Tatton Brown Rahman Syndrome

Disease Overview

Summary

Tatton Brown Rahman syndrome (TBRS), also known as DNMT3A overgrowth syndrome, 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 changes (variants) in the DNMT3A gene. 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.

Introduction

TBRS was first identified in 2014. As of 2024, approximately 450 individuals have been diagnosed with TBRS, though the number of individuals with TBRS is likely much higher.

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Synonyms

• TBRS
• DNMT3A overgrowth syndrome

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Signs & Symptoms

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).

Overgrowth
Most individuals with TBRS have a larger head circumference than average at birth (macrocephaly) and/or tall stature.

Obesity
Many individuals with TBRS are overweight and may be diagnosed with obesity.

Intellectual Disability and Developmental Delay
Intellectual disability can vary with a spectrum of mild to severe. Affected people also have developmental delays (DD) which may be present in motor function, speech, language, cognitive abilities and social skills. Severity of DD varies, though nonverbal and spatial reasoning skills appear to be more significantly affected 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 is autism spectrum disorder. Other psychiatric and behavioral problems that have been identified include anxiety, aggression, psychotic disorders, bipolar disorder, obsessive behaviors and compulsive eating.

Joint Hypermobility
Excessive range of motion of joints (hypermobility) has been observed in many people with TBRS with varying degrees of severity.

Hypotonia
Low muscle tone (hypotonia) is common from infancy in children with TBRS.

Kyphoscoliosis
Abnormal spine curvature including kyphosis, scoliosis, or combination of both (kyphoscoliosis) are relatively common in individuals with TBRS.

Seizures
Seizures, with and without fever, have been reported in 20% of people with TBRS. Neuroimaging or EEG abnormalities are also common. Less is known about the prevalence of recurrent seizures (epilepsy) in people with TBRS.

Cardiac Conditions
Cardiac (heart) conditions have also been reported with relatively high frequency in TBRS. Aortic root dilation has been reported most often, though other conditions such as congenital heart defects, mitral valve prolapse, cardiomyopathy and arrhythmias have also been reported.

Cancer and Malignancies
Cancer, tumors and other malignancies have been reported in individuals with TBRS. The most common malignancy is acute myeloid leukemia (AML). Some publications suggest a 200% increase in risk for AML in some people with TBRS. Lifetime cancer risk is unknown.

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Causes

TBRS is caused by changes (pathogenic variants) in the DNMT3A (DNA methyltransferase 3 alpha) gene which produces the DNMT3A enzyme. The function of this enzyme is not completely understood, but it is believed that it is responsible for methylating DNA. Methylation is a process involving the addition of methyl groups to DNA. People with TBRS have 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), though inherited variants do occur as well.

TBRS follows autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

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Affected populations

The incidence and prevalence of TBRS are unknown. Since 2014, the TBRS Community is aware of more than 450 individuals with TBRS. Individuals have been diagnosed at different ages. This syndrome seems to affect males and females equally.

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Disorders with Similar Symptoms

Genetically Related Disorders

There are several disorders that are genetically similar to TBRS. Heyn-Sproul-Jackson syndrome (commonly abbreviated as HESJAS) is one such disorder. This disorder is characterized by pathogenic variants in DNMT3A as well. However, these pathogenic variants cause a gain-of-function in the DNMT3A enzyme, resulting in symptoms that have been described as the opposite of TBRS. These symptoms include a small head (microcephaly) and short stature (dwarfism).

Sporadic tumors like those in acute myeloid leukemia and myelodysplastic syndrome result from a sporadic gene variant that occurs later in life and is not inherited.

Phenotypically (Symptomatic) Related Disorders

Prior to the discovery of TBRS, many people with TBRS were misdiagnosed with Sotos syndrome due to the similarities between the conditions, including overgrowth and developmental disabilities. Commonalities also include behavioral issues, intellectual disability and neurological issues. Sotos syndrome presents with craniofacial features that are similar but distinct from TBRS. Sotos syndrome is caused by pathogenic variants in the NSD1 gene. Sotos syndrome and TBRS can be differentiated by genetic testing.

Weaver syndrome is another disorder similar to TBRS. This condition is also characterized by overgrowth, intellectual disability and low muscle tone (hypotonia). Joint problems may also be common in this disorder. Affected individuals have craniofacial features that are similar but distinct from those present in TBRS. Weaver syndrome is caused by variants in the EZH2 gene.

Individuals with Marfan syndrome have similar characteristics to those diagnosed with TBRS. Marfan syndrome is characterized by tall stature and lax joints. These individuals may also present with scoliosis, eye and heart problems and chest wall differences. However, intellectual disability is not usually associated with Marfan syndrome. Marfan syndrome is caused by variants in the FBN1 gene and can be inherited in an autosomal dominant pattern.

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Diagnosis

Clinical features that may lead to suspicion of TBRS include:

– Generalized overgrowth in infancy, adolescence or childhood

– Mild-to-severe 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

–Cardiovascular conditions and structural issues

–Orthopedic issues such as spine curvature (scoliosis or kyphosis)

–Seizures or abnormal neurological readings

–Acute myeloid leukemia or other hematologic malignancies

Diagnosis is confirmed by genetic testing that shows 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 are associated with different overgrowth syndromes.

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Standard Therapies

Current therapies for TBRS involve the management of symptoms. Creation of a treatment plan may aid in this process.

Genetic counseling is recommended to help affected individuals and their family members understand the implications of TBRS, the risks associated with the syndrome and treatments that may be needed.

Clinical and developmental assessments can help determine what motor, speech, language, cognitive, early intervention and adaptive therapies are needed and the risk for continued overgrowth. Neuropsychiatric evaluation may aid in screening for behavioral health or mental health concerns. Evaluation by a neurologist may be recommended if the person has seizures and to identify new neurological symptoms. If sleep apnea is diagnosed and is obstructive, a respiratory physician will likely need to be involved.

Speech therapy and occupational therapy may help individuals develop necessary skills. Behavioral therapy may also be helpful for individuals with TBRS. Physical therapy may be useful to treat low muscle tone and orthopedic problems.

Spine curvature may require therapies, devices, or surgery.

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 the TBRS Community.

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Clinical Trials and Studies

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:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES

Grens K, et al. Epilepsy and overgrowth–intellectual disability syndromes: a patient organization perspective on collaborating to accelerate pathways to treatment. Therapeutic Advances in Rare Disease. 2024;5. doi:10.1177/26330040241254123

Cecchi AC, et al. Aortic root dilatation and dilated cardiomyopathy in an adult with Tatton-Brown-Rahman syndrome. American Journal of Medical Genetics Part A. 2021. doi: 10.1002/ajmg.a.62541

Chen M, et al. Tatton-Brown-Rahman syndrome associated with the DNMT3A gene: a case report and literature review. Chinese Journal of Contemporary Pediatrics. 2021; 22(10):1114-1118. doi: 10.7499/j.issn.1008-8830.2004078

Chen DY, et al. Dnmt3a deficiency in the skin causes focal, canonical DNA hypomethylation and a cellular proliferation phenotype. PNAS. 2021;118(16):e2022760118. doi: 10.1073/pnas.2022760118

Lennartsson O, et al. Case report: Bilateral epiphysiodesis due to extreme tall stature in a girl with a de novo DNMT3A variant associated with Tatton-Brown-Rahman syndrome. Frontiers in Endocrinology. 2021;12:752756. doi: 10.3389/fendo.2021.752756

Smith AM et al. Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome. Nature Communications. 2021;12:4549.

Tovy A, et al. Perturbed hematopoiesis in individuals with germline DNMT3A overgrowth Tatton-Brown-Rahman syndrome. Haematolgica. 2021. doi: 10.3324/haematol.2021.278990

Aref-Eshghi E, et al. Evaluation of DNA methylation episignatures for diagnosis and phenotype correlations in 42 Mendelian neurodevelopmental disorders. American Journal of Human Genetics. 2020;106:356-370.

Balci TB, et al. Tatton‐Brown‐Rahman syndrome: Six individuals with novel features. American Journal of Medical Genetics. 2020. doi:10.1002/ajmg.a.61475

Christian DL, et al. DNMT3A haploinsufficiency results in behavioral deficits and global epigenomic dysregulation shared across neurodevelopmental disorders. Cell Reports. 2020; 33:108416.

Ketkar S, et al. Remethylation of Dnmt3a−/− hematopoietic cells is associated with partial correction of gene dysregulation and reduced myeloid skewing. PNAS. 2020;117(6):3123-3134. doi: 10.1073/pnas.1918611117

Paz-Alegría M-C, et al. Behavioral and dental management of a patient with Tatton-Brown-Rahman syndrome: Case report. Spec Care Dentist. 2020;40(6):597-604. doi: 10.1111/scd.12513

Tovy A, et al. Tissue-biased expansion of DNMT3A-mutant clones in a mosaic individual is associated with conserved epigenetic erosion. Cell Stem Cell. 2020; 27:326-335.e4.

Yokoi T, et al. Tatton-Brown-Rahman syndrome with a novel DNMT3A mutation presented severe intellectual disability and autism spectrum disorder. Human Genome Variation. 2020; 7:15. doi: 10.1038/s41439-020-0102-6

Hage C, et al. Acromegaly in the setting of Tatton-Brown-Rahman syndrome. Pituitary. 2019. doi:10.1007/s11102-019-01019-w

Lane C, et al. Tatton‐Brown‐Rahman syndrome: cognitive and behavioural phenotypes. Developmental Medicine & Child Neurology. 2019. doi:10.1111/dmcn.14426

Lee CG, et al. First identified Korean family with Tatton-Brown-Rahman syndrome caused by the novel DNMT3A variant c.118G>C p.(Glu40Gln). Annals of Pediatric Endocrinology & Metabolism. 2019;24:253-6.

Sweeney KJ, et al. The first case report of medulloblastoma associated with Tatton‐Brown–Rahman syndrome. American Journal of Medical Genetics. 2019. doi:10.1002/ajmg.a.61180

Tenorio J. Further delineation of neuropsychiatric findings in Tatton-Brown-Rahman syndrome due to disease-causing variants in DNMT3A: seven new patients. European Journal of Human Genetics. 2019. doi:10.1038/s41431-019-0485-3

Miyoshi Y, et al. Seventeen-year observation in a Japanese female case of Tatton-Brown-Rahman syndrome: overgrowth syndrome with intellectual disability. ESPE Abstracts 2018;89:P-P2-273.

Tatton-Brown K, et al. The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants. Wellcome Open Research 2018;3:46.

Hollink IHIM, et al. Acute myeloid leukaemia in a case with Tatton-Brown-Rahman syndrome: the peculiar DNMT3A R882 mutation. Journal of Medical Genetics. 2017;54:805-8.

Lemire G, et al. A case of familial transmission of the newly described DNMT3A‐Overgrowth Syndrome. American Journal of Medical Genetics. 2017. doi:10.1002/ajmg.a.38119

Shen W, et al. The spectrum of DNMT3A variants in Tatton–Brown–Rahman syndrome overlaps with that in hematologic malignancies. American Journal of Medical Genetics. 2017. doi:10.1002/ajmg.a.38485

Tatton-Brown K, et al. Mutations in epigenetic regulation genes are a major cause of overgrowth with intellectual disability. AJHG. 2017;100:725-6.

Kosaki R, et al. Acute myeloid leukemia-associated DNMT3A p.Arg882His mutation in a patient with Tatton-Brown-Rahman overgrowth syndrome as a constitutional mutation. American Journal of Medical Genetics. 2016. doi:10.1002/ajmg.a.37995

Okamoto N, et al. Tatton-Brown-Rahman syndrome due to 2p23 microdeletion. American Journal of Medical Genetics. 2016. doi:10.1002/ajmg.a.37588

Tlemsani C, et al. SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort. Journal of Medical Genetics. 2016;53(11):743-751. doi: 10.1136/jmedgenet-2015-103638

Xin B, et al. Novel DNMT3A germline mutations are associated with inherited Tatton-Brown-Rahman syndrome. Clinical Genetics. 2016. doi:10.1111/cge.12878

Tatton-Brown K, et al. Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nature Genetics. 2014 46:385-8.

INTERNET

Ostrowski PJ, Tatton-Brown K. Tatton-Brown-Rahman Syndrome. 2022 Jun 30. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK581652/ Accessed Feb 24, 2025.

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Patient Organizations

Tatton Brown Rahman Syndrome Community

NORD Member

Email: [email protected]

Related Rare Diseases: Tatton Brown Rahman Syndrome, Síndrome de Tatton Brown Rahman

https://rarediseases.org/organizations/tatton-brown-rahman-syndrome-community/

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More Information

The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.

GARD Disease Summary

The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).

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Orphanet

Orphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.

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OMIM

Online Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.

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GeneReviews

GeneReviews has an article on this condition covering diagnosis, management, and inheritance. Each article is written by one or more experts on the specific disease and is reviewed by other specialists. The article contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. The GeneReviews database is managed by the University of Washington.

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MedlinePlus

MedlinePlus has information about this condition that may include a description, frequency, causes, inheritance, and links to more information. The information is written for the public, including patients, caregivers and families. MedlinePlus is a service of the National Library of Medicine (NLM), which is part of the National Institutes of Health (NIH).

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