Bannayan Riley Ruvalcaba Syndrome: Symptoms, Types, Causes and Treatment

Bannayan Riley Ruvalcaba Syndrome (BRRS) is a rare, inherited disorder that affects multiple body systems and presents with a unique constellation of symptoms. With advances in genetic research, our understanding of BRRS has evolved significantly, linking it to PTEN gene mutations and connecting it to a spectrum of related conditions. This article provides a comprehensive overview of BRRS, including its symptoms, types, causes, and treatment options, synthesizing the most current evidence from the scientific literature.

Symptoms of Bannayan Riley Ruvalcaba Syndrome

BRRS is recognized for its distinct combination of overgrowth features, skin lesions, and developmental challenges. However, the syndrome's presentation can be highly variable, even among affected family members. Early recognition of BRRS symptoms can help guide medical management and screening for associated risks.

Symptom	Description	Frequency/Presentation	Source(s)
Macrocephaly	Abnormally large head circumference	Nearly universal; often severe	2 3 4 5
Lipomas	Multiple subcutaneous benign fatty tumors	Common; can be extensive	1 3 4 5 12
Vascular anomalies	Hemangiomas, arteriovenous malformations	Frequent; may cause complications	1 3 4 13
Intestinal polyps	Hamartomatous polyps in gastrointestinal tract	Common; risk of GI complications	2 3 4 12
Genital lentigines	Speckled pigmented macules on penis/vulva	Characteristic, especially in males	1 3 4
Developmental delay	Delayed milestones, cognitive impairment	Variable; often present	2 4 5
Musculoskeletal	Skeletal abnormalities, myopathy, neuropathy	Occasionally reported	4 5 7
Thyroid lesions	Benign/malignant thyroid tumors or Hashimoto's	Increased risk	1 5 7 12
Other cutaneous	Acanthosis nigricans, facial verrucae, acrochordons	Variable; simulate other disorders	1 4

Table 1: Key Symptoms of Bannayan Riley Ruvalcaba Syndrome

Macrocephaly: The Hallmark Feature

Macrocephaly—an abnormally large head—is the most consistent and often earliest recognized feature of BRRS. In many cases, infants present with extreme macrocephaly, prompting evaluation. Notably, macrocephaly may occur even before other signs appear, making it a crucial diagnostic clue, especially when there's a family history of large head size or related symptoms 5.

Skin and Soft Tissue Manifestations

BRRS is marked by multiple benign fatty tumors (lipomas) and vascular anomalies, such as hemangiomas or arteriovenous malformations. These can be widespread and, at times, disfiguring or cause complications like pain or nerve compression. Other skin changes include lentigines on the genitalia, facial verrucae-like lesions, acrochordons (skin tags), and, occasionally, acanthosis nigricans 1 3 4.

Gastrointestinal and Genitourinary Findings

Hamartomatous intestinal polyps are common and can lead to gastrointestinal bleeding, anemia, or, rarely, obstruction. Genital lentiginosis—speckled dark spots on the penis in males or vulva in females—is highly characteristic and may aid in diagnosis 2 3 4.

Neurological and Developmental Issues

Developmental delay and intellectual disability are observed in a significant proportion of patients but vary widely in severity. Some may have only mild learning difficulties, while others experience more pronounced impairment 2 4 5.

Endocrine and Other Systemic Features

Patients with BRRS are at increased risk for thyroid abnormalities, including benign adenomas, Hashimoto thyroiditis, and, potentially, malignancy. Musculoskeletal anomalies (myopathy, neuropathy, skeletal changes) and other rare findings have also been described, highlighting the syndrome's variable nature 4 5 7 12.

Types of Bannayan Riley Ruvalcaba Syndrome

While BRRS is often described as a single clinical entity, genetic research has shown that it exists on a spectrum with other PTEN-related disorders, such as Cowden syndrome. Understanding these types and overlaps is essential for accurate diagnosis and management.

Type/Overlap	Distinguishing Features	Clinical Importance	Source(s)
Classic BRRS	Macrocephaly, lipomas, GI polyps, lentigines	Most common presentation	2 3 4 5 10
BRRS/Cowden overlap	Features of both BRRS and Cowden syndrome	Cancer surveillance needed	2 6 9 10
PTEN Hamartoma Tumor Syndrome (PHTS)	Includes BRRS, Cowden, Proteus, Proteus-like	Unified genetic basis	8 10
Mutation-negative	Clinical BRRS without detectable PTEN mutation	May have different risks	6 8

Table 2: Clinical Types and Overlaps in Bannayan Riley Ruvalcaba Syndrome

Classic BRRS

The "classic" form consists of macrocephaly, multiple lipomas, intestinal polyposis, and speckled lentigines of the genitals. This constellation of symptoms is recognized as the signature presentation of the syndrome 2 3 4 5 10.

Overlap with Cowden Syndrome

BRRS and Cowden syndrome (CS) share overlapping features and are both caused by mutations in the PTEN gene. Some families have members with BRRS symptoms and others with Cowden syndrome, or individuals with a mixture of both. Cowden syndrome is notable for its higher risk of malignancies (especially breast, thyroid, endometrial, and renal cancers), prompting recommendations for similar cancer surveillance protocols in BRRS patients with PTEN mutations 2 6 9 10.

PTEN Hamartoma Tumor Syndrome (PHTS) Spectrum

BRRS is part of the broader PTEN Hamartoma Tumor Syndrome spectrum, which also includes Cowden, Proteus, and Proteus-like syndromes. While each has distinguishing clinical criteria, they share a common genetic basis and can show overlapping features 8 10.

Mutation-Negative Cases

A subset of individuals with classic BRRS features do not have detectable PTEN mutations using standard testing methods. Research suggests that large deletions, promoter mutations, or rare haplotypes may underlie disease in these cases. The risks associated with mutation-negative BRRS may differ somewhat and are an area of ongoing study 6 8.

Causes of Bannayan Riley Ruvalcaba Syndrome

BRRS is primarily a genetic disorder. Understanding its causes can provide insight into its varied manifestations and inform genetic counseling for affected families.

Cause	Mechanism/Genetics	Inheritance/Pattern	Source(s)
PTEN mutation	Tumor suppressor gene defect on 10q23	Autosomal dominant	2 3 5 6 8 10
Large gene deletions	Encompassing part or all of PTEN	Autosomal dominant	6 8
Promoter mutations	Affect PTEN expression	Autosomal dominant	6 8
Rare haplotypes	Modifying loci, low-penetrance alleles	Complex inheritance	8
Unknown/genetic modifier	No detectable mutation, unknown basis	Variable	6 8

Table 3: Genetic and Molecular Causes of BRRS

PTEN Mutations—The Central Cause

The PTEN gene, located on chromosome 10q23, encodes a tumor suppressor protein that regulates cell growth. Pathogenic mutations in PTEN are the primary cause of BRRS, found in approximately 60% of cases. These mutations can be inherited or arise de novo, and follow an autosomal dominant inheritance pattern—meaning a single copy of the mutated gene can cause disease 2 3 5 6 8 10.

Gene Deletions and Promoter Mutations

Some individuals with BRRS have larger deletions that remove part or all of the PTEN gene, or mutations in regulatory regions (promoters) that control how the gene is expressed. These genetic changes can also lead to insufficient or nonfunctional PTEN protein, resulting in the BRRS phenotype 6 8.

Rare Haplotypes and Genetic Modifiers

Research has identified rare haplotypes (stretches of DNA near or within PTEN) that may increase disease risk, especially in mutation-negative cases. These may act as genetic modifiers, influencing the severity or presentation of the syndrome 8.

Inheritance and Family Implications

BRRS is typically inherited in an autosomal dominant manner. This means that an affected individual has a 50% chance of passing the altered gene to each child. However, variable expressivity means that symptoms can differ widely, even within the same family 2 5.

Treatment of Bannayan Riley Ruvalcaba Syndrome

While there is currently no cure for BRRS, treatment focuses on managing symptoms, monitoring for complications, and proactive surveillance for associated risks, particularly those related to tumors.

Approach	Intervention/Strategy	Purpose	Source(s)
Surveillance	Tumor/cancer screening protocols	Early detection	2 5 12
Surgical	Excision of lipomas, polyps, thyroid lesions	Symptom relief/prevention	3 12
Symptom management	Spinal cord stimulation, pain management	For intractable pain	11
Developmental	Early intervention, special education	Support development	5
Anesthesia care	Special airway/spine precautions	Safety during procedures	13 14
Genetic counseling	Family risk assessment, planning	Inform family members	2 5

Table 4: Treatment and Management Strategies in BRRS

Tumor Surveillance and Cancer Risk Management

Given the overlap with Cowden syndrome and the risk for certain cancers (breast, thyroid, endometrial, renal), BRRS patients with PTEN mutations should follow the same surveillance protocols as for Cowden syndrome. This may include regular thyroid ultrasounds, breast imaging, endometrial assessments, renal imaging, and annual physical exams 2 5 12.

Surgical and Symptom-Specific Interventions

• Lipomas and Vascular Malformations: Surgical excision may be needed for symptomatic or disfiguring lesions, or if there is risk of nerve or organ compression 3 12.
• Intestinal Polyps: Removal (polypectomy) may be necessary to prevent complications such as bleeding or obstruction.
• Thyroid Lesions: Surgical management for nodules or tumors, with regular monitoring.

Management of Pain and Neurological Complications

For some patients, traditional pain management may not be sufficient. There are reports of successful use of spinal cord stimulation for severe, intractable pain related to BRRS complications 11.

Developmental and Supportive Care

Early intervention programs, speech and occupational therapy, and individualized education plans can help address developmental delays and optimize patient outcomes 5.

Special Considerations for Anesthesia

Macrocephaly, airway anomalies, and vascular malformations can complicate anesthesia. Preoperative assessment with imaging and careful airway planning are essential to ensure patient safety during procedures 13 14.

Genetic Counseling

Because BRRS is autosomal dominant, genetic counseling is recommended for affected families. This helps determine risks for future children and guides testing of potentially affected family members 2 5.

Conclusion

Bannayan Riley Ruvalcaba Syndrome is a complex, multisystem disorder with a strong genetic basis. Early recognition, multidisciplinary care, and regular surveillance are key to improving quality of life and reducing complications.

Key Points:

• BRRS is characterized by macrocephaly, lipomas, vascular anomalies, intestinal polyps, and developmental delay.
• The syndrome is caused by mutations or deletions in the PTEN gene, with autosomal dominant inheritance.
• There is significant clinical overlap with Cowden syndrome and other PTEN-related disorders.
• Management requires coordinated care, including tumor surveillance, surgical intervention when needed, and support for developmental challenges.
• Genetic counseling and family assessment are essential components of care.

By understanding the symptoms, types, causes, and treatment options for BRRS, patients and clinicians can work together to navigate the challenges of this rare but important condition.