Bardet Biedl Syndrome
Bardet Biedl Syndrome
National Organization for Rare Disorders, Inc.
It is possible that the main title of the report Bardet Biedl Syndrome is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.
Related Disorders List
Information on the following diseases can be found in the Related Disorders section of this report:
- Alstrom Syndrome
- Laurence-Moon Syndrome
- McKusick-Kaufman Syndrome
- Prader-Willi Syndrome
Bardet-Biedl syndrome is a rare, genetic multisystem disorder characterized primarily by deterioration of the cells that receive light stimuli (cone and rod cells), in the retina of the eyes (progressive cone-rod dystrophy), an extra finger near the pinky or an extra toe near the fifth toe (postaxial polydactyly), a condition in which fat is disproportionately distributed on the abdomen and chest rather than the arms and legs (truncal obesity), diminished size and decreased function of the gonads (testes), in males (hypgonadism), kidney (renal), ,abnormalities, and learning difficulties. Visual abnormalities usually become progressively worse and may ultimately result in blindness. Kidney (renal) abnormalities may progress to cause life-threatening complications. Learning difficulties are a common finding due, in part, to vision loss. Only a minority of affected individuals have severe mental impairment. Most cases of Bardet-Biedl syndrome are inherited as an autosomal recessive trait.
Bardet-Biedl syndrome shows significant overlap with a disorder called Laurence-Moon syndrome. In fact, in the past, these disorders were considered the same and referred to as Laurence-Bardet-Biedl syndrome. Eventually, researchers decided that the two disorders despite numerous similarities were distinct entities. However, recent research has demonstrated that some individuals with the clinical findings of Laurence-Moon syndrome have had mutations in genes linked to Bardet-Biedl syndrome. This discovery has led some researchers to suggest that little evidence exists to continue to classify these two disorders as distinct entities.
The symptoms and severity of Bardet-Biedl syndrome varies greatly even among individuals within the same family. Affected individuals will not have all of the symptoms discussed below. In addition, the severity of specific symptoms may vary greatly as well. The main features of this disorder are cone-rod dystrophy, postaxial polydactyly, truncal obesity, kidney abnormalities and learning difficulties.
Cone-rod dystrophy is a form of retinal dysfunction. The retina is the light-sensitive membrane upon which images are focused at the back of the eye. The cells in the retina (cones and rods [photoreceptors]) that convert light into nerve impulses gradually deteriorate (cone-rod dystrophy), causing vision loss. Symptoms associated with cone-rod dystrophy may not become apparent until 7 or 8 years of age when an impaired ability to see in dim light or the dark (nightblindness), may develop.
The progression and degree of visual impairment varies among affected individuals. In most cases, vision becomes progressively worse through the first and second decade. Affected individuals often lose side (peripheral) vision, a condition sometimes termed tunnel vision. At some point during childhood or adolescence, many affected individuals eventually lose central vision as well resulting in severe visual impairment or blindness. In some cases, the degeneration of the retina may follow the characteristic course of retinitis pigmentosa, with night blindness, loss of the ability to discriminate color, and progressive tunnel vision. (For more information, choose "Retinitis Pigmentosa" as your search term in the Rare Disease Database).
Additional ocular findings may occur including crossed eyes (strabismus), abnormal, involuntary rapid eye movements (nystagmus), clouding of the lens of the eyes (cataracts) and damage to the optic nerve often associated with increased pressure within the eyes (glaucoma).
Affected individuals also have abnormalities of the hands and feet including the presence of an extra finger near the pinky or an extra toe near the fifth "little" toe, a condition termed postaxial polydactyly. This finding occurs in approximately 70 percent of cases. Webbing (syndactyly) of the fingers or toes, especially between the second and third toes, may also occur. In addition, the fingers and toes may be abnormally short (brachydactyly) and the feet may be short, wide and flat, with no arch. In rare cases, other similar abnormalities may occur such as curving of the pinky toward the ring finger (clinodactyly).
Another common finding associated with Bardet-Biedl syndrome is truncal obesity, which refers to a condition in which fat is disproportionately distributed on the abdomen and chest rather than the arms and legs. Weight is usually normal at birth, but weight gain may be seen in the first year of life.
Mild-to-moderate learning difficulties are common in individuals with Bardet-Biedl syndrome. In early reports, learning disabilities were attributed to mental retardation. However, studies have demonstrated that while some affected individuals may have significant learning disabilities, only a small number of individuals have significantly low IQ testing. Learning disabilities may occur, in part, as a result of visual abnormalities. Affected individuals may experience delays in reaching developmental milestones.
Bardet-Biedl syndrome may also be associated with diminished size and decreased function of the gonads (testes) in males (hypogonadism). Additional abnormalities may include a small penis, failure of the testes to descend into the scrotum (cryptorchidism) and a delay in reaching puberty. Affected females may have complex genitourinary abnormalities including underdeveloped (hypoplastic) fallopian tubes, uterus and ovaries; a divided (septate) vagina; duplex uterus; partial or complete narrowing (atresia) of the vagina; a collection of watery fluid in the uterus and vagina (hydrometrocolpos); an abnormal passage between the bladder and the vagina (vesico-vaginal fistula); and absence of the vaginal or urethral orifice. Menstrual irregularities have been reported in some affected females.
Some individuals with Bardet-Biedl syndrome may also develop anomalies of the structure and/or function of the kidneys, potentially resulting in abnormal accumulation of urine in the kidneys (hydronephrosis) or inflammation of the kidneys and the pelvis (pyelonephritis). In some cases, kidney abnormalities can potentially lead to severe kidney (renal) impairment in some cases, even to the extent of renal failure, dialysis, and need for transplantation.
Children with Bardet-Biedl syndrome may experience delays in speaking or speech impairment. Affected children may have a high-pitched, nasally voice and poor articulation. For example, they may have difficulty vocalizing certain sounds (such as the substituting consonants at the start of a word and omitting consonants at the end of a word).
Behavioral abnormalities have reported in Bardet-Biedl syndrome. Affected individuals have displayed anxiety, depression, mood disorders and obsessive-compulsive disorder (OCD). Some individuals may have symptoms that can be classified within the spectrum of autism.
Bardet-Biedl syndrome may also be associated with high blood pressure (hypertension), loss of the ability to smell (anosmia), and an impaired ability to coordinate voluntary movements (ataxia) resulting in clumsiness and an abnormal gait. Less common findings associated with Bardet-Biedl syndrome include chronic middle ear infections (otitis media), hearing loss; dental abnormalities; scarring of the liver (hepatic fibrosis); asthma; congenital heart malformations; abnormal positioning of internal organs (situs inversus); and diabetes mellitus.
A subgroup of affected individuals exhibited similar, distinct facial features including deep-set, widely-spaced eyes, a flat bridge of the nose with nostrils that are flared forward (anteverted nares), a long groove (philtrum) in the center of the upper lip, and downward-slanting eyelid folds (palpebral fissures).
Most cases of Bardet-Biedl syndrome are inherited as an autosomal recessive 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.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Investigators have determined 12 separate genes known to cause Bardet-Biedl syndrome. In rare cases, some individuals have required the occurrence of three mutations (i.e., two in one gene and a third in another gene or three separate genes) to develop the disorder (triallelic inheritance). However, most cases occur from the presence of one mutation on one gene.
The most common defective gene associated with Bardet-Biedl syndrome is the BBS1 gene located on the long arm (q) of chromosome 11 (11q13). The BBS1 gene accounts for approximately 30 percent of cases. Chromosomes, which are present in the nucleus of human cell, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 11q13" refers to band 13 on the long arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The BBS2 gene is located on long arm of chromosome 16 (16q21). The BBS3 gene (also known as the ARL6 gene) is found between the short and long arms of the chromosome 3 (3p12-q13). The BBS4 gene is located on the long arm of chromosome 15 (15q22.3-q23). The BBS5 gene is located on the long arm of chromosome 2 (2q31). The BBS6 gene is located on the short arm of chromosome 20 (20p12). The BBS7 gene is located on the long arm of chromosome 4 (4q27). The BBS8 gene is located on the long arm of chromosome 14 (14q32.1). The BBS9 gene is located on the long arm of chromosome 7 (7q14). The BBS10 gene is located on the long arm of chromosome 12 (12q21.2). The BBS11 gene is located on the short arm of chromosome 9 (9p31-p34.1). The BBS12 gene is located on the long arm of chromosome 4 (4q27).
Researchers have determined that approximately 20-30 percent of individuals with Bardet-Biedl syndrome do not have a mutation of one of the 12 identified genes indicating that more, as-yet-unidentified, genes may cause Bardet-Biedl syndrome.
The genes associated for Bardet-Biedl syndrome contain instructions for developing (encoding) certain proteins. Mutations of these genes results in deficiency or dysfunction of these proteins. Investigators have determined that most of the Bardet-Biedl proteins are associated with cilia, the hair-like structures that cover almost all types of cells in the body, and some related structures such as the basal body (which "anchors" the cilia to a cell) or flagella (nearly-identical, hair-like structures also attached to cells).
Cilia are classified as motile or immotile. In Bardet-Biedl syndrome, it appears that immotile cilia are affected.
For years, researchers have believed that motile cilia move or propel the cell or allow for substances to move around the cell. Immotile (or primary) cilia were believed to play a sensory role or to have no modern function. However, researchers now know that immotile cilia are active structures required for normal health and development, and that motile cilia may have a role as sensory structures and immotible cilia may have a role in cell movement. Researchers know that the Bardet-Biedl proteins play a role in the formation, maintenance, and function of cilia such as intraflagellar transport (IFT), a transport system that moves particles from the cell body to the tip of cilia and flagella. Researchers also believe that some of the Bardet-Biedl proteins have broader roles in the body beyond the cilia.
Certain symptoms associated with Bardet-Biedl syndrome can be attributed to ciliary dysfunction including kidney abnormalities, cone-rod dystrophy, anosmia, hearing loss, and situs inversus. As yet, certain symptoms associated with Bardet-Biedl syndrome cannot be directly attributed to ciliary dysfunction. Research is ongoing to determine the exact manner in which the different Bardet-Biedl proteins ultimately cause the varied symptoms associated with the disorder and all of the functions in which these proteins play a role.
Researchers are also trying to determine why so many different genetic mutations produce a syndrome with such consistent findings or why individuals with the same exact mutation can display different symptoms and different severity of this disorder.
Bardet-Biedl syndrome affects males and females in equal numbers. The prevalence is estimated to be 1 in 100,000 in the non-related (nonconsanguineous) populations of Northern Europe and America. In Sweden, the prevalence is estimated to be 1 in 160,000. The disorder occurs in with greater frequency in the Bedouin population of Kuwait (1 in 13,500) and in certain populations of Newfoundland (1 in 17,500).
The disorder was first described by doctors Bardet and Biedl in the 1920s. Laurence-Moon syndrome, which some researchers believe is the same as Bardet-Biedl syndrome, was first described in the medical literature by doctors Laurence and Moon in 1865.
Symptoms of the following disorders can be similar to those of Bardet-Biedl syndrome. Comparisons may be useful for a differential diagnosis.
Alström syndrome is a rare genetic disorder most often characterized by vision and hearing abnormalities, childhood obesity, diabetes mellitus, and slowly progressive kidney (renal) dysfunction (chronic nephropathy). Specific features vary from case to case. Initial symptoms are usually an insensitivity to light (photophobia) and rapid, involuntary eye movements (nystagmus). Additional features sometimes associated with Alström syndrome include disease of the heart muscle (cardiomyopathy), skin abnormalities and abnormalities affecting additional organ systems. Intelligence is not affected. Alström syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose "Alström" as your search term in the Rare Disease Database.)
Meckel syndrome, also known as Meckel-Gruber syndrome, is a rare genetic disorder characterized by abnormalities affecting several organ systems of the body (multisystem). Characteristic findings include protrusion of part of the brain and its surrounding membranes (meninges) through a defect in the back or front of the skull (encephalocele), an extra finger or toe (polydactyly), and multiple cysts on the kidneys (polycystic kidney disease). Additional findings may occur including scarring (fibrosis) of the liver, central nervous system abnormalities, underdevelopment of the lungs, and genital abnormalities. Meckel syndrome is inherited as an autosomal recessive trait. Mutations in certain Bardet-Biedl genes (i.e., BBS2, BBS4 and BBS6) have been detected in some individuals with Meckel syndrome, meaning that in such cases Bardet-Biedl syndrome and Meckel syndrome occur from different mutations of the same gene (allelic). (For more information on this disorder, choose "Meckel" as your search term in the Rare Disease Database.)
McKusick-Kaufman syndrome (MKKS) is an extremely rare genetic disorder an extra finger near the pinky or an extra toe near the fifth toe (postaxial polydactyly), congenital heart defects, and, in females, a collection of watery fluid in the uterus and vagina (hydrometrocolpos). Additional symptoms include genitourinary abnormalities, underdeveloped (hypoplastic) lungs, gastrointestinal abnormalities, and kidney defects. McKusick-Kaufman syndrome is inherited as an autosomal recessive trait. The disorder occurs due to mutations of the MKKS gene located on chromosome 20. This gene is also known as the BBS6 gene and has been linked to Bardet-Biedl syndrome.
Biemond II syndrome is an extremely rare genetic disorder characterized by absence of tissue from the colored portion of the eye (iris coloboma), mental retardation, obesity, genitourinary abnormalities, and an extra finger near the pinky or an extra toe near the fifth toe (postaxial polydactyly). Biemond II syndrome is inherited as an autosomal recessive trait. No genes that cause or are associated with this disorder have been identified.
Prader-Willi syndrome is a genetic disorder characterized in infancy by diminished muscle tone (hypotonia), feeding difficulties, and failure to grow and gain weight (failure to thrive). In childhood, features of the disorder include short stature, genital abnormalities and an excessive appetite. Progressive obesity results because of a lack of feeling satisfied after completing a meal (satiety) that leads to overeating. Without appropriate treatment, individuals with severe progressive obesity may have an increased risk of cardiac insufficiency, diabetes or other serious conditions that may lead to potentially life-threatening complications. All individuals with Prader-Willi syndrome have some cognitive impairment that ranges from borderline normal with learning disabilities to mild mental retardation. Behavior problems are common and can include temper tantrums, obsessive/compulsive behavior, and skin picking. Prader-Willi syndrome occurs when the genes in a specific region of chromosome 15 do not function. The abnormal genes usually result from random errors in development, but are sometimes inherited. (For more information on this disorder, choose "Prader Willi" as your search term in the Rare Disease Database.)
Bardet-Biedl syndrome is usually diagnosed in childhood based upon thorough clinical evaluation and detection of characteristic findings (e.g., visual problems due to retinal dystrophy, obesity, polydactyly). Diagnosis of retinal disease can be made by an ophthalmologist after an examination and sometimes with the assistance of specialized tests, including an electroretinogram (ERG), a procedure that measures the electrical response of the retina to light stimulation.
If available, genetic testing may assist in diagnosing the disorder in selected cases (e.g., individuals with certain BBS1 and BBS10 gene mutations). However, such testing is currently available only through research laboratories with a special interest in the disease complex.
The treatment of Bardet-Biedl 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, orthopedic surgeons, cardiologists, dental specialists, speech pathologists, specialists who asses and treat hearing problems (audiologists), specialists who asses and treat vision problems (ophthalmologists), physicians who specialize in the diagnosis and treatment of kidney diseases (nephrologists), and other healthcare professionals may need to systematically and comprehensively plan an affect child's treatment.
There are currently no proven therapies available for retinal dystrophy associated with Bardet-Biedl syndrome. Standard care from an ophthalmologist is required for management of refractive errors (e.g., myopia) and assistance with low-vision aids as vision decreases.
In some cases, abnormalities of the fingers and/or toes may be corrected surgically. Surgery may also be performed to correct certain genitourinary abnormalities or congenital heart defects.
Measures to manage obesity may include age-appropriate diets, exercise programs, and behavioral modifications. In addition, affected individuals should be evaluated by kidney specialists to determine appropriate intervention for kidney disease. Hormone replacement therapy may be necessary for males with hypogonadism.
Individuals with Bardet-Biedl syndrome should undergo regular ophthalmologic examinations as well as periodic assessments to determine the presence of complications potentially associated with the disorder such as kidney dysfunction, diabete mellitus, liver function and high blood pressure.
Early intervention is important in ensuring that children with Bardet-Biedl syndrome reach their highest potential. Services that may be beneficial may include special education for children with cognitive impairment, special services for children with vision problems, and other medical, social, and/or vocational services. Genetic counseling may be of benefit for affected individuals and their families.
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
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For information about clinical trials sponsored by private sources, contact:
The Baylor College of Medicine and the Cullen Eye Institute has a long-term commitment to identify the genes and genetic mechanisms of Bardet-Biedl syndrome. Approved protocols through the Institutional Review Board for Human Subject Research will require recovery of records for documentation of diagnosis and blood samples for DNA analysis. Interested families, counselors, and physicians may contact:
Richard Alan Lewis M.D., M.S.
Cullen Eye Institute, NC-206
Baylor College of Medicine
One Baylor Plaza
Houston, Texas 77030
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FROM THE INTERNET
Ross AJ, Beales PL. Updated:03/06/2007. Bardet-Biedl Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at http://www.genetests.org.
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