Bannayan–Riley–Ruvalcaba syndrome

Overview

Bannayan–Riley–Ruvalcaba syndrome (BRRS) is a rare inherited disorder characterized by the presence of multiple hamartomas (benign growths), macrocephaly (an unusually large head), developmental delays, and pigmented spots on the penis in males. It is considered part of the PTEN hamartoma tumor syndromes (PHTS) and shares overlapping features with Cowden syndrome. Though typically benign, individuals with BRRS have an increased lifetime risk for certain cancers due to mutations in the PTEN gene.

Causes

Bannayan–Riley–Ruvalcaba syndrome is caused by mutations in thePTEN genelocated on chromosome 10q23.3. The PTEN gene is a tumor suppressor gene that helps regulate cell growth. When mutated, it leads to uncontrolled cell proliferation and the development of hamartomas and other features. Key causes include:

• Germline mutations in the PTEN gene

• Autosomal dominant inheritance pattern – one copy of the mutated gene is sufficient to cause the disorder

• De novo mutations – in some cases, the mutation arises spontaneously with no family history

Symptoms

BRRS presents with a wide range of clinical features that may vary between individuals:

• Macrocephaly – present in nearly all individuals

• Multiple lipomas – benign fatty tumors under the skin

• Hemangiomas – benign vascular skin lesions

• Developmental delay or intellectual disability

• Intestinal hamartomatous polyps – may cause abdominal pain or bleeding

• Pigmented macules on the glans penis – considered pathognomonic for BRRS in males

• Joint hypermobility and hypotonia

• Thyroid and other organ anomalies in some cases

Because of PTEN involvement, individuals are also at elevated risk for developing certain malignancies later in life, including breast, thyroid, and endometrial cancers.

Diagnosis

Diagnosis is made based on clinical presentation and confirmed with genetic testing:

• Physical examination showing macrocephaly, skin lesions, and developmental issues

• Colonoscopy or imaging to identify intestinal polyps

• Genetic testing confirming a pathogenic PTEN mutation

• Family history review for inherited PTEN-related conditions

• Differential diagnosis to exclude related syndromes like Cowden syndrome and Proteus syndrome

Treatment

There is no cure for BRRS, and treatment focuses on symptom management and cancer surveillance:

• Developmental and educational support for children with delays

• Surgical removal of lipomas or polyps if symptomatic

• Routine cancer screening – including breast, thyroid, and colon screening based on guidelines for PTEN mutation carriers

• Thyroid ultrasound and dermatologic exams annually

• Multidisciplinary care involving geneticists, gastroenterologists, endocrinologists, and developmental specialists

Prognosis

The prognosis for individuals with Bannayan–Riley–Ruvalcaba syndrome depends on the severity of symptoms and the effectiveness of cancer surveillance:

• Normal lifespan is possible with appropriate management and monitoring

• Developmental outcomes vary; some individuals may have mild delays, while others need long-term support

• Increased cancer risk necessitates lifelong surveillance and preventive care

• Regular follow-up can help prevent complications and improve quality of life

With early diagnosis and ongoing care, most individuals can lead fulfilling lives while managing associated health risks.