About TBRS

Tatton Brown
Rahman Syndrome

Overview

Tatton Brown Rahman Syndrome (TBRS) is a rare genetic disease caused by pathogenic variants (previously called mutations) in the DNMT3A gene and for that reason it is also called DNMT3A Overgrowth Syndrome. Individuals with TBRS have overgrowth—typically, tall stature, increased weight, and large head circumference (also known as macrocephaly)—mild to severe intellectual disability, and subtle but distinctive facial characteristics. There are a variety of other symptoms that are also associated with TBRS, such as low muscle tone, behavioral and mental health issues, orthopedic problems, cardiac defects, and autism, but not all individuals have every clinical finding reported, and the syndrome varies considerably in its severity.

TBRS was first identified in 13 individuals by Dr. Katrina Tatton-Brown, Dr. Nazneen Rahman, and colleagues in 2014 as part of a research study, based in London, into the genetic causes of overgrowth. Since then, a number of other clinicians around the world have identified additional TBRS individuals with pathogenic variants in DNMT3A. In 2018, Dr. Tatton-Brown and her collaborators described 55 individuals with the syndrome, including the original 13.

As of 2020, roughly 150 people have been diagnosed with TBRS. It is not clear how common the syndrome is, but many more individuals are likely to be diagnosed as whole genome sequencing methods becomes more accessible. There is currently no cure for TBRS, and clinical care is focused on managing the particular clinical findings in each individual.

Download our two-page fact sheet or our pamphlet that includes individual profiles to share with doctors, teachers, care givers, and anyone interested in learning about TBRS.

Symptoms

The main features of TBRS are overgrowth, intellectual disability, and certain facial characteristics. Some people may develop other clinical findings, and as researchers continue to learn more about the syndrome they will have a better handle on just how common these additional symptoms and signs are. The severity of each finding listed below varies for each person.

Overgrowth

Overgrowth is the most common aspect of TBRS. Among 55 individuals with TBRS, 44 of them, or 83 percent, had overgrowth, according to a study by Dr. Tatton-Brown and colleagues published in 2018. Overgrowth is defined by being at least two standard deviations above average for height and/or head circumference. In addition, 67 percent of people in the study were obese.

Intellectual disability

In the 2018 study, all 55 individuals had intellectual disability (ID)—in 18 percent of them it was mild, in 65 percent moderate, and in 16 percent it was severe. Children with mild ID needed some supports in school but attended a mainstream classroom and adults with mild ID could live independently with some additional help. Those with moderate and severe ID required more intensive special education and supports as adults. A study in 2019 of 18 individuals identified a similar finding, with 15 individuals reported as having intellectual disability (ranging from mild to severe) and three individuals who had borderline intellectual functioning. Learning disability is also common among individuals with TBRS.

Facial characteristics

Certain facial characteristics are associated with TBRS, but these are usually more evident in teens and adults rather than children. These may include horizontal and thick eyebrows, narrow eye slits (also called palpebral fissures) that are occasionally deep set and down-slanting, a round face, broad forehead, and large, protruding front teeth (the top incisors), smooth philtrum, and thin upper lip. For the most part, these are subtle characteristics, although it is not uncommon for individuals with TBRS to require extensive orthodontic interventions to correct dental issues.

Joint hypermobility

One of the most common features of TBRS is joint hypermobility, in which the joints are loose, causing double jointedness. This can occasionally lead to joint dislocation, recurring injuries, and a susceptibility to cartilage, tendon, and ligament tears and joint pain.

Low muscle tone

Low muscle tone, or hypotonia, can lead to delayed physical milestones—such as sitting up, crawling, or walking—and poor posture, coordination, and balance. Although uncommon, some individuals with TBRS use a wheelchair. Others have benefited from physical therapy or orthotics.

Kyphoscoliosis

About one-third of individuals with TBRS have reported having kyphoscoliosis, in which the spine curves from side to side and/or from front to back of the torso.

Mental and behavioral health disorders

In 2019, researchers described seven individuals with TBRS who were identified from the Spanish Overgrowth Syndromes Registry. Four had one or more neuropsychiatric disorders, including schizophrenia, attention deficit hyperactivity disorder, psychosis, or aggression.

Also in 2019, Dr. Chloe Lane reported on the analysis of 18 people with TBRS and found a heightened prevalence of autistic traits, with eight scoring on the autism spectrum. Parents of children with TBRS have also reported aggressive outbursts, autistic features, and anxiety.

Seizures

Some people with TBRS have experienced seizures with and without a concurrent fever (those that occur in the presence of a fever are called febrile seizures).

The following are less frequently reported than the conditions above:

Cardiac defects, such as atrial septal defect (a hole in the heart)

Brain malformations, such as enlarged ventricles (ventriculomegaly) and Chiari formation (in which the brain dips down into the spinal column)

Undescended testes

Strabismus (crossed eye)

Sleep disorder including sleep apnea

Hyperphagia, or increased appetite

Insensitivity to pain

Genetics

TBRS is caused by variants in the DNA sequence for the gene DNMT3A. Each gene consists of a string of building blocks called nucleotides, or molecular letters that spell out its sequence. Variants, also referred to as mutations, are deviations from the usual spelling of that gene. Although all cases of TBRS involve variants in DNMT3A, the exact spelling change is not the same for all individuals. For example, the DNMT3A gene is nearly 120,000 base pairs long; some individuals may have some or all of the gene missing, while others may have a single “letter” misspelled.

The DNMT3A sequence instructs the body’s cells to produce a protein called DNA methyltransferase 3 alpha. The protein is involved in a process called DNA methylation, which adds molecules called methyl groups to one kind of base in the DNA, called cytosine. The presence of a methyl group on certain cytosine residues near a gene can sometimes influence or control the activity of that gene. It is thought that abnormal methylation caused by DNMT3A variants in individuals with TBRS leads to dysfunctional gene regulation, resulting in the TBRS-associated symptoms.

Schematic of the DNMT3A-mediated de novo DNA methylation, showing the methyl group as a green ball added to DNA (purple and yellow helix)
Courtesy of Jikui Song, University of California, Riverside

Mutations in DNMT3A that cause TBRS are always heterozygous, meaning they are only on one of the two copies of the gene that each person has. Therefore, individuals with TBRS have one normal copy of DNMT3A that produces a normal protein and one copy that makes an abnormally functioning protein.

It appears that most documented cases of TBRS arose from spontaneous and brand new changes in the gene (called de novo mutations), rather than variants inherited from the person’s parents. Rarely, individuals may have inherited the DNMT3A variant from a parent who does not have TBRS but has the mutation in a subset of cells. This is called mosaicism. If the subset of cells with a pathogenic variant in DNMT3A includes the sperm or eggs, known as the germline, this is called germline mosaicism and means it is possible to pass down the DNMT3A variant to their children. Researchers have identified one family in the US in which the children inherited a DNMT3A variant from their healthy father who had mosaicism and they were diagnosed with TBRS. For the screening process it is highly important to test cells or tissues other than the blood, such as in a check swab, as DNMT3A mutations can be found in normal aging of blood cells.

For individuals with TBRS, because each parent provides one copy of a gene to their child, and someone with TBRS has one normal copy and one abnormal copy, individuals with the syndrome have a 50 percent chance of having a child with the genetic mutation.

To date, doctors have documented two families in which a parent with TBRS has had children who also have TBRS. In Korea, a woman passed down the DNMT3A variant to her daughter, and both of them have TBRS. The mother also has an unaffected son who has a normal DNMT3A sequence. In Canada, a father passed down a DNMT3A variant to both his children, and all three have TBRS.

Genetic counseling is important to help clarify the inheritance pattern of TBRS.

Leukemia connection

In 2010, Dr. Timothy Ley at Washington University School of Medicine and his collaborators first found that many patients with acute leukemia have mutations in the DNMT3A gene. These are newly acquired mutations that occur only in blood forming cells, and are now known to be the most common mutations that initiate leukemia in adults. These patients do not have TBRS, because the mutations are present only in blood forming cells and their progeny (the generations of cells that emerge from repeated rounds of cell division), and these mutations are therefore not passed down to children. Many of the DNMT3A mutations associated with acute myeloid leukemia (AML) development are also found in TBRS patients, raising the concern that some inherited DNMT3A mutations may create an increased risk of leukemia or other cancers in TBRS patients.

There have been several patients with inherited DNMT3A mutations who have developed cancer (leukemia in six patients, a neuroblastoma and a secondary leukemia in one patient, and a medulloblastoma in one patient). However, it is not clear at this time the precise risk for malignancy and what proportion of individuals with TBRS will end up developing cancer. Of particular concern are individuals with TBRS who have mutations in particular location of the DNMT3A gene, called Arg882, which also is the most common site of mutations in leukemia. So far, three children with TBRS whose DNMT3A variant occurs at Arg882 have developed leukemia.

If someone with TBRS shows possible signs of leukemia, such as unexplained bruising, infections, paleness, or fatigue, a qualified physician should be immediately contacted to have blood counts tested.

For these reason, Dr. Ley, Dr. Ayala Tovy at Baylor College of Medicine, and other researchers are investigating the symptoms associated with TBRS. They also investigate whether TBRS is linked with an increased risk for malignancy. If you are interested in participating in this research by donating blood samples, please contact us. One goal of this work is to make cell lines from these patients that could be distributed to investigators around the world to facilitate the study of TBRS-associated DNMT3A mutations.

Prevalence

Doctors do not yet know how common TBRS is in the general population, because it was discovered so recently. So far, more than 150 people have been diagnosed, according to an informal list of individuals gathered by The TBRS Community, and around 70 individuals documented in the medical literature. There are likely many more people who will be diagnosed as genetic sequencing becomes more commonplace in medicine. Contact us if you have been diagnosed to receive our essential packet of information and to join our community.

The TBRS Community is working in partnership with the National Organization for Rare Disorders (NORD) to develop a global patient registry, and we will update the website with more information as we have it.

Diagnosis and interpreting genetic results

TBRS is diagnosed through a clinical evaluation and molecular genetic testing. Specifically, individuals have both a variant in the sequence for the DNMT3A gene that is thought to disrupt its function and, commonly, overgrowth, intellectual disability, and distinct facial characteristics. For those seeking a diagnosis, a visit with a medical geneticist is in order. Your primary care physician or your child’s pediatrician can help arrange an appointment. Genetic sequencing can be extremely expensive without insurance coverage, so it is critical to ask about benefits and out-of-pocket costs in advance.

Doctors typically obtain a biological sample as a source of DNA (genetic material) through a cheek swab, which involves rubbing a q-tip along the inside of the mouth, or through a blood specimen. The sample is then sent to a laboratory for sequencing and then analysis. The results typically take several weeks or longer to come back. The geneticist and a genetic counselor will arrange a counseling visit to help you understand the results of the test.

Geneticists have a variety of sequencing tests at their disposal. Most commonly in the search for a diagnosis of a rare genetic disease, doctors will order a chromosomal microarray or whole-exome sequencing as an initial investigation. A chromosomal microarray hunts for abnormalities in chromosomes—the bundles of DNA in our cells. Each person has two versions of 23 chromosomes, totalling 46. A microarray can detect if a chromosome is missing a chunk of DNA (called a deletion) or has extra material (called a duplication). A chromosomal microarray will not detect the sequence variants that are the usual cause of TBRS.

Because a microarray cannot determine the exact sequence of a gene, other methods are used to read the sequencing of the gene (also called DNA sequencing), including gene panel sequencing or whole-exome sequencing (WES). The genome has stretches of DNA that provide instructions for making proteins (these are the “coding” regions and, combined, these sequences are called the exome) and stretches of DNA in between these regions that do not code for proteins. Gene panel testing will investigate families of genes associated with similar clinical presentations (for example, genes associated with overgrowth and intellectual disability). Whole-exome sequencing determines the molecular spelling of each gene in the exome. Both techniques can pinpoint any abnormalities down to a single nucleotide of DNA, but WES includes more genes than gene panel testing. The molecular diagnosis for the majority of reported cases was established using next generation sequencing methods such as whole exome sequencing.

When geneticists spot an atypical sequence in a gene, they investigate whether that difference might influence the instructions for making its corresponding protein. In some cases, a change in sequence will make a protein dysfunctional or completely impair its production. These are called pathogenic variants or mutations. In other situations, a change in sequence will make no difference to the structure of function of the protein; these are called benign variants.

With TBRS, changes to the DNMT3A gene alter the function of the DNA methyltransferase 3 alpha protein or eliminate it altogether. Most frequently, the DNMT3A alterations that cause TBRS affect one or two of the nucleotides in the gene. Less frequently, larger deletions have been shown to cause TBRS. When a genetic alteration is known to affect a protein and cause disease, it is called it a pathogenic variant. If a change has not yet been confirmed to cause disease, but very likely disrupts the protein, it’s called likely pathogenic. Changes that do not affect the protein or are unlikely to are called benign and likely benign, respectively. In some cases, it’s not clear whether the genetic abnormality will affect the protein, and this is called a variant of uncertain significance.

Medical care and preventive screening

Doctors familiar with TBRS recommend patients see the following specialists:

  • Physical therapist, speech therapist, occupational therapist
    Physical therapy can help address individuals’ hypotonia, or low muscle tone, by strengthening muscles and coordination. Physical therapists also work with orthotists to determine if orthotics (foot inserts or braces) are appropriate. Occupational therapy can help address deficiencies in fine motor skills and day-to-day functional activities, while speech therapy can improve people’s expressive (spoken) and receptive (comprehension) language.
    For young children, states’ Early Intervention programs can screen for eligibility to receive subsidized services. Older children may access these services through the school district, and adults, through their medical insurance or local adult services programs.
  • Developmental support
    Some parents have reported that their children have learning disabilities and sensory processing disorder, in which people have difficulty integrating information coming from various inputs, such as visual, aural, and touch. Anecdotally, families have identified similar learning styles among their loved ones with TBRS. It may be important to allow a lot of opportunity and repetition to practice new skills, to encourage social interaction and participation in extra-curricular groups, and to encourage peer mentorship opportunities. In addition, it may be helpful to provide visual cues (visual models, visual schedule, visual timers, picture exchange cards, etc.) in conjunction with any verbal information or instruction. It may be necessary to keep verbal instructions more concise, and to gain joint attention before providing information. Multi-sensory learning modalities are also beneficial.
  • Geneticist and genetic counselor
    To coordinate care and screenings, and keep families updated on new developments with the diagnosis.
  • A neurologist, orthopedic physician, psychiatrist, or behavioral therapist should be consulted if specific issues arise.
  • Cardiologist
    Some individuals with TBRS have congenital cardiac defects (that is, defects they were born with), such as atrial or ventral septal defects or patent ductus arteriosus. In other individuals, cardiac problems such as aortic root enlargement and tachycardia develop later. Patients should see a cardiologist at diagnosis for a baseline echocardiogram and then follow up as indicated by this initial screen and ongoing symptoms.