NORD gratefully acknowledges Zsolt Urban, PhD, Associate Professor of Human Genetics, Graduate School of Public Health, University of Pittsburgh, for assistance in the preparation of this report.
Cutis laxa is a general term for a group of rare disorders that may occur in several inherited (congenital) forms or acquired at some point during life (acquired cutis laxa). This group of disorders involves a wide spectrum of symptoms and signs that result from defects in connective tissue, the material between cells of the body that gives the tissue form and strength. Connective tissue is found throughout the body in muscles, joints, skin and other organs. Cutis laxa is characterized by skin that is loose (lax), wrinkled, sagging, redundant, and lacking elasticity (inelastic). When stretched, inelastic skin returns to place abnormally slowly. The skin around the face, arms, legs and trunk is most commonly affected. Abnormal skin may give affected individuals and children a prematurely-aged appearance and they can look much older than their true age. Unlike similar skin disorders, easy bruising and scarring are generally not associated with cutis laxa. The joints are often abnormally loose (hypermobility) because of lax ligaments and tendons. Several inherited forms of the disorder have been identified. Most cases are inherited as either an autosomal dominant or recessive disorder. An X-linked form of cutis laxa, known as occipital horn syndrome, is now considered a mild form of disorders of copper metabolism caused by a mutation in the ATP7A gene and is not discussed in this report.
Cutis laxa encompasses a wide variety of disorders. The specific symptoms present, severity and prognosis can vary greatly depending upon the specific type of cutis laxa and the presence and extent of associated symptoms. The specific symptoms and severity can vary even among individuals with the same subtype and even among members of the same family. In addition, some subtypes of cutis laxa have only been reported in a handful of individuals, which prevents physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. Despite the wide variety in presentation, most affected individuals develop the characteristic skin abnormalities and joints problems described above.
In the past, cutis laxa subtypes were defined by clinical symptoms. However, cutis laxa is now separated based upon the molecular basis of the disorders (i.e. mutated gene). The information below is broken down by specific subtype.
EFEMP2-RELATED CUTIS LAXA
This disorder is also known as FBLN4-related cutis laxa or autosomal recessive cutis laxa type 1B (ARCL1B). It is a highly variable disorder that range from severe, life-threatening complications early in life (i.e. heart or lung [cardiopulmonary] failure) to cases that are limited to vascular disease and abnormalities of the head and face (craniofacial abnormalities).
Individuals with EFEMP2-related cutis laxa develop the skin symptoms of cutis laxa as well as systemic involvement, particularly the cardiovascular and skeletal systems. The skin symptoms may be mild. Affected infants may have distinctive facial features including eyes that are farther apart than normal (ocular hypertelorism), low-set, malformed (dysplastic) ears, highly arched palate, and a small, receding jaw (retrognathia). Joint laxity and arachnodactyly, a condition in which the fingers and toes are abnormally long, thin and curved, are common findings.
Affected individuals may develop abnormalities affecting various blood vessels including twisting or distortion of arteries (arterial tortuosity), a stretched or bulging section of the wall of the main artery of the heart (aortic aneurysm), and underdevelopment of the arteries of the lungs (pulmonary arterial hypoplasia). In some cases, affected individuals may also develop abnormal enlargement of the heart (cardiac hypertrophy) and a slower than normal heart rate (bradycardia). In severe cases, the various vascular and cardiac abnormalities can progress to cause heart failure.
Some individuals with EFEMP2-related cutis laxa develop pulmonary emphysema, a chronic lung disease in which the tiny air sacs in the lungs (alveoli) are damaged or do not function properly, resulting in shortness of breath and a chronic cough. Pulmonary emphysema can progress to cause lung failure.
Additional symptoms can develop in some cases of EFEMP2-related cutis laxa including diminished muscle tone (hypotonia), a sunken chest (pectus excavatum), and fragile bones that are prone to fracture. Diaphragmatic hernia, a condition in which part of the stomach and/or the small intestines can protrude into the chest cavity, can also occur.
FBLN5-RELATED CUTIS LAXA
This disorder is also known as autosomal recessive cutis laxa type 1A (ARCL1A). The symptoms and age of onset are highly variable. Affected individuals develop the skin and joint symptoms of cutis laxa. Growth deficiencies and delayed motor development have been reported in some cases.
There is usually childhood onset of serious complications such as narrowing (stenosis) of the pulmonary artery, hernias, and the formation of diverticula within the intestines and bladder. In some cases, stenosis of the aorta just above the valve that connects the aorta to the heart may occur (supravalvular aortic stenosis). In severe cases, the disorder can progress to cause life-threatening complications such as pulmonary or cardiac insufficiency or failure during childhood. In affected individuals who survive early childhood, additional serious complications such as failure of the right side of the heart (cor pulmonale) and severe pulmonary emphysema may develop.
LTBP4-RELATED CUTIS LAXA
This disorder is also known as Urban-Rifkin-Davis syndrome or autosomal recessive cutis laxa type 1C (ARCL1C). In addition to the skin symptoms of cutis laxa, affected individuals can develop joint laxity, diminished muscle tone, growth delays, and severe complications affecting the pulmonary, gastrointestinal, and urinary systems. Cardiovascular involvement is relatively mild.
Affected individuals may develop severe breathing difficulties (respiratory distress) associated with cystic changes in the lungs as well as collapse of part of the lung (atelectasis). In some cases, pulmonary issues can be worsened by narrowing of the pulmonary artery and by the occurrence of diaphragmatic hernia and/or softening or weakening of the cartilage of the trachea (tracheomalacia), which can potentially result in the collapse of the air passage. Severe emphysema can develop. Eventually, affected individuals may experience respiratory failure.
Gastrointestinal abnormalities include the formation of diverticula and narrowing, twisting or enlargement of segments of the intestinal tract. Urinary tract abnormalities can include abnormal accumulation of urine in the kidneys (hydronephrosis) and the formation of sac-like protrusions or pouches in the intestines (diverticulosis).
Individuals with LTBP4-related cutis laxa may have distinctive facial features including an abnormally small jaw (micrognathia), receding forehead, widened soft spots near the back of the head (wide anterior fontanels), widely spaced eyes (hypertelorism), and, in some cases, prominent ears. The middle of the face may appear flattened. Growth deficiencies during infancy have also been reported.
ATP6V0A2-RELATED CUTIS LAXA
This disorder is also known autosomal recessive cutis laxa 2A (ARCL2A) and represents a spectrum of disease ranging from wrinkly skin syndrome on the mild end to Debre-type cutis laxa on the severe end. Generally, individuals with the Debre-type have more severe neurological and developmental abnormalities, but less severe skin symptoms. Individuals with wrinkled skin syndrome have only mild developmental delays and subsequent neurodegeneration.
Affected individuals may have wrinkled or furrowed skin over the entire body. The skin may be redundant, saggy and inelastic as well. Skin symptoms often improve with age, but degenerative scars may remain in some cases.
Infants may experience diminished muscle tone (hypotonia), abnormal fat distribution, feeding difficulties, growth deficiency, and failure to thrive. In addition, affected infants may have an enlarged soft spot (fontanel) that closes later than normal and distinctive facial features that are present at birth and become more distinctive as they grow older. Such features include downward slanting of the opening between the eyelids (down slanting palpebral fissures), a broad, flat bridge of the nose, abnormally large nostrils that are tipped upward (anteverted nares), large ears, and a small mouth.
Affected infants may also exhibit nearsightedness (myopia), eyes that do not line up in the same direction such as crossed-eyes (strabismus), dislocation of the hip that is present at birth, joint laxity, and microcephaly, a condition in which head circumference is smaller than would normally be expected based upon age and gender. Some infants may have protrusion of abdominal tissue or part of the small intestines through a bulge in the abdominal muscles near the groin (inguinal hernia).
Most affected children have malformations of certain areas of the brain (cortical and cerebellar malformations) that result in delays in reaching developmental milestones (developmental delays) and intellectual disability. Progressive neurological decline (regressions) may begin near the end of the first decade of life. Some children may experience generalized or partial seizures usually between the ages of 8-12.
Neurological regression can be associated with a variety of symptoms including slurred speech, an inability to coordinate voluntary movements (ataxia), and increased muscle tone and stiffness (spasticity). Some affected children may eventually require a wheelchair.
Cardiovascular and pulmonary complications common in other forms of cutis laxa are rare in ATP6V0A2-related cutis laxa.
This disorder is also classified as a congenital disorder of glycosylation, which is an umbrella term for an expanding group of rare metabolic disorders that share similar but not identical genetic changes (mutations) and biochemical activity. These disorders involve a normal, but complex, chemical process known as glycosylation. (For more information, choose “congenital disorders of glycosylation” as your search term in the Rare Disease Database.)
PYCR1-RELATED CUTIS LAXA
This disorder is also known as autosomal recessive cutis laxa 2B (ARCL2B). The skin symptoms of cutis laxa are more pronounced in the arms and legs. Affected individuals may experience growth delays, developmental delays, failure to thrive, intellectual disability, joint laxity and skeletal malformations. Underdevelopment (hypoplasia) of the thick band of nerve fibers that separates the cerebellum into right and left hemispheres (corpus callosum) is common. Affected individuals may also have distinctive facial features including an abnormally large forehead, large ears, a rounded (bulbous) nose, a protruding jaw (prognathism), bluish discoloration of the whites of the eyes (blue sclera), and a triangular-shaped face with a prematurely-aged appearance. The circumference of the head may be smaller than expected based upon an infant’s age and gender (microcephaly).
Skeletal malformations may include sideways curvature of the spine (scoliosis), bowing of the long bones of the arms and legs, clasped thumbs, abnormally long fingers and toes, reduced bone density (osteopenia), fragile bones that are prone to fracture (osteoporosis), and congenital dislocation of the hip.
The specific symptoms and severity of PYCR1-related cutis laxa can vary greatly. Individuals originally diagnosed with gerodermia osteodysplastica, wrinkled skin syndrome and De Barsy syndrome have been found to carry a PYCR1 gene mutation.
ALDH18A1-RELATED CUTIS LAXA
This disorder is also known as autosomal recessive cutis laxa type 3 (ARCL3). Affected individuals develop the characteristic skin symptoms of cutis laxa along with growth deficiencies, moderate to severe intellectual disability, loose joints, cataracts and corneal abnormalities. Additional symptoms may eventually develop including dystonia, a group of movement disorders that vary in their symptoms, causes, progression, and treatments. This group of neurological conditions is generally characterized by involuntary muscle contractions that force the body in abnormal, sometimes painful, movements and positions (postures). Individuals with this form of cutis laxa usually do not have cardiovascular or pulmonary complications. Many individuals with de Barsy syndrome were found to have a mutation in the ALDH18A1 gene. NORD has an individual report on de Barsy syndrome. For more information, choose “De Barsy” as your search term in the Rare Disease Database.
AUTOSOMAL DOMINANT CUTIS LAXA
Most cases of autosomal dominant cutis laxa are caused by mutations in the elastin (ELN) gene and are also known as ELN-related cutis laxa or autosomal dominant cutis laxa type 1 (ADCL1). One case, classified as autosomal dominant cutis laxa type 2 (ADCL2), was caused by a mutation in the fibulin-5 (FBLN5) gene; this gene also causes autosomal recessive cutis laxa 1A.
The symptoms of ELN-related cutis laxa can appear at any point between birth and young adulthood. Generally, onset is later than seen in autosomal recessive forms of the disorder. Affected individuals may have distinctive facial features, which can include a beaked nose, an abnormally long groove that runs from the base of the nose to the upper lip (philtrum), a high forehead, and large ears. In some cases, individuals will only develop the characteristic skin symptoms of cutis laxa, although the affected skin may worsen with age. The cutis laxa skin symptoms in the autosomal forms are generally milder than the skin symptoms in the recessive forms. Less often, affected individuals will also develop more serious complications including cardiovascular and pulmonary abnormalities such as aortic aneurysms, pulmonary artery disease, or emphysema. Inguinal hernia has also been reported. Gastrointestinal abnormalities are uncommon with this form of cutis laxa.
Autosomal recessive ELN-related cutis laxa has been reported
This rare disorder is also known as gerodermia osteodysplastica or Walt Disney dwarfism and is sometimes classified as a subtype of autosomal recessive cutis laxa type 2. Geroderma osteodysplasticum primarily occurs in infants or young children and is characterized by loose skin, particularly affecting the hands, feet, face and stomach. Affected individuals may have distinctive facial features including underdevelopment of the cheeks (malar hypoplasia), a protruding jaw (prognathism), and a prematurely aged appearance. Joint laxity, hernias, frequent hip dislocations, and varying degrees of growth deficiency and short stature can also occur. Osteoporosis may also present, resulting in fragile bones that are prone to fracture. More severe complications such as cardiovascular or pulmonary symptoms rarely develop.
RIN2-RELATED CUTIS LAXA
This extremely rare disorder, also known as (M)acrocephaly, (A)lopecia, (C)utis laxa (S)coliosis or MACS syndrome, has only been reported in several individuals from four families (kindreds) from different ethnic origins. Symptoms include an abnormally large head (macrocephaly), partial or complete hair loss (alopecia) and the skin symptoms of cutis laxa. Cutis laxa is mild with redundant skin on the face the most common manifestation. However, because the disorder has been reported in so few individuals, the complete clinical picture and the symptoms that most often associated with the disorder are unknown. Additional symptoms that were reported in the affected families include joint laxity, moderate to severe scoliosis, and characteristic facial features including abnormal enlargement of the gums (gingival hyperplasia), a lower lip that is turned or rolled outward (everted), a receded jaw (retrognathia), puffy eyelids, and abnormal positioning of the teeth. Some infants may have dry, scaly, thickened skin. Widening (dilation) of the aorta and generalized osteoporosis have also been reported. Mild intellectual disability was seen in some, but not all, affected individuals.
ACQUIRED CUTIS LAXA
This form of cutis laxa is generally seen in adults. Affected individuals develop the characteristic skin symptoms associated with cutis laxa. Acquired cutis laxa may begin in the face and progresses downward. Systemic involvement including emphysema, vascular abnormalities, intestinal diverticula, and hernias has also been reported in some cases. The disorder has developed in some individuals following exposure to specific environmental factors such as certain medications, infections or autoimmune diseases.
Acquired cutis laxa is sometimes broken down into type 1 and type 2. Type 1 may be associated with cutis laxa that is widespread through the body or localized to a specific area and can occur at any age, although most cases begin in adulthood. Localized forms frequently affect the face or the hands and feet. Systemic involvement may occur in some cases. Type 2 usually develops following acute inflammatory skin lesions, in which the areas affected by the skin lesions develop cutis laxa skin symptoms.
Cutis laxa is caused by mutations in specific genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. For disorders classified as cutis laxa, these mutations can be inherited in an autosomal recessive or autosomal dominant trait.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. In some cases, an autosomal dominant mutation results from a spontaneous (de novo) mutation that occurs randomly and is not inherited.
A significant number of individuals diagnosed with cutis laxa do not have a mutation in one of the genes known to cause a subtype of cutis laxa. Most likely, additional, as-yet-unidentified genes cause cutis laxa in these cases.
EFEMP2-related cutis laxa is caused by mutations in the EFEMP2 gene, which is located on the long arm (q) on chromosome 11 (11q13.1). EFEMP2-related cutis laxa is inherited as an autosomal recessive disorder.
FBLN5-related cutis laxa is caused by mutations in the FBLN5 gene, which is located on the long arm of chromosome 14 (14q32.12). FBLN5-related cutis laxa is inherited as an autosomal recessive disorder. In one case, a mutation in this gene has been inherited in an autosomal dominant manner.
LTBP4-related cutis laxa is caused by mutations in the LTBP4 gene, which is located on the long arm of chromosome 19 (19q13.2). LTBP4-related cutis laxa is inherited as an autosomal recessive disorder.
ATP6V0A2-related cutis laxa is caused by mutations in the ATP6V0A2 gene, which is located on the long arm of chromosome 12 (12q24.31). ATP6V0A2-related cutis laxa is inherited as an autosomal recessive disorder.
PYCR1-related cutis laxa is caused by mutations in the PYCR1 gene, which is located on the long arm of chromosome 17 (17q25.3). PYCR1-related cutis laxa is inherited as an autosomal recessive disorder.
RIN2-related cutis laxa is caused by mutations in the RIN2 gene, which is located on the short arm of chromosome 20 (20p11.23). RIN2-related cutis laxa is inherited as an autosomal recessive disorder.
The exact cause of De Barsy syndrome is not fully understood. Individuals with a diagnosis of De Barsy syndrome have been found to have mutations in the PYCR1 or ALDH18A1 genes. The ALDH18A1 gene is located on the long arm of chromosome 10 (10q24.1). De Barsy syndrome is believed to be inherited as an autosomal recessive disorder.
Geroderma osteodysplasticum is caused by mutations in the GORAB or SCYL1BP1 gene, which is located on the long arm of chromosome 1 (1q24.2). Gerodermia osteodysplastica is inherited as an autosomal recessive disorder.
ELN-related cutis laxa is caused by mutations in the ELN gene, which is located on the long arm of chromosome 7 (7q11.23). ELN-related cutis laxa is generally inherited as an autosomal dominant disorder, but autosomal recessive inheritance of ELN-related cutis laxa has been observed in two related families to date.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered.
The genes that are involved in the cutis laxa syndromes create (encode) specific proteins that are necessary for the proper health, development, transport, and/or function of elastic fibers. Elastic fibers are protein bundles found in various connective tissues of the body including within the skin, lungs and arterial blood vessels such as the aorta. Elastic fibers provide elasticity and resilience to skin and other tissues. Mutations in specific cutis laxa genes result in deficient levels of functional versions of proteins necessary for the proper development, health and function of elastic fibers. Consequently, elastic fibers may develop improperly or insufficiently. The specific manner in which these defective proteins ultimately result in the signs and symptoms of cutis laxa is not fully understood for all subtypes of cutis laxa.
The cause of acquired cutis laxa is unknown. The disorder often develops following specific environmental exposures including certain medications such as isoniazid or penicillin, various infections, certain cancers such as multiple myeloma or lymphoma, inflammatory diseases such as Celiac disease or Sweet syndrome, autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis, and additional disorders including nephrotic syndrome, alpha-1 antitrypsin deficiency, mastocytosis and amyloidosis. Some researchers suspect that certain affected individuals are genetically predisposed to developing cutis laxa following such exposures. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental or immunologic factors.
Cutis laxa is a rare disorder that affects males and females in equal numbers. The disorder has been reported in approximately 400 families worldwide. Cutis laxa is estimated to affect 1 in 1,000,000 individuals in the general population. However, because cases may go misdiagnosed or undiagnosed determining the true frequency of cutis laxa in the general population is difficult. Cutis laxa affects individuals of all races and every ethnic group.
A diagnosis of cutis laxa is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Surgical removal and microscopic examination (biopsy) of affected skin can reveal characteristic changes in elastic fibers. Distinguishing between the specific genetic forms of cutis laxa can be difficult. Molecular genetic testing can confirm a diagnosis of an inherited form cutis laxa and establish the specific, underlying subtype in some cases. Molecular genetic testing can detect mutations in specific genes known to cause cutis laxa, but is available only as a diagnostic service at specialized laboratories.
The treatment of cutis laxa is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, dermatologists, cardiologists, pulmonologists, neurologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.
Specific therapies for individuals with cutis laxa can include surgery to repair hernias, skeletal malformations or intestinal diverticula. Some individuals elect for plastic (cosmetic) surgery to improve skin symptoms. Results are typically good, but loose, lax skin often recurs.
Medications such as beta-blockers to prevent aortic aneurysms may be prescribed. Regular cardiac and pulmonary follow up is necessary to detect cardiovascular and pulmonary complications potentially associated with certain forms of cutis laxa.
Affected individuals should avoid environmental triggers that can worsen cutis laxa or associated symptoms. For example, cigarette smoking can worsen emphysema and sunbathing can damage the skin.
The Cutis Laxa Research Study at the University of Pittsburgh is focused on studying cutis laxa disorders. This study uses clinical and laboratory research to find disease-causing mutations in know cutis laxa genes, and to identify new genes that cause cutis laxa. The research is also studying the effects of the mutations and how they cause cutis laxa. This study is important for discovering ways of diagnosing cutis laxa by DNA testing as well as leading to new treatments for the disease. The website also provides information on these disorders. For more information, contact:
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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