GENE GUIDE

PPP2CA-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 PPP2CA-Related Syndrome.
a doctor sees a patient

PPP2CA-related syndrome is also called Houge-Janssens syndrome 3. For this webpage, we will be using the name PPP2CA-related syndrome to encompass the wide range of variants observed in the people identified.

PPP2CA-related syndrome happens when there are changes to the PPP2CA gene. These changes can keep the gene from working as it should.

Key Role

The PPP2CA gene plays an important role in the development and function of brain cells.

Symptoms

Because the PPP2CA gene is important in brain activity, many people who have PPP2CA-related syndrome have:

  • Global developmental delay
  • Intellectual disability
  • Speech delay
  • Mild delay in walking
  • Autism
  • Brain changes seen on magnetic resonance imaging (MRI)
  • Feeding challenges

PPP2CA-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 PPP2CA 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 PPP2CA plays a key role in development, de novo variants in this gene can have a meaningful effect. 

Research shows that PPP2CA-related syndrome is often the result of a de novo variant in PPP2CA. Many parents who have had their genes tested do not have the PPP2CA genetic variant found in their child who has the syndrome. In some cases, PPP2CA-related syndrome happens because the genetic variant was passed down from a parent.

Autosomal dominant conditions

PPP2CA-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in PPP2CA they will likely have symptoms of PPP2CA-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

Why does my child have a change in the PPP2CA gene?

No parent causes their child’s PPP2CA-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.

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 PPP2CA-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 PPP2CA-related syndrome, the sibling’s risk of having a child who has GENE-related syndrome depends on the sibling’s genes and their parents’ genes. 

  • If neither parent has the same genetic variant causing PPP2CA-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit  PPP2CA-related syndrome. 
  • If one biological parent has the same genetic variant causing PPP2CA-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 PPP2CA-related syndrome, the risk of having a child who has the syndrome is about 50 percent.

As of 2024, at least 38 people with PPP2CA-related syndrome have been identified in a medical clinic.

People who have PPP2CA-related syndrome may look different. Appearance can vary and can include some but not all of these features:

  • Larger or smaller than average head size
  • Taller than average forehead
  • Wide-set eyes
  • A noticeable nasal tip
  • Lower than average muscle tone

Scientists and doctors have only just begun to study PPP2CA-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 PPP2CA-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/…t-is-epilepsy/seizure-types

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.

There are few research publications on people with PPP2CA-related syndrome. The information below includes 17 people. The oldest person included was 23 years old.

Speech and Learning

All people with PPP2CA-related syndrome had intellectual disability or developmental delay. Most people had speech delays.

  • 17 out of 17 people had intellectual disability or developmental delay (100 percent)
  • 10 out of 14 people had speech delay (71 percent)

Behavior

About one-half of people had autism or other behavioral issues, such as attention deficit hyperactivity disorder, also called ADHD. A few people had a developmental regression or psychotic episode.

  • 8 out of 16 people had autism (50 percent)
  • 2 out of 16 people had reported regression in skills (13 percent)
  • 1 out of 15 people had psychotic episodes (7 percent)
50%
8 out of 16 people had autism.
13%
2 out of 16 people had reported regression in skills.
7%
1 out of 15 people had psychotic episodes.

Brain

Some people with PPP2CA-related syndrome had a smaller or larger than average head. Many had brain changes seen on magnetic resonance imaging (MRI). Brain imaging showed dilated ventricles, delayed myelination, and dysplasia or absence of the corpus callosum.

  • 2 out of 15 people had a larger than average head size, macrocephaly (13 percent)
  • 5 out of 15 people had a smaller than average head size, microcephaly (33 percent)
  • 10 out of 16 people had findings on MRI (63 percent)
13%
2 out of 15 people had a larger than average head size, macrocephaly.
33%
5 out of 15 people had a smaller than average head size, microcephaly.
62%
10 out of 16 people had findings on MRI.

Seizures were common for people with PPP2CA-related syndrome. There were various seizure types observed, including fever-induced seizures, epileptic encephalopathy, focal seizures, generalized tonic-clonic seizures, Jeavons syndrome, and hypsarrhythmia.

  • 10 out of 16 people had seizures (63 percent)

Other issues

Many people had lower than average muscle tone and feeding difficulties. Fewer than one-half had vision issues.

  • 11 out of 16 people had lower than average muscle tone (69 percent)
  • 10 out of 16 people had feeding difficulties (63 percent)
  • 6 out of 14 people had vision problems (43 percent)
69%
11 out of 16 people had lower than average muscle tone.
63%
10 out of 16 people had feeding difficulties.
43%
6 out of 14 people had vision problems.

Where can I find support and resources?

Jordan’s Guardian Angels Website

Jordan’s Guardian Angels’ mission is to conduct research seeking answers to rare genetic mutations affecting children and adults, and assist and improve the quality of life for children and families.

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 PPP2CA-related syndrome.

  • Reynhout, S., … Vissers, L. (2019). De novo mutations affecting the catalytic Cα subunit of PP2A, PPP2CA, cause syndromic intellectual disability resembling other PP2A-related neurodevelopmental disorders. American Journal of Human Genetics, 104(2), 357. doi:10.1016/j.ajhg.2019.01.003
  • Verbinnen, I., Procknow, S. S., Lenaerts, L., Reynhout, S., Mehregan, A., Ulens, C., Janssens, V., & King, K. A. (2022). Clinical and molecular characteristics of a novel rare de novo variant in PPP2CA in a patient with a developmental disorder, autism, and epilepsy. Frontiers in Cell and Developmental Biology, 10, 1059938. doi:10.3389/fcell.2022.1059938

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