Bannayan-Riley-Ruvalcaba syndrome
Synonyms and keywords: BRRS, Ruvalcaba-Myhre syndrome, Ruvalcaba-Myhre-Smith syndrome, Riley-Smith syndrome, Bannayan syndrome, or Bannayan-Zonana syndrome

# Overview
(BRRS)/Bannayan-Zonana syndrome is a rare hamartomatous disorder with occurrence of multiple subcutaneous lipomas, macrocephaly and hemangiomas. Bannayan-Riley-Ruvalcaba syndrome (BRRS) is transmitted in autosomal dominant pattern. Bannayan-Riley-Ruvalcaba syndrome (BRRS) was first discovered by Ruvalcaba, in 1980. It is understood that Bannayan-Riley-Ruvalcaba syndrome (BRRS) is caused by genetic mutations. The symptoms of BRRS usually develop in the first decade of life. The prognosis is unknown for Bannayan-Riley-Ruvalcaba syndrome (BRRS). Bannayan-Riley-Ruvalcaba syndrome must be differentiated from CLOVE syndromes. The incidence of Bannayan-Riley-Ruvalcaba syndrome is approximately 1 per 200,000 individuals worldwide. Head MRI may be helpful in the diagnosis of Bannayan-Riley-Ruvalcaba syndrome. There is no treatment for Bannayan-Riley-Ruvalcaba syndrome.

# Historical Perspective
- Bannayan-Riley-Ruvalcaba syndrome (BRRS) was first discovered by Ruvalcaba, in 1980.
- Bannayan-Riley-Ruvalcaba syndrome was also mentioned with different names previously by different doctors thinking that they were describing a new condition and the names are as follows:
Ruvalcaba-Myhre syndrome
Riley-Smith syndrome
Bannayan-Zonana syndrome
- Ruvalcaba-Myhre syndrome
- Riley-Smith syndrome
- Bannayan-Zonana syndrome
- The overlap of symptoms between Cowden syndrome and Bannayan-Ruvalcaba-Riley syndrome was made in 1996.

# Classification
- There is no established system for the classification of Bannayan-Riley-Ruvalcaba syndrome (BRRS) .

# Pathophysiologya
- Bannayan-Riley-Ruvalcaba syndrome (BRRS) is transmitted in autosomal dominant pattern, but sporadic cases have been reported.
- The disease belongs to a family of hamartomatous polyposis syndromes, which also includes Peutz-Jeghers syndrome, juvenile polyposis and Cowden syndrome.
- It is understood that Bannayan-Riley-Ruvalcaba syndrome (BRRS) is the result caused by  the following gene mutations:
Germline phosphatase and
Tensin homolog (PTEN) mutations.
- Germline phosphatase and
- Tensin homolog (PTEN) mutations.
- Patients who have Bannayan-Riley-Ruvalcaba syndrome (BRRS), have a positive association with PTEN mutations in 55 to 60 % of cases.
- PTEN track backs to 10q23 which encodes and plays a significant role in the following:
Phosphatidylinositol 3,4,5-triphosphate, a phospholipid in the phosphatidylinositol 3-kinase pathway/Akt pathway
Effects G1 cell cycle arrest and apoptosis
Cellular proliferation and
Migration
- Phosphatidylinositol 3,4,5-triphosphate, a phospholipid in the phosphatidylinositol 3-kinase pathway/Akt pathway
- Effects G1 cell cycle arrest and apoptosis
- Cellular proliferation and
- Migration

# Causes
Genetic Cause
- Bannayan-Riley-Ruvalcaba syndrome (BRRS) is caused by a mutation in the phosphatase and tensin homolog (PTEN) gene.
- Different types of mutations occurs in PTEN gene and are as follows:
Germline intragenic mutations in PTEN gene
Gross gene deletions in PTEN gene
Mutations in the PTEN gene promoter region results in heterozygous germline mutations
Deletion in exons 1-5 of PTEN gene
- Germline intragenic mutations in PTEN gene
- Gross gene deletions in PTEN gene
- Mutations in the PTEN gene promoter region results in heterozygous germline mutations
- Deletion in exons 1-5 of PTEN gene

# Differentiating Bannayan-Riley-Ruvalcaba syndrome from Other Diseases
- Bannayan-Riley-Ruvalcaba syndrome must be differentiated from CLOVE syndrome which include the following:
Congenital lipomatous overgrowth
Vascular malformations
Epidermal nevi and
Cowden syndrome
Proteus syndrome
Lhermitte-Duclos syndrome
Birt-Hogg-Dube syndrome
- Congenital lipomatous overgrowth
- Vascular malformations
- Epidermal nevi and
- Cowden syndrome
- Proteus syndrome
- Lhermitte-Duclos syndrome
- Birt-Hogg-Dube syndrome

# Epidemiology and Demographics

## Incidence
- The incidence of Bannayan-Riley-Ruvalcaba syndrome is approximately 1 per 200,000 individuals worldwide.

## Prevalence
- The prevalence of PTEN mutations Bannayan-Riley-Ruvalcaba syndrome is approximately 65%.

## Age
- Bannayan-Riley-Ruvalcaba syndrome commonly affects individuals of younger age.
- The median age for Bannayan-Riley-Ruvalcaba syndrome diagnosis is as young as five years.

# Risk Factors
- Apart from mutations in PTEN gene there are no established risk factors for Bannayan-Riley-Ruvalcaba syndrome (BRRS).

# Screening
- There is insufficient evidence to recommend routine screening for Bannayan-Riley-Ruvalcaba syndrome (BRRS).

# Natural History, Complications, and Prognosis
Natural History
- The symptoms of BRRS usually develop in the first decade of life, and start with symptoms such as developmental delay, macrocephaly and penile lentigines.
Complications
- Common complications of Bannayan-Riley-Ruvalcaba syndrome (BRRS) include:
Increased risk of following cancers:
Thyroid cancer: Mostly commonly follicular, very rarely papillary, but never medullary thyroid cancer
Breast cancer
Renal cell cancer
Granulosa cell tumor of the ovary
- Increased risk of following cancers:
Thyroid cancer: Mostly commonly follicular, very rarely papillary, but never medullary thyroid cancer
Breast cancer
Renal cell cancer
Granulosa cell tumor of the ovary
- Thyroid cancer: Mostly commonly follicular, very rarely papillary, but never medullary thyroid cancer
- Breast cancer
- Renal cell cancer
- Granulosa cell tumor of the ovary
Prognosis
- The prognosis is unknown for Bannayan-Riley-Ruvalcaba syndrome (BRRS).

# Diagnosis

## Diagnostic Criteria
- The diagnostic criteria of Bannayan-Riley-Ruvalcaba syndrome (BRRS) is based on the Cowden syndrome/PHTS criteria, which include:
Pilarski et al diagnostic criteria:
- Pilarski et al diagnostic criteria is proposed by National Comprehensive Cancer Network (NCCN) which include
- Diagnosis require
Any two major positive criteria symptoms or
One major and two minor positive criteria symptoms  or
Three minor positive criteria symptoms
- Any two major positive criteria symptoms or
- One major and two minor positive criteria symptoms  or
- Three minor positive criteria symptoms

## History and Symptoms
The most common symptoms of Bannayan-Riley-Ruvalcaba syndrome (BRRS) include head enlargement, intellectual disability, pigmented skin lesions on penis, and eye and ear morphology abnormality.

## Physical Examination
Skin
- Lipomas
HEENT
- Macrocephaly: Very prominent and important feature of Bannayan-Riley-Ruvalcaba syndrome 
Macrocephaly (occipital frontal circumference 97th percentile)
The macrocephaly of BRRS is symmetrical, and does not cause widening of the ventricles or raised ICP (intracerebral pressure).
- Macrocephaly (occipital frontal circumference 97th percentile)
- The macrocephaly of BRRS is symmetrical, and does not cause widening of the ventricles or raised ICP (intracerebral pressure).
- High palate
- Downslanting palpebral fissures of the eyes
- Strabismus
- Amblyopia
Neck
- Thyromegaly-Hashimoto thyroiditis
Abdomen
- Hamartomatous polyps in gastrointestinal tract
- Intestinal juvenile polyposis
Genitourinary
- Penile lentigines or speckled penis: Hallmark of Bannayan-Riley-Ruvalcaba syndrome (BRRS)
Pigmentation spots of the male genitalia
- Pigmentation spots of the male genitalia
- Fistulae
Neuromuscular
- Developmental delay: Could be mild to severe
- PTEN hamartoma of soft tissue
- Joint hypermobility
- Arteriovenous shunts

## Laboratory Findings
Mutation testing
- PTEN mutation testing by following:
Sequence analysis of coding region
Deletion/duplication analysis
Sequence analysis of promoter region
- Sequence analysis of coding region
- Deletion/duplication analysis
- Sequence analysis of promoter region

## Imaging Findings
- Head MRI may be helpful in the diagnosis of Bannayan-Riley-Ruvalcaba syndrome. Findings on MRI suggestive of Bannayan-Riley-Ruvalcaba syndrome include:
White matter cysts in the parietal lobe, frontal lobe, and temporal lobe
T2 hyperintensities associated with macrocephaly
- White matter cysts in the parietal lobe, frontal lobe, and temporal lobe
- T2 hyperintensities associated with macrocephaly

## Other Diagnostic Studies
- There are no other diagnostic studies associated with Bannayan-Riley-Ruvalcaba syndrome.

# Treatment

## Medical Therapy
- There is no treatment for Bannayan-Riley-Ruvalcaba syndrome; the mainstay of therapy is treating the symptoms present in the individual like:
Mucocutaneous Manifestations
- Mucocutaneous manifestations can be treated with the help of:
- Preferred regimen (1): 5-Fluorouracil
- Curettage
- Cryosurgery
- Laser ablation

## Surgery
- Surgery is not the mainstay of treatment for Bannayan-Riley-Ruvalcaba syndrome.

## Prevention
- There are no established measures for the primary or secondary prevention of Bannayan-Riley-Ruvalcaba syndrome.