GENE GUIDE

ZBTB20-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 ZBTB20-Related Syndrome.
a doctor sees a patient

ZBTB20-related syndrome is also called Primrose syndrome and intellectual disability-cataracts-calcified pinnae-myopathy syndrome. For this webpage, we will be using the name ZBTB20-related syndrome to encompass the wide range of variants observed in the people identified.

ZBTB20-related syndrome happens when there are changes in the ZBTB20 gene. These changes can keep the gene from working as it should.

Key Role

The ZBTB20 gene plays a key role in development.

Symptoms

Because the ZBTB20 gene is important for brain activity, many people who have ZBTB20-related syndrome have:

  • Intellectual disability
  • Hearing loss
  • Outer ear calcification
  • Speech delay
  • Vision issues
  • Large head
  • Obesity
  • Muscle wasting and contractures
  • Brain changes observed on magnetic resonance imaging (MRI)
  • Behavior issues, such as autism, self-injury, aggression

ZBTB20-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 ZBTB20 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 ZBTB20 plays a key role in development, de novo variants in this gene can have a meaningful effect.

Research shows that ZBTB20-related syndrome is often the result of a de novo variant in ZBTB20. Many parents who have had their genes tested do not have the ZBTB20 genetic variant found in their child who has the syndrome. In some cases, ZBTB20-related syndrome happens because the genetic variant was passed down from a parent.

Autosomal dominant conditions

ZBTB20-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in ZBTB20 they will likely have symptoms of ZBTB20-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 ZBTB20 gene?

No parent causes their child’s ZBTB20-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 ZBTB20-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 ZBTB20-related syndrome, the sibling’s risk of having a child who has ZBTB20-related syndrome depends on the sibling’s genes and their parents’ genes.

  • If neither parent has the same genetic variant causing ZBTB20-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit ZBTB20-related syndrome.

As of 2024, about 78 people with ZBTB20-related syndrome have been identified in a medical clinic.

People who have ZBTB20-related syndrome may look different. Appearance can vary and can include some but not all of these features:

  • Deeply set eyes
  • Higher hairline
  • Drooping eyelids
  • Larger than average ears and jaw
  • Changes inside the mouth, such as a high roof of the mouth and a bony growth on the roof of the mouth

Scientists and doctors have only just begun to study ZBTB20-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 ZBTB20-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.

Speech and Learning

People with ZBTB20-related syndrome had intellectual disability (ID) and speech delay. Most people had moderate to severe ID and about 1 in 7 people had mild ID. Most people had better receptive speech (the ability to understand information) than expressive speech (the use of words and gestures to communicate).

  • 55 out of 55 people had intellectual disability (100 percent)

Behavior

Behavioral disorders occurred in people with ZBTB20-related syndrome, including autistic behavior, attention-deficit/hyperactivity disorder, temper tantrums, self-injurious behavior, and sleep disturbances.

  • 29 out of 39 people had autism (74 percent)

Brain

Some people with ZBTB20-related syndrome had seizures. People had brain changes observed on magnetic resonance imaging (MRI), including developmental defects of the corpus callosum, delayed brain myelination and brain calcification.

  • 7 out of 33 people had seizures (21 percent)
  • 20 out of 40 people had developmental defects of the corpus callosum (50 percent)
  • 7 out of 38 people had delayed brain myelination (18 percent)
  • 5 out of 38 people had brain calcification (14 percent)
21%
7 out of 33 people had seizures.
50%
20 out of 40 people had developmental defects of the corpus callosum.
18%
7 out of 38 people had delayed brain myelination.
14%
5 out of 38 people had brain calcification.

Most people with ZBTB20-related syndrome had a larger than average head size, also called macrocephaly.

  • 9 out of 22 newborns had macrocephaly (41 percent)
  • 23 out of 28 children had macrocephaly (82 percent)
  • 8 out of 21 adults had macrocephaly (38 percent)
Human head showing brain outline

Vision and hearing

Some people had strabismus (crossed eyes) and cataracts, and most people had hearing loss. Many people had calcification of the external ear cartilage.

  • 12 out of 34 people had strabismus (35 percent)
  • 7 out of 34 people had cataracts (21 percent)
  • 37 out of 45 people had hearing loss (83 percent)
35%
12 out of 34 people had strabismus.
21%
7 out of 34 people had cataracts.
83%
37 out of 45 people had hearing loss.

Movement

Most people were able to walk by 2 or 3 years old, and they had hypotonia (low muscle tone). As people got older, they had muscle wasting of the arms and legs and muscle contractures in the knees and elbows. Some people had ataxia (poor muscle control that causes clumsy movements).

  • 28 out of 37 people had hypotonia (76 percent)
  • 14 out of 37 people had muscle wasting of the arms and legs (38 percent)
  • 16 out of 35 people had muscle contractures (46 percent)
  • 10 out of 26 people had a movement disorder called ataxia (38 percent)
76%
28 out of 37 people had hypotonia.
38%
14 out of 37 people had muscle wasting of the arms and legs.
46%
16 out of 35 people had muscle contractures.
38%
10 out of 26 people had a movement disorder called ataxia.

Hormones

People with ZBTB20-related syndrome had very little body hair, delayed puberty with an average age of onset at 16 years old, and diabetes. Some people had hypothyroidism.

  • 15 out of 16 people had very little body hair (93 percent)
  • 5 out of 14 people had delayed puberty (36 percent)
  • 11 out of 29 people had diabetes (39 percent)

Other issues

About one-half of males had undescended testicles. Some people had bone deformities or curvature of the spine, also called scoliosis.

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

  • Cordeddu V. et al. Nature Genetics, 46, 815-817, (2014). Mutations in ZBTB20 cause Primrose syndrome, www.nature.com/articles/ng.3035.
  • Stellacci E. et al. Human Mutation, 39, 959-964, (2018). Clinical and functional characterization of two novel ZBTB20 mutations causing Primrose syndrome, onlinelibrary.wiley.com/doi/abs/10.1002/humu.23546.
  • Melis D. et al. Clinical Genetics, 97, 890-901, (2020). Primrose syndrome: Characterization of the phenotype in 42 patients, www.ncbi.nlm.nih.gov/pmc/articles/PMC7384157/.
  • Arora, V., Ferreira, C. R., Dua Puri, R., & Verma, I. C. Primrose syndrome. 2021 Jun 17. 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/NBK570205/
  • Li, J., Zhang, C., Tian, X., Zhou, B., Chen, X., Wang, Y., Hao, S., Hui, L., & Meng, Z. (2024). Novel de novo mutation in ZBTB20 in a Chinese Primrose syndrome family and a review of the literature. Molecular Genetics & Genomic Medicine, 12(1), e2304. https://pubmed.ncbi.nlm.nih.gov/38087819/
  • Moon, Y. M., Park, S. E., Smith-Hicks, C., & Hauptman, A. (2024). Resolution of severe neurobehavioral difficulties in an individual with Primrose syndrome with sertraline. American Journal of Medical Genetics Part A, 194(8), e63610. https://pubmed.ncbi.nlm.nih.gov/38517161/

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