Information on the following diseases can be found in the Related Disorders section of this report:

• Multiple hamartoma syndrome (Cowden disease)
• Sotos syndrome
• Associated congenital disorders

In Bannayan-Riley-Ruvalcaba syndrome, excessive growth occurs prior to birth. As a result, at birth, affected infants usually exhibit abnormally increased birth weight and length. After birth, the growth rate slows and older children and adults with this disorder often attain height that is within the normal range.

Infants with Bannayan-Riley-Ruvalcaba syndrome often exhibit diminished muscle tone (hypotonia); excessive drooling; delayed speech development; and/or a significant delay in the attainment of developmental milestones such as the ability to sit, stand, walk, etc. Most affected individuals are delayed in acquiring skills that require coordination of muscles and voluntary movements (delayed psychomotor development). Approximately half of all affected individuals experience mental retardation ranging from mild to severe. In addition, in 25 percent of cases, affected infants experience episodes of uncontrolled electrical disturbances in the brain (seizures).

Infants with Bannayan-Riley-Ruvalcaba syndrome also have various abnormalities of the head and facial (craniofacial) area. In most cases, affected infants have an abnormally large head (macrocephaly). In some cases, the head may appear long and unusually narrow (scaphocephaly). In a few cases, the soft spots between the bones in the front of the skull (anterior fontanels) may close later than expected. Abnormalities affecting the eyes are also associated with this disorder. Some affected infants may exhibit crossed eyes (strabismus); widely spaced eyes (ocular hypertelorism); downward slanting eyelid folds (downslanting palpebral fissures); deviation of one eye away from the other (exotropia); visual impairment (amblyopia) in an eye that appears structurally normal; and/or abnormal elevation of the optic disc so that it appears swollen (pseudopapilledema). In addition, affected individuals may have a highly arched roof of the mouth (palate).

In most cases, Bannayan-Riley-Ruvalcaba syndrome is associated with noncancerous (benign), tumor-like growths (hamartomas). These growths are composed of mature cells and tissues that are normally found in an affected area. In approximately 75 percent of cases, the hamartomatous growths consist of mature fat cells (lipomas). Less often, they are made up of newly formed blood vessels (hemangiomas) or widened lymphatic vessels (lymphangiomas). In approximately 20 percent of affected individuals, these abnormal growths are of a "mixed type." In approximately 50 percent of cases, affected individuals have lipomas that consist of clusters of blood vessels (angiolipomas). Hamartomas may vary in size, number, and location with most occurring in the tissues just below the skin (subcutaneous). In some cases, such abnormal growths may develop within the skull (intracranial) or bones (osseous). In some cases, lipomas may grow aggressively and, depending upon their location, may lead to serious complications.

In approximately 45 percent of individuals with Bannayan-Riley-Ruvalcaba syndrome, small multiple growths (hamartomatous polyps) develop in the intestines (intestinal polyposis) and, in rare cases, the back of the wall of the throat (pharynx) and/or tonsils. These polyps may develop in the intestines during childhood or, in some cases, during adulthood. In severe cases, polyps may cause bleeding from the rectum and/or sinking (prolapse) of one portion of the intestine into an adjoining portion (intussusception).

In most cases, males with Bannayan-Riley-Ruvalcaba syndrome may exhibit additional abnormalities affecting the skin particularly the development of dark freckle-like spots (pigmented macules) on the shaft and glans of the penis. In affected females, this discoloration may occur on the external genitals (vulva). In some cases, affected individuals may have small, coffee-colored spots on the skin (cafe-au-lait spots) and/or abnormal widening of small blood vessels, resulting in red lesions on the skin (telangiectasias). In a few cases, certain areas of skin may appear to be "marbled" (cutis marmorata).

In some individuals with Bannayan-Riley-Ruvalcaba syndrome, skeletal abnormalities may also be present including fingers that are abnormally long; unusually broad thumbs and great toes; excessive joint mobility (hyperextensibility); a sunken breastbone (pectus excavatum); and/or abnormal side-to-side curvature of the spine (scoliosis).

Approximately 60 percent of individuals with Bannayan-Riley-Ruvalcaba syndrome develop problems affecting the muscles characterized by muscle weakness, especially affecting the arms and legs. Some affected infants have difficulty nursing due to weak facial muscles. According to the medical literature, in some cases, muscle weakness may result from abnormal accumulation of certain fats (lipids) within the muscles (lipid storage myopathy).

In rare cases, individuals with Bannayan-Riley-Ruvalcaba syndrome may have additional abnormalities. Affected males may have an enlarged penis and/or testes. Affected individuals may be more prone to developing certain malignancies (e.g., intracranial tumors, thyroid tumors, testis tumors, etc.) than the general population. In rare cases, affected individuals may develop arteriovenous malformations, characterized by abnormally large and twisted (tortuous) arteries and veins (blood vessels) that connect directly rather than being connected by small fine blood vessels (capillaries).

In addition, in some cases, affected individuals may develop an autoimmune disorder known as Hashimoto thyroiditis. This disease affects the gland responsible, in part, for the regulation of metabolism (thyroid). Hashimoto thyroiditis may result in abnormal enlargement of the thyroid gland (goiter); unusually low levels of thyroid hormone secretion (hypothyroidism); and/or fatigue, weight gain, and/or muscle weakness. (For more information on this disorder, choose "Hashimoto" as your search term in the Rare Disease Database.)
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Bannayan-Riley-Ruvalcaba syndrome is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

Investigators have determined that approximately 60 percent of cases of BRRS are caused by disruption or changes (mutations) of the (PTEN) gene. located on the long arm (q) of chromosome 10 (10q23.3). Chromosomes, which are present in the nucleus of human cells, carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." Chromosomes are further subdivided into many bands that are numbered. For example, "chromosome 10q23.3" refers to band 23.3 on the long arm of chromosome 10.

PTEN stands for phosphatase, tensin homologue, deleted on chromosome 10. PTEN is a tumor suppressor gene – 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 cancer. The PTEN gene regulates the production of an enzyme (protein tyrosine phosphatase), which is believed to mediate cell arrest and apoptosis. Researchers believe that the PTEN gene plays a broad role in the development of human malignancies.

A group of disorders including approximately 85 percent of cases of Cowden syndrome, some cases of Proteus-like syndrome, and possibly 20 percent of cases of Proteus (although this is debated in the medical literature) have been associated with a PTEN gene mutation. These disorders along with the cases of BRRS that are caused by a PTEN mutation are collectively known as the PTEN hamartoma tumor syndrome.

Bannayan-Riley-Ruvalcaba syndrome is a rare inherited disorder that appears to affect males more often than females. Some researchers believe that females are generally mildly affected by the disorder and often remain undiagnosed. More than 50 cases within 15 multigenerational families (kindreds) have been reported in the medical literature.

Bannayan-Riley-Ruvalcaba is the name used to denote the combination of three conditions formerly recognized as separate disorders. These disorders are Bannayan-Zonana syndrome, Riley-Smith syndrome, and Ruvalcaba-Myhre-Smith syndrome.

Approximately 60 percent of cases of BRRS are associated with mutations of the PTEN gene and may be referred to as part of the PTEN hamartoma tumor syndrome (PHTS). PHTS, which incudes Cowden syndrome, is a spectrum of disorders caused by mutations of the PTEN gene. These disorders are characterized by multiple hamartomas that can affect various areas of the body. Hamartoma is a general term for benign tumor-like malformations that can affect any area of the body. Hamartomas are composed of mature cells and tissue normally found in the affected area.

Symptoms of the following disorders can be similar to those of Bannayan-Riley-Ruvalcaba syndrome. Comparisons may be useful for a differential diagnosis:

Multiple hamartoma syndrome, also known as Cowden disease, is an extremely rare inherited disorder characterized by the development of many benign, tumor-like growths (hamartomas) affecting multiple organ systems of the body, especially the skin, mucous membranes, breasts, and thyroid. Affected individuals also develop characteristic skin abnormalities such as wart-like lesions (verrucous) of the face and limbs; small raised areas (papules) on the face; bumps resembling cobblestones on the gums and mucous membranes lining the cheeks (buccal mucosa); and/or tiny, benign tumors in the roots of the hair on the face (trichilemmomas). Hamartomas affecting the skin include those made up of connective tissue cells (fibromas), fat cells (lipomas), or small blood vessels just under the surface of the skin (hemangiomas). Affected individuals may have abnormalities affecting the thyroid gland including inflammation (thyroiditis) of the thyroid gland, unusual enlargement of the thyroid gland (goiter), over or under production of thyroid hormones (hyper- or hypothyroidism), and/or the development of other benign tumors (adenomas). Approximately 70 percent of females with multiple hamartoma syndrome have breast lesions including multiple cysts (fibrocystic disease) and/or benign tumors consisting of fibrous tissue (fibroadenomas). Affected males may have abnormally enlarged breasts (gynecomastia). Hamartomatous growths may also occur in the gastrointestinal tract and/or genitourinary system. Individuals with multiple hamartoma syndrome are more prone to develop breast, thyroid, and other forms of cancer. In addition, other characteristic findings associated with this disorder may include neurological symptoms such as tremors, seizures, impaired ability to coordinate voluntary movements (ataxia), and delayed development of skills that require coordination of voluntary movements (psychomotor retardation). In some cases, skeletal abnormalities may be present including abnormal side-to-side (scoliosis), front-to-back (kyphosis), or increased (lordosis) curvature of the spine. Multiple hamartoma syndrome is inherited as an autosomal dominant genetic trait, and is the result of mutation(s) in the PTEN gene on chromosome 10. There are cases reported in the medical literature in which multiple hamartoma syndrome and Bannayan-Riley-Ruvalcaba syndrome have occurred in different members of the same family.

Sotos syndrome is a rare genetic disorder characterized by excessive growth that occurs prior to and after birth (prenatally and postnatally). At birth, affected infants have unusually increased body length that is abnormal in proportion to weight, which may also be above average; in addition, newborns typically demonstrate advanced bone growth, abnormally large hands and/or feet, and characteristic facial features. Abnormally rapid growth continues after birth until approximately four or five years of age, at which time growth may slow to a normal rate. An affected individual's final height often is within normal range. Affected infants and children may also demonstrate developmental abnormalities including delays in reaching developmental milestones (e.g., sitting, crawling, walking); delays in the acquisition of skills requiring the coordination of muscular and mental activity (psychomotor retardation); delayed language skills; and mild to severe mental retardation. Characteristic facial abnormalities may include an unusually large head (macrocephaly) that may appear elongated (dolichocephalic) with an abnormally prominent forehead (frontal bossing); widely-spaced eyes (ocular hypertelorism); downwardly slanting eyelid folds (palpebral fissures); a highly-arched roof of the mouth (palate); protrusion of the lower jaw (prognathism); and/or a pointed chin. Most cases of Sotos syndrome occur randomly, for no known reason (sporadically). In rare cases, however, when a positive family history is found, the disorder may be inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose "Sotos" as your search term in the Rare Disease Database.)

There may be other disorders characterized by symptoms or physical findings associated with Bannayan-Riley-Ruvalcaba syndrome (i.e., excessive growth or intestinal polyposis). Such disorders may include Beckwith-Wiedemann syndrome, Weaver syndrome, Simpson dysmorphia syndrome, Peutz-Jehgers syndrome, juvenile intestinal polyposis, and Turcot syndrome. These disorders usually have other characteristics that distinguish them from Bannayan-Riley-Ruvalcaba syndrome. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis
The diagnosis of Bannayan-Riley-Ruvalcaba syndrome may be suspected based upon characteristic symptoms and physical findings (e.g., macrocephaly, hypotonia, excessive birth weight and length, excessive prenatal growth rate, etc.) that are present at birth (congenital). A diagnosis is usually confirmed during infancy or early childhood after the development of hamartomas and slowing of the growth rate. Computerized tomography (CT) scanning may be used to reveal normal sized cavities within the brain (ventricles) associated with Bannayan-Riley-Ruvalcaba syndrome. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of the brain's tissue structure.

Abnormalities of the inner eye (e.g., pseudopapilledema and/or unusually prominent Schwalbe lines and/or corneal nerves) may be detected through examination with instruments used to study and illuminate the interior of the eyes (ophthalmoscopy and slit lamp). Hamartomas in the intestines may be suspected when rectal bleeding is observed, and a diagnosis of these and other hamartomas within the body may be confirmed using advanced imaging techniques such as CT scanning and x-rays.

Other symptoms and physical findings associated with Bannayan-Riley-Ruvalcaba syndrome (e.g., developmental delays, mental retardation, etc.) may not become apparent until late infancy or early childhood. For example, developmental delays and psychomotor retardation become apparent when an affected infant or child fails to attain certain developmental milestones (e.g., crawling, walking, speaking, etc.). Mental retardation may not be detected until the child is old enough to respond to clinical testing.

Muscle activity may be tested through administering electrical charges (electromyography) and microscopic examination of muscle tissue (biopsy).

Treatment
The treatment of Bannayan-Riley-Ruvalcaba syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, speech pathologists, specialists who diagnose and treat skeletal disorders (orthopedists), physicians who diagnose and treat eye disorders (ophthalmologists), physical therapists, and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.

Hamartomas that cause serious complications may require surgical removal. Physical therapy may be required to aid in motor development. In addition, speech therapy may be useful in helping affected individuals develop speech.

Individuals with the disorder should be monitored for the development of gastrointestinal polyps. In addition, to hamartomatous growths, a small percentage of individuals with Bannayan-Riley-Ruvalcaba syndrome may be more prone to developing other tumors and/or malignancies (e.g., intracranial tumors, thyroid tumors, etc.) than the general population. Physicians may closely monitor affected individuals to ensure early detection and appropriate early treatment.

Early intervention is important to ensure that children with Bannayan-Riley-Ruvalcaba syndrome reach their potential. Special services that may be beneficial to affected children may include special remedial education, special social support, physical therapy, and other medical, social, and/or vocational services.

Genetic counseling will be of benefit for affected individuals and their families. Family members of affected individuals should also receive periodic clinical evaluations to detect any symptoms and physical characteristics that may be potentially associated with Bannayan-Riley-Ruvalcaba syndrome. Other treatment for this disorder is symptomatic and supportive.

Investigational Therapies
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.

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: prpl@cc.nih.gov

TEXTBOOKS
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Gorlin RJ, et al., eds. Syndromes of the Head and Neck, 3rd ed. New York, NY: Oxford University Press; 1990:336-38.

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Marsh DJ, et al. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet. 1998;7:507-15.

Eng C. Genetics of Cowden syndrome: through the looking glass of oncology. Int J Oncol. 1998;12:701-10.

Sotos JF. Overgrowth: a comprehensive study on the topic of overgrowth presented in six sections. Section VI: Syndromes and Other Disorders Associated with Overgrowth. Clinical Pediatrics. 1997:162-64.

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Arch EM, et al. Deletion of PTEN in a patient with Bannayan-Riley-Ruvalcaba syndrome suggests allelism with Cowden disease. Am J Med Genet. 1997;71:489-93.

Fargnoli MC, et al. Clinicopathic findings in the bannayan-riley-ruvalcaba syndrome. Arch Dermatol. 1996;132:1214-18.

Fryburg JS, et al. Long-chain 3 hydroxyacyl-coenzyme A dehydrogenase (L-CHAD) deficiency in a patient with the Bannayan-Riley-Ruvalcaba syndrome. Am J Med Genet. 1994;52:97-102.

Powell BR, et al. Dominantly inherited megalencephaly, muscle weakness, and myoliposis: a carnitine-deficient myopathy within the spectrum of the Ruvalcaba-Myhre-Smith syndrome. J Pediatr. 1993;123:70-75.

Hayashi Y, et al. Bannayan-Zonana syndrome associated with lipomas, hemangiomas, and lymphangiomas. J Pediatr Surg. 1992;27:722-23.

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Klein JA, et al. Bannayan-Zonana syndrome associated with lymphangiomyomatous lesions. Pediatr Dermatol. 1990;7:48-53.

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Dvir M, et al. Heredofamilial syndrome of mesodermal hamartomas, macrocephaly, and pseudopapilledema. Pediatrics. 1988;81:287-90.

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Miles JH, et al. Macrocephaly with hamartomas: Bannayan-Zonana syndrome. Am J Med Genet. 1984;19:225-34.

DiLiberti JH, et al. Ruvalcaba-Myhre-Smith syndrome: a case with probable autosomal-dominant inheritance and additional manifestations. Am J Med Genet. 1983;15:491-95.

Ruvalcaba RH, et al. Sotos syndrome with intestinal polyposis and pigmentary changes of the genitalia. Clin Genet. 1980;18:413-16.

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