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Cornelia de Lange Syndrome

Table of Contents

Cornelia de Lange Syndrome

CdLS; Brachmann de Lange Syndrome; BDLS; De Lange Syndrome; Typus Degenerativus Amstelodamensis

Cornelia de Lange syndrome (CdLS) is a developmental disorder that may include distinctive facial characteristics, growth delays, intellectual disability and limb defects. It is usually due to an acquired change (mutation) in one of seven important developmental genes at or shortly after conception. Explore symptoms, causes, and genetics.

Eli diagnosed with Cornelia de Lange syndrome

Image by Joris

About

Boy with Cornelia de Lange syndrome

Image by GeneReviews, © 1993-2020 University of Washington

Boy with Cornelia de Lange syndrome

Image by GeneReviews, © 1993-2020 University of Washington

What Is Cornelia De Lange Syndrome?

Cornelia de Lange syndrome is a developmental disorder that affects many parts of the body. The features of this disorder vary widely among affected individuals and range from relatively mild to severe.

Cornelia de Lange syndrome is characterized by slow growth before and after birth leading to short stature; intellectual disability that is usually moderate to severe; and abnormalities of bones in the arms, hands, and fingers. Most people with Cornelia de Lange syndrome also have distinctive facial features, including arched eyebrows that often meet in the middle (synophrys), long eyelashes, low-set ears, small and widely spaced teeth, and a small and upturned nose. Many affected individuals also have features similar to autism spectrum disorder, a developmental condition that affects communication and social interaction.

Additional signs and symptoms of Cornelia de Lange syndrome can include excessive body hair (hypertrichosis), an unusually small head (microcephaly), hearing loss, and problems with the digestive tract. Some people with this condition are born with an opening in the roof of the mouth called a cleft palate. Seizures, heart defects, and eye problems have also been reported in people with this condition.

Source: MedlinePlus Genetics

Additional Materials (8)

Living with Cornelia de Lange Syndrome

Video by National Organization for Rare Disorders (NORD)/YouTube

Spotlight On Cornelia de Lange Syndrome

Video by Cornelia de Lange Syndrome/YouTube

Cornelia de Lange Syndrome - CRASH! Medical Review Series

Video by Paul Bolin, M.D./YouTube

Learn about the Cornelia de Lange Syndrome Foundation, Inc.

Video by National Organization for Rare Disorders (NORD)/YouTube

Cornelia de Lange Syndrome - PSA

Video by Cornelia de Lange Syndrome/YouTube

Cornelia de Lange Syndrome (CdLS) Awareness Video

Video by Cornelia de Lange Syndrome/YouTube

Genetic Testing and CdLS

Video by Cornelia de Lange Syndrome/YouTube

My Friend with Cornelia de Lange Syndrome (Altered Genes)

Video by Special Books by Special Kids/YouTube

3:14

Living with Cornelia de Lange Syndrome

National Organization for Rare Disorders (NORD)/YouTube

5:33

Spotlight On Cornelia de Lange Syndrome

Cornelia de Lange Syndrome/YouTube

16:20

Cornelia de Lange Syndrome - CRASH! Medical Review Series

Paul Bolin, M.D./YouTube

2:15

Learn about the Cornelia de Lange Syndrome Foundation, Inc.

National Organization for Rare Disorders (NORD)/YouTube

0:30

Cornelia de Lange Syndrome - PSA

Cornelia de Lange Syndrome/YouTube

1:51

Cornelia de Lange Syndrome (CdLS) Awareness Video

Cornelia de Lange Syndrome/YouTube

1:04:41

Genetic Testing and CdLS

Cornelia de Lange Syndrome/YouTube

10:45

My Friend with Cornelia de Lange Syndrome (Altered Genes)

Special Books by Special Kids/YouTube

Causes

NIPBL

Image by Jimcricket90/Wikimedia

NIPBL

Crystal structure of Ashyba gossypii Scc2 residues 378–1,479. From Chao et al. 2017

Image by Jimcricket90/Wikimedia

What Causes Cornelia De Lange Syndrome?

Cornelia de Lange syndrome can result from variants (also called mutations) in one of several genes. Variants in the NIPBL gene have been identified in more than half of all people with this condition. Variants in other genes, including SMC1A, HDAC8, RAD21, SMC3, and others, are much less common.

The proteins produced from most of the genes involved in Cornelia de Lange syndrome contribute to the structure or function of the cohesin complex, a group of proteins with an important role in directing development before birth. Within cells, the cohesin complex helps regulate the structure and organization of chromosomes, stabilize cells' genetic information, and repair damaged DNA. The cohesin complex also regulates the activity of certain genes that guide the development of the face, limbs, and other parts of the body. Other genes that are involved in rare cases of Cornelia de Lange syndrome also control gene activity and are likely important during development.

Variants in the NIPBL, SMC1A, HDAC8, RAD21, and SMC3 genes cause Cornelia de Lange syndrome by impairing the function of the cohesin complex, which disrupts gene regulation during critical stages of early development. Variants in other genes are also thought to disrupt the regulation of genes important for development.

The features of Cornelia de Lange syndrome vary widely, and the severity of the disorder can differ even in individuals with the same gene variant. Researchers suspect that additional genetic or environmental factors may be important for determining the specific signs and symptoms in each individual. In general, SMC1A, RAD21, and SMC3 gene variants cause milder signs and symptoms than NIPBL gene variants. Variants in the HDAC8 gene cause a somewhat different set of features, including delayed closure of the "soft spot" on the head (the anterior fontanelle) in infancy, widely spaced eyes, and dental abnormalities. Like affected individuals with NIPBL gene variants, those with HDAC8 gene variants may have significant intellectual disability.

In about 15 percent of cases, the cause of Cornelia de Lange syndrome is unknown. Researchers are looking for additional changes in the known genes, as well as variants in other genes, that may cause this condition.

Source: MedlinePlus Genetics

Inheritance

Autosomal Dominant and Baby

Image by TheVisualMD / Domaina

Autosomal Dominant and Baby

Image by TheVisualMD / Domaina

How Is Cornelia De Lange Syndrome Inherited?

When Cornelia de Lange syndrome is caused by variants in the NIPBL, RAD21, or SMC3 gene, the condition is considered to have an autosomal dominant pattern of inheritance. Autosomal dominant inheritance means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases result from new gene variants and occur in people with no history of the condition in their family.

When Cornelia de Lange syndrome is caused by variants in the HDAC8 or SMC1A gene, the condition has an X-linked dominant pattern of inheritance. A condition is considered X-linked if the altered gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. Studies of X-linked Cornelia de Lange syndrome indicate that one copy of the altered gene in each cell may be sufficient to cause the condition. Affected females, who have two X chromosomes, may have milder signs and symptoms than affected males, who have only one X chromosome. Most X-linked cases result from new variants in the HDAC8 or SMC1A gene and occur in people with no history of the condition in their family.

Source: MedlinePlus Genetics

Symptoms

Long eyelashes (ciliary trichomegaly)

Image by Elements of Morphology, National Human Genome Research Institute

Long eyelashes (ciliary trichomegaly)

Image by Elements of Morphology, National Human Genome Research Institute

What Are the Signs and Symptoms of Cornelia De Lange Syndrome?

The signs and symptoms of Cornelia de Lange syndrome (CdLS) vary widely among affected people and can range from relatively mild to severe. Affected people may experience:

Slowed growth before and after birth
Intellectual disability
Developmental delay
Autistic and/or self-destructive behaviors
Skeletal abnormalities of the arms and hands
Gastrointestinal problems
Hirsutism (excess hair growth)
Hearing loss
Myopia
Congenital heart defects
Genital abnormalities (i.e. cryptorchidism)
Seizures

Affected people typically have distinctive craniofacial features, as well, which may include microcephaly; arched eyebrows that often grow together in the middle (synophrys); long eyelashes; low-set ears; small, widely spaced teeth; and a small, upturned nose.

Source: Genetic and Rare Diseases (GARD) Information Center

Diagnosis

Genetic testing

Image by TheVisualMD

Genetic testing

Genetic testing existed before the Human Genome Project and the list of diseases that we can already screen for may be longer than you think.

Image by TheVisualMD

How Is Cornelia De Lange Syndrome Diagnosed?

The diagnosis is suspected when the following signs and symptoms are present:

Head and face appearance (>95%): Very small and flat head (microbrachycephaly), unibrow (synophrys) and highly arched eyebrows (in 98% of the cases), long and thick eyelashes, low-set abnormally placed ears with a thick helix (curve of the outer ear), short nose with upturned tip with nares that are easily seeing from the front (anteverted nares), long space between the nose and the superior lip, thin downturned lips, high and arched palate with clefts (30% of the cases), very small jaw (micrognathia) in 80% of the cases, with spurs (42% of the cases), and short neck.
Growth failure (>95%): Growth failure that starts while the baby is growing inside the womb, resulting in a very low height and weight throughout life, and failure to thrive secondary to gastroesophageal reflux and other issues with feeding.
Intellectual disability (>95%) Severe-to-profound developmental delay
Limb abnormalities (>95%). Small or absent forearms and missing fingers in about 30% of the cases. Some people do not have limb deficiencies but have micromelia (small hands), abnormal placed thumbs, and an abnormal curvature of the fifth finger (clinodactyly). A fusion of the bones of the forearm (radioulnar synostosis) is common and may result in a defect of the elbows. Small feet and joined toes (syndactyly) in more than 80% of the cases.
Excess of hair in the face, back and arms (hirsutism) in more than 80% of the cases.

People with the milder syndrome usually have many of the characteristic facial features but with less severe cognitive and upper extremities defects, and mild intellectual disability (intelligence is normal in some cases). A milder syndrome is more common in people with variants in the SMC3, RAD21, HDAC8 or SMC1A genes.

The diagnosis of CdLS is established with the presence of the clinical features and/or by the genetic test showing a variation in any of the genes associated with the syndrome. However, about 30% of the people affected by the syndrome do not have any known cause.

Source: Genetic and Rare Diseases (GARD) Information Center

Genetic Testing

Genetic Testing

Also called: DNA Testing, Mutation Screening, Genetic Test

Genetic testing is a type of test that analyze your cells or tissue to look for any changes in your DNA. Genetic tests may be used to identify increased risks of health problems, to choose treatments, or to assess responses to treatments.

Genetic Testing

Also called: DNA Testing, Mutation Screening, Genetic Test

Genetic testing is a type of test that analyze your cells or tissue to look for any changes in your DNA. Genetic tests may be used to identify increased risks of health problems, to choose treatments, or to assess responses to treatments.

{"label":"Genetic test reference range","scale":"lin","step":0.25,"hideunits":true,"items":[{"flag":"negative","label":{"short":"Negative","long":"Negative","orientation":"horizontal"},"values":{"min":0,"max":1},"text":"A negative (normal) result means that the test did not find a change that is known to affect health or development in the gene, chromosome, or protein under consideration. This result can indicate that a person is not affected by a particular disorder, is not a carrier of a specific genetic variant, or does not have an increased risk of developing a certain disease. It is possible, however, that the test missed a disease-causing genetic alteration because many tests cannot detect all genetic changes that can cause a particular disorder.","conditions":[]},{"flag":"borderline","label":{"short":"Uncertain","long":"Uncertain","orientation":"horizontal"},"values":{"min":1,"max":2},"text":"An uncertain (variant of unknown or uncertain significance) result means there isn\u2019t enough information about that genetic change to determine whether it is benign (normal) or pathogenic (disease causing). This type of result may be also called uninformative, indeterminate, inconclusive, or ambiguous.","conditions":[]},{"flag":"positive","label":{"short":"Positive","long":"Positive","orientation":"horizontal"},"values":{"min":2,"max":3},"text":"A positive (abnormal) result means that the test found a change in a particular gene, chromosome, or protein of interest. Depending on the purpose of the test, this result may confirm a diagnosis, indicate that a person is a carrier of a particular genetic variant, identify an increased risk of developing a disease (such as cancer), or suggest a need for further testing.","conditions":[]}],"value":0.5}[{"negative":0},{"borderline":0},{"positive":0}]
Use the slider below to see how your results affect your health.
Your result is Negative.
A negative (normal) result means that the test did not find a change that is known to affect health or development in the gene, chromosome, or protein under consideration. This result can indicate that a person is not affected by a particular disorder, is not a carrier of a specific genetic variant, or does not have an increased risk of developing a certain disease. It is possible, however, that the test missed a disease-causing genetic alteration because many tests cannot detect all genetic changes that can cause a particular disorder.
Related conditions
Genetic testing may be done for many different reasons, including to:
- Find genetic diseases in unborn babies. This is one type of prenatal testing.
- Screen newborn babies for certain treatable conditions
- Lower the risk of genetic diseases in embryos that were created using assisted reproductive technology
- Find out if you carry a gene for a certain disease that could be passed on to your children. This is called carrier testing.
- See whether you are at increased risk of developing a specific disease. This may be done for a disease that runs in your family.
- Diagnose certain diseases
- Identify genetic changes that may be causing or contributing to a disease that you were already diagnosed with
- Figure out how severe a disease is
- Help guide your doctor in deciding the best medicine and dosage for you. This is called pharmacogenomic testing.
There are no known risks to having a saliva test. There is very little risk to having a blood test. You may have slight pain or bruising at the spot where the needle was put in, but most symptoms go away quickly.
The physical risks of the different types of genetic testing are small. But there can be emotional, social, or financial drawbacks:
- Depending on the results, you may feel angry, depressed, anxious, or guilty. This can be especially true if you are diagnosed with a disease that does not have effective treatments.
- You may be worried about genetic discrimination in employment or insurance
- Genetic testing may give you limited information about a genetic disease. For example, it cannot tell you whether you will have symptoms, how severe a disease might be, or whether a disease will get worse over time.
- Some genetic tests are expensive, and health insurance might only cover part of the cost. Or they may not cover it at all.
- Positive – the test found a genetic change known to cause disease.
- Negative – the test did not find a genetic change known to cause disease. Sometimes a negative result occurs when the wrong test was ordered or there isn’t a genetic cause for that person’s symptoms. A “true negative” is when there is a known genetic change in the family and the person tested did not inherit it. If your test results are negative and there is no known genetic change in your family, a negative test result may not give you a definite answer. This is because you might not have been tested for the genetic change that runs in your family.
- Uncertain – a variant of unknown or uncertain significance means there isn’t enough information about that genetic change to determine whether it is benign (normal) or pathogenic (disease causing).
1. Genetic Testing | CDC. Sep 23, 2022 [accessed on Feb 23, 2022]
2. Genetic Testing: MedlinePlus. National Library of Medicine. Jun 11, 2021 [accessed on Feb 23, 2022]
3. What is genetic testing?: MedlinePlus Genetics [accessed on Feb 23, 2022]
4. Genetic Testing FAQ. Genome.gov [accessed on Feb 23, 2022]
5. Genetic testing and your cancer risk: MedlinePlus Medical Encyclopedia [accessed on Feb 23, 2022]

Normal reference ranges can vary depending on the laboratory and the method used for testing. You must use the range supplied by the laboratory that performed your test to evaluate whether your results are "within normal limits."

Additional Materials (21)

Genetic testing

Genetic testing fact sheet

Image by genome.gov

Genetic testing

Genetic testing existed before the Human Genome Project and the list of diseases that we can already screen for may be longer than you think.

Image by TheVisualMD

Genes and Genetic Defects

Genetic testing isn't new. In the 1960s, doctors were able to test newborn babies for certain rare single-gene disorders, such as phenylketonuria (PKU), a rare metabolic disease that causes mental retardation. (PKU can be prevented with a special diet if it's detected early, which was why it was critical to test newborns.)

Image by TheVisualMD

Mapping Your Future: Screening for Disease Risk

Image by TheVisualMD

Each person with Down syndrome has different talents and the ability to thrive.

Down syndrome is a lifelong condition. Services early in life will often help babies and children with Down syndrome to improve their physical and intellectual abilities. Most of these services focus on helping children with Down syndrome develop to their full potential. These services include speech, occupational, and physical therapy, and they are typically offered through early intervention programs in each state. Children with Down syndrome may also need extra help or attention in school, although many children are included in regular classes.

Image by CDC

genetic analysis

Biotechnology - DNA analysis and treatment

Image by OpenClipart-Vectors/Pixabay

Family history (medicine)

An extended family in Spain

Image by Ojedamd

Biotechnology

This diagram shows the basic method used for extraction of DNA.

Image by CNX Openstax

Genetic Counselor at Sanford Health Explains the Benefits to Genetic Testing

Video by Sanford Health/YouTube

What Is A Genetic Counselor & The Importance of Genetic Counselling | Ambry Genetics

Video by Ambry Genetics/YouTube

How Does The Genetic Testing Process Work? Genetic Testing FAQ | Ambry Genetics

Video by Ambry Genetics/YouTube

Should You Get Genetic Testing During Your Pregnancy?

Video by St. Louis Children's Hospital/YouTube

Debating Embryonic Genetic Testing -- The Doctors

Video by The Doctors/YouTube

Genetic Testing for Cancer — AMITA Health | NBC Chicago Ask the Doc

Video by AMITA Health/YouTube

MedGenome BRCA - Breast Cancer Genetic Testing

Video by MedGenome/YouTube

Genetic Testing for Hereditary Forms of Kidney Cancer - Brian Shuch, MD

Video by UCLA Health/YouTube

Do I need Genetic Testing for Ichthyosis?

Video by foundation for ichthyosis/YouTube

What Is Genetic Testing? Understanding the Process and Its Results

Video by uvahealth/YouTube

How to Understand Your Genetic Testing Results

Video by Breast Cancer Answers®/YouTube

Genetic Testing 101 for People with Rare Diseases

Video by National Organization for Rare Disorders (NORD)/YouTube

What's the difference between genetic and genomic testing?

Video by Cancer Treatment Centers of America - CTCA/YouTube

Genetic testing

genome.gov

Genetic testing

TheVisualMD

Genes and Genetic Defects

TheVisualMD

Mapping Your Future: Screening for Disease Risk

TheVisualMD

Each person with Down syndrome has different talents and the ability to thrive.

CDC

genetic analysis

OpenClipart-Vectors/Pixabay

Family history (medicine)

Ojedamd

Biotechnology

CNX Openstax

1:57

Genetic Counselor at Sanford Health Explains the Benefits to Genetic Testing

Sanford Health/YouTube

1:06

What Is A Genetic Counselor & The Importance of Genetic Counselling | Ambry Genetics

Ambry Genetics/YouTube

0:45

How Does The Genetic Testing Process Work? Genetic Testing FAQ | Ambry Genetics

Ambry Genetics/YouTube

3:04

Should You Get Genetic Testing During Your Pregnancy?

St. Louis Children's Hospital/YouTube

4:40

Debating Embryonic Genetic Testing -- The Doctors

The Doctors/YouTube

1:31

Genetic Testing for Cancer — AMITA Health | NBC Chicago Ask the Doc

AMITA Health/YouTube

2:10

MedGenome BRCA - Breast Cancer Genetic Testing

MedGenome/YouTube

1:37

Genetic Testing for Hereditary Forms of Kidney Cancer - Brian Shuch, MD

UCLA Health/YouTube

1:43

Do I need Genetic Testing for Ichthyosis?

foundation for ichthyosis/YouTube

2:01

What Is Genetic Testing? Understanding the Process and Its Results

uvahealth/YouTube

3:58

How to Understand Your Genetic Testing Results

Breast Cancer Answers®/YouTube

1:00:31

Genetic Testing 101 for People with Rare Diseases

National Organization for Rare Disorders (NORD)/YouTube

2:05

What's the difference between genetic and genomic testing?

Cancer Treatment Centers of America - CTCA/YouTube

Treatment

Treatment and Prognosis varies depending on the type of condition and the age of symptom onset.

Image by 4144132

Treatment and Prognosis varies depending on the type of condition and the age of symptom onset.

Prognosis varies depending on the type of MND and the age of symptom onset.

Image by 4144132

How Might Cornelia De Lange Syndrome Be Treated?

Because Cornelia de Lange syndrome (CdLS) affects many different systems of the body, medical management is often provided by a team of doctors and other healthcare professionals. Treatment for this condition varies based on the signs and symptoms present in each person. It may include:

Supplemental formulas and/or gastrostomy tube placement to meet nutritional needs and improve the growth delay
Ongoing physical, occupational, and speech therapies
Surgery to treat skeletal abnormalities, gastrointestinal problems, congenital heart defects and other health problems
Medications to prevent or control seizures.

Source: Genetic and Rare Diseases (GARD) Information Center

Prognosis

Prognosis Icon

Image by mcmurryjulie/Pixabay

Prognosis Icon

Image by mcmurryjulie/Pixabay

What Is the Long-Term Outlook for People with Cornelia De Lange Syndrome?

Life expectancy is relatively normal for people with Cornelia de Lange syndrome and most affected children live well into adulthood. For example, one article mentioned a woman with Cornelia de Lange syndrome who lived to age 61 and an affected man who lived to age 54. However, certain features of this condition, particularly severe malformations of the heart or throat, may decrease life expectancy in some affected people.

Source: Genetic and Rare Diseases (GARD) Information Center

Related HealthJournals

Genetic Testing

Genetic testing is a type of medical test that identifies changes in chromosomes, genes, or proteins. Over 2000 tests are available. Genetic testing may be done for many reasons, from newborn baby screening to diagnosing certain diseases. Read about why you might consider testing.

Genetic Counseling

Genetic counseling provides support to people who have, or may be at risk for, genetic disorders. There are many reasons to seek genetic counseling. Learn more about these reasons and what to expect.

Genetic Disorders

A mutation in a person's genes can cause a medical condition called a genetic disorder. Learn more about the types of genetic disorders and how they're diagnosed.

Prenatal Testing

Prenatal testing provides information about your baby's health before he or she is born. Some tests are routine, and some are for women at high risk. Learn how prenatal testing checks on the health of you and your baby during pregnancy.

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Cornelia de Lange Syndrome

Cornelia de Lange syndrome (CdLS) is a developmental disorder that may include distinctive facial characteristics, growth delays, intellectual disability and limb defects. It is usually due to an acquired change (mutation) in one of seven important developmental genes at or shortly after conception. Explore symptoms, causes, and genetics.

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