Tatton-Brown Syndrome
Tatton-Brown-Rahman Syndrome (TBRS)
Overview
Tatton-Brown-Rahman Syndrome is a rare genetic condition characterized by overgrowth, distinctive facial features, and intellectual disability. First described in 2014, it is caused by mutations in the DNMT3A gene.
Key Points
- Also known as DNMT3A-overgrowth syndrome
- Characterized by constitutional overgrowth from birth
- Associated with variable intellectual disability
- Autosomal dominant inheritance pattern
- Most cases result from de novo mutations
Epidemiology
- Rare condition with approximately 100 reported cases worldwide
- Affects males and females equally
- No ethnic predisposition identified
Clinical Manifestations
Growth Characteristics
- Increased height (>2 SD above mean)
- Increased head circumference (macrocephaly)
- Advanced bone age
- Rapid growth velocity during childhood
Facial Features
- Broad forehead
- Horizontal eyebrows
- Heavy, horizontal eyelids
- Prominent chin
- Low-set ears
- Narrow, high-arched palate
- Coarse facial features
Neurological Features
- Intellectual disability (mild to severe)
- Speech delay
- Motor developmental delay
- Behavioral issues:
- Autism spectrum features
- Anxiety
- Social communication difficulties
- Attention deficit hyperactivity disorder
Skeletal Features
- Joint hypermobility
- Kyphosis/scoliosis
- Long, slender fingers
- Large hands and feet
Additional Features
- Hypotonia
- Cardiac anomalies (in some cases)
- Renal abnormalities
- Vision problems
- Increased cancer risk
Genetic Basis
Molecular Genetics
- Caused by mutations in DNMT3A gene
- Located on chromosome 2p23.3
- Encodes DNA methyltransferase 3A
- Critical for DNA methylation
- Role in epigenetic regulation
- Essential for normal development
- Involved in gene expression control
- Important in cellular differentiation
Inheritance Pattern
- Autosomal dominant
- Most cases are de novo mutations
- 50% transmission risk if parent affected
Genotype-Phenotype Correlations
- Variable expressivity
- Specific mutations may correlate with severity
- Ongoing research in phenotypic spectrum
Diagnostic Approach
Clinical Diagnostic Criteria
- Tall stature (>2 SD above mean)
- Macrocephaly
- Characteristic facial features
- Intellectual disability/developmental delay
Genetic Testing
- Molecular genetic testing options:
- Single-gene testing of DNMT3A
- Multi-gene panel
- Genome/exome sequencing
- Interpretation considerations
Differential Diagnosis
- Sotos syndrome
- Weaver syndrome
- Marshall-Smith syndrome
- Beckwith-Wiedemann syndrome
- Other overgrowth syndromes
Treatment and Management
Multidisciplinary Care
- Clinical geneticist
- Developmental pediatrician
- Neurologist
- Orthopedic specialist
- Educational specialist
- Behavioral therapist
Surveillance Recommendations
- Regular growth monitoring
- Annual developmental assessment
- Orthopedic evaluation
- Cardiac screening
- Vision and hearing assessments
- Cancer surveillance protocol
Interventions
- Early intervention programs
- Speech therapy
- Occupational therapy
- Physical therapy
- Behavioral support
- Educational support
Current Research and Future Directions
Active Research Areas
- Natural history studies
- Genotype-phenotype correlations
- Cancer risk assessment
- Therapeutic interventions
- Epigenetic mechanisms
Clinical Trials
- Registry studies
- Natural history studies
- Potential therapeutic approaches
