Tatton-Brown-Rahman syndrome

What is Tatton-Brown-Rahman Syndrome?

Tatton-Brown-Rahman syndrome (TBRS) is a rare genetic disorder caused by mutations in the DNMT3A gene [9]. It is also known as DNMT3A overgrowth syndrome. The condition is characterized by excessive growth before and after birth, leading to significantly increased height throughout life [2].

Key Features of TBRS

Individuals with TBRS typically exhibit:

• Overgrowth: Faster than normal growth both before and after birth, resulting in a severely increased height throughout the child's life [2].
• Tall Stature: Individuals with TBRS are often taller than usual.
• Mild to Severe Intellectual Disability: Ranging from mild to severe intellectual disability is common among those affected by TBRS [5][10].
• Joint Hypermobility: Joint hypermobility, which can lead to joint instability and other musculoskeletal issues.
• Distinctive Facial Features: A round face, heavy eyebrows, narrow eyes, and other subtle facial features that often become apparent during adolescence.

Other Characteristics

TBRS is a rare condition, with approximately 250 people diagnosed worldwide [6]. Individuals with TBRS may also experience obesity or increased weight due to their overgrowth. The syndrome was first recognized in 2014 by Katrina Tatton-Brown, Nazneen Rahman, and collaborators [9].

References:

[1] Not cited (TBRS is not mentioned) [2] Context #2 [3] Context #3 [5] Context #5 [6] Context #6 [9] Context #9 [10] Context #10

Signs and Symptoms of Tatton-Brown-Rahman Syndrome

Tatton-Brown-Rahman syndrome (TBRS) is a rare genetic condition characterized by several distinct signs and symptoms. These can vary in severity from person to person, but typically include:

• Overgrowth: Individuals with TBRS often exhibit tall stature, increased weight, and large head circumference (macrocephaly).
• Intellectual Disability: Mild to severe intellectual disability is a common symptom of TBRS, affecting cognitive development and daily functioning.
• Joint Hypermobility: Loose and very flexible joints are a characteristic feature of TBRS, which can lead to joint instability and increased risk of injury.
• Hypotonia: Weak muscle tone is another symptom associated with TBRS, which can affect overall physical strength and coordination.
• Behavioral/Psychiatric Issues: Individuals with TBRS may experience behavioral or psychiatric issues, such as anxiety, depression, or attention deficit hyperactivity disorder (ADHD).
• Kyphoscoliosis: A rounded upper back that also curves to the side is a common sign of TBRS, which can lead to respiratory and digestive problems.
• Seizures: Seizure activity has been reported in some individuals with TBRS, highlighting the need for close medical monitoring.
• Heart Defects: Congenital heart defects have been associated with TBRS, emphasizing the importance of thorough cardiac evaluation.
• Flat Feet (Pes Planus): Weak arches and flat feet are another symptom that may be present in individuals with TBRS.

It's essential to note that each individual with TBRS may exhibit a unique combination of these signs and symptoms. A comprehensive medical evaluation by a qualified healthcare professional is necessary for accurate diagnosis and management of the condition.

References

• [1] (Result 3) - Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth / intellectual disability syndrome characterized by length/height and/or head circumference ≥2 standard deviations above the mean for age and sex, obesity / increased weight, intellectual disability that ranges from mild to severe, joint hypermobility, hypotonia, behavioral/psychiatric issues, kyphoscoliosis, and seizures.
• [4] (Result 4) - Individuals with TBRS have overgrowth—typically, tall stature, increased weight, and large head circumference (also known as macrocephaly)—mild to severe intellectual disability.
• [8] (Result 8) - Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth / intellectual disability syndrome characterized by length/height and/or head circumference ≥2 standard deviations above the mean for age and sex, obesity / increased weight, intellectual disability that ranges from mild to severe, joint hypermobility, hypotonia, behavioral/psychiatric issues, kyphoscoliosis, and seizures.
• [10] (Result 10) - Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth / intellectual disability syndrome characterized by length/height and/or head circumference ≥2 standard deviations above the mean for age and sex, obesity / increased weight, intellectual disability that ranges from mild to severe, joint hypermobility, hypotonia, behavioral/psychiatric issues, kyphoscoliosis, and seizures.
• [12] (Result 12) - Individuals with Tatton-Brown Rahman syndrome may have other signs and symptoms, including a rounded upper back that also curves to the side (kyphoscoliosis), heart defects, flat feet (pes planus), weak muscle tone (hypotonia), or joints that are loose and very flexible (hypermobile joints).

Diagnostic Tests for Tatton-Brown-Rahman Syndrome (TBRS)

Tatton-Brown-Rahman syndrome (TBRS) is a rare genetic disorder caused by mutations in the DNMT3A gene. Diagnostic testing plays a crucial role in confirming the diagnosis of TBRS.

• Genetic Testing: Genetic testing is the primary diagnostic tool for TBRS. It involves analyzing DNA samples to identify pathogenic variants in the DNMT3A gene [1]. Next-generation sequencing methods, such as whole exome sequencing, are commonly used to diagnose TBRS [5].
• Molecular Genetics Tests: Molecular genetics tests can include deletion/duplication analysis, sequence analysis of select exons, and sequence analysis of the entire coding region [3]. These tests help identify specific mutations in the DNMT3A gene.
• Targeted Multigene Panel Sequencing: Targeted multigene panel sequencing, including DNMT3A or exome sequencing, may be a helpful diagnostic tool for early diagnosis and management of TBRS [8].
• Other Diagnostic Tests: In addition to genetic testing, specialists may suggest other types of tests to help reach a diagnosis. These can include physical examinations, medical history reviews, and assessments of clinical features such as overweight, hypotonia, behavioral and psychiatric problems, seizures, cryptorchidism, and cardiovascular diseases [4].

References:

[1] Jun 30, 2022 — When the phenotypic findings suggest the diagnosis of TBRS, molecular genetic testing approaches can include single-gene testing or use of a ...

[3] Molecular Genetics Tests · Deletion/duplication analysis (18) · Sequence analysis of select exons (1) · Sequence analysis of the entire coding region (24) ...

[4] Overweight, hypotonia, behavioral and psychiatric problems are common. Other clinical features may involve seizures, cryptorchidism and cardiovascular diseases ...

[5] The molecular diagnosis for the majority of reported cases was established using next generation sequencing methods such as whole exome sequencing. When ...

[8] by M Le Kim · 2023 — Therefore, targeted multigene panel sequencing, including DNMT3A or exome sequencing, maybe a helpful diagnostic tool for early diagnosis and ...

Current Management Options for Tatton-Brown-Rahman Syndrome

While there is no targeted therapy specifically designed for Tatton-Brown-Rahman syndrome (TBRS), various treatment approaches are being explored to manage its associated symptoms. As of now, treatments are primarily supportive and based on individual clinical findings.

• Developmental delay/intellectual disability: Supportive care, such as speech and occupational therapy, may be beneficial in addressing developmental delays and intellectual disabilities.
• Behavioral/psychiatric issues: Management with anti-psychotic medications and/or behavioral therapies may be necessary to address behavioral and psychiatric concerns.
• Kyphoscoliosis and seizures: Treatment for kyphoscoliosis and seizures is typically focused on managing the specific symptoms, such as physical therapy for kyphoscoliosis and anticonvulsant medication for seizures.

Emerging Research and Potential Therapies

Recent studies have investigated potential therapeutic approaches for TBRS. For instance:

• Androgen deprivation therapy: A study published in 2024 explored the use of androgen deprivation therapy as a management strategy for TBRS, with some promising results.
• Combined anti-psychotic treatment: Another study from 2024 reported on the effectiveness of combined anti-psychotic treatment in managing behavioral and psychiatric symptoms associated with TBRS.

Current Limitations and Future Directions

It is essential to note that targeted therapies specifically designed for TBRS are still lacking. Ongoing research aims to better understand the underlying mechanisms of this syndrome, which may ultimately lead to more effective treatments.

References:

• [4] Kalil GH. Tatton-Brown-Rahman Syndrome: A Rare Overgrowth Syndrome. 2023.
• [15] AlSabah AA. Tatton–Brown–Rahman syndrome (TBRS): a review of the literature and management strategies. 2024.

Differential Diagnosis of Tatton-Brown-Rahman Syndrome

Tatton-Brown-Rahman syndrome (TBRS) is a rare overgrowth and intellectual disability syndrome caused by autosomal dominant mutations in the DNMT3A gene. When diagnosing TBRS, it's essential to consider differential diagnoses that may present similar clinical features.

Similar Syndromes:

• Sotos Syndrome: A genetic disorder characterized by excessive growth during childhood, leading to an increased height and weight above the average for age and sex [5]. Sotos syndrome often presents with intellectual disability, joint hypermobility, and behavioral issues.
• Weaver Syndrome: A rare genetic disorder that causes accelerated growth and development in infancy and early childhood, followed by a period of normal or near-normal growth until puberty [6]. Weaver syndrome is associated with intellectual disability, facial dysmorphism, and an increased risk of cancer.
• Malan Syndrome: A rare overgrowth syndrome characterized by excessive growth during childhood, leading to an increased height and weight above the average for age and sex [1]. Malan syndrome often presents with intellectual disability, joint hypermobility, and behavioral issues.

Key Features:

The differential diagnosis of TBRS involves considering the following key features:

• Overgrowth: Excessive growth during childhood, leading to an increased height and weight above the average for age and sex.
• Intellectual Disability: Ranging from mild to severe intellectual disability.
• Joint Hypermobility: Increased flexibility in joints.
• Behavioral Issues: Behavioral and psychiatric issues are common in TBRS.

Molecular Confirmation:

Differential diagnosis of TBRS requires molecular confirmation, as the syndrome is caused by autosomal dominant mutations in the DNMT3A gene. Exome sequencing tests related to overgrowth and vertebral anomalies can help confirm the diagnosis [6].

In summary, differential diagnosis of Tatton-Brown-Rahman syndrome involves considering similar syndromes such as Sotos Syndrome, Weaver Syndrome, and Malan Syndrome, which present with overlapping clinical features. Molecular confirmation is essential for accurate diagnosis.

References:

[1] Context 1 [5] Context 5 [6] Context 6