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John Ayers
John Ayers


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.


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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 inpoor 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.

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).

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.

ELN-related cutis laxa is characterized by generalized cutis laxa (ranging from generalized skin redundancy causing excessive skin folds to skin hyperextensibility without obvious skin folds) and distinctive facial features that may become more prominent with age. Other common findings are joint hyperlaxity in infancy and increasing risk of inguinal hernia at all ages. Progressive findings that may be present as early as childhood include ptosis, aortic root dilatation, and emphysema.

The diagnosis of ELN-related cutis laxa is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in ELN identified by molecular genetic testing.

Treatment of manifestations: There is no cure for ELN-related cutis laxa. Experience in treating individuals with ELN-related cutis laxa is very limited. Supportive care to improve quality of life, maximize function, and reduce complications is recommended and ideally involves multidisciplinary care by specialists in general surgery, cardiothoracic surgery, cardiology, pulmonology, urology, physical therapy, ophthalmology, and medical genetics.

Pregnancy management: Perinatal complications for mothers with ELN-related cutis laxa or affected neonates have not been reported to date. Nonetheless, recommended evaluations for women with ELN-related cutis laxa before conception and during pregnancy are pulmonary function testing and cardiovascular assessment (including aortic root diameter). Continued cardiac surveillance for six months post partum is also recommended. Additionally, women taking a beta-blocker should continue it during pregnancy; however, some other classes of medications, such as angiotensin receptor-blocking agents, are teratogenic and should be discontinued or changed to beta-blocking agents, given the increased risk for teratogenicity typically related to second- and third-trimester exposure.

ELN-related cutis laxa is inherited in an autosomal dominant manner. About one third of individuals diagnosed with ELN-related cutis laxa have an affected parent; about two thirds of affected individuals have the disorder as the result of a de novoELN pathogenic variant. Each child of an individual with ELN-related cutis laxa has a 50% chance of inheriting the pathogenic variant. Once the ELN pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Clinical findings include generalized cutis laxa (ranging from generalized skin redundancy causing excessive skin folds to skin hyperextensibility without obvious skin folds) (Figure 1) with or without the following:

The diagnosis of ELN-related cutis laxa is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in ELN identified by molecular genetic testing (see Table 1).

Because the phenotype of ELN-related cutis laxa may be difficult to distinguish from many other inherited disorders with cutis laxa, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing. 041b061a72


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