Bannayan-Ruvalcaba-Riley syndrome (BRRS)

This material supplements information provided by physicians, nurses, genetic counselors, and other members of your health care team about Bannayan-Ruvalcaba-Riley syndrome. It does not replace regular medical care or discussions with your health care team. If you see an unfamiliar term, please see the Glossary of Terms at the end.

That's not the name my doctor gave me

Bannayan-Ruvalcaba-Riley syndrome (BRRS), which is named after the doctors who described the syndrome, is not the only name used for this condition. You may have seen it referred to as Ruvalcaba-Myhre syndrome, Riley-Smith syndrome or Bannayan-Zonana syndrome. The use of different names can be confusing. The problem started when several different groups of physicians and researchers began describing collections of features they observed in their patients. Each group believed that they were describing a new condition. Because BRRS consists of various features that occur at different times, or not at all, different people will show different features even though they have the same genetic condition. That was enough to make researchers at the time believe they were describing different conditions.

In fact, scientists did not realize that all these names were describing one condition until 1986, when it was proposed that Bannayan syndrome and Ruvalcaba-Myhre syndrome were one and the same. In 1996, the overlap of features in Bannayan-Ruvalcaba-Riley syndrome and another condition known as Cowden syndrome (CS) was recognized and shortly after it was shown that CS and BRRS were caused by harmful changes (called mutations) in the same gene. Since then, many names have been added to the list of related syndromes. Below are several other names that you may encounter as well.

• Bannayan-Riley-Ruvalcaba
• Ruvalcaba-Myhre-Smith syndrome
• Bannayan syndrome
• Cowden/ Bannayan-Ruvalcaba-Riley overlap syndrome
• PTEN Hamartoma Tumor syndrome

What is Bannayan-Ruvalcaba-Riley syndrome (BRRS)?

BRRS is a rare hereditary condition that most often can cause polyps (hamartomas) of the small and large intestine, an increased head size (macrocephaly), benign fatty tumors (lipomas), blood vessel changes (hemangiomas), and thyroid problems. Males with BRRS often have some freckling on the penis.

The features of BRRS usually start showing up in childhood. Babies are typically born with a larger head, longer body, and a weight over 9 pounds (4kg). After birth their growth slows and as a result, children and adults are of normal height and size. Sometimes children will also have decreased muscle tone (hypotonia) and/or learning difficulties and developmental delay. Benign fatty tumors under the skin or in the abdomen and intestinal polyps (most commonly hamartomatous polyps) are common. Hemangiomas, or raised red birthmarks caused by blood vessel changes, may also be present. Hemangiomas can be either on internal organs or on the skin.

People diagnosed with BRRS do not necessarily have all the same features. Only 50 percent of children have developmental delays and learning problems, while the other 50 percent have normal development. About 45 to 80 percent of affected individuals will develop polyps on the intestine. Table 1 lists the features that have been associated with BRRS and the percentage of people that develop each feature (incidence). People with BRRS who have a mutation in the PTEN gene may also be at risk for the features associated with Cowden syndrome. Therefore, we have also included Table 2 with those features as well.

Common characteristics of Bannayan-Ruvalcaba-Riley syndrome

The most common characteristics of BRRS can be found in the table below. People with BRRS who have a mutation in the PTEN gene may also be at risk for the features associated with Cowden syndrome. Table 2 includes the common characteristics of Cowden syndrome.

Table 1: Common Characteristics of Bannayan-Ruvalcaba-Riley Syndrome (Please see the glossary for definitions of the terms.)

Class	Feature	Incidence
Growth	Birth weight greater than 4 kg/9 lbs. Birth length above the 97th percentile (girls: 53 cm or 21 in, boys 55 cm or 21.5 in) Normal adult height	Majority Majority Majority
Development	Low muscle tone (hypotonia) Motor delay, speech Delay, and/or mild developmental delay Myopathic process in proximal muscles Seizures	50% 50% 60% 25%
Head	Macrocephaly	50%
Intestine	Hamartomatous polyps	45%
Skeletal	Joint hyperextensibility Pectus Excavatum Scoliosis	50% 50% 50%
Skin	Tan, nonelevated spots (freckling) on penis Angiolipomas	Majority 50%
Tumors (benign)	Lipomas Hemangiomas	75% 10-40%

 

Table 2: Common Characteristics of Cowden Syndrome

Class	Feature	Incidence
Skin and mouth lesions	Trichilemmomas Acral keratoses Papillomatous papules	90-100%
Head	Macrocephaly	80%
Development	Intellectual disability/developmental delay	15-20%
Thyroid problems	Goiter Adenomas, nodules	40-60%
Breast Problems (females)	Fibroadenomas Fibrocystic disease	40%
Gastrointestinal	Hamartomatous polyps, ganglioneuromas	80%
Gynecologic problems	Uterine fibroids (multiple and early onset)	25%
Other benign growths	Lipomas Hemangiomas	40-50% 10-40%
Cancer	Thyroid cancer Breast cancer Endometrial cancer	3-10% 25-50% 6-8%

What causes Bannayan-Ruvalcaba-Riley syndrome?

BRRS is a genetic syndrome usually caused by a mutation in a gene known as PTEN. Mutations in this gene have been found in about 60 percent of all people with a clinical diagnosis of Bannayan-Ruvalcaba-Riley syndrome and about 40-80 percent of people with a clinical diagnosis of Cowden syndrome. The fact that both conditions are caused by mutations in the same gene explains why they share many similarities and why a physician must consider both possibilities when deciding upon a diagnosis and your health care management plan.

Genes serve as the basic unit of heredity, providing the body’s instructions for growth and development. Every cell of the human body has a complete set of this genetic information. Genes are composed of DNA and are housed on structures called chromosomes. There are 23 pairs of chromosomes (46 total). A child receives one chromosome of each pair from his or her mother's egg and one from their father's sperm. In this way, a child inherits half the information needed for development (including one copy of the PTEN gene) from each parent. Tests can be done to look mutations in genes that can lead to disease.

The PTEN gene functions as a tumor suppressor. Tumor suppressor genes normally ensure that cells do not grow or divide more than they are supposed to. Only one copy of a tumor suppressor gene is needed to control cell growth. This means that when a person has inherited one PTEN gene with a mutation, the other, functional copy is still able to successfully control cell growth. However, if anything damages the second, functional copy of the PTEN gene in any cell, that person can develop either a benign and cancerous growth. Thus, although a person with BRRS inherits an increased risk for tumor development, they do not inherit the tumor or cancer itself.

How is Bannayan-Ruvalcaba-Riley syndrome inherited?

BRRS can be inherited or passed from an affected parent to a child. BRRS has an autosomal dominant pattern of inheritance. This means that each child (male or female) with an affected parent has a 50 percent chance of inheriting the PTEN mutation and developing BRRS. Likewise each child has a 50 percent chance of not inheriting the mutation and not developing BRRS (see diagram 1).

An evaluation of your family history can determine if a pattern exists. A family tree or a pedigree is a diagram of the members of your extended family, showing your family history.

This diagram shows how one gene from each parent is passed to a child. In the case above the father has one working gene, indicated by the lower case letter n, and one gene with a mutation, indicated by the capital letter N. The mother has two copies of normal genes. There are four possibilities of gene combinations for the child. Each child has a 50 percent chance of inheriting the mutation (N), regardless of the sex of the child.

 

Below is a pedigree that demonstrates the pattern of autosomal dominant inheritance within a family.

This pedigree tells us several things about this family.

1. Sue and Tom have three children, two of whom are affected. Since Sue was affected, each of her children had a 50 percent chance of inheriting her PTEN mutation and developing BRRS; Joe and Jim inherited the mutation.
2. Sara did not inherit the mutation and does not have BRRS. She cannot pass this mutation on to her children, nor will they develop BRRS.
3. Joe has one daughter who had a 50 percent chance of inheriting the mutation and developing BRRS. Jen did not inherit the mutation, will not develop BRRS, and cannot pass it to her children.
4. Kay and Jim have two children. Tim inherited the mutation and he now has a 50 percent chance of passing it on to his children. Lori did not inherit the mutation and can not pass it to her children.

New Mutations

Sometimes individuals with BRRS inherit their PTEN mutation from one of their parents. However, some individuals with BRRS have a PTEN mutation that occurred in either the egg or the sperm from which they were conceived; this is called a “new mutation.” A new mutation is not the result of something that did or did not happen in pregnancy, nor can it be prevented. When someone has BRRS as a result of a new mutation, they usually will not have relatives with BRRS. However they can have affected children.

Are tests for Bannayan-Ruvalcaba-Riley syndrome available?

Genetic testing of the PTEN gene can identify if someone has a mutation causing BRRS. There is a charge for these services when provided by clinically approved laboratories. These charges may or may not be covered by insurance and should be discussed with your doctor or genetic counselor.

The usual test for BRRS is called gene sequencing. In sequencing, the individual components (“letters”) of the PTEN gene are examined in detail looking for a mutation. This test is very accurate, but only about 60% of people meeting the criteria for BRRS have an identifiable mutation. This means that 40 percent of people who meet the criteria for BRRS will not have an identifiable mutation and will have a normal test result even though they do have BRRS. This could be due to a limitation in the test, and some labs offer additional testing to detect rare mutations missed by sequencing. It may also be possible, although this has not been proven, that BRRS could be cause by a mutation in another gene that has not been identified yet.

PTEN testing may also be available to you through a research study. Unlike clinical testing, research-based testing may take many months or years, but it is usually done without any cost to you. It may also provide information and results that are not available on a clinical basis. You may want to consider these issues as you decide whether you wish to pursue either clinical or research-based testing. Your physician and genetic counselor can help you if you are interested in participating in a research study.

What should I be doing about this condition?

While there are no standardized recommendations for how the healthcare of people with BRRS should be managed, it is currently suggested that people with BRRS who have a documented PTEN gene mutation should follow the screening guidelines for Cowden syndrome. At present it is not clear whether people who have a clinical diagnosis of BRRS but do not have a detectable PTEN mutation should follow these guidelines as well. You should discuss this further with your healthcare providers.

Recommendations for cancer screening for people with Cowden syndrome are updated and published each year by the National Comprehensive Cancer Network (NCCN). In many cases, screening can help manage benign growths and detect any cancer at an early stage, when it is best treated. The recommended screenings for people with CS are summarized in Table 3 below.

Because of the risk for breast cancer, women with CS should have increased breast cancer screening. Currently this includes performing monthly breast self-examination, getting a breast exam from your doctor every 6 months beginning at 25 years of age, and an annual mammogram and breast MRI beginning at 30 to 35 years of age (or 5-10 years before the earliest known breast cancer in the family; whichever comes first). For some women with dense breast tissue that can make it harder to detect breast cancers, preventative mastectomy may be an option. Women should also be aware of the signs and symptoms of possible uterine cancer, such as abnormal vaginal bleeding, pelvic pain, pain during intercourse and painful urination.

Both men and women should receive thyroid cancer screening that includes an ultrasound of the thyroid at age 18 and annual thyroid palpation (having a doctor feel the thyroid) after that. You might also consider having an annual ultrasound. Because thyroid nodules can be a common feature, an experienced endocrinologist should evaluate any thyroid nodules to determine if they require follow-up, such as a biopsy.

Skin cancer screenings should also be considered. Yearly visits to a dermatologist can help manage the CS skin findings and also screen for skin cancer.

Recent evidence suggests that the risk for colon cancer may be increased in people with CS. Currently it is recommended that people with CS have colonoscopy every 10 years beginning at age 50 like anyone in the general population. However, these recommendations could change and it is important to ask your doctor or genetic counselor about the most current guidelines.

Check Yourself: Are you getting the screening you need?

Screenings for Women

Recommended Screenings	Beginning Age	Frequency
Thyroid palpation and ultrasound	18*	Annually for palpation; consider annually for ultrasound
Breast self-examination	18	Monthly
Comprehensive physical exam	18*	Annually
Clinical breast examination	25*	Every six months
Mammography and breast MRI	30-35*	Annually
Endometrial cancer screening	30-35	Consider annually
Dermatology	Adults	Consider annually
Colonoscopy	50	Every 10 years, if normal

 

Screenings for Men

Recommended Screenings	Beginning Age	Frequency
Thyroid palpation and ultrasound	18*	Annually for palpation; consider annually for ultrasound
Comprehensive physical exam	18*	Annually
Dermatology	Adults	Consider annually
Colonoscopy	50	Every 10 years, if normal

* or 5-10 years before the earliest related cancer in the family.

Resources and support groups for BRRS

Because BRRS can be complicated to diagnose, it is important to address your questions and concerns with your physician and genetic counselor. Remember that no two people with this diagnosis will have exactly the same symptoms. Pay particular attention to physical changes and discuss them with your physician regularly. Living with any type of genetic condition can be a challenge, but living with BRRS is a challenge you can face with a good medical team as your partner.

Remember that different people deal with this diagnosis in different ways. For some the path may be long and difficult while others adjust in a shorter time with less difficulty. Just remember to give yourself time to acknowledge your feelings. The members of your health care team--physicians, genetic counselors, and nurses--serve as an excellent resource and you should discuss your situation with them. Another valuable resource can be other people who have been in similar situations. Support groups can connect people who are dealing with similar issues and bring them together in a supportive environment. Here are several groups that may benefit you or someone you know.

American Cancer Society
1599 Clifton Road NE
Atlanta, GA 30329
800-ACS-2345
www.cancer.org

Genetic Alliance
4301 Connecticut Avenue NW Suite 404
Washington, DC 20008-2369
202-966-5557
www.geneticalliance.org

National Society of Genetic Counselors – NSGC
401 N. Michigan Avenue
Chicago, IL 60611
312-321-6834
www.nsgc.org (includes a search tool to find a genetic counselor in your area)

Patient run support groups*:

• https://groups.yahoo.com/neo/groups/cowdensyndrome/info

* These sites are for personal support for individuals and families with Cowden syndrome, but should also be useful for people with BRRS. These sites are not monitored by medical professionals.

Glossary of terms

Acral keratoses:

small callous (thickening of the skin) usually located on the extremities

Adenoma:

a type of benign tumor in which the cells form glands

Angiolipomas:

benign growth of fat cells found in blood vessels

Baseline:

normal background level used for comparisons

Benign:

term describing a growth that is not cancerous

Benign Breast Disease:

a variety of conditions characterized by benign growths in breast tissue. See fibrocystic breast disease, ductal hyperplasia, intraductal papillomatosis, , fibrocystic breast disease, and fibroadenoma

Chromosomes:

the structures made of DNA chains that contain genes

Colonoscopy:

examination of the colon using a long flexible scope (camera)

Cutaneous:

relating to the skin

DNA:

the genetic information that cells need for growth and development

Ductal Hyperplasia:

overgrowth of cells lining the ducts in the breast. This is a common change in fibrocystic disease. Changes can range in severity from a benign growth to a pre-malignant condition that is associated with an increased risk for cancer development

Endometrium:

cells that line the inside of the uterus

Fibroadenomas:

a common benign growth that can occur in many different organs

Fibrocystic Breast Disease:

condition where the breast has lumpy and cystic fibrous tissue that is not due to tumor development.

Fibromas:

benign growth made of fibrous or fully developed connective tissue

Ganglioneuroma:

a benign tumor composed of nerve (ganglion) cells.

Gastrointestinal:

relating to the stomach and intestine

Gene:

the smallest units of heredity

Goiter:

enlargement of the thyroid gland.

Hamartoma:

benign growth of disorganized cells from normal tissue that stops itself from growing once the cells have reached maturity

Hamartomatous Polyp:

a benign growth of disorganized cells from normal tissue that is found on a mucosal membrane (ie: inside lining of colon, mouth, nose, etc.). These polyps have a low chance of being malignant

Hemangioma:

common benign growth developed from blood vessels

Hereditary:

the genetic transmission of a particular trait from parent to child

Hyperextensibility:

extension of a part of the body beyond the usual limit

Hypotonia:

decreased or low muscle tone

Lhermitte-Duclos Disease (LDD):

a benign tumor (called a dysplastic gangliocytoma) in the part of the brain known as the cerebellum (found at the back of the head toward the base of the skull). LDD is believed to be a hamartomatous growth

Lipoma:

benign tumor made of fat tissue

Malignant:

cancerous growth that tends to become progressively worse and often invades other tissues.

Mammograms:

low-dose x-ray that can detect breast cancer up to two years before a woman or a health professional can feel any signs of it

Macrocephaly:

larger head size

Mucocutaneous:

affecting the skin and inside of the mouth

Myopathic:

a muscle problem

Pectus excavatum:

depression of the breastbone and rib cartilage.

Papillomatous:

multiple benign growth arising from specific types of cells (epithelial cells) which line many organs and tissues in the body.

Pathognomonic Criteria:

characteristic or indicative of a disease, i.e. one or more symptoms, findings, or pattern of findings specific for a given condition that are usually not found in any other condition

Pedigree:

pictorial relation of yourself and your family history, see page 7

Palpation:

light touch by a clinician to feel structures under the skin

Papillomatous Lesions:

benign growth that is wart-like (but are not warts)

Prophylactic tissue and organ removal (mastectomy):

surgical removal of tissue or organ used as a method of risk reduction for cancer

PTEN:

tumor suppressor gene located on chromosome 10 that when mutated can cause Cowden syndrome and other conditions.

Scoliosis:

curvature of the spine

Sequencing:

a detailed laboratory test that can detect very small changes in a gene

Syndrome:

set of features that occur together

Trichilemmomas:

hamartoma of the lower outer root and sheath of the hair root.

Tumor Suppressor Gene:

a gene whose function is to monitor and control cell growth

Ultrasound:

technique that uses sound waves to visualize internal structures of the body

References

DiLiberti JH. Inherited macrocephaly-hamartoma syndromes. Am J Med Genet 1998: 79: 284-290
Gorlin RJ, Cohen MM, Condon LM, Burke BA. Bannyan-Riley-Ruvalcaba sydrome. Am J Med Gent 1992: 44: 307-314
Heald, B, Mester, J., Rybicki, L., Orloff, M.S., Burke, C.A, and Eng, C. Frequent Gastrointestinal Polyps and Colorectal Adenocarcinomas in Prospective Series of PTEN Mutation Carriers. Gastroenterology, epub 27 Jun 2010.
Jones, Kenneth Lyons. Smith's Recognizable Patterns of human Malformation. 5th Ed., WB Sanders Co 1997: 522-523.
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology - Genetic/Familial High-Risk Assessment: Breast and Ovarian. http://www.nccn.org/professionals/physician_gls/PDF/genetics_screening.pdf
Pilarski, R. Cowden syndrome: a Critical Review of the Clinical Literature. J Genet Counsel 2009;18:13-27.
Pilarski, R., Stephens, J., Noss, R., Fisher J.L. and Prior, T (2011). Predicting PTEN mutations: an evaluation of Cowden syndrome and Bannayan-Ruvalcaba-Riley syndrome clinical features.

Credits

2010 revisions by:

• Joy Larsen Haidle, MS, CGC, Genetic Counselor, Humphrey Cancer Center
• Heather Hampel, MS, CGC, Genetic Counselor, Clinical Cancer Genetics Program and Division of Human Genetics, The Ohio State University
• Robert Pilarski, MS, CGC, MSW, LSW, Genetic Counselor, Clinical Cancer Genetics Program and Division of Human Genetics, The Ohio State University

Original version written by:

• Sarah Burton, University of Iowa Health Care
• Joy Larsen Haidle, MS, CGC
• Heather Hampel, MS, CGC,
• Illustrations by Terry Demmer