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Last updated: January 20, 2021
Years published: 1994, 1998, 2006, 2021
NORD gratefully acknowledges Nardin Farag, MDCM Candidate, McGill University School of Medicine, Charis Eng, MD, PhD, FACP, Sondra J. & Stephen R. Hardis Chair in Cancer Genomic Medicine; Chair and Director, Genomic Medicine Institute; Director, Center for Personalized Genetic Healthcare; American Cancer Society Clinical Research Professor, Cleveland Clinic Lerner Research Institute and Lamis Yehia, PhD, Ambrose Monell Cancer Genomic Medicine Fellow, Genomic Medicine Institute, Cleveland Clinic, for assistance in the preparation of this report.
Summary
Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a rare genetic disorder that is present at birth and is characterized by a large head size (macrocephaly), pigmented spots (maculae) on the penis and benign tumors and tumor-like growths in the intestine called hamartomas. Other possible features include multiple vascular malformations, skeletal abnormalities, as well as developmental delay, autism spectrum disorder, and/or intellectual disability. BRRS is inherited in an autosomal dominant pattern.
Introduction
BRRS was previously described as three separate conditions: Riley-Smith syndrome, Bannayan-Zonana syndrome and Ruvalcaba-Myhre-Smith syndrome. BRRS is now known to be a component of PTEN hamartoma tumor syndrome when a germline PTEN mutation is also present: https://rarediseases.org/rare-diseases/pten-hamartoma-tumor-syndrome/
Approximately 60% of patients with BRRS have an inborn change (mutation) in the PTEN tumor suppressor gene in all cells of their bodies (germline). These patients can be given the diagnosis of PTEN hamartoma tumor syndrome.
Individuals with BRRS have clinical findings that vary from one person to another. They can be separated into different categories: skin, facial differences, skeletal abnormalities, thyroid gland tumors, gastrointestinal tract, central nervous system, ocular abnormalities, muscular system and other findings. Children with BRRS also tend to be bigger and longer at birth and can have blood vessel changes (hemangiomas) which are seen as raised red birthmarks. Growth slows down with age and patients tend to have normal size and height as adults. This is not a complete list of possible findings. Some are found in case reports and are added to the list of possible findings.
Macrocephaly is a hallmark for the diagnosis of BRRS (head circumference greater than or equal to the 97th percentile).
Hamartomatous polyposis in the gastrointestinal tract (in the colon and rectum) is seen in 35-45% of patients. Hamartomatous polyposis is defined as a disorganized accumulation of cells and their components from the region where they are located.
Skin features are extensive in BRRS. Patients may have multiple subcutaneous or visceral (related to the internal organs) lipomas. Spots (hyperpigmented macules) on the skin of the penis are a very characteristic feature (penile lentigines). Other skin features are dark discoloration of the body folds and creases (acanthosis nigricans) and overgrowths of cells on the face called papillomatous papules.
Neuromuscular and neurodevelopmental abnormalities are common and can include low muscle tone (hypotonia), delayed psychomotor development, seizures (less commonly), developmental delay, autism spectrum disorder, and/or intellectual disability.
Children with BRRS may also have skeletal malformations such as a funnel chest (pectus excavatum) and abnormal side-to-side and/or front-to-back curvature of the spine (scoliosis, kyphosis or kyphoscoliosis if both). They can also have joint hypermobility.
Muscular system abnormalities include an abnormal mixture of fat tissue, fibrous tissue and abnormal vessels found inside the muscle (intramuscular lesions).
Approximately 60% of patients with BRRS have an inborn change (mutation) in the PTEN tumor suppressor gene in all cells of their bodies. A tumor suppressor is a gene that slows down cell division, repairs damage to the DNA of cells, and tells cells when to die, a normal process called apoptosis. Mutations in a tumor suppressor gene often lead to overgrowth and/or cancer. The PTEN gene results in the production of an enzyme called phosphatase and tensin homolog (from which the name โPTENโ is derived). PTEN is important for stopping cell growth and starting apoptosis. Researchers believe that the PTEN gene plays a broad role in the development of human cancers.
BRRS is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated (changed) gene that first occurs in the affected individual (known as de novo). The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
BRRS was previously reported as three different conditions: Riley-Smith, Bannayan-Zonana and Ruvalcaba-Myhre-Smith syndromes. To facilitate diagnosis and medical care, BRRS is considered to be a component of PTEN hamartoma tumor syndrome (PHTS) for all patients having a germline PTEN mutation. Males and females are affected equally and PHTS is found in all racial and ethnic groups.
It is likely that some patients with BRRS remain undiagnosed, making it difficult to determine its true frequency in the general population.
BRRS may be suspected based upon identification of characteristic physical features (e.g., macrocephaly, penile lentigines, hamartomatous polyposis, characteristic facial abnormalities, skeletal malformations, etc.). The diagnosis may be confirmed by a thorough clinical evaluation and detailed patient and family histories. The diagnosis can also be confirmed when a germline mutation in the PTEN gene is identified.
Treatment
Due to the effects on various organ systems in BRRS, it is important to involve a multidisciplinary team and offer genetic counselling to the patient and their family.
Individuals with germline PTEN mutations should undergo cancer surveillance and screening following the National Comprehensive Cancer Network (NCCN) practice guidelines to enable healthcare providers to detect any tumors at the earliest, most treatable stages. For each cancer type, there are specific surveillance guidelines, including when to start screening. Screening does not start at the time of diagnosis for all cancers and depends on the patientโs age at diagnosis
Pediatric (under age 18)
The same surveillance protocol for (malignant) tumors as is currently recommended for Cowden syndrome is also recommended for BRRS. Guidelines are available from the NCCN. This protocol includes hamartoma surveillance from early infancy through yearly hemoglobin tests, yearly surveillance for thyroid cancer from age 7 years, which consists of an ultrasound of thyroid gland as well as annual thyroid palpitation performed by a physician for detection of thyroid nodules. Breast cancer surveillance starts at age of 25 for both males and females, with monthly self-examination as well as a breast exam performed every 6 months with a physician. Urinalysis is also recommended yearly for early detection of kidney cancer (renal carcinoma). However, it is unclear if patients with BRRS without a germline PTEN mutation have the same cancer risks as those who have a germline PTEN mutation.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
A clinical trial with the mTOR inhibitor Everolimus is completing accrual of pediatric, adolescent, and young adult patients with germline pathogenic PTEN mutations and autism spectrum disorder (NCT02461446).
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Yehia L, Ngeow J and Eng C. PTEN-opathies: from biological insights to evidence-based precision medicine. JCI. 2019. 129:2. https://www.annualreviews.org/doi/full/10.1146/annurev-med-052218-125823
Yehia L and Eng C. 65 YEARS OF THE DOUBLE HELIX: One gene, many endocrine and metabolic syndromes: PTEN-opathies and precision medicine. Endocrine-Related Cancer. 2018. 25:8: T121-T140. https://erc.bioscientifica.com/view/journals/erc/25/8/ERC-18-0162.xml
INTERNET
Eng C. PTEN Hamartoma Tumor Syndrome. 2001 Nov 29 [Updated 2016 Jun 2]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1488/ Accessed Jan 19, 2021.
Bannayan-Riley-Ruvalcaba syndrome. Genetic and Rare Diseases Information Center. Last updated: 5/13/2020. https://rarediseases.info.nih.gov/diseases/5887/bannayan-riley-ruvalcaba-syndrome Accessed Jan 19, 2021.
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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
View report