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 2021, roughly 250 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

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