November 22, 2022
Years published: 2022
NORD gratefully acknowledges Kit Church, Research Coordinator, TBRS Community, Kerry Grens, MS, Vice President, TBRS Community, Dept of Neuroscience Director of Marketing Services, Washington University School of Medicine in St. Louis, Jill Kiernan, Executive Director, TBRS Community, and Kate Tatton-Brown, MD, Consultant Clinical Geneticist, Institute of Cancer Research and St. George’s Universities NHS Foundation Trust, for the preparation of this report.
Tatton Brown Rahman Syndrome (TBRS), also known as DNMT3A overgrowth syndrome, was first identified in 2014. TBRS is a complex multisystem disorder involving many different tissues including the nervous system, muscle and blood. It is associated with tall stature, increased weight and/or large head circumference (macrocephaly). Individuals typically have mild to severe intellectual disability, as well as subtle but distinctive facial characteristics. There are a variety of other symptoms associated with TBRS, such as low muscle tone, behavioral and mental health issues, orthopedic problems, heart defects and autism, but not all individuals have every clinical finding reported and the syndrome varies considerably in its severity.
TBRS is caused by germline/constitutional variants (pathogenic variants) in the DNMT3A gene. Germline/constitutional refers to a variant that is present in all cells. Most DNMT3A gene variants occur spontaneously (de novo) which means they are not inherited from a parent. Some individuals have inherited the disorder from an affected parent in an autosomal dominant pattern. As of 2022, approximately 300 individuals have been diagnosed with TBRS, though the number of individuals with TBRS is likely much higher.
The severity and symptoms of TBRS vary from person to person. Patients and parents should consult with their physician to determine risks for specific symptoms and a plan for medical management.
Distinctive Facial Appearance
Individuals with TBRS tend to have facial characteristics that include low-set, heavy, horizontal eyebrows, prominent upper central incisors, rounded face and a reduction in the vertical space between the upper and lower eyelids (narrow palpebral fissures).
Most individuals with TBRS have a larger head circumference than average at birth (macrocephaly) and/or tall stature.
Many individuals with TBRS are overweight and may be diagnosed with obesity.
Intellectual Disability and Developmental Delay
Intellectual disability (ID) can vary across patients, with a spectrum of mild to severe ID. Patients also experience developmental delays (DD), which may be present in motor function, speech, language, cognitive abilities and social skills. Severity of DD varies among patients, though nonverbal and spatial reasoning skills appear to be more significantly affected in these individuals than verbal reasoning.
Psychiatric and Behavioral Disorders
Psychiatric and behavioral disorders are common in individuals with TBRS and may take different forms. The most common behavioral diagnosis in TBRS patients is autism spectrum disorder. Other psychiatric and behavioral problems that have been identified in TBRS patients include anxiety, aggression, psychotic disorders, bipolar disorder, obsessive behaviors and compulsive eating.
TBRS is caused by pathogenic variants in the DNMT3A (DNA methyltransferase 3 alpha) gene, which produces the DNMT3A enzyme. The function of DNMT3A is not completely understood, but it is believed that this enzyme is responsible for methylating DNA. Methylation is a process involving the addition of methyl groups to DNA: methylation results in transcriptional repression. Patients with TBRS have pathogenic variants in the DNMT3A gene that prevent the DNMT3A enzyme from functioning properly, causing a suspected decreased methylation (hypomethylation).
Many of the identified gene variants are unique to the individual. Most of these variants are not inherited but arise for the first time in the affected individual (de novo inheritance), though inherited variants do occur as well. DNMT3A variants are autosomal dominant. Autosomal dominant genetic conditions occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
The incidence and prevalence of TBRS are unknown. Since 2014, the TBRS Community is aware of more than 300 individuals with TBRS. Individuals have been diagnosed at different ages. This syndrome seems to affect males and females equally.
Rare Disease Database.)
Clinical features that may lead to suspicion of TBRS include:
– Generalized overgrowth in infancy, adolescence or childhood
– Intellectual disability or developmental delay
– Distinctive facial features
– Joint hypermobility
– Low muscle tone (hypotonia)
– Behavioral problems including autism spectrum disorder and a variety of other characteristics
Diagnosis is confirmed by genetic testing revealing a pathogenic variant in the DNMT3A gene. Variants that disrupt the function of DNMT3A cause TBRS, so the specific variant is necessary for diagnosis. Due to the similarities between this syndrome and other overgrowth syndromes, genetic testing may include a gene panel consisting of many genes that cause different overgrowth syndromes.
Current therapies for TBRS involve management of symptoms. Genetic counseling may help to inform affected individuals and caregivers of the implications of TBRS, the risks associated with the syndrome and medical actions that may be needed. Creation of a treatment plan may aid in this process.
Clinical and developmental assessment can aid in motor, speech, language, cognitive and adaptive evaluation, evaluation for early intervention and risk for continued overgrowth beyond a healthy threshold. Neuropsychiatric evaluation may aid in screening for behavioral health or mental health concerns. Evaluation by a neurologist may be recommended if the patient experiences seizures, as well as to identify new neurological manifestations. Similarly, if sleep apnea is diagnosed and obstructive, a respiratory physician will likely need to be involved.
Speech therapy may be useful for individuals following evaluation. Occupational therapy is frequently utilized by these patients as well to develop necessary skills. Behavioral therapy may also be utilized for individuals with TBRS. Physical therapy may be useful for low muscle tone and orthopedic problems.
Routine cardiovascular screening is suggested due to the increased frequency of heart conditions in patients with TBRS. Monitoring by a hematologist may be suggested due to the potential increased risk for acute myeloid leukemia (AML) and other blood conditions.
Family support and resources are available for individuals affected by TBRS and their families/caregivers from TBRS Community via Facebook or the following link: https://tbrsyndrome.org.
There are currently no clinical trials being conducted for TBRS. More information regarding clinical trials can be found through the Tatton Brown Rahman Syndrome Community at https://tbrsyndrome.org
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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