NIPBL-Related Syndrome
NIPBL-related syndrome is also called Cornelia de Lange syndrome 1. For this webpage, we will be using the name NIPBL-related syndrome to encompass the wide range of variants observed in the people identified.
Genetic variants in other genes can also result in a person having Cornelia de Lange syndrome.
What is NIPBL-related syndrome?
NIPBL-related syndrome happens when there are changes in both copies of the NIPBL gene. These changes can keep the gene from working as it should.
Key Role
The NIPBL gene plays an important role in human development and cell division throughout the body.
Symptoms
Because the NIPBL gene is important for development, some people may have:
- Intellectual disability
- Language delay
- Heart defects
- Frequent pneumonia
- Gastrointestinal reflux and feeding issues
- Genital issues in males
- Various kidney structure and function problems
- Higher than average muscle tone
- Low-pitched growling cry in infants
- Hearing loss
- Seizures
- Self-injury behavior
What causes NIPBL-related syndrome?
NIPBL-related syndrome is a genetic condition, which means that it is caused by variants in genes. Our genes contain the instructions, or code, that tell our cells how to grow, develop, and work. Every child gets two copies of the NIPBL gene: one copy from their mother’s egg, and one copy from their father’s sperm. In most cases, parents pass on exact copies of the gene to their child. But the process of creating the egg or sperm is not perfect. A change in the genetic code can lead to physical issues, developmental issues, or both.
Sometimes a spontaneous variant happens in the sperm, egg or after fertilization. When a brand new genetic variant happens in the genetic code is called a ‘de novo’ genetic variant. The child is usually the first in the family to have the genetic variant.
De novo variants can take place in any gene. We all have some de novo variants, most of which don’t affect our health. But because NIPBL plays a key role in development, de novo variants in this gene can have a meaningful effect.
Research shows that NIPBL-related syndrome is often the result of a de novo variant in NIPBL. Many parents who have had their genes tested do not have the NIPBL genetic variant found in their child who has the syndrome. In some cases, NIPBL-related syndrome happens because the genetic variant was passed down from a parent.
Autosomal dominant conditions
NIPBL-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in NIPBL they will likely have symptoms of NIPBL-related syndrome. For someone with an autosomal dominant genetic syndrome, every time they have a child there is a 50 percent chance they pass on the same genetic variant and a 50 percent chance they do not pass on the same genetic variant.
Autosomal Dominant Genetic Syndrome
Why does my child have a change in the NIPBL-related syndrome gene?
No parent causes their child’s NIPBL-related syndrome. We know this because no parent has any control over the gene changes that they do or do not pass on to their children. Please keep in mind that nothing a parent does before or during the pregnancy causes this to happen. The gene change takes place on its own and cannot be predicted or stopped.
What are the chances that other family members of future children will have NIPBL-related syndrome?
Each family is different. A geneticist or genetic counselor can give you advice on the chance that this will happen again in your family.
The risk of having another child who has NIPBL-related syndrome depends on the genes of both biological parents.
- If neither biological parent has the same genetic variant found in their child, the chance of having another child who has the syndrome is on average 1 percent. This 1 percent chance is higher than the chance of the general population. The increase in risk is due to the very unlikely chance that more of the mother’s egg cells or the father’s sperm cells carry the same genetic variant.
- If one biological parent has the same genetic variant found in their child, the chance of having another child who has the syndrome is 50 percent.
For a symptom-free brother or sister of someone who has NIPBL-related syndrome, the sibling’s risk of having a child who has NIPBL-related syndrome depends on the sibling’s genes and their parents’ genes.
- If neither parent has the same genetic variant causing NIPBL-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit NIPBL-related syndrome.
- If one biological parent has the same genetic variant causing NIPBL-related syndrome, the symptom-free sibling has a 50 percent chance of also having the same genetic variant. If the symptom-free sibling has the same genetic variant, their chance of having a child who has the genetic variant is 50 percent.
For a person who has NIPBL-related syndrome, the risk of having a child who has the syndrome is about 50 percent.
How many people have NIPBL-related syndrome?
As of 2025, about 471 people with NIPBL-related syndrome have been identified in medical research. Cornelia de Lange syndrome is estimated to occur in 1 in 10,000 to 1 in 30,000 births.
Cornelia de Lange syndrome is caused by a genetic variant in NIPBL in more than one-half of people identified.
Do people who have NIPBL-related syndrome look different?
People who have NIPBL-related syndrome may look different. Facial features can include some or all of the following:
- Short height, following their own growth curves
- Growth failure that might be seen on ultrasound
- Smaller than average head size
- Small jaw
- Low-set ears
- Heavy eyelids
- Long curly eyelashes
- Thin upper lip
- Short neck
- Blushing more often than average
- Limb and hand development issues
How is NIPBL-related syndrome treated?
Scientists and doctors have only just begun to study NIPBL-related syndrome. At this point, there are no medicines designed to treat the syndrome. A genetic diagnosis can help people decide on the best way to track the condition and manage therapies. Doctors can refer people to specialists for:
- Physical exams and brain studies.
- Genetics consults.
- Development and behavior studies.
- Other issues, as needed.
A developmental pediatrician, neurologist, or psychologist can follow progress over time and can help:
- Suggest the right therapies. This can include physical, occupational, speech, or behavioral therapy.
- Guide individualized education plans (IEPs).
Specialists advise that therapies for NIPBL-related syndrome should begin as early as possible, ideally before a child begins school.
If seizures happen, consult a neurologist. There are many types of seizures, and not all types are easy to spot. To learn more, you can refer to resources such as the Epilepsy Foundation’s website: www.epilepsy.com/learn/types-seizures.
This section includes a summary of information from major published articles. It highlights how many people have different symptoms. To learn more about the articles, see the Sources and references section of this guide.
Behavior and development concerns linked to NIPBL-related syndrome
People with NIPBL-related syndrome may have the characteristic Cornelia de Lange syndrome 1 medical features. But, as more people are being identified, researchers have found that there are people with NIPBL-related syndrome who have milder features.
People with mild features might have more variable cognitive disabilities and changes in the limbs.
Research suggests that people who have a loss of function variant or a truncating variant in the end region of the NIPBL gene may have more severe medical features compared with people who have missense variants or truncating variants in the beginning region of the NIPBL gene.
Speech and learning
Most, but not all, people with NIPBL-related syndrome had developmental delays or intellectual disabilities. Often people had more difficulty with expressing themselves than with understanding what was being communicated to them.
- 95 percent of people had developmental delays or intellectual disabilities
Behavior
People with NIPBL-related syndrome had behavioral issues, such as autism or features of autism, repetitive behavior, anxiety, attention-deficit/hyperactivity disorder (ADHD), and self-injury behavior.
- 56 to 70 percent of people had self-injury behavior
Brain
Exactly 1 in 4 people with NIPBL-related syndrome had seizures, most commonly partial epilepsy that developed before the age of 2 years. Some people had a smaller than average head size (microcephaly) and sleeping difficulties, such as frequent waking during the night or extremely short sleep requirements.
- 25 percent of people had seizures
Medical and physical concerns linked to NIPBL-related syndrome
Birth defects
Exactly 4 out of 5 people with NIPBL-related syndrome had foot defects, and 1 out of 4 people had severe hand or arm defects, such as a reduction or absence of hands or arms. Just over 1 in 10 people had kidney or genital changes, such as small genitalia or the opening of the urethra on the underside of the penis in males, or a uterus divided into two parts in females. Some people were born with heart defects. These included a hole in the heart (ventral or atrial septal defect), a narrowing of the valve within the heart, or a narrowing of the arteries that branch off to the lungs.
- 80 percent of people had foot defects, such as webbed toes
- 25 percent of people had severe hand or arm defects
- 12 percent of people had kidney or genital changes
- 30 percent of people had heart defects
Eyes and hearing
Many people who have NIPBL-related syndrome had vision problems, typically droopy upper eyelids (ptosis), nearsightedness, and uncontrolled eye movements (nystagmus). Some people had sensorineural hearing impairment and or conductive hearing impairment, and some people had hearing loss that improved with time.
- 60 percent had ptosis
- 60 percent had nearsightedness
- 37 percent had nystagmus
- 40 percent had sensorineural hearing impairment
- 40 percent had conductive hearing impairment
Walking
One-half of people were walking by the age of 2 years old, and almost all were walking by the age of 10 years old.
Feeding and digestion issues
Most people had gastroesophageal reflux disease (GERD) and complications of GERD, such as aspiration and inflammation of the esophagus. About 1 in 3 people had aspiration, and some people with aspiration needed a feeding tube.
Puberty
Delayed puberty was seen in both males and females.
Where can I find support and resources?
Cornelia de Lange Syndrome Foundation
The Cornelia de Lange Syndrome (CdLS) Foundation provides a host of services for anyone touched by this little-known genetic syndrome and other isolating conditions.
Simons Searchlight
Simons Searchlight is an online international research program, building an ever growing natural history database, biorepository, and resource network of over 175 rare genetic neurodevelopmental disorders. By joining their community and sharing your experiences, you contribute to a growing database used by scientists worldwide to advance the understanding of your genetic condition. Through online surveys and optional blood sample collection, they gather valuable information to improve lives and drive scientific progress. Families like yours are the key to making meaningful progress. To register for Simons Searchlight, go to the Simons Searchlight website at www.simonssearchlight.org and click “Join Us.”
- Learn more about Simons Searchlight: www.simonssearchlight.org/frequently-asked-questions
- Simons Searchlight webpage with more information on NIPBL: www.simonssearchlight.org/research/what-we-study/nipbl
- Simons Searchlight NIPBL Facebook community: https://www.facebook.com/groups/nipbl
Sources and References
The content in this guide comes from published studies about NIPBL-related syndrome. Below you can find details about each study.
- Deardorff, M.A., Noon, S.E., & Krantz, I.D. Cornelia de Lange syndrome. 2020 Oct 15. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1104/
- Gruca-Stryjak, K., Doda-Nowak, E., Dzierla, J., Wróbel, K., Szymankiewicz-Bręborowicz, M., & Mazela, J. (2024). Advancing the clinical and molecular understanding of Cornelia de Lange syndrome: A multidisciplinary pediatric case series and review of the literature. Journal of Clinical Medicine, 13(8), 2423. https://pmc.ncbi.nlm.nih.gov/articles/PMC11050916/
- Ng, R., O’Connor, J., Summa, D., & Kline, A. D. (2024). Neurobehavioral and developmental profiles: Genotype-phenotype correlations in individuals with Cornelia de Lange syndrome. Orphanet Journal of Rare Diseases, 19(1), 111. https://pmc.ncbi.nlm.nih.gov/articles/PMC10926648/