels, and the nervous system. The signs and symptoms of occipital horn syndrome are caused by the reduced activity of these copper-containing enzymes.

Variants in the genes described above account for only a small percentage of all cases of cutis laxa. Variants in other genes, some of which have not been identified, can also cause the condition.

About 20 percent of cases of cutis laxa are acquired, which means they do not appear to be caused by gene variants. Acquired cutis laxa appears later in life and is related to the destruction of normal elastic fibers. The causes of acquired cutis laxa are unclear, although it may occur after an infection or an episode of inflammation in the skin (such as eczema or hives), or as a side effect of treatment with certain medications, such as those that remove copper from the body (copper chelating drugs).

Normal Function

The ELN gene provides instructions for making a protein called tropoelastin. Multiple copies of the tropoelastin protein attach to one another and are processed to form a mature protein called elastin. Elastin is the major component of elastic fibers, which are a major component of the tissue that supports the body's joints and organs (connective tissue). Elastic fibers are found in the intricate lattice that forms in the spaces between cells (the extracellular matrix). They can be stretched and then snap back into place, which is how they provide resilience and flexibility to organs and tissues such as the heart, skin, lungs, ligaments, and blood vessels.

Health Conditions Related to Genetic Changes

Cutis laxa

At least 18 variants (also known as mutations) in the ELN gene have been identified in people with a skin disorder called cutis laxa. ELN gene variants cause a form of the condition called autosomal dominant cutis laxa type 1 (ADCL1), which is characterized by loose, sagging skin; an increased risk of an abnormal bulging (an aneurysm) in a large blood vessel called the aorta; and a lung disease called emphysema, which can make it difficult to breathe.

The ELN gene variants that cause ADCL1 lead to the production of an abnormal version of the tropoelastin protein. The abnormal protein is less able to be incorporated into mature elastin, which impairs the formation of strong elastic fibers. This defect in elastic fibers weakens connective tissue in the skin and blood vessels and makes it difficult for tissue to snap back into shape when stretched. The problems with connective tissue underlie the major features of cutis laxa.

Supravalvular aortic stenosis

More than 70 variants in the ELN gene have been found to cause supravalvular aortic stenosis (SVAS), a blood vessel defect most commonly identified in infancy or early childhood that is characterized by a narrowing of the large blood vessel that carries blood from the heart to the rest of the body (the aorta). Most of the ELN gene variants that cause SVAS lead to a decrease in the production of tropoelastin. A shortage of tropoelastin reduces the amount of mature elastin protein that is processed and available for forming elastic fibers. As a result, elastic fibers that make up the aorta are thinner than normal. To compensate, the smooth muscle cells that line the aorta increase in number, making the aorta thicker and narrower than usual. A thickened aorta is less flexible and delivers blood too forcefully, which can damage organs. Aortic narrowing causes the heart to work harder to pump blood through the aorta, which can lead to shortness of breath, chest pain, and ultimately heart failure.

7q11.23 duplication syndrome

The ELN gene is located in a region of chromosome 7 that is duplicated in people with 7q11.23 duplication syndrome. As a result of this duplication, people with 7q11.23 duplication syndrome have an extra copy of the ELN gene and several other genes in each cell. 7q11.23 duplication syndrome can cause a variety of neurological and behavioral problems as well as other abnormalities.

Some individuals with 7q11.23 duplication syndrome have mild to moderate enlargement (dilatation) of the aorta; this enlargement can get worse over time. Aortic dilatation in people with this condition can very rarely lead to life-threatening complications if the wall of the aorta separates into layers (aortic dissection) or breaks open (ruptures). Individuals with 7q11.23 duplication may have other heart or blood vessel abnormalities. An extra copy of the ELN gene in each cell may lead to the production of a greater than normal amount of tropoelastin, and researchers suggest that this excess might be related to the increased risk for aortic dilatation in 7q11.23 duplication syndrome; however, the specific cause of the aortic dilatation remains unclear.

Williams syndrome

The ELN gene is located in a region of chromosome 7 that is deleted in people with Williams syndrome, which is a developmental disorder that is characterized by mild to moderate intellectual disability or learning problems, unique personality characteristics, distinctive facial features, and heart and blood vessel (cardiovascular) problems. As a result of the deletion, people with Williams syndrome are missing one copy of the ELN gene in each cell. This loss reduces the production of elastin by approximately half, which disrupts the normal structure of elastic fibers in many connective tissues. As a result, large blood vessels such as the aorta are often thicker and less resilient than normal. These vessels can narrow (as in SVAS, described above), increasing the resistance to normal blood flow and leading to serious medical problems.

In addition to cardiovascular problems like SVAS, a loss of the ELN gene is associated with other connective tissue abnormalities, such as joint problems, soft skin, and mild lung problems. Loss of the ELN gene may also play a role in other features of the condition, such as premature skin wrinkling and abnormalities of the digestive tract.

Other Names for This Gene

• elastin
• ELN_HUMAN
• tropoelastin

Genomic Location

Cutis laxa can have an autosomal dominant, autosomal recessive, or X-linked recessive pattern of inheritance.

Autosomal dominant inheritance means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases of this form of the disorder are caused by variants in the ELN gene. Rarely, cases of cutis laxa resulting from FBLN5 gene variants or ALDH18A1 gene variants can have an autosomal dominant pattern of inheritance.

Variants in the FBLN5, EFEMP2, LTBP4, ATP6V0A2, PYCR1, and ALDH18A1genes can cause autosomal recessive forms of cutis laxa. Autosomal recessive inheritance means both copies of the gene in each cell have variants. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

Occipital horn syndrome has an X-linked recessive pattern of inheritance. It results from variants in the ATP7A gene, which is located on the X chromosome. The X chromosome is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a variant would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

The signs and symptoms of cutis laxa vary depending on the specific type the person has. Cutis laxa can be acquired or inherited. The inherited types are classified by their inheritance pattern. The recessive types are usually more severe than the dominant types. X-linked cutis laxa is known as occipital horn syndrome.

Cutis laxa is a rare disorder. More than 450 affected families worldwide have been reported.