NORD gratefully acknowledges Xenia Parisi, MD, Department of Pathology, Beth Israel Deaconess Medical Center, for assistance in the preparation of this report.
Bardet-Biedl syndrome (BBS) is a genetic condition that impacts multiple body systems. It is classically defined by six features. Patients with BBS can experience problems with obesity, specifically with fat deposition along the abdomen. They often also suffer from intellectual impairments. Commonly, the kidneys, eyes and function of the genitalia will be compromised. People with BBS may also be born with an extra digit on the hands. The severity of BBS varies greatly even among individuals within the same family. The symptoms discussed below are those generally seen with BBS. They may or may not be seen in any given person with the syndrome.
Bardet-Biedl syndrome was historically termed Laurence-Moon-Biedl-Bardet syndrome by the physicians who described the first cases of the syndrome. It is now generally considered that Bardet-Biedl syndrome and Laurence-Moon syndrome (see Related Disorders) are distinct conditions.
The cardinal features of BBS are truncal obesity, intellectual impairment, renal anomalies, polydactyly, retinal degeneration and hypogenitalism. Each feature is discussed in detail below. The term ‘truncal obesity’ refers to a condition where fat is disproportionately distributed onto the abdomen and chest rather than the arms and legs. Individuals can be described as having an apple-shape body type. Weight is usually normal at birth but weight gain is quickly evident through the first year of life in as many as 90% of people with BBS. Diabetes mellitus (specifically, type II diabetes, non-insulin dependent) has been estimated to affect up to 45% of patients with BBS. Weight management problems may further complicate problems with the heart and blood vessels seen in patients with BBS. The heart functions as a pump for the blood, moving the blood through the vessels that bring it throughout the body. The heart relies on valves that keep the flow moving in the forward direction. With age, stiffening of the heart valves is completely normal. The stiffening is due to calcium laying down on the valves, and this process if described by the word “stenosis”. Patients with BBS may experience stenosis of their heart valves prematurely. They may also have defects of the heart’s muscular walls. The heart muscle is designed such that every motion is smoothly orchestrated. Defects in the heart muscle predispose people with BBS to heart beat abnormalities, referred to as “arrhythmias”. Most patients with BBS will experience the loss of a particular population of cells in the eye, specifically in the retina. The retina is part of the eye involved in detecting and decoding incoming images. Incoming light is focused onto the retina at the back of the eye. The retina is composed of cells called “rods and cones”. They translate incoming light into nerve impulses the brain can use. This gradual loss of the rod and cone cells on the retina is described as “dystrophy”. Symptoms associated with cone-rod dystrophy may not become apparent until 7 or 8 years of age when children begin to complain of an inability to see in dimly lit environments, such as a sidewalk lit only by streetlights. This “night blindness” may progress to variable degrees. In most people, the vision becomes progressively weaker through the first and second decades of life. Affected individuals often first lose peripheral vision, and see only what is directly in front of their focus point. They see in what is termed ‘tunnel vision’. Many affected individuals also eventually lose central vision and become legally blind, often by their mid-teens. In some people, the degeneration of the retina may follow a characteristic course, referred to as “retinitis pigmentosa”, (RP). RP begins with night blindness, followed by a loss of the ability to discriminate colors from one another, and finally to a progressive tunnel vision. (For more information, choose “Retinitis Pigmentosa” as your search term in the Rare Disease Database). Additional effects on the eye characteristic to individuals with BBS include: lazy eye (strabismus), clouding of the lens of the eyes (cataracts), and an increased pressure within the eyes that can result in damage to the optic nerve conducting signals to the brain (glaucoma).
Of note, many people with BBS also have problems with smell. They have a decreased ability to sense smells due to a change in the size to a brain center called the “olfactory bulb”. This is a relatively a mild problem but may impact safety if people are unable to sense for example, a gas leak from the stove.
People with BBS also experience an abnormality of the hands and feet. They may be born with an extra digit near the pinky or an extra toe near the fifth “little” toe. This finding occurs in approximately 70 percent of patients. Specifically, the presence of an extra toe is more common than that of an extra finger. In medical terminology, this is described as ‘postaxial polydactyly’. Fingers and toes may also show webbing, called “syndactyly”. Syndactyly is especially common between the second and third toes. Fingers and toes may occasionally be abnormally short in length. This characteristic is called “brachydactyly”. The feet may overall be short in length, of wide width and carry a flat arch.
Another cardinal feature of BBS is a small size and poor function of the male gonads, termed “testicular hypogonadism”. This may manifest as a small penis, failure of the testes to descend into the scrotum (termed “cryptorchidism”) or a delay in the onset of puberty. Undescended testicles are a concern because they are associated with a greater risk for testicular cancer and should not be left unaddressed. Affected females may also have complex genital and urinary tract abnormalities. They may demonstrate an underdeveloped uterus, fallopian tubes, or ovaries. Menstruation cycles are often delayed from the average first age of onset and may also follow an irregular cycle.
Problems with fertility arise in both men and women. Pregnant women with BBS should be followed closely by obstetricians that are well trained in dealing with high-risk pregnancies.
Some individuals with BBS may develop anomalies of the structure and function of the kidneys. Renal defects are highly variable but generally result in an accumulation of urine in the kidneys that results in inappropriate pressures within the kidneys, leading to stretching of important structures. The dilation resulting from this fluid accumulation is called “hydronephrosis”. It can be monitored by medical imaging such as ultrasound, abdominal x-ray, etc. One common risk that accompanies hydronephrosis includes bacterial infection of the kidneys. The inflammation associated with infection of the kidneys is called “pyelonephritis”. These complications to renal functions can often predispose individuals with BBS to renal failure. Other manifestations of BBS include the development of a cysts and damage to the microscopic filtration unit of the kidney. Kidneys are responsible for filtering the blood and damage to the filtration systems manifest with urine that is dark red blood, possibly even foamy. In scenarios of kidney failure, patients may require dialysis and kidney transplantation. In the scenario that a patient requires kidney transplantation, the use of kidney-protective immunosuppressive medications have been associated with an extra increase in weight gain. This extra weight gain can further complicate any pre-existing diabetes.
Mild-to-moderate learning difficulties are common in individuals with BBS. Often, learning disabilities are attributed to weakened cognitive capacity. Some individuals affected with BBS may have true learning disabilities due to dysfunction of brain development. However, it is important to be sure that suspected disabilities (eg: delayed speech or reading skills) are not due to underlying visual impairment. Neurological impairments may manifest in poor coordination, gross and fine motor skills, and social milestones (eg: ability to play complicated games with other children). Many patients report a significant degree of clumsiness and often walk with legs in a wide-based stance. Walking heel-to-toe may be difficult.
Some individuals with BBS may also experience problems with their liver. The liver is responsible for many body processes. Among them, it produces a green-brown digestive fluid that the body needs to break food down properly. Specifically, the liver conducts bile through thin ducts that can develop dilation or stricture and leak digestive fluid into the liver, where it causes damage in the form of scarring. More rarely, problems with digestion may be due to Hirschsprung disease. Hirschsprung disease describes an absence of the nerves normally found in the colon that control the innate motion of the colon and move food along the tract.
A subgroup of affected individuals may exhibit some distinct facial features. These features including deep-set, widely-spaced eyes with downward-slanting lid folds, a flat nasal bridge with nostrils that flare forward, and a long groove (philtrum) in the center of the upper lip. Individuals may have a high-arched palate, with fewer teeth than expected The teeth may have short roots and lie crowded within the mouth.
BBS can be caused by changes (mutations) in more than 20 different genes. It is usually inherited as an autosomal recessive condition. Below you will find a more technical description of the genetic changes that underlie BBS and known clinical associations.
There are many gene mutations that are known to lead to the development of BBS, some of which are below.
BBS1, BBS2, ARL6 (BBS3), BBS4, BBS5, MKKS (BBS6), BBS7, TTC8 (BBS8), BBS9, BBS10, TRIM32 (BBS11), BBS12,MKS1 (BBS13), CEP290 (BBS14), WDPCP (BBS15),SDCCAG8 (BBS16), LZTFL1 (BBS17), BBIP1 (BBS18), IFT27 (BBS19), IFT72 (BBS20), and C8ORF37(BBS21).
Despite the great number of genes already identified as being associated with BBS, gene mutations have not been identified in an estimated 20-30 percent of individuals with BBS.
There is moreover no clear link between the different mutations identified and disease severity, but some trends have emerged. Patients with mutations in the BBS1 gene seem to have milder ophthalmologic involvement. In comparison, patients with mutations in the BBS2, BBS3 and BBS4 genes experience classic deterioration of their vision. Patients with mutations in the BBS10 gene generally have significantly increased tendency to obesity and insulin resistance.
Human DNA is organized into genes that contain the instructions cells need to produce proteins. Proteins are the major building block of the human body. Mutations in different genes can result in dysfunctional proteins or insufficient amounts of protein. Most of the genes associated with BBS encode proteins called ‘cilia’ and related structures called ‘basal bodies’. Cilia are the tiny hair-like structures that cover different types of cells in the body. The basal bodies are architectural elements which anchor cilia to the cell. Cilia are classified as motile or immotile. Motile cilia help in the beating of fluids through the local environment (eg: protective mucus covering the nasal sinuses). Immotile cilia function as in sensory processes (eg: light-perceptive rod cells of the retina in the eye). Immotile cilia are also required for normal health and development of the body. In BBS, it appears that gene mutations generally affect immotile cilia.
Certain symptoms associated with BBS can be attributed specifically to ciliary dysfunction. These features include the classic cone-rod dystrophy and renal abnormalities previously discussed, as well as less commonly seen, anosmia (inability to smell), hearing loss, and situs inversus. Situs inversus is the term used to describe the condition wherein the major body organs exist in a mirror image to the expected anatomy. Other symptoms associated with BBS cannot clearly be attributed to ciliary dysfunction and active research in this domain is on-going.
BBS is usually inherited in an autosomal recessive pattern. Recessive genetic disorders manifest when an individual inherits two abnormal alleles (variants, one coming from the mother and one from the father) for a gene. If an individual receives one normal allele and one mutated allele (that is responsible for causing illness), the person will be a carrier for the disease, but usually will not present with symptoms. The risk for two carrier parents to both pass the altered gene and, therefore have an affected child, is 25% with each pregnancy. The risk to have a child who is a carrier for the illness like the parents, is 50% with each pregnancy. The chance for the couple to have a child who receives a set of normal alleles is 25%. With respect to autosomal traits, both males and females are equally affected by allele changes. Rarely, patients may have multiple mutations in multiple genes. For example, when there are two mutations in one gene and a third mutation in a separate gene, the individual is said to have BBS due to a “triallelic inheritance pattern”.
Given that BBS manifests in physical features, it is possible to inquire about the status of some babies prenatally. In a family with a history of individuals affected with BBS, a prenatal ultrasound may help in identifying polydactyly discussed above or enlarged kidneys. These findings may raise clinical suspicion for BBS in the baby and help give families time to better plan for the future care of their child ahead of their birth.
BBS affects males and females in equal numbers. The prevalence is estimated to be 1 in 100,000 in the non-related (non-consanguineous) populations of Northern Europe and America. In Sweden, the prevalence is estimated to be 1 in 160,000. The disorder occurs with greater frequency in the Bedouin population of Kuwait (1 in 13,500) and in certain populations of Newfoundland (1 in 17,500). A specific mutation (K243lfsX15) in the BBS10 gene is particularly common in South Africa.
BBS is generally diagnosed based upon identification of characteristic findings described above (eg: visual problems due to retinal dystrophy, truncal obesity, post-axial polydactyly). As diagnosis is based on clinical findings and BBS is associated with variable expression of the classical features, some patients may not have a clear diagnosis for many years. Difficulties with diagnosis arise when a child demonstrates learning disabilities and problems with weight management but who was not born with any congenital abnormality. For these children, diagnosis may remain uncertain until they begin to manifest vision loss symptoms. Diagnosis of retinal disease may require consultation with an ophthalmologist and an examination including an electroretinogram (ERG). The ERG is a procedure that measures the electrical response of the retina to light stimulation. Genetic testing may help confirm the diagnosis for some patients (e.g., individuals with certain BBS1 and BBS10 gene mutations). However, such testing may not be covered by insurance and available only through research laboratories with a special interest in BBS.
The primary treatment goal for patients with BBS involves treating the specific symptoms affecting each individual. Early intervention for anticipated problems can ensure that people with BBS reach their greatest potential. As many body systems are involved, care often requires the coordinated effort of a team of specialists.
Puberty is a stressful period in the life of any person. It is beneficial to individuals with BBS to seek the guidance of an experienced counselor. Patients with low hormone levels may be prescribed supplements under the guidance of an endocrinologist.
Some of the physical abnormalities associated with BBS can be corrected with surgery, including extra digits, and some genitourinary abnormalities and congenital heart defects. Kidney transplantation may be appropriate later in life if severe kidney disease develops. Surgery is a point of particular concern for patients with BBS. General anesthesia requires a series of highly coordinated steps that rely on the anatomy of the airways. Some patients with BBS may have significant anatomical anomalies in the airways and this might result in increased difficulty holding the airway open during general anesthesia. If this is the case, anesthetic medications may be introduced in the form of direct nerve blocks to a region of the body with while the patient is breathing for themselves.
As obesity is a common component to BBS, this is a particularly important factor to address. This feature manifests typically by an age of two-three years. An active lifestyle incorporating athletic hobbies can make a significant impact. Both diet and exercise programs are also highly recommended. Good diet management can prevent the weight-related problems that manifest in later life. Consulting with a primary care physician and a dietician can help in planning for adequate nutrition and prevention of excess weight gain. If problems with high cholesterol and diabetes exist, they are treated as in the general population. Bariatric surgery with gastric banding or sleeve surgery has been attempted only in very few patients with BBS. In those patients, surgery was associated with a weight loss of 25% maintained at 12 months after procedure. Long-term follow-up of these patients is being conducted to determine the possible role for bariatric surgery in patients with BBS.
The eye problems are of central concern with BBS. The first symptom onset is usually that of night-blindness, typically seen around age 8-9 years of age. Vitamin A deficiency can exacerbate visual difficulties and age-appropriate vitamin and mineral supplements can help support best function. While there are currently no proven therapies available to cure the retinal dystrophy associated with BBS, care under the supervision of an ophthalmologist is critical. Ophthalmologists can help correct refractive errors (e.g., myopia/near-sightedness or hyperopia/far-sightedness) and low-visual acuity problems. Individuals with BBS should undergo regular ophthalmologic examinations and keep up with their changing prescription lenses. As visual impairment is a major hurdle to learning in the classroom, special services might be organized between a child’s physician and their school.
In 2022, the U.S. Food and Drug Administration (FDA) approved setmelanotide (Imcivree) as a treatment option for chronic weight management in adult and pediatric patients 6 years and older with obesity due to BBS.
Finally, as with any genetic condition, genetic counseling is recommended for affected individuals and their families.
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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.
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The Clinical Registry Investigating Bardet-Biedl Syndrome (CRIBBS)
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