Cornelia de Lange Syndrome

This disorder is named for Cornelia Catharina de Lange, a Dutch pediatrician who first described the condition back in 1933.

While this condition, also known as CdLS, has been around a while, if the diagnosis is new to you, you probably have questions.

That's why here are YourDNA, we've created this guide to help you get a better understanding of the disorder and explain key points about it in terms you can understand.

What Is Cornelia de Lange Syndrome (CdLS)? 

Cornelia de Lange Syndrome is a developmental disorder that is caused by a genetic mutation in the body. The severity of this disorder varies from person to person. 

Many patients with CdLS exhibit characteristic signs such as distinct facial features, impaired growth, intellectual disabilities and limb defects.

This disorder is commonly misdiagnosed or undiagnosed because many only experience mild Cornelia de Lange syndrome symptoms.

Signs and Symptoms of Cornelia de Lange Syndrome 

The signs and symptoms of Cornelia de Lange syndrome (CdLS) vary greatly between those who are affected. Some are affected mildly and others are affected more severely. 

Overall, there are a few similar symptoms that occur throughout the community of those diagnosed with this disorder. Symptoms include but are not limited to: 

• Slowed growth in the womb and after birth
• Autistic and/or self-destructive behaviors (also known as Cornelia de Lange syndrome behaviors)
• Progressive intellectual disability 
• Developmental delays 
• Skeletal abnormalities of the arms and/or hands
• Gastrointestinal issues 
• Hirsutism (excessive hair growth), often the reason for CdLS eyebrows 
• Hearing impairment and loss
• Myopia (nearsightedness) 
• Congenital heart defects
• Genital abnormalities such as cryptorchidism (undescended testicles) 
• Seizures

Affected people typically have distinctive facial features, which can sometimes include microcephaly; eyebrows that are arched and often grow together in the middle (synophrys); longer eyelashes than the normal; low-set ears; small, widely spaced teeth; and a small nose that’s upturned.

If you are curious as to what this disorder looks like, you can find Cornelia de Lange syndrome pictures with a simple internet search. 

Prevalence and Risk Factors of Cornelia de Lange Syndrome 

So, just how common and how rare is Cornelia de Lange syndrome? 

While the exact number of diagnosed cases of Cornelia de Lange syndrome is unknown, it is thought to affect 1 in every 10,000 to 30,000 newborns ¹.

Cornelia de Lange syndrome often goes undiagnosed when individuals present with less severe symptoms and characteristics of the syndrome.

Those with uncommon characteristics and features may not be recognized with this disease. It is considered a rare disorder.

Causes of Cornelia de Lange Syndrome 

If your child has been diagnosed with CdLS, you are probably wondering, "is Cornelia de Lange syndrome genetic?" 

Overall, 60% of the cases of Cornelia de Lange syndrome can be traced to mutations in the NIPBL gene ². There are many kinds of mutations that can occur in this gene to make a person develop CdLS.

However, most of the mutations lead to a production of abnormally short and nonfunctional delangin proteins. 

This mutation decreases the total amount of delangin produced in cells. This decrease most likely alters the body's ability to regulate the genes responsible for normal fetal development. 

Although there is no research that explains why this change causes Cornelia de Lange syndrome, it is suspected that the impaired gene regulation function is the cause of many of the developmental problems and characteristic symptoms of Cornelia de Lange syndrome.

Approximately 30% of all cases of Cornelia de Lange syndrome have an unknown cause and the remaining 10% of all cases of this disorder are caused by mutations in either the SMC1A, SMC3, HDAC8 or RAD21 genes ³.

• SMC1A - A mutation in this gene can cause Cornelia de Lange syndrome. In general, this specific mutation of the gene causes milder symptoms and features than other forms. There are usually fewer delays in development, growth and birth defects. This gene mutation results in changes to amino acids in the SMC1 protein. These are the protein building blocks. This alters the structure and function of the protein and causes the impaired gene function. Similar to the NIPBL gene, this affects the ability of the cohesin complex needed to regulate genes that are important for normal development. 
• SMC3 - Similarly to the SMC1 gene mutation, this mutation either impairs the function of amino acids (or the building blocks of proteins) or adds or deletes a small number of amino acids in this protein. This impairs the structure and function of the protein which interferes with the ability of the cohesin complex to regulate genes required for normal development. 
• HDAC8 - With this gene mutation, there is a single change that occurs within the amino acids of histone deacetylase 8. The mutation can also add or delete a small number of amino acids. This impairs enzyme activity which then alters the ability to regulate genes crucial for normal development. 
• RAD21 - With a mutation in this specific gene, an entire gene is missing from one copy of the chromosome in each cell. This causes a reduced amount of RAD21 protein to be created in the body. It is also possible for there to be mutations within this gene that alter the function of the RAD21 protein. Either way, this nonfunctioning or deleted RAD21 protein alters the regulation of important genes needed for normal and healthy development. 

The Genetic Pattern of Inheritance of Cornelia de Lange Syndrome 

The specific genetic pattern of inheritance of Cornelia de Lange syndrome is autosomal dominant, meaning that only one single copy of an altered gene is needed in order to cause the syndrome.

This means that only one parent has to have a mutated gene to pass Cornelia de Lange down to their child. 

However, most new cases of this syndrome actually result from a new gene mutation. So, in some cases, patients with CdLS have no previous family history of the disorder.

If Cornelia de Lange is caused by mutations in HDAC8 or SMC1A genes then there is always an X-linked dominant pattern of inheritance.

An X-linked dominant pattern means that the mutated gene is located on the X-chromosome, one of the sex chromosomes. 

Although X-linked recessive conditions tend to affect more males than females, X-linked dominant Cornelia syndrome appears to affect both males and females equally.

These genes are also responsible for most of the new mutations that occur in people with no family history of this disorder. 

Diagnosis of Cornelia de Lange Syndrome 

If you are concerned someone you know has Cornelia de Lange syndrome you may wonder how is CdLS diagnosed? 

A Cornelia de Lange syndrome diagnosis is generally suspected when the following signs or symptoms are noticed ⁴. 

Head and Face Abnormalities

When a patient presents with microbrachycephaly, or a very small and flat head, a unibrow and very arched eyebrows (which occurs in 98% of cases), there is a good chance that this individual has the syndrome. 

Other common symptoms that are used diagnostically are long, thick eyelashes and abnormally placed ears that are low-set with a thick curve of the outer ear.

A short nose with tips that are upturned with nares (nostrils) that are easily seen from the front (aka anteverted nares) is also a common sign. 

A long space between the upper lip and nose, thin downturned lips, and a high/arched palate with cleft occur in 30% of these cases.

Micrognathia or an abnormally small jaw occurs in 80% of the cases, bone spurs occur in 42% of the cases, and a short neck can also be a commonly recognized characteristic. 

Growth Failure

Another common sign that a child may have Cornelia de Lange syndrome is growth failure that begins while the baby is inside the womb.

He or she will also have a very low height and weight throughout their life. Failure to thrive and gastroesophageal reflux is also a sign that is used to diagnose CdLS.

Approximately 95% of people with this disorder experience these symptoms. 

Intellectual Disability

Another diagnostic sign is severe to profound developmental delays. These are experienced in more than 95% of individuals with Cornelia de Lange syndrome. 

Limb Abnormalities

In more than 30% of CdLS cases, patients have either small or absent forearms and missing fingers.

Some individuals do not have limb abnormalities but do have micromelia or in other words small hands. 

They may also have abnormally placed thumbs and curvature of the fifth finger called clinodactyly which is abnormal.

Radioulnar synostosis, a fusion of the bones in the forearm, is also a very common issue and can result in defected elbows. 

Lastly, syndactyly or small feet and joined toes occur in more than 80% of all cases of this disorder.

Overall, limb abnormalities are present in more than 95% of patients with Cornelia de Lange syndrome. This is why it is used as a diagnostic tool. 

Hirsutism or excess hair on the face, back and arms, is present in more than 80% of patients diagnosed with Cornelia de Lange.

Due to the high percentage of patients experiencing this symptom, physicians also use this to confirm the diagnosis. 

Is There a Genetic Test for Cornelia de Lange Syndrome? 

It is possible to have genetic testing done to determine the exact gene mutation that is occurring in the body. 

However, approximately 30% of patients diagnosed with CdLS do not have a gene abnormality. This 30% have an unknown cause of the disease.

Therefore, a genetic test may need to be combined with symptoms in order to diagnose this disorder. 

Treatment and Care Options for Cornelia de Lange Syndrome 

Unfortunately, there is no cure for Cornelia de Lange syndrome. However, because this disorder causes a great deal of impairment to various body systems, treatment is often multi-interprofessional.

Specific treatment needs depend on the signs and symptoms experienced with each individual patient.

Some may need supplemental nutrition and or a gastrostomy tube placed in order to ensure proper nutrition needs are being met and to improve growth outcomes. 

Others may need physical therapy, occupational therapy or speech therapy in order to promote the optimum function of their bodies.

Surgery can also be used to treat any skeletal, limb, congenital heart defects or gastrointestinal issues. Lastly, medications can also be used to manage any other symptoms such as seizures. 

The Prognosis of Cornelia de Lange Syndrome 

The life expectancy for someone with Cornelia de Lange syndrome is actually normal. Most children survive into adulthood and their outlook is typically very good. 

While some patients may have issues and need extra care due to developmental delays or physical deformities, it is possible for patients with this disorder to live fully functioning lives.

Although the disorder itself usually isn't fatal, the typical cause of death in CdLS patients is from deformations in the heart or throat.

This can shorten the life expectancy for those with Cornelia de Lange.

What to Do Next: Living With Cornelia de Lange Syndrome 

If someone you know has just been diagnosed with Cornelia de Lange syndrome it is important to visit a children’s hospital to discuss your options with a physician who knows how to treat this disease. 

Living with CdLS is possible as long as the affected person is being cared for and any potential issues such as growth delays or heart defects are being treated at an appropriate time. 

If you suspect that your child may have Cornelia de Lange syndrome and would like more information about your options, you can learn more at the CdLS Foundation ⁵.

They help families understand the resources that are available to them if their child has this diagnosis.