September 22, 2015
Years published: 1993, 2003, 2014
NORD gratefully acknowledges Eva Morava, MD, PhD, Professor, Pediatrics, Clinical Biochemical Geneticist, Hayward Genetics Center, Tulane University Medical School, for assistance in the preparation of this report.
De Barsy syndrome is a rare genetic disorder characterized by eye abnormalities, growth retardation, intellectual disability, a prematurely-aged appearance (progeroid features), and loose (lax), wrinkled, sagging, redundant skin that lacks elasticity (cutis laxa). Distinctive facial features, skeletal malformations, and neurological abnormalities can also occur. The specific symptoms present and the severity of de Barsy syndrome can vary greatly from one individual to another. Some cases of de Barsy syndrome have been linked to mutations in either the PYCR1 or ALDH18A1 genes; in other cases, a specific genetic mutation has not yet been identified. De Barsy syndrome is inherited in an autosomal recessive manner.
De Barsy syndrome was first reported in the medical literature by Dr. De Barsy in 1968 in one patient. The disorder is now classified as a form of cutis laxa and also known as autosomal recessive cutis laxa type 3. Cutis laxa is 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.
Cutis laxa syndromes were once broken down mainly by clinical characteristics, but are now classified based upon the specific mutation present. Consequently, individuals with de Barsy syndrome caused by a PYCR1 mutation are said to have PYCR1-related cutis laxa (autosomal recessive cutis laxa type 3B) and individuals with de Barsy syndrome caused by an ALDH18A1 mutation are said to have ALDH18A1-related cutis laxa (autosomal recessive cutis laxa type 3A). NORD has a general report on cutis laxa that explains the various subtypes and genetics of cutis laxa. For more information, choose “cutis laxa” as your search term in the Rare Disease Database.
In ALDH18A1-related de Barsy syndrome, approximately one third of ALDH18A1 mutation carriers show biochemical signs of metabolic disease due to ALDH18A1 related abnormal purine synthesis in blood. Abnormal amino acid levels include variable degrees of decrease in arginine, ornithine, citrulline and sometimes low proline concentrations. Young patients might present with symptoms of elevated levels of ammonia in the blood (hyperammonemia) and secondary urea cycle disturbance. It is extremely important to screen for the specific purine synthesis defect related metabolites in suspected ALDH18A1-related cases. These metabolites are not always abnormal and might show variable degree of abnormalities. Ammonia elevation is usually not exceeding a second fold increase. In case of abnormal results there is a potential dietary and amino acid supplementation therapy.
Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about de Barsy syndrome is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent 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. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.
An extremely wide and varied group of symptoms have been reported in individuals with de Barsy syndrome. The prematurely-aged appearance that commonly affects children with de Barsy syndrome is caused by underdevelopment of the skin and structures in the middle of the face (midface hypoplasia). Loose, sagging, inelastic skin that characterizes cutis laxa contributes to the prematurely-aged appearance. Less often, the skin may be thin and appear translucent so the underlying veins may be easily visible. In some cases, affected individuals may have reduced subcutaneous fat, which is the layer of fat just below the skin’s surface.
Infants with de Barsy syndrome may also have distinctive facial features including an unusually prominent forehead (frontal bossing), thin lips, widely spaced eyes (hypertelorism), a small, upturned nose, and large, malformed (dysplastic) ears. Some affected infants may experience delayed closure of the soft spot on top of the skull (delayed closure of the anterior fontanel). The anterior fontanel may be abnormally large as well. In some cases, the circumference of an infant’s or child’s head may be smaller than would be expected based upon age and gender (microcephaly).
Affected infants may also have diminished muscle tone (hypotonia) and joints that are abnormally loose (hypermobility) because of lax ligaments and tendons. Skeletal abnormalities may occur including frequent dislocations and partial dislocations (subluxations) including congenital dislocation of the hip, and hands that are stuck in a clenched position (contracture) with thumbs that turned inward (adducted thumbs). A sunken breastbone known as pectus excavatum, low bone mineral density, and weakened, fragile bones (osteoporosis) have also been reported.
Ocular abnormalities are also common in de Barsy syndrome and may include clouding of the lenses of the eyes (cataracts) and clouding of the corneas of the eyes (bilateral corneal opacification). The cornea is the clear (transparent) outer layer of the eye that helps let light in. Corneal opacification may not cause any symptoms or it can lead to varying degrees of vision loss. Less common ocular abnormalities include bluish discoloration of the whites of the eyes (blue sclera), nearsightedness (myopia), and eyes that do not line up in the same direction such as crossed-eyes (strabismus).
Varying degrees of intellectual disability may also occur, ranging from moderate to severe. Affected infants and children may experience delays in attaining developmental milestones (developmental delays) and have reflex responses that are stronger than normal (hyperreflexia). As affected individuals grow older they may develop seizures and involuntary, slow, writhing movements (athetoid-like movements) of the hands, feet, arms and legs.
Growth delays occur before birth and after birth (intrauterine and postnatal growth deficiency). In addition, affected infants may fail to grow and gain weight at the expected rate for age and gender (failure to thrive). Individuals with de Barsy syndrome may display height that is below what would normally be expected based upon age and gender (short stature).
Additional symptoms have been reported in some cases including inguinal and umbilical hernias.
Some cases of de Barsy syndrome are caused by mutations in either the PYCR1 or ALDH18A1 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. Some individuals with de Barsy syndrome do not have mutations in either of these genes suggesting that as-yet-unidentified genes cause the disorder.
De Barsy syndrome is inherited as an autosomal recessive disorder. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. 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.
Investigators have determined that the PYCR1 gene is located on the long arm of chromosome 17 (17q25.3) and that the ALDH18A1 gene is located on the long arm of chromosome 10 (10q24.1). 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. For example, “chromosome 17q25.3” refers to band 25.3 on the long arm of chromosome 17. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
De Barsy syndrome affects males and females in equal numbers. Fewer than 50 cases have been reported in the medical literature. The exact incidence and prevalence of this disorder is unknown. Because cases may go misdiagnosed or undiagnosed, determining the true frequency of de Barsy syndrome in the general population is difficult. De Barsy syndrome is usually obvious at birth or early infancy.
A diagnosis of de Barsy syndrome 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.
As previously stated, it is extremely important to screen for the specific purine synthesis defect related metabolites in suspected ALDH18A1-related cases. These metabolites are not always abnormal and might show variable degree of abnormalities.
The treatment of de Barsy syndrome 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, orthopedists, neurologists, ophthalmologists, 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.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with de Barsy syndrome.
Specific therapies for individuals with cutis laxa can include surgery to repair skeletal problems, ocular abnormalities, or hernias. Some individuals elect for plastic (cosmetic) surgery to improve skin symptoms. Results are typically good, but loose, lax skin often recurs.
Individuals with ALDH18A1-related de Barsy syndrome who present with hyperammonemia and low arginine, ornithine and citrulline levels should be treated by drugs known as ammonia scavengers as well as supplementation with citrulline or arginine.
Early developmental intervention is important to ensure that affected children reach their potential. Physiotherapy may be useful to help prevent contractures. Additional medical, social and/or vocational services including special remedial education may be necessary.
Affected individuals should avoid environmental triggers that can worsen cutis laxa or associated symptoms. For example, sunbathing can damage the skin and should be avoided.
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
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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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