CREBBP-Related Syndrome
CREBBP-related syndrome is also called Rubinstein-Taybi syndrome 1 and Menke-Hennekam syndrome-1. For this webpage, we will be using the name CREBBP-related syndrome to encompass the wide range of variants observed in the people identified.
What is CREBBP-related syndrome?
CREBBP-related syndrome happens when there are changes in the CREBBP gene. These changes can keep the gene from working as it should.
A related gene called EP300 has a similar function to the CREBBP gene.
Key Role
The CREBBP and EP300 genes play a key role in controlling the activity of other genes.
Symptoms
Because the CREBBP gene is important in brain development and function, many people who have CREBBP-related syndrome have:
- Developmental delay
- Intellectual disability
- Growth problems, short height, smaller than average head size
- Hearing loss
- Upper airway infections
- Feeding difficulties
- Autism
- Seizures
- Speech delay
- Risk for tumor formation, especially in the head
- Risk for leukemia
What causes CREBBP-related syndrome?
CREBBP-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 CREBBP 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 CREBBP plays a key role in development, de novo variants in this gene can have a meaningful effect.
Research shows that CREBBP-related syndrome is often the result of a de novo variant in CREBBP. Many parents who have had their genes tested do not have the CREBBP genetic variant found in their child who has the syndrome. In some cases, CREBBP-related syndrome happens because the genetic variant was passed down from a parent.
Autosomal dominant conditions
CREBBP-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in CREBBP they will likely have symptoms of CREBBP-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 CREBBP gene?
No parent causes their child’s CREBBP-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 CREBBP-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 CREBBP-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 CREBBP-related syndrome, the sibling’s risk of having a child who has CREBBP-related syndrome depends on the sibling’s genes and their parents’ genes.
- If neither parent has the same genetic variant causing CREBBP-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit CREBBP-related syndrome.
How many people have CREBBP-related syndrome?
As of 2024, at least 493 people with CREBBP-related syndrome have been identified in a medical clinic. The first case of Rubinstein-Taybi syndrome was described in 1995. Scientists estimate that the condition happens in 1 in 100,000 to 1 in 125,000 live births.
Do people who have CREBBP-related syndrome look different?
People who have CREBBP-related syndrome may look different. Appearance can vary and can include some but not all of these features:
- Short height
- A small head, also called microcephaly
- Facial features that are different from those of other family members
- Thick eyebrows
- Wide thumbs that may be positioned differently on the hand
- Big first toes
How is CREBBP-related syndrome treated?
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:
- Genetics consults
- Development and behavior studies
- Neurological studies
- Orthopedic studies
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 CREBBP-related syndrome should begin as early as possible, ideally before a child begins school.
People who have CREBBP-related syndrome may have a higher risk of developing tumors. These may be cancerous or non-cancerous. Your doctor can recommend whether you need additional screening or to consult a specialist.
In 2024, international experts collaborated on guidelines and care for people with Rubinstein-Taybi syndrome. Go to this link to read the recent recommendations, which include clinical criteria to distinguish between Rubinstein-Taybi syndrome and Menke-Hennekam syndrome. Feel free to share this with your medical team.
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 Rubinstein-Taybi syndrome caused by a variant in CREBBP
The information below includes information on Rubinstein-Taybi syndrome (RTS) caused by a variant in CREBBP. Variants in CREBBP that cause Menke-Hennekam syndrome are summarized in the next section below. Variants that cause Menke-Hennekam syndrome are pathogenic missense variants or in-frame deletion variants in exons 30 and 31. Talk to your genetics team to find out what type of variant was identified in your family.
Speech and Learning
Almost all people with RTS CREBBP-related syndrome had developmental delay or intellectual disability (ID). People had moderate to severe ID. Infants spoke their first words around 2 years of age.
- 306 out of 309 people had developmental delay or intellectual disability (99 percent)
Behavior
About one-half of people with RTS CREBBP-related syndrome had behavioral issues, such as autism, self-injurious behavior, and aggressive behavior. People were often described as motivated to interact with others and ‘overly-friendly’.
- 151 out of 309 people had autism (49 percent)
Brain
Some people with RTS CREBBP-related syndrome had seizures, and more than one-half of people had non-specific abnormalities on electroencephalogram (EEG). About one-half had a smaller than average head size, also known as microcephaly. Some people with CREBBP-related syndrome had brain changes seen on magnetic resonance imaging (MRI).
- 77 out of 309 people had seizures (25 percent)
- 167 out of 309 people had microcephaly (54 percent)
Medical and physical concerns linked to Rubinstein-Taybi syndrome caused by a variant in CREBBP
Growth
Some people with RTS CREBBP-related syndrome were born with heart defects. This includes patent ductus arteriosus, persistent foramen ovale, and atrial and ventricular septal defect.
Often babies had delayed growth after birth, which appeared as a child dropping off the standard growth curve chart. In general, people did not have a growth spurt during puberty. Obesity was a problem for about one in three people.
- 108 out of 309 people had heart defects (35 percent)
- 232 out of 309 people had postnatal growth delay (75 percent)
- 90 out of 309 people had obesity (29 percent)
Gastrointestinal tract and urinary tract issues
It was common for people with RTS CREBBP-related syndrome to have constipation into adulthood. Some people had urinary tract issues, such as horseshoe kidney, kidney duplication, kidney agenesis, kidney dysplasia, hydronephrosis, nephrolithiasis, and vesicoureteral reflux.
- 235 out of 309 people had constipation (76 percent)
- 86 out of 309 people had urinary tract defects (28 percent)
Behavior and development concerns linked to Menke-Hennekam syndrome
The information below includes information on Menke-Hennekam (MKHK) syndrome caused by a variant in CREBBP or EP300. Variants in these two genes that cause Menke-Hennekam syndrome are pathogenic missense variants or in-frame deletion variants in exons 30 and 31. Talk to your genetics team to find out what type of variant was identified in your family.
Some researchers organize MKHK into sub-types. The information in this summary does not include sub-types.
Speech and Learning
Almost all people with MKHK syndrome had developmental delay or intellectual disability (ID). People spoke their first words at an average age of 2.6 years.
- 39 out of 40 people had developmental delay or intellectual disability (98 percent)
Behavior
Many people with MKHK syndrome had behavioral issues, such as autism.
- 27 out of 38 people had behavioral issues (71 percent)
Brain
Some people with MKHK syndrome had seizures.
- 7 out of 43 people had seizures (16 percent)
Medical and physical concerns linked to Menke-Hennekam syndrome
Growth
Some people with MKHK syndrome were born with heart defects. People were often shorter than average, underweight, and had a smaller than average head circumference. Some babies were born premature and were smaller than average at birth.
- 11 out of 42 people had heart defects (26 percent)
- 6 out of 44 babies were born premature (14 percent)
Feeding and digestion
Many people with MKHK syndrome had feeding issues, constipation, and acid reflux.
- 36 out of 43 people had feeding issues (84 percent)
- 20 out of 37 people had constipation (54 percent)
- 16 out of 35 people had acid reflux (46 percent)
Musculoskeletal issues
People with MKHK syndrome had curvature of the spine, both scoliosis and kyphosis. People also had hip dysplasia; higher than average muscle tone and/or lower than average muscle tone; and defects of the extremities, including clubbed feet. Dental defects, including missing teeth, were common.
Vision and hearing issues
Some people with MKHK syndrome had strabismus (crossed eyes), other vision impairments, and hearing impairments.
- 24 out of 40 people had strabismus (60 percent)
- 12 out of 43 people had other vision impairments (28 percent)
- 15 out of 40 people had hearing impairments (38 percent)
Where can I find support and resources?
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 CREBBP – www.simonssearchlight.org/research/what-we-study/crebbp
- Simons Searchlight CREBBP Facebook community – https://www.facebook.com/groups/crebbp
Sources and References
The content in this guide comes from published studies about CREBBP-relaetd syndrome. Below you can find details about each study, as well as links to summaries or, in some cases, the full article.
- Milani D. et al. Italian Journal of Pediatrics, 41, 4, (2015). Rubinstein-Taybi syndrome: Clinical features, genetic basis, diagnosis, and management www.ijponline.biomedcentral.com/articles/10.1186/s13052-015-0110-1
- López M. et al. BMC Medical Genetics, 19, 36, (2018). Rubinstein-Taybi 2 associated to novel EP300 mutations: Deepening the clinical and genetic spectrum www.ncbi.nlm.nih.gov/pubmed/29506490
- Haghshenas, S., Bout, H. J., Schijns, J. M., Levy, M. A., Kerkhof, J., Bhai, P., McConkey, H., Jenkins, Z. A., Williams, E. M., … Menke, L. A. (2024). Menke-Hennekam syndrome; delineation of domain-specific subtypes with distinct clinical and DNA methylation profiles. Human Genetic and Genomics Advances, 5(3), 100287. https://pubmed.ncbi.nlm.nih.gov/38553851/
- Lacombe, D., Bloch-Zupan, A., Bredrup, C., Cooper, E. B., Houge, S. D., García-Miñaúr, S., Kayserili, H., Larizza, L., Lopez Gonzalez, V., … Hennekam, R. C. (2024). Diagnosis and management in Rubinstein-Taybi syndrome: First international consensus statement. Journal of Medical Genetics, 61(6), 503-519. https://pubmed.ncbi.nlm.nih.gov/38471765/
- Stevens, C. A. Rubinstein-Taybi syndrome. 2003 Nov 9. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1526/