BRRS Syndrome: Genetic Insights, Indicators, and Care

BRRS syndrome, or Bannayan-Riley-Ruvalcaba syndrome, is a rare genetic disorder affecting multiple body systems. It is often identified in early childhood due to distinctive physical features and developmental differences. Early recognition is crucial for managing complications and improving quality of life.

A multidisciplinary approach is essential for diagnosis and care. Understanding its genetic basis, key symptoms, and associated conditions helps guide medical management and support strategies.

Genetic Mechanisms

BRRS syndrome is primarily caused by pathogenic variants in the PTEN gene, which regulates cell growth, proliferation, and apoptosis by modulating the PI3K/AKT signaling pathway. When PTEN function is disrupted, unchecked cellular expansion occurs, contributing to the overgrowth features seen in BRRS. The condition follows an autosomal dominant inheritance pattern, meaning a single altered gene copy is sufficient to cause the disorder. However, its severity varies among affected individuals.

PTEN mutations reduce tumor suppressor activity, linking BRRS to other PTEN hamartoma tumor syndromes (PHTS), including Cowden and Proteus syndromes. A range of mutations, from missense and nonsense variants to large deletions, influence the disorder’s severity. Advances in genetic testing, including whole-exome sequencing and targeted gene panels, have improved early diagnosis and risk assessment.

PTEN normally acts as a negative regulator of the PI3K/AKT/mTOR axis, preventing excessive cell division and promoting apoptosis. In BRRS, reduced PTEN activity increases signaling through this pathway, contributing to hamartomatous growths and macrocephaly. Mouse models with PTEN deletions exhibit similar traits, reinforcing the gene’s role in neurodevelopment and tissue regulation. These findings have spurred interest in potential treatments, such as mTOR inhibitors, to mitigate overgrowth-related complications.

Physical Indicators

A key physical trait of BRRS is macrocephaly—an enlarged head circumference exceeding the 97th percentile for age and sex. This feature is often present at birth or becomes evident in infancy. Unlike isolated macrocephaly, the enlargement in BRRS is associated with diffuse brain overgrowth, which neuroimaging can confirm. Though macrocephaly in BRRS does not always indicate hydrocephalus, careful monitoring is advised to detect signs of intracranial pressure.

Beyond cranial enlargement, individuals with BRRS often exhibit generalized overgrowth, with height and weight above average for age. Some display hemihypertrophy, where one side of the body is larger, leading to orthopedic complications such as scoliosis or leg length discrepancies. Lipomas—benign fatty tumors—commonly appear on the trunk and extremities, sometimes affecting mobility and comfort.

Distinctive dermatological features also characterize BRRS. Many individuals develop pigmented macules on the glans penis, a highly specific finding for PTEN-related disorders that aids early diagnosis. Café-au-lait spots, though less common than in neurofibromatosis type 1, may be present. Mucocutaneous manifestations, including trichilemmomas and oral papillomas, are more frequent in adulthood but can appear in adolescence. Dermatologic assessment helps distinguish these growths from other lesions.

Neurological Presentation

Cognitive and behavioral differences are common in BRRS, reflecting the impact of PTEN mutations on neurodevelopment. Many individuals experience developmental delays, particularly in speech and motor skills. Language acquisition difficulties range from mild articulation issues to more pronounced deficits requiring speech therapy. Motor delays, including coordination and balance difficulties, suggest disruptions in neural connectivity.

A subset of individuals with BRRS exhibit autism spectrum disorder (ASD) traits. Studies estimate up to 25% of those with germline PTEN variants meet ASD diagnostic criteria. These individuals often present with social communication difficulties, restricted interests, and repetitive behaviors. Unlike idiopathic autism, PTEN-associated ASD is frequently accompanied by macrocephaly, aiding early identification. Functional MRI studies indicate atypical connectivity patterns in PTEN-related neurodevelopmental conditions. Early behavioral interventions, such as applied behavior analysis (ABA) and social skills training, support adaptive functioning.

Seizures are another concern in BRRS, though prevalence varies. Some individuals develop epilepsy, with seizure types ranging from focal to generalized. Electroencephalography (EEG) may reveal abnormal cortical activity even in asymptomatic individuals, underscoring the need for monitoring. While antiepileptic medications are the primary treatment, emerging research suggests dysregulated PI3K/AKT signaling may contribute to neuronal hyperexcitability, raising possibilities for targeted therapies.

Gastrointestinal Aspects

Gastrointestinal symptoms are a common but often underrecognized aspect of BRRS. A key finding is the presence of hamartomatous polyps throughout the gastrointestinal (GI) tract, particularly in the colon and small intestine. Though benign, these growths can cause abdominal pain, diarrhea, and rectal bleeding. Endoscopic evaluations often reveal multiple polyps, necessitating surveillance to assess for complications like intussusception, a condition requiring urgent intervention.

Altered gut motility is another concern, leading to symptoms such as constipation or gastroesophageal reflux disease (GERD). Delayed gastric emptying contributes to bloating and post-meal discomfort. GERD symptoms, including heartburn and regurgitation, may require acid suppression therapy. Dietary modifications, such as reducing acidic and fatty foods, can help manage symptoms. Given the potential for nutritional deficiencies due to malabsorption, regular monitoring of vitamin and mineral levels—particularly iron, vitamin B12, and fat-soluble vitamins—is recommended.

Diagnostic Tools

Diagnosing BRRS requires clinical evaluation, genetic testing, and imaging studies to confirm characteristic features and rule out other conditions. Given the variability in presentation, diagnosis typically begins with a thorough physical examination focusing on macrocephaly, developmental history, and dermatological or musculoskeletal findings. Growth charts and head circumference percentiles help assess disproportionate overgrowth, an early indicator of the disorder. Family history is also significant, as BRRS follows an autosomal dominant inheritance pattern.

Genetic testing is the definitive diagnostic method, targeting PTEN mutations. Sequencing techniques, including whole-exome sequencing and targeted PTEN gene panels, have improved accuracy and early detection. In inconclusive cases, deletion and duplication analyses identify structural variations. Imaging studies such as MRI and ultrasound assess internal manifestations, including hamartomatous growths and soft tissue abnormalities. Long-term monitoring is recommended to track symptoms and manage complications proactively.

Associated Conditions

Individuals with PTEN mutations face an increased risk for conditions under the PTEN hamartoma tumor syndromes (PHTS) umbrella, including Cowden and Proteus syndromes. While BRRS itself is a nonmalignant overgrowth syndrome, affected individuals have a heightened cancer risk, particularly for breast, thyroid, and endometrial cancers. Regular screenings, including thyroid ultrasounds, breast MRIs, and endometrial biopsies, are recommended based on PTEN-associated cancer risk guidelines.

Vascular anomalies, including arteriovenous malformations (AVMs), have been documented in BRRS. These abnormalities can cause complications such as spontaneous bleeding or neurological deficits if they occur in critical areas. Magnetic resonance angiography (MRA) aids in detecting these irregularities for early intervention. Additionally, immune dysregulation has been proposed as a possible feature in PTEN-related conditions, though further research is needed. Given BRRS’s multisystem involvement, coordinated care involving specialists in genetics, oncology, neurology, and gastroenterology is essential for optimizing long-term health outcomes.