Tatton-Brown-Rahman Syndrome

Tatton-Brown-Rahman syndrome (DNMT3A overgrowth syndrome) is an overgrowth and intellectual disability syndrome caused by heterozygous loss-of-function variants in DNMT3A, with tall stature, a round face, thick eyebrows, hypotonia and a recognised risk of haematological malignancy. Most variants are de novo.

Pathophysiology. DNMT3A encodes a de novo DNA methyltransferase that establishes CpG methylation during development. Haploinsufficiency alters methylation and gene expression, with overgrowth and neurodevelopmental effects.

Somatic DNMT3A variants are common in clonal haematopoiesis and acute myeloid leukaemia, which links the germline syndrome with the malignancy risk.

Surveillance for haematological disease is a point of ongoing study.

• Tall stature and macrocephaly, with advanced bone age in some
• Intellectual disability from mild to moderate, and speech delay
• Facial features: a round face, thick horizontal eyebrows, narrow palpebral fissures, and a prominent central incisor
• Hypotonia and joint hypermobility
• Obesity in later childhood and adulthood
• Behavioural issues: autism features, anxiety and attention problems
• Seizures in a minority
• Kyphoscoliosis, and congenital heart disease in some
• Reported haematological malignancy (acute myeloid leukaemia, lymphoblastic leukaemia, myelodysplasia) and clonal haematopoiesis
• Persistent primary dentition and dental crowding

• DNMT3A sequencing with deletion and duplication analysis, within an overgrowth gene panel or exome sequencing. Testing should use blood or buccal DNA because a mosaic or somatic variant detected in blood can have a different meaning.
• Peripheral blood DNA methylation signature to interpret uncertain variants.
• Parental testing to confirm de novo origin.
• Growth and bone age assessment.
• Blood count and film at diagnosis.
• Developmental assessment, echocardiography and spinal assessment.

Differential diagnosis.

• Sotos syndrome (NSD1)
• Weaver syndrome (EZH2) and Cohen-Gibson syndrome (EED)
• Malan syndrome (NFIX)
• Marfan syndrome
• Clonal haematopoiesis with a somatic DNMT3A variant

• Growth and weight: growth monitoring, dietary advice, structured exercise, and screening for glucose intolerance in obese patients (fasting glucose and HbA1c yearly).
• Haematological surveillance: full blood count at diagnosis and when unexplained fever, bruising, bleeding, bone pain or pallor occurs. Consider a yearly blood count after discussion with the family, because the benefit of routine screening is not established.
• Epilepsy: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily.
• Behaviour and mental health: behavioural support, sertraline 25 to 50 mg daily increasing to a maximum of 200 mg daily for anxiety, and methylphenidate 5 mg once or twice daily increasing weekly by 5 to 10 mg to a usual maximum of 60 mg daily after cardiac review for ADHD.
• Sleep: melatonin 2 to 5 mg 30 to 60 minutes before bed (up to 10 mg if needed).
• Orthopaedic care: yearly spine review, bracing for curves of 20 to 40 degrees, and surgery for progressive curves over 40 degrees.
• Cardiac care: echocardiography at diagnosis, and treatment of structural disease.
• Development and education: early intervention, speech therapy and special education.
• Genetic counselling: de novo variants carry low recurrence risk, with a small risk of germline mosaicism.

Special groups.

• Adults: continue weight, metabolic and mental health care, and keep a low threshold for a blood count with unexplained symptoms.

Monitoring. Growth, weight and development every 6 to 12 months. Blood count at diagnosis and when symptoms occur, glucose yearly in obesity, and spine review yearly.

Referral and escalation. Refer to clinical genetics and paediatric endocrinology. Urgent for pancytopenia, blasts on a blood film, unexplained bleeding or persistent fever.