Cornelia de Lange syndrome

Unless an individual with Cornelia de Lange syndrome has major medical problems present at birth such as a serious congenital diaphragmatic hernia or a complex heart defect, individuals with Cornelia de Lange syndrome can live well into adulthood. Life expectancy in Cornelia de Lange syndrome is largely dependent on the level of medical care an individual receives as well as their general health. As is true for many individuals with developmental disabilities, people with Cornelia de Lange syndrome are more likely to be injured in accidents and are more vulnerable to common illnesses even if they are generally healthy. Therefore, the life expectancy of an individual with Cornelia de Lange syndrome may be shorter than the general population by approximately 10-20 years.

All individuals with Cornelia de Lange syndrome should be seen by a medical geneticist and receive genetic counseling. Genetics professionals can oversee the health management of an individual with Cornelia de Lange syndrome to ensure that the affected individual is being screened appropriately for possible medical and developmental issues associated with Cornelia de Lange syndrome. Additionally, medical geneticists and genetic counselors can assist with ordering and interpreting genetic test results for individuals with Cornelia de Lange syndrome and their families, as well as provide support resources and reproductive counseling. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website . Genetic counselors in the United States can be found on the National Society of Genetic Counselors website. Genetic counselors in Canada can be found at the Canadian Association of Genetic Counselors website.

The other specialists that an individual with Cornelia de Lange syndrome should see depends on the specific medical problems that the person has. Many individuals with Cornelia de Lange syndrome have heart defects that should be managed by cardiology. Limb abnormalities are also common in Cornelia de Lange syndrome and are managed by orthopedics. Because of the high incidence of developmental issues, speech, occupational and physical therapists are often involved in the care of individuals with Cornelia de Lange syndrome. Other specialists such as immunology, neurology, and surgery may be important depending on the specific medical issues present in a given affected individual.

Cornelia de Lange syndrome is usually abbreviated as CdLS.

Cornelia de Lange syndrome (CdLS) is a genetic disorder that affects many parts of the body. The features that are more commonly found as part of the condition include:

Because people with Cornelia de Lange syndrome each have a unique set of symptoms, their doctors will need to manage each person based on their individual symptoms and health issues. However, there are some medical issues that are commonly seen in people with Cornelia de Lange syndrome that their doctors should monitor. The following is a list of health issues more common in individuals with Cornelia de Lange syndrome for which people with Cornelia de Lange syndrome should be monitored:

There are several genes known to be associated with Cornelia de Lange syndrome when they have disease causing changes or mutations including:

Although the diagnosis of Cornelia de Lange syndrome can be made clinically based on physical examination and history without genetic testing, genetic testing can be used to confirm the diagnosis in an individual with symptoms suspicious for the disorder. About 30% of individuals with a clinical diagnosis of Cornelia de Lange syndrome have no identifiable genetic change causing their disorder by current genetic testing methodologies. A smaller number of affected individuals are found to have a change in the spelling of one of the five genes associated with Cornelia de Lange syndrome, but it is unknown whether the specific gene change found would cause disease, and so the genetic test result is not conclusive.

We all have differences in the way our genes are spelled (gene variants). In many cases, these spelling changes do not appear to change the protein that the gene produces and therefore do not seem to lead to any health or developmental problems. Some changes, though, can alter the way a gene works, leading to an abnormal protein product being made. When this happens, a disease can occur. There are several changes that have been identified in the five genes associated with Cornelia de Lange syndrome that are known to cause the disorder. In other cases, however, a "variant" or "variant of unknown significance" is found, the effect of which, if any, is unknown.

When a person who is suspected to have Cornelia de Lange syndrome has genetic testing and a variant in one of those genes is found, we can not be sure whether that gene change is the cause of the symptoms that person has. If the person had enough symptoms to allow for the diagnosis of Cornelia de Lange syndrome to be made clinically, the finding of a variant will likely not lead to the doctor changing or removing the diagnosis. Over time, as more people have genetic testing for Cornelia de Lange syndrome, unclear gene variants may be reclassified as disease-causing if identified in enough affected individuals.

It is also possible that a person with signs of Cornelia de Lange syndrome but with only a variant identified on genetic testing may have a change or changes in other genes that have not yet been identified as being associated with Cornelia de Lange syndrome. Over time, we may identify more genes that cause Cornelia de Lange syndrome, leading to more extensive genetic testing for this condition to be possible.

Cornelia de Lange syndrome is a variable condition, and not all individuals with Cornelia de Lange syndrome are affected in the same ways. The following is a list of the most common symptoms of Cornelia de Lange syndrome with their approximate frequencies:

Getting a diagnosis of Cornelia de Lange syndrome can be overwhelming for a family. Because it is a relatively rare disorder, most families have not heard of Cornelia de Lange syndrome prior to their family member being diagnosed. The first step to take once the diagnosis is made is to have a visit with a medical geneticist or genetic counselor to learn about Cornelia de Lange syndrome, the implications for the family, and how to manage the medical and developmental issues that may affect the individual with Cornelia de Lange syndrome. Medical geneticists and genetic counselors can help ensure that an appropriate management and treatment plan is in place for the affected individual, as well as provide resources for more information for the family from trustworthy sources.

In addition, families may wish to connect with CdLs support and advocacy groups such as The CdLs Foundation that may help with daily living questions related to living with Cornelia de Lange syndrome.

The National Society of Genetic Counselor "Find a Genetic Counselor" online directory can be used to locate genetic counselors throughout the United States and Canada.

There are a few different ways to test for Cornelia de Lange syndrome. In addition to a clinical diagnosis (made by a physician on the basis of physical examination and history), genetic testing may identify gene changes known to be associated with Cornelia de Lange syndrome. There are many different types of genetic tests that could diagnose Cornelia de Lange syndrome. These tests are performed on a sample (usually blood, but also potentially saliva or another tissue type) from an individual. The testing is most typically performed with the involvement of a genetic counselor or medical geneticist.

There are five genes known to be associated with Cornelia de Lange syndrome. About 70% of people with a diagnosis of Cornelia de Lange syndrome based on symptoms alone have an identifiable change in one of these genes. There are a small number of laboratories in the United States that perform testing on the genes associated with Cornelia de Lange syndrome. Some of these labs test for these genes one a time (sequentially), while some of them test for multiple or all five of them on a panel at the same time, and still others test for some or all of these five genes as part of a much larger panel that also includes genes associated with other conditions in addition to Cornelia de Lange syndrome. For example, there are panels of genes associated with learning disorders that not only include testing of the Cornelia de Lange syndrome genes, but also include hundreds of other genes associated with other genetic conditions that affect learning or development. Changes in one of the five genes associated with Cornelia de Lange syndrome may also be detected by array comparative genomic hybridization (chromosome microarray analysis), which identifies copy number changes (deletions or duplications) across all of the chromosomes, as well as through whole exome or whole genome sequencing.

The question of which genetic test (panel vs. single gene testing) is best for a specific individual may be based on many factors. In some cases, it may be more financially appropriate to start by testing for gene changes in the most common Cornelia de Lange syndrome gene, NIPBL, and then going onto other genes if NIPBL testing is negative. In other cases, testing all five genes at once may be the most efficient. In some situations, if an individual’s symptoms could be due to several other genetic disorders in addition to Cornelia de Lange syndrome, a larger gene panel or even a more comprehensive genetic test known as whole exome or whole genome sequencing, may be most appropriate.

Although it is rare for Cornelia de Lange syndrome to be inherited from an affected parent, once an affected individual’s specific gene change is identified, targeted genetic testing can be performed in that individual’s relatives, if clinically appropriate.

Researchers at Johns Hopkins University and the Kennedy Krieger Institute are working together to study the epilepsy characteristics in Cornelia de Lange syndrome. The study involves a short online survey and submission of certain medical records. The purpose is to better understand epilepsy in affected individuals, medications that are helpful, and factors that contribute to epilepsy severity. For more information, please contact Dr. Sid Srivastava at sid@jhmi.edu or Dr. Marco Grados at mjgrados@jhmi.edu.

Researchers at Sanford Health in South Dakota are interested in enrolling individuals with certain rare diseases, including Cornelia de Lange syndrome, to create a patient registry that can act as a central resource connecting scientists to affected individuals interested in participating in research. Information on how to enroll can be obtained here.

The following are other resources that can update you on further research.

There is no cure for Cornelia de Lange syndrome. However, there are many treatments that can help address specific symptoms that a person with Cornelia de Lange syndrome may experience. Because no two individuals with Cornelia de Lange syndrome are exactly the same, the particular treatments one affected individual undergoes will likely be different from another affected individual. Treatments may also be dependent on the age of the affected individual.

At birth, individuals with Cornelia de Lange syndrome may have birth defects of the heart, gastrointestinal system, limbs, and/or palate that require surgical treatment. All babies with Cornelia de Lange syndrome should receive early intervention services for initiation of developmental therapies such as speech, occupational and physical therapies. These services should continue throughout childhood and beyond, if possible.

Over time, individuals with Cornelia de Lange syndrome may develop gastrointestinal problems that require evaluation and, in some cases, surgery. Many individuals will also have hearing and/or vision problems. People with Cornelia de Lange syndrome should be evaluated frequently by an audiologist (hearing) and ophthalmologist (vision) and, if problems are detected, treatments such as hearing aids or glasses can be initiated at the earliest possible time. These evaluations should be done periodically through childhood and into adulthood.

Individuals with Cornelia de Lange syndrome who are school age should be provided with educational supports appropriate to their specific needs.

The CdLs Foundation website includes suggested treatment protocols that may help in the management of an individual with Cornelia de Lange syndrome.

In general, most individuals with Cornelia de Lange syndrome have at least a few symptoms of the disorder (known as high penetrance). Often, the diagnosis of Cornelia de Lange syndrome can be made by a medical geneticist or other physician similar with the condition based on an individual’s clinical features and history. In some cases, however, there are so few features, or the features are so mild, that it is very difficult to make a diagnosis just based on examination.

The inheritance pattern of Cornelia de Lange syndrome is dependent upon the specific gene involved. In a little over 60% of cases (those caused by the NIPBL, RAD21, and SMC3 genes), Cornelia de Lange syndrome is inherited in an autosomal dominant fashion. Autosomal dominant means that the gene change is present on one of the first 22 pairs of chromosomes, which are referred to as autosomes, and dominant means that the gene change must be present on only one of the two copies of the gene in order to cause in the condition. In less than 10% of cases (those caused by the HDAC8 and SMC1A genes), Cornelia de Lange syndrome is inherited in an X-linked fashion. X-linked means that the gene change is present on the X chromosome, one of the 23rd pair of chromosomes that determines gender. Unlike many X-linked conditions, males and females are both affected equally when the gene change for CdLS is on the X chromosome. In the remaining cases, the inheritance is unknown.

The gene change present in most individuals with Cornelia de Lange syndrome occurs as a new finding in that individual (de novo), rather than being inherited from a parent. If an individual with Cornelia de Lange syndrome has children, the children of the affected individual may inherit the Cornelia de Lange gene change from the affected parent and be affected themselves. Since many individuals with Cornelia de Lange syndrome do not have children, it is estimated that less than 1% of people with Cornelia de Lange syndrome inherit the gene change from an affected parent. When a couple has a child affected with Cornelia de Lange syndrome, it is recommended that both parents have careful clinical examinations and genetic testing, if appropriate, since a parent may have a very mild form of Cornelia de Lange syndrome that was not known prior to the affected child’s birth.

Genes are the "blueprints" (instructions) that direct the body how to grow and develop. Cells use the information contained in genes to make proteins, which then build, regulate and maintain the body. The proteins made by the five genes known to be associated with Cornelia de Lange syndrome appear to be very important in helping cells develop correctly from the beginning of fetal development and throughout life. The gene changes in Cornelia de Lange syndrome cause changes in how these proteins function in the body, and changes in these proteins appear to lead to the health and developmental problems associated with Cornelia de Lange syndrome.

There are several different groups and foundations who are working to make the world a better place for people with Cornelia de Lange syndrome. Most of these groups depend on donations from people interested in this cause. The primary foundation dedicated to Cornelia de Lange syndrome in the United States is the Cornelia de Lange Syndrome Foundation. Information on donating to the CdLS Foundation can be found here.

The National Organization for Rare Disorders (NORD) is a patient advocacy organization dedicated to individuals with rare diseases and the organizations that serve them, including Cornelia de Lange syndrome. Donations to NORD can be made here.

The Children’s Hospital of Philadelphia (CHOP) has a long history of both research and clinical services for individuals with Cornelia de Lange syndrome and is a Clinical Center for Excellence. Information on donating to CHOP can be found here.

The Greater Baltimore Medical Center is a Clinical Center for Excellence for Cornelia de Lange syndrome. Information on donating to them can be found here.

The University of California at Irvine is a Research Center for Excellence in Cornelia de Lange syndrome. Information on donating to their efforts can be found here.

Saint Louis University is a Research Center for Excellence for Cornelia de Lange syndrome. Information on donating to their center can be found here.

Finally, Stowers Institute for Medical Research is a Research Center for Excellence for Cornelia de Lange syndrome. Information on donating can be found here.

There are two different ways to diagnose Cornelia de Lange syndrome. The first, most common way, is a clinical diagnosis. This means that a medical geneticist or another doctor familiar with Cornelia de Lange syndrome performs a thorough physical examination to look for signs of the condition. Because Cornelia de Lange syndrome is a relatively rare condition symptoms in mildly affected individuals may be subtle, it is recommended that anyone desiring testing for this condition do so with a medical geneticist. A medical geneticist is a doctor who is trained not only in general medicine (such as pediatrics or adult medicine) but also in genetics. Primary care doctors or pediatricians who do not have specific genetic training typically do not have enough familiarity with Cornelia de Lange syndrome to be able to diagnose or rule out this condition. In addition to the clinical examination, the doctor may also order additional evaluations, such as an echocardiogram to look for heart defects, or a hearing evaluation. Often, as part of this clinical evaluation, genetic counseling is also performed. Genetic counseling allows for a thorough medical and family history review. These reviews can help determine how likely the diagnosis of Cornelia de Lange syndrome is, as well as whether any other conditions should be considered. Furthermore, a consult with a genetic counselor can help a family understand the potential impact of the diagnosis on their family, as well as the pros and cons of pursuing genetic testing. The National Society of Genetic Counselors "Find a Genetic Counselor" searchable directory can help you locate genetic counseling services throughout the United States and Canada.

The second way Cornelia de Lange syndrome can be diagnosed is through genetic testing. Genetic testing for Cornelia de Lange syndrome can be complicated. For this reason, it is recommended that the testing be handled by a medical geneticist. Because the symptoms of Cornelia de Lange syndrome can overlap with other, more common disorders, testing for those other conditions may be ordered first. Once the diagnosis of Cornelia de Lange syndrome is specifically suspected, a sample (most often blood, but possibly saliva or another tissue type) is taken from the individual and sent for testing of a gene, or a panel of multiple genes, associated with Cornelia de Lange syndrome. If a change that is known to cause disease is found in a gene associated with Cornelia de Lange syndrome, a diagnosis of Cornelia de Lange syndrome is then genetically confirmed in the affected individual.

Clinical trials are listed through a government website and are updated frequently. To keep up to date on any new trials related to Cornelia de Lange syndrome, you can visit clinicaltrials.gov and enter "Cornelia de Lange syndrome" in the search box.

The Cornelia de Lange Syndrome Foundation also keeps updated information about ongoing research projects on their website. Such information can be found here.

The CdLS Foundation maintains a list of centers of excellence for Cornelia de Lange syndrome. As of July 2019, the following centers of excellence are recognized.

Cornelia de Lange syndrome is thought to occur in around 1 in 10,000 to 1 in 30,000 newborns. It is difficult to determine the true prevalence of CdLS, as it is likely that there are many individuals with milder features of CdLS that have not been diagnosed. As of 2019, the CdLS Foundation reports serving around 2800 individuals with CdLS in the United States.

Typically, when a couple has a child with Cornelia de Lange syndrome, neither of the parents is affected. Most often the genetic change causing Cornelia de Lange syndrome in the child occurred for the first time (de novo) in the child, rather than being inherited from a parent. When a genetic change is de novo, it is unlikely to occur again in a future pregnancy. There are rare instances, however, of an unaffected couple having more than one affected baby. This is due to a condition known as germline, or gonadal, mosaicism. In gonadal mosaicism, a gene change can be found in the reproductive cells (sperm or egg cells) of an individual that is not present in the cells of the rest of their body. Individuals with mosaicism can produce multiple egg or sperm cells that carry a gene change. When an unaffected couple has had one child with Cornelia de Lange syndrome, the chance for recurrence in a future pregnancy is estimated to be approximately 1.5%. If the gene change causing Cornelia de Lange syndrome in the affected child is known, prenatal diagnostic testing or preimplantation genetic diagnosis is an option in subsequent pregnancies. Additionally, careful prenatal ultrasound examination can be used to screen for birth defects present in some fetuses with Cornelia de Lange syndrome. However, not all babies with Cornelia de Lange syndrome are born with birth defects that are detectable by ultrasound, and so a normal ultrasound cannot be used to rule out Cornelia de Lange syndrome.

No, there is nothing in particular that is known to make Cornelia de Lange syndrome worse. The health and developmental problems associated with Cornelia de Lange syndrome are thought to be the result of a gene change, and there are no known lifestyle or environmental factors that are known to influence the effect of these genes in the body. Based on the particular symptoms an individual with Cornelia de Lange has, there may be management recommendations for that individual. For example, an individual with Cornelia de Lange syndrome who has Gastroesophageal Reflux Disease (GERD) may need to avoid certain foods or avoid laying on their back after they have eaten.

In general, most individuals with Cornelia de Lange syndrome do not have children. But, individuals with Cornelia de Lange syndrome do not necessarily have reduced fertility. Many individuals with Cornelia de Lange syndrome have developmental and social issues that may reduce the chances that they would have children. There have been several cases reported of a parent with Cornelia de Lange syndrome having children. When a parent has Cornelia de Lange syndrome, the risk for the disorder in their offspring depends on the genetic basis of the Cornelia de Lange syndrome (whether autosomal dominant or X-linked). Individuals with Cornelia de Lange syndrome of reproductive age who are not intending to have children should consider utilizing birth control as appropriate to prevent unintended pregnancy.

Cornelia de Lange syndrome may also be called:

There are several support groups dedicated to improving the lives of individuals with Cornelia de Lange syndrome as well as increasing awareness and research on the disorder. In the United States, the Cornelia de Lange Syndrome Foundation is very active in these efforts. The CdLS Foundation holds a biannual conference for families during which medical experts will provide free consultations. There are also educational workshops and opportunities to meet other families who have members with Cornelia de Lange syndrome.

There is also a large group focused on these issues based in the United Kingdom and Ireland known as the CdLS Foundation UK & Ireland.
Finally, there is an international organization known as the CdLS World Federation that identifies worldwide experts in Cornelia de Lange syndrome and puts them in touch with one another. They also act as a forum of best practice for support groups serving people with this disorder, including holding a biannual international conference. Lastly, they act as a resource base to help researchers and families worldwide get in contact with one another.

Several social media networks for individuals and families with Cornelia de Lange syndrome can be found on Facebook.

Sometimes Cornelia de Lange syndrome is broken up into subtypes. Cornelia de Lange syndrome-1 describes people with this diagnosis who are known to have a change in the gene NIPBL. This is the most common form of Cornelia de Lange syndrome and is usually the most severe. Cornelia de Lange syndrome types 2, 3 and 4 are associated with changes in genes SMC1A, SMC3, and RAD21, respectively. People with these three types often have milder and fewer signs of the disorder. Cornelia de Lange syndrome-5 is caused by changes in the gene HDAC8. Individuals with this type are more likely to have differences in their skull and teeth, widely spaced eyes, and intellectual disability that falls toward the profound end of the spectrum.

If you have questions about the genetics of Cornelia de Lange syndrome, the National Society of Genetics Counselors "Find a Genetic Counselor" online directory can be used to locate genetic counseling services throughout the United States and Canada.

While there are many other conditions that share a few features with Cornelia de Lange syndrome, these conditions can typically be distinguished from Cornelia de Lange syndrome based on their other features common to them that are not shared with Cornelia de Lange syndrome. There are no other known disorders associated with changes in the five genes known to cause Cornelia de Lange syndrome. The following are some of the conditions that share features in common with Cornelia de Lange syndrome: