GENE GUIDE

PHF21A-Related Syndrome

This guide is not meant to take the place of medical advice. Please consult with your doctor about your genetic results and health care choices. This Gene Guide was last updated on 2024. As new information comes to light with new research we will update this page. You may find it helpful to share this guide with friends and family members or doctors and teachers of the person who has PHF21A-Related Syndrome.
a doctor sees a patient

PHF21A-related syndrome is also called intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures. For this webpage, we will be using the name PHF21A-related syndrome to encompass the wide range of variants observed in the people identified.

PHF21A–related syndrome happens when there are changes in the PHF21A gene. These changes can keep the gene from working as it should.

Some people are missing a large segment of DNA that includes the PHF21A gene. This is called Potocki-Shaffer syndrome or 11p11.2-related syndrome, because the missing segment is on part of chromosome 11. Other people have a small change within the PHF21A gene itself. People who have these different syndromes have symptoms that overlap.

Key Role

The PHF21A gene helps to control other genes and is important for the development of the brain.

Symptoms

Because the PHF21A is important in brain activity, many people who have PHF21A-related syndrome have:

  • Developmental delay
  • Intellectual disability
  • Autism
  • Seizures
  • Brain changes seen on magnetic resonance imaging (MRI)
  • Increased weight, height, head size
  • Anxiety
  • Attention deficit hyperactivity disorder, or ADHD

PHF21A-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 PHF21A 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 PHF21A plays a key role in development, de novo variants in this gene can have a meaningful effect. 

Research shows that PHF21A-related syndrome is often the result of a de novo variant in PHF21A. Many parents who have had their genes tested do not have the PHF21A genetic variant found in their child who has the syndrome. In some cases, PHF21A-related syndrome happens because the genetic variant was passed down from a parent.

Autosomal dominant conditions

PHF21A-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in PHF21A they will likely have symptoms of PHF21A-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

GENE / gene
GENE / gene
Genetic variant that happens in sperm or egg, or after fertilization
GENE / gene
Child with de novo genetic variant
gene / gene
Non-carrier child
gene / gene
Non-carrier child

No parent causes their child’s PHF21A-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 foreseen or stopped.

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 PHF21A-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 PHF21A-related syndrome, the sibling’s risk of having a child who has PHF21A-related syndrome depends on the sibling’s genes and their parents’ genes. 

  • If neither parent has the same genetic variant causing PHF21A-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit  PHF21A-related syndrome. 
  • If one biological parent has the same genetic variant causing PHF21A-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 PHF21A-related syndrome, the risk of having a child who has the syndrome is about 50 percent.

As of 2024, at least 32 people with PHF21A-related syndrome have been identified in a medical clinic. The first case of PHF21A-related syndrome was described in 2012.

In Potocki-Shaffer syndrome, people are missing a large segment of DNA that includes the PHF21A gene. Potocki-Shaffer syndrome is more common than PHF21A-related syndrome, but it is also very rare. 

People who have PHF21A-related syndrome may look different. Appearance can vary and can include some but not all of these features:

  • Increased weight, height, head size
  • Flatter than average forehead
  • Prominent bone structure above the eye
  • Broad nasal bridge
  • Down-slanting corners of the mouth

Scientists and doctors have only just begun to study PHF21A-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 PHF21A-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: 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.

Speech and Learning

All people with PHF21A-related syndrome had developmental delay, intellectual disability, and language delay. Intellectual disability ranged from mild to severe.

  • 16 out of 16 people had developmental delay and intellectual disability (100 percent)
  • 12 out of 12 people had language delay (100 percent)

Behavior

Many people with PHF21A-related syndrome had autism, attention deficit hyperactivity disorder (ADHD), or anxiety.

  • 5 out of 14 people had autism (36 percent)
  • 8 out of 11 people had ADHD (73 percent)
  • 7 out of 10 people had an anxiety disorder (70 percent)
36%
5 out of 14 people had autism.
73%
8 out of 11 people had ADHD.
70%
7 out of 10 people had an anxiety disorder.

Brain

Some people with PHF21A-related syndrome had seizures in infancy or childhood. Seizure types included flexor spasms, complex partial seizures, repeated eye blinking and eye-rolling seizures, and generalized tonic-clonic seizures.

Some people had a head size that was larger than average, also called macrocephaly. One person had a head size that was smaller than average, also called microcephaly. Almost all people had brain changes seen on magnetic resonance imaging (MRI).

  • 7 out of 15 people had seizures (47 percent)
  • 6 out of 9 people had macrocephaly (67 percent)
  • 11 out of 13 people had abnormal MRI findings (85 percent)
Human head showing brain outline
47%
7 out of 15 people had seizures.
67%
6 out of 9 people had macrocephaly.
85%
11 out of 13 people had abnormal MRI findings.

Some people had seizures that were difficult to treat, even with more than 2 medications.

Mobility

People who have PHF21A-related syndrome had impaired motor skills, and many people had low muscle tone.

  • 7 out of 11 people had impaired motor skills (64 percent)
  • 7 out of 11 people had low muscle tone (64 percent)

Weight issues

People with PHF21A-related syndrome were at risk of developing obesity.

  • 5 out of 9 people had obesity (56 percent)

Other physical findings

People with PHF21A-related syndrome sometimes had bone formation issues. Physical findings included facial changes and overgrowth issues.

  • 11 out of 12 people had facial findings (92 percent)
  • 11 out of 12 people had overgrowth issues (92 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.”

Sources and References

The content in this guide comes from published studies about PHF21A-related syndrome. Below you can find details about each study, as well as links to summaries or, in some cases, the full article.

  • Kim HG. et al. American Journal of Human Genetics, 91, 56-72, (2012). Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies www.ncbi.nlm.nih.gov/pubmed/22770980
  • Hamanaka K. et al. European Journal of Human Genetics, 27, 378-383, (2019). De novo truncating variants in PHF21A cause intellectual disability and craniofacial anomalies www.ncbi.nlm.nih.gov/pubmed/30487643
  • Butera, A., Nicotera, A. G., Di Rosa, G., Musumeci, S. A., Vitello, G. A., Musumeci, A., Vinci, M., Gloria, A., Federico, C., … Calì, F. (2022). PHF21A related disorder: Description of a new case. International Journal of Molecular Sciences, 23(24), 16130. https://pubmed.ncbi.nlm.nih.gov/36555772/
  • Chen, H., Chen, Y., Wu, H., Qiu, X., Yu, X., Wang, R., Zhong, J., & Peng, J. (2023). De novo variants in PHF21A cause intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures: A case report and literature review. Seizure, 111, 138-146. https://pubmed.ncbi.nlm.nih.gov/37633153/
  • Kim, H. G., Rosenfeld, J. A., Scott, D. A., Bénédicte, G., Labonne, J. D., Brown, J., McGuire, M., Mahida, S., Naidu, S., … Kim, C. H. (2019). Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism. Molecular Autism, 10, 35. https://pubmed.ncbi.nlm.nih.gov/31649809/