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Bannayan-Riley-Ruvalcaba syndrome (BRRS) also known as Bannayan-Zonana syndrome, Riley-Smith syndrome, and Ruvalcava-Myhre-Smith syndrome is a rare genetic overgrowth syndrome and hamartomatous with the occurrence of multiple subcutaneous lipomas, macrocephaly and hemangiomas disorder that is present at birth and is characterized by a large head size (macrocephaly), and pigmented spots (maculae) on the penis and benign tumors, and tumor-like growths in the intestine called hamartomas and phosphatase and tensin homolog hamartoma tumor syndrome with a PTEN gene mutation. It is a rare dominant autosomal disorder characterized by cutaneous lipomas, macrocephaly, intestinal polyps, and developmental delay. 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.
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
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.
Symptoms
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 including the presence of macrocephaly, lipomas, hamartomatous intestinal polyposis, developmental delay, and mental retardation, as well as pigmented macules on the glans penis in males. 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).
Bannayan–Riley–Ruvalcaba syndrome is associated with an enlarged head and benign mesodermal hamartomas (multiple hemangiomas, and intestinal polyps). Dysmorphia, as well as delayed neuropsychomotor development, can also be present. The head enlargement does not cause widening of the ventricles or raised intracranial pressure; these individuals have a higher risk of developing tumors, as the gene involved in BRRs is phosphatase and tensin homolog.
Some individuals have thyroid issues consistent with multinodular goiter, thyroid adenoma, differentiated non-medullary thyroid cancer, most lesions are slowly growing. Visceral as well as intracranial involvement may occur in some cases and can cause bleeding and symptomatic mechanical compression.
Causes
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 ‘PTEN’ 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.
Diagnosis
BRRS may be suspected based upon the 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 counseling 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 patient’s age at diagnosis
Pediatric (under age 18)
- Yearly thyroid ultrasound starting at the age of 7 years
- Yearly skin check with physical examination
- Consider neurodevelopmental evaluation
- Yearly hemoglobin test for early detection of intestinal hamartomas to prevent severe complications
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 the 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 the 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.
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