Bardet-Biedl Syndrome
Table of Content
- DISEASE DEFINITION
- GENETICS AND INHERITANCE OF THE DISEASE
- SYMPTOMS
- DIAGNOSIS
- TREATMENT
- SUPPORTIVE CARE
- GLOSSARY
- REFERENCES
- Download this Information Brochure
DISEASE DEFINITION
Bardet-Biedl syndrome (BBS) is a rare disease affecting several organs, including the kidneys:
Bardet-Biedl syndrome (BBS) is caused by an abnormally functioning cell component called a cilium (or cilia, plural) which is present on many cell types from different organs.
Cilia are long, thin, hair-like projections that enable the cell to receive signals from outside and inside the cell. Bardet-Biedl syndrome is therefore categorized as a ‘ciliopathy’.
History of the disease
The disease was first described independently in 1920 by a French doctor, Georges Bardet, and in 1922 by Hungarian-Austrian pathologist, Artur Biedl. Since then, more than 200 cases of BBS have been reported in the world’s medical literature. In 2000, researchers discovered a gene mutation causing Bardet Biedl syndrome. New data indicates that at least 24 genes are involved in the development of BBS. These genes are often called BBS genes and they play a critical role in cilia function.
In the past, the Laurence-Moon-Bardet-Biedl syndrome was described as a single disease, later the Laurence-Moon syndrome (LMS) and the Bardet-Biedl syndrome were separated, but the differences between BBS and LMS were not clearly defined. It is often considered, but still debated, whether LMS is a distinct condition or a variant of the BBS. Unlike BBS is LMS associated with difficulty in controlling body movements and spastic paraplegia, not typically seen in BBS.
Laurence-Moon Syndrome ≠ Bardet Biedl Syndrome
Ciliopathies
Ciliopathies are a group of diseases caused by genetic mutations, which result in cilia dysfunction, affecting many organs of the human body. Since cilia are located on many body cells, the diseases usually appear more complex and include multiple organs, which is the reason they are called syndromes.
► The role of cilia in most tissues remains unknown and how ciliary dysfunction leads to such severe disease is a subject of current research.
Other known Ciliopathies:
Alström Syndrome, Jeune Syndrome, Ellis-van Creveld Syndrome, Joubert Syndrome, Leber Congenital Amaurosis, McKusick-Kaufman Syndrome, Asphyxiating Thoracic Dysplasia (ATD), Meckel-Gruber syndrome, Nephronophthisis, Orofaciodigital Syndrome,Polycystic Kidney Disease, Primary Ciliary Dyskinesia, Senior-Loken Syndrome, Sensenbrenner Syndrome, Short Rib-Polydactyly Syndrome
GENETICS AND INHERITANCE OF THE DISEASE
Bardet-Biedl syndrome is caused by the change (mutation) of only one single gene andis therefore called monogenic. The syndrome is inherited in an autosomal recessive manner. What does this mean?
For an autosomal recessive disease to occur, a child has to inherit two mutated/faulty copies of the gene, located on other than the sex chromosomes, one from each parent.
If only one mutated/faulty gene is inherited, the child will not have BBS, but will be a carrier of the syndrome. The child from each pregnancy has a 25% chance of receiving both mutated/faulty genes and thus having BBS. Both sexes are equally affected.
To date (2023), mutations in 24 BBS genes have been identified. The BBS genes are the blueprints for various BBS proteins that are important in cilia function and some cellular transport mechanisms.
In this sense, if one of the BBS proteins is not functioning (due to a mutation in the respective gene) the whole apparatus will not work as it should, and it leads to the same disease – Bardet Biedl syndrome.
Why does my child have BBS?
In most cases, an individual has BBS because they inherited one copy of the faulty gene from each parent and therefore have two copies of the same, faulty gene. Carriers generally do not have any signs and symptoms of the disease, because in addition to the faulty gene, they also have a second, normal gene.
For parents who have a child with BBS, the risk to future pregnancies is:
- 25% that the child will have BBS
- 50% that the child will not have BBS but will be a carrier of the defective gene
- 25% that the child will not have BBS andwill not be a carrier of the defective gene
In this example, you can see the genetic tree of a family with BBS:
The prevalence of this disease in Europe is estimated at 1 of 150000 – 175000 people. In some isolated populations (e.g. among Israeli Bedouins and Puerto Ricans), it is found to be more common: approximately 1 of 100000. The presence of specific clinical signs may prompt the genetic testing.
Can the disease appear in other family members?
Where one family member has a genetically confirmed diagnosis of BBS, siblings and other relatives can be tested to see if they carry the faulty gene for family planning purposes.
Knowledge of the BBS mutation in the family can also form the basis of prenatal screening, should parents wish to find out in early pregnancy, whether the foetus is affected.
Genetic Counselling - Family planning for people affected by BBS
People with BBS who wish to have children, should receive genetic counselling. The partner of the person who has BBS should be tested for carriers’ status, to determine if they carry a disease-causing mutation in the same gene. If the partner is a carrier of a mutation in the same gene, each child has a 50% chance of having the syndrome. If both parents have BBS, with mutations in the same genes, then all children will have BBS.
The pathology of BBS
What are Cilia and how do they work?
The mechanism that leads to BBS is still unclear, however the main cause of the disorders that occur in BBS is due to abnormally functioning or structured cilia. Cilia are thin, hair-like structures that are only visible under a microscope. They occur on the surface of almost all cells of our body. There are different types of cilia performing different functions. The length of a single cilia is 1-10 micrometers and the width is less than 1 micron. There are different types of Cilia:
Cilia which can move are called motile cilia. They are located on the surface of the lung, respiratory cells, or the middle ear, where they help to remove mucus and infectious agents by way of rhythmic, wavy movements. These cilia also play an important role in the movement of sperm
Cilia that are not able to move are called non-motile cilia/primary cilia. These structures receive signals from outside of the cell and transmit them to the inside, allowing neighbouring cells to communicate with each other. For example, in the kidney, cells can receive signals about the level of chemicals in the urine
Cilia play a very important role, even before birth, enabling embryo development, cell migration and organ differentiation. A main function of cilia is sensory and they play an important role in terms of smell, vision, touch, and temperature sensation.
In BBS, the function of primary cilia is impaired
It has been shown that the genes involved in BBS encode proteins, that are responsible for the function or development of cilia. A primary cilium consists of a basal body (dark blue) and a tube-like structure (green) build of microtubules. The 24 different BBS proteins have different functions within the cilium.
BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9 and BBS18
These eight BBS proteins build a stable complex known as the BBSome, which regulates molecule trafficking to the ciliary membrane. Some others constitute a chaperon in complex that is important for the correct construction of the BBSome. Some other BBS proteins help to locate the BBSome to its final position. The partially overlapping functions of BBS proteins explain why different mutations in different BBS genes result in similar disease signs and symptoms.
SYMPTOMS
BBS affects many organs, and the symptoms can vary significantly between patients, even between individuals within the same family. Classically defined by six features (regarding: the brain, eyes, weight, hand and foot abnormalities, reproductive system, kidneys). BBS is usually diagnosed in infancy. Common symptoms include obesity, visual impairment, additional fingers and/or toes, reduced function of the testes in boys, kidney defects and learning disability. Although BBS may be diagnosed based on genetic tests revealing mutations within specific genes, the presence of primary and secondary symptoms may be used to indicate which patients are suspected of having BBS and need the genetic examination. Diagnostics, based on the presence of primary and secondary characteristics, was proposed by Forsy the and Beales in 2003.
BBS could be diagnosed if the person is known to have at least three primary and two secondary characteristics, or if they have at least four primary characteristics.
The usefulness of these clinical criteria may be limited by the fact that many of these clinical characteristics appear gradually as the child develops and thus the sensitivity of the proposed diagnostic criteria is low in young children. Further, some patients who have a genetic diagnosis, do not always meet the clinical diagnostic criteria and there may also be a variability of symptoms, even for those with the same genetic mutation. Therefore, it is important that: The presence of these clinical criteria is periodically verified in a child considered for a diagnosis of BBS.
BBS Symptomes summarized
| Primary criteria | Secondary criteria |
| Retinal degeneration (Rod-cone dystrophy) | Squint (strabismus) Blurring of lenses (cataracts) Bending of the cornea (astigmatism) |
| Additional fingers/toes (polydactyly) | Shorter fingers/toes (brachydactyly) Fused fingers/toes (syndactyly) |
| Central obesity | Speech disorders |
| Learning disabilities | Delayed development/ behavioural disorders |
| Kidney malformations | Abnormally large production or output of urine (polyuria) Excessive thirst (polydipsia) Diabetes insipidus |
| Reduced function of the testes (hypogonadism) (male) / genital abnormalities (female) | Dental crowding/hypodontia /small roots/high arched palate Craniofacial dysmorphism |
► Details on the major and minor symptoms are following below
Mayor features of BBS
1. Obesity
Obesity is an excessive accumulation of adipose tissue in the body. The classification of obesity was determined by the WHO (World Health Organization) and is now based on body mass index (BMI), which is calculated from the body weight in kg divided by the height squared (m2).
Body mass index: BMI=kg/m²
In adults, being overweight is defined as having a BMI ≥25 and obesity as having a BMI ≥30. In children and adolescents, being overweight is defined as a BMI ≥85 percentile (pc) for age and gender, and obesity as a BMI ≥ 95 pc.
- obesity in BBS is not the result of an improper diet or parental neglect but is due to an imbalance between hunger and satiety (feeling full)
- Ciliary defects in the hypothalamus (the hormone producing area of the brain) affects the function of the satiety hormone, leptin, impairing the body’s ability to know when it is full
- BBS may also lead to an excessive appetite, leading to excessive food intake (hyperphagia)
- obesity appears in infancy and progresses with age (usually normal weight at birth)
- 90% of people with BBS exhibit rapid weight gain through the first year of life
- obesity in BBS is dominated by a particularly dangerous type, called abdominal obesity, in which adipose tissue accumulates mainly in the abdomen and internal organs and produces hormonally active substances that disrupt the functioning of other organs ► can lead to type 2 diabetes (due to insulin resistance)
- Diabetes mellitus has been estimated to affect up to 45% of patients with BBS.
- Poor weight management may further complicate problems with the heart and blood vessels.
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Frequency and severity of obesity varies between patient
Did you know?
Leptin is a hormone produced by fat (adipose) cells that helps to regulate energy balance by inhibiting hunger. The main function of leptin is to send a signal to the brain reporting how much fat is stored in the body’s fat cells. Leptin acts on cell receptors in the hypothalamus, consequently mediating eating. In obesity, a decreased sensitivity to leptin occurs (like insulin resistance in type 2 diabetes), resulting in an inability to detect feeling full, despite high energy stores and high levels of leptin. The condition is known as a leptin resistance. Leptin resistance causes irrepressible hunger and reduces the number of burned calories.BBS proteins are shown to affect the leptin response and the loss of BBS genes results in leptin resistance. This is a reason why many BBS patients are obese.
2. Retinitis pigmentosa / Rod-Cone Dystrophy
The eye problems are of central concern in patients with BBS as almost all patients experience progressive vision loss. The first symptom onset is usually that of night-blindness, typically seen around age 8-9 years of age.
The first symptom is usually night blindness, which occurs in children as young as 8-9 years old. Field of vision is usually affected from the age of 10. By the age of 17, so-called tunnel vision is usually established. From the second to the third decade of life, visual acuity gradually declines to 10% or less in almost all patients.
What is the reason for this vision loss?
The retina is a very thin layer at the back of the eye which receives visual signals. The precise function of the retina is to convert light signals into nerve impulses, which are further transmitted to the brain and thus allow vision.
The retina contains two types of visual receptors (photoreceptors) namely rods and cones. There are more rods than cones (about 120 million vs 6 million), and they are more sensitive. Rods are sensitive to light intensity, allow for black and white vision and are found mainly in the peripheral parts of the retina. Cones are concentrated in the central part of the retina and are responsible for colour vision and visual focus.
Process of retinal degeneration / Major common visual symptoms
The process of retinal degeneration in BBS patients usually begins in early childhood, initially with the development of night blindness (loss of rods), followed by the development of tunnel vision. The degeneration of rods and cons causes a gradual narrowing of the visual field. Patients may experience a hypersensitivity to light and difficulties with adapting to changing lighting conditions. The order in which symptoms appear will depend on which photoreceptors, the rods or the cones, degenerate first.
Further, the degeneration of neural cells occurs, which results the damage of the optic nerve (optic atrophy). Since the optic nerve transmits retinal information to the brain, optic atrophy is associated with vision loss. Also, the narrowing of the small retinal vessels is seen and cause ischemic changes.
► Most people with BBS (over 90%) will be registered as severely sight impaired during puberty or early adulthood.
Did you know?
For more insight into the biology behind the rod-conedegeneration: Rods and cones are photoceptor cells of the retina and have a special light-absorbing segment. These segments are modified cilia. The BBS mutation leads to an impaired protein transport between the light-absorbing segment and other parts of the cell. This transport deficiency results in the deathof rods and cones and in total retinal degeneration and blindness.
Minor common visual symptoms
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3. Polydactyly
Polydactyly is the presence of additional fingers or toes at birth and is a key indication of Bardet-Biedl syndrome. Since these are usually removed in early childhood, their presence may be forgotten, thus impacting on the diagnostic process.
Polydactyly occurs in approximately 70% of BBS patients, with the presence of an extra toe more common than an extra finger. Fingers and toes may also be fused (syndactyly) and this is especially common between the second and third toes. Fingers and toes may occasionally be abnormally short in length (brachydactyly), feet may be wide, short in length and have a flat arch. Syndactyly or brachdactyly are categorised as secondary symptoms of BBS.
4. Hypogonadism
In men, a small size and poor function of the testes, is termed “testicular hypogonadism”. This may manifest as a small penis, failure of the testes to descend into the scrotum (“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. Males are almost invariably infertile.
A wide variety of genital malformations have been observed in females, contributing to the low rates of fertility in BBS. This may manifest as an underdeveloped uterus, fallopian tubes, or ovaries. Menstruation cycles are often delayed and may also follow an irregular cycle. The rate of fertility is low, but individuals from both sexes have been known to have biological children.
5. Delay in intellectual development
Patients can present with intellectual disability, speech and language impairment, attention deficit, poor reasoning, and emotional immaturity
- The extent of developmental delay in Bardet-Biedl syndrome can be diverse ►Severe learning difficulties affect only a minority of BBS patients, and many demonstrate normal mental development
- Some BBS children need additional support at school as their problems mainly are related to the memorization processes, especially learning by heart
- Developmental delay can be noticeable quite early on, although basic skills are achieved within a normal or slightly delayed timeframe. Speech development is often delayed.
- BBS is quite often linked to anxiety disorders, low mood, panic attacks, obsessions and compulsions, anger and poor emotional control
- Children with BBS may show autistic tendencies, compulsive behaviour, aversion to change, emotional immaturity, lack of drive and attention deficit hyperactivity disorder
How the intellectual development of BBS patients is determined remains unclear
6. Malformation and dysfunction of the kidneys
Cilia are present in kidney cells which explains why BBS patients are affected by kidney dysfunction and malformation. Kidney abnormalities affect at least 50% of BBS patients.
The development of kidney cystsis the most common change and can lead to dangerous complications such as the development of chronic kidney disease (CKD) or kidney failure. The kidney cysts are often detected before childbirth or in early childhood and are caused by impaired cilia function in the kidney cells of the tubule. The lack of cilia function within kidney tubuli causes excessive urine output of unconcentrated urine. The fluid pools within the kidney tissue and leads to the formation of cysts (fluid-filled sacs) that destroy and gradually replace kidney tissue. The damaged kidneys cannot perform their function.
Polyuria, excessive urine output and polydipsia, the resulting excessive thirst, are among early symptoms of BBS and results of the destroyed urin concetration.
► A spectrum of kidney disease can be seen in BBS including, urinary tract malformations: vesicoureteral reflux, hydronephrosis, dysplastic cystic disease, absent, duplex, horseshoe or ectopic kidneys, neurogenic bladder; chronic glomerulonephritis and defective tubular concentrating ability.
Recent scientific data shows:
- Serious kidney changes observed in infants and young children with BBS, indicates a significantly increased risk of subsequent renal impairment.
- Where the changes are mild in infants and young children with BBS, as is the case with specific mutations in the BBS1 gene, there is a low risk of subsequent renal impairment.
- In adulthood, regardless of early changes in the kidneys, obesity, hypertension and the development of diabetes lead to an additional risk of developing kidney failure.
- Overall, approximately 31% of children and 42% of adults had CKD; 6% of children and 8% of adults had advanced stage CKD.
- End stage renal disease (ESRD) requires dialysis or a transplant.
- Favourable long-term outcomes have been reported in those who have had a renal transplant.
Did you know these terms?
Malformations of kidney and urinary tract seen in BBS
Solitary kidney, (one kidney is missing), or kidney dysplasia (the kidney is not fully developed), may occur. If both kidneys are dysplastic, depending on the severity of the abnormalities, kidney function may be impaired and renal replacement therapy (dialysis or kidney transplantation) may be necessary.
Vesicoureteral reflux – this is where urine flows from the bladder to the kidneys (instead of from the kidneys to the bladder) and can contribute to the development of urinary tract infections
Horseshoe kidney is where the two kidneys join (fuse) together at the bottom during pregnancy, to form a ‘U’ shape which gives it the name “horseshoe”. Kidney drainage can be affected, resulting in increased frequency of kidney stones and urinary tract infections. Horseshoe kidney can occur alone or with other disorders.
Crossed fused ectopia occurs when both kidneys develop on the same side of the body. In many cases, the two kidneys could also be fused together retaining their own vessels and ureters.
Multicystic dysplastic kidney (MCDK) is a common and well-recognizable example of unilateral kidney dysplasia. Affected children typically have good overall kidney function with contralateral compensatory kidney hypertrophy. In contrast, children with bilateral kidney dysplasia are at risk for severe chronic decline of kidney function, even though there is major clinical variability in the disease course.
Kidney dysplasia occurs when the internal structures of one or both kidneys fail to develop normally. Kidney dysplasia may be unilateral or bilateral, segmental or diffuse. Dysplastic kidneys are often cystic but unlike in typical presentations of polycystic kidney diseases, these kidneys are not massively enlarged but are about the size of normal for age kidneys or smaller. As differential diagnoses in bilateral cystic kidney dysplasia. Kidney dysplasia is one of the most frequent causes of chronic kidney failure in children.
Neurogenic bladder – this is caused by a malfunction in the nerves that control bladder function and the bladder may not fill or empty in the right way. The muscles of the bladder may become overactive and contract abnormally, even before the bladder is full, or the muscles may become too loose leading to incontinence. In other cases, the muscles become underactive and even if the bladder is full the muscles do not contract, and the person may not feel a sensation or an urge to go to the toilet.
Minor symptoms of BBS
Neurological abnormalities |
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Brachydactyly | (short fingers and toes) and syndactyly (fused fingers or toes) |
Polyuria/Polydipsia | (see above) as symptoms of urinary concentration defects, are prevalent even in patients with near-normal kidney function and no major cysts. |
Type 2 diabetes mellitus | and metabolic syndrome may develop as a result of obesity. |
Dental development disorders | including hypodontia (congenitally missing teethes), teeth crowding, short roots and high-arched palate. |
Congenital heart defects | (valvular stenosis, patent ductus arteriosus, cardiomyopathies) |
Liver changes | range from fibrosis to cystic dilatation of the bile duct and all connecting ducts |
Diseases of the gastrointestinal tract | such as Hirschsprung’s disease, coeliac disease, Crohn’s disease |
Dysmorphism (abnormally shaped body part) | The most frequent reported features of BBS are:
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Have you heard of this before?
As recently shown BBS patients have also a higher prevalence of certain autoimmune diseases:
Inflammatory bowel diseases as Crohn ́s disease, Diabetes Typ 1, Rheumatoid arthritis, Hypothyroidism and Hashimoto’s thyroiditis
Some study reveals a connection between a ciliopathy and dysregulated immune and hematopoietic systems and immunity. Some of these alterations are associated with BBS-induced obesity which leads to elevated concentration of white blood cells in BBS patients. Obesity can induce the state of low-grade metabolic inflammation and one of the major players in obesity-associated inflammation is leptin, an adipocyte-derived hormone which acts as a pro-inflammatory cytokine. It has been shown that leptin signalling in the central nervous system regulates immune responses. Thus, it is possible that defective leptin signalling in the nervous system directly contributes to high prevalence of autoimmunity in BBS patients.
DIAGNOSIS
BBS is such a rare condition that many paediatricians, throughout their careers, have never met a patient with the syndrome. Early diagnosis gives you a better chance of providing your child with the right medical care.
To make a diagnosis, knowledge of the patient’s medical history, symptoms, and physical and intellectual development are needed, as well as the results of laboratory tests. Due to the high variability in the occurrence of clinical manifestations and the different times of their appearance, the patient suspected of BBS requires regular assessment. Ultimately, a genetic test confirms a clear diagnosis, although new mutations responsible for BBS are still to be identified.
BBS is an autosomal recessive disease, which means that two abnormal copies of a particular gene are required for it to occur. Most often, parents are healthy carriers and show no symptoms, because each of them has only one abnormal copy. However, the gene mutation may also be non-hereticate, i.e., the formation of an abnormal copy of the gene occurred spontaneously during embryo development. This is called “de novo mutation”.
General Check of body height, body weight, body mass index (BMI) and blood pressure measurement as part of the routine monitoring for patients with suspected BBS should take place at each consultation. It is recommended to also monitor and preferably record these measurements regularly at home.
To detect the presence of cysts or other abnormalities of the urinary system, testes and liver.
- Ultrasound: shows the presence of kidney cysts or other malformations of the urinary or reproductive system.
- Cardiac ultrasound: to diagnose heart defects that feature with heart hypertrophy.
- Abdomen magnetic resonance imaging (MRI): is more accurate in assessing the number, place and size of cysts andis used primarily to monitor the progression of the disease.
Complete eye examination: to detect the degeneration of the retina e.g. the presence of pigmentary retinopathy. Pigmentary retinopathy can be detected by an examination of the eyeball, using a special lamp, after the pupil has been dilated.
Field of vision measurement is usually carried out after the age of about 7 years, because it requires active cooperation with the patient.
Electroretinogram (ERG): is an eye test used to diagnose retinopathy and can be done at any age. It involves recording the electrical reaction of the retina to the stimulation of light and may show early changes within the first two years of life, although significant changes are rarely visible before the age of five.
Blood and urine tests are carried out regularly, mainly to monitor kidney function, detect and treat diabetes, as well as common lipid disorders.
Endocrinological assessment must include assessment for any signs and symptoms of diabetes mellitus with subsequent oral glucose tolerance testing if appropriate. Assessment of thyroid function, lipid profile and the development of secondary sexual characteristics is important. If appropriate, further pituitary function testing can be done and hormone replacement therapy instigated. During adolescence, blood tests will detect and prompt common sex hormone secretion disorders (testosterone or oestrogen).
Since BBS can be caused by mutations in different genes and symptoms may suggest other syndromes also associated with the malfunction of cilia, molecular methods of genetic testing, including gene oriented research (multigene panel) or comprehensive genomic testing (exon sequencing) are recommended.
- Genomic studies may reveal pathogenic variants in known genes that have not yet been included in gene panels ornew pathogenetic variants in genes previously known to be BBS-related.
- Currently, genetic mutations in more than 24 genes, that cause this syndrome, have been discovered. All these mutations lead to the abnormal structure and/or impaired action of the primary cilia.
The most common mutations involve the following genes:
BBS 1 – 23.4% of all BBS patients
BBS10 – 14.5% of all BBS patients
BBS 2 – 9.6% of all BBS patients
BBS12 – 6.4% of all BBS patients
Can BBS be confused with other diseases and how do we tell the difference?
Family history
BBS is an autosomal recessive disease, which means that two abnormal copies of a particular gene are required for it to occur. Most often, parents are healthy carriers and show no symptoms, because each of them has only one abnormal copy. However, the gene mutation may also be non-hereticate, i.e., the formation of an abnormal copy of the gene occurred spontaneously during embryo development. This is called “de novo mutation”.
General Check
General Check of body height, body weight, body mass index (BMI) and blood pressure measurement as part of the routine monitoring for patients with suspected BBS should take place at each consultation.
It is recommended to also monitor and preferably record these measurements regularly at home.
Blood and urine tests
Blood and urine tests are carried out regularly, mainly to monitor kidney function, detect and treat diabetes, as well as common lipid disorders.
MRI
Abdomen magnetic resonance imaging (MRI): is more accurate in assessing the number, place and size of cysts andis used primarily to monitor the progression of the disease.
Radiological/Ultrasound examinations
Radiological, ultrasound examinations: to detect the presence of cysts or other abnormalities of the urinary system, testes and liver.
- Kidney ultrasound: shows the presence of kidney cysts or other malformations of the urinary or reproductive system.
- Cardiac ultrasound: to diagnose heart defects that feature with heart hypertrophy.
Complete eye examination
Complete eye examination to detect the degeneration of the retina e.g. the presence of pigmentary retinopathy. Pigmentary retinopathy can be detected by an examination of the eyeball, using a special lamp, after the pupil has been dilated.
- Field of vision measurement: usually carried out after the age of about 7 years, because it requires active cooperation with the patient.
ERG
Electroretinogram (ERG) is an eye test used to diagnose retinopathy and can be done at any age. It involves recording the electrical reaction of the retina to the stimulation of light and may show early changes within the first two years of life, although significant changes are rarely visible before the age of five.
Endocrinological assessment
Endocrinological assessment must include assessment for any signs and symptoms of diabetes mellitus with subsequent oral glucose tolerance testing if appropriate. Assessment of thyroid function, lipid profile and the development of secondary sexual characteristics is important. If appropriate, further pituitary function testing can be done and hormone replacement therapy instigated. During adolescence, blood tests will detect and prompt common sex hormone secretion disorders (testosterone or oestrogen).
Genetic testing
Since BBS can be caused by mutations in different genes and symptoms may suggest other syndromes also associated with the malfunction of cilia, molecular methods of genetic testing, including gene oriented research (multigene panel) or comprehensive genomic testing (exon sequencing) are recommended.
Genomic studies may reveal pathogenic variants in known genes that have not yet been included in gene panels ornew pathogenetic variants in genes previously known to be BBS-related. Currently, genetic mutations in more than 24 genes, that cause this syndrome, have been discovered. All these mutations lead to the abnormal structure and/or impaired action of the primary cilia. The most common mutations involve the following genes:
BBS 1 – 23.4% of all BBS patients
BBS10 – 14.5% of all BBS patients
BBS 2 – 9.6% of all BBS patients
BBS12 – 6.4% of all BBS patients
Can we confuse BBS with other diseases?
How do we tell the difference?
Yes, BBS can be confused with other syndromes with similar symptoms. It is notalways easy to make the diagnosis quickly. Patients often present with signs and symptoms common to different syndromes.
Laurence-Moon syndrome, long confused with Bardet-Biedl syndrome, among other symptoms causes neurological disorders (balance disorders or lack of coordination and / or paralysis of the legs) and polydactyly. The genes responsible are different from those that cause Bardet-Biedl syndrome.
Alström syndrome is characterized by abnormalities of the retina, obesity, progressive hearing loss, kidney abnormalities, diabetes and poor sexual organ development (hypogonadism) in boys. Some of these symptoms and manifestations coincide with Bardet-Biedl syndrome, however, there is no polydactyly or learning difficulties. The gene responsible for Alström syndrome has been identified and is different from those involved in Bardet-Biedl syndrome.
Cohen’s syndrome combines retinopathy with myopia (nearsightedness), obesity and specific dental abnormalities. The gene in question is also identified and is different from those involved in Bardet-Biedl syndrome.
McKusick-Kaufman syndrome causes genital abnormalities, supernumerary fingers, and heart defects. However, it does not include retinopathy pigmentosa, which distinguishes it from Bardet-Biedl syndrome.
TREATMENT
A properly made diagnosis in early childhood can support the effective management of Bardet-Biedl syndrome. Research is ongoing to develop a drug for BBS, but so far, no causal treatment has been developed. The life expectancy of the patient is not reduced by the syndrome, but people with BBS require specialist care and, in many cases, are dependent on the help of other people in their everyday lives.
The medical interventions for BBS patients consist in alleviating the symptoms and side effects of the condition, but most of them are difficult to treat. And although treatment usually focuses on specific symptoms in a person, patients require multidisciplinary care involving a nephrologist, ophthalmologist, endocrinologist, and genetics specialist. Patients and their families also need learning and psychological support.
Likewise, the development of children may be significantly delayed and limited by the syndrome. Anxiety disorders can also occur. Not infrequently, BBS may lead to psychological disorders and depression in relatives or parents of those with BBS. BBS patients may be significantly limited in their everyday lives and suffer from a greatly reduced visual field. The blindness itself can lead to severe psychological discomfort or even depression. BBS may also lead to behavioral problems, and children especially may experience bullying or teasing as a result.
Recent studies have demonstrated that the common point for all BBS symptoms and cilia disfunction is the dysregulation of the glycosphingolipid (GSL) metabolism. Research is exploring how this metabolic defect may be targeted, to maintain cilia structure and signalling, and therefore lead to an improvement of pathology in multiple organs. This therapy option is only at experimental stages and is yet to be proven.
Vision problems
There is currently no treatment for progressive vision loss and adapting to vision loss is an ongoing lifestyle challenge. The vision loss in BBS causes numerous difficulties for the young patient when attending school, in their free time and regarding their physical safety. The risk of accidents increases significantly, for example in respect of road traffic. The education of children who have BBS should include planning for future sight loss.
- instruction in the use of Braille, mobility training, adaptive living skills and computing skills (including voice recognition and transcription software), as well as the use of large-print reading materials
- living spaces should be designed/adapted to remove any sources of danger
- early cane-training is essential to support independence and may be commenced in younger children who have night-blindness
- early assessment by a VI specialist can help with providing mobility training and support the development of independent living skills
- visual disturbances should be discussed with the GP or optometrist
- corrective glasses will protect your eyes from the sun (special contact lenses are used with a centrally located red filter)
Obesity
Obesity treatment may include diet management, exercise, and behavioural therapies. Complications resulting from obesity such as high cholesterol and diabetes are treated as they are in the general population. Approximately 60% of BBS patients also have hypertension (high blood pressure) requiring medication. To support the BBS patient, the whole family should change their eating and lifestyle habits.
Parents should model healthy behaviours for their children, including eating healthily, being active and setting activity goals for the family, of at least 1 hour of physical activity each day. Some helpful tips:
- look for opportunities to walk; avoid using the lift and if possible, avoid taking the car or bus.
- take advantage of the offers of local sports clubs and give you /your child the possibility to meet regularly with other children and be a part of sports group
- decrease the screen-time on mobile phones, gadgets, TVs and computers
- Don’t provide food as a reward or take it away as a punishment
- Encourage children to drink water rather than beverages with added sugar, such as soft drinks, sports drinks, and fruit juice drinks.
- Take care with portion sizes and try to reduce them.
- Regularly monitor your child’s body weight, height and blood pressure.
As hyperphagia and early-onset severe obesity in patients with BBS arise from the impairment of the hypothalamic melanocortin-4 receptor (MC4R) pathway, very promising treatment option may be a setmelanotide, the MC4R agonist, recently specifically approved for chronic weight management in adult and paediatric patients 6 years of age and older with BBS.
Behavioural disorders
Developmental delay is addressed through early intervention, physiotherapy, special education, and speech therapy. The majority of adults with Bardet-Biedl syndrome are able to develop independent life skills.
- Active life style started early inhibits the development of obesity, improves the development of motility and also positively affects the development of cognitive skills, including learning.
- The approach to developmental delay and/or cognitive impairment should be individualised based on age and identified needs
Impaired kidney function
Patients with BBS may experience chronic kidney disease. There is no cure for CKD, but early detection of impaired renal function and the implementation of appropriate treatment, significantly slows down the progression of the disease and can delay the need for renal replacement therapy (kidney transplantation, dialysis) for many years. The presence of complications of impaired renal function, such as renal anaemia or renal metabolic acidosis, is an indication for pharmacological correction. Some dietary changes may be needed, especially if the disease progresses and kidney function is further impaired. The dietary guidelines would be based on the stage of chronic kidney disease, which ranges from stage 1 for minimal impairment to stage 5 for ESRD (End-Stage Renal Disease).
It is usually best, particularly in the early stages, to work with a certified dietitian to tailor a diet appropriate to kidney function. The goals of a CKD diet are to slow the progression of the disease and minimise any harm the accumulation of waste and fluids can do to other organs, most predominately the heart and cardiovascular system.
- generally, the reduction of sodium intake is recommended.
- limiting the intake of protein could be eventually recommended (based on the stage of disease)
- as the disease progresses and renal function drops below 70 percent of what it should be, a restriction of phosphorus and potassium may be recommended
- a number of supplements are commonly used to correct nutritional deficits that can occur in later stages of CKD
- in case of development of end-stage renal failure, renal replacement therapy/dialysis or kidney transplantation may be necessary ► Patients with renal insufficiency have a good prognosis associated with kidney transplantation.
Polydactyly / genital abnormalities
Additional fingers or toes are generally removed and joined fingers may be separated. The operation is usually performed in early childhood, aged 1-2 years. Sometimes surgical correction of abnormalities concerning the genital organs is performed. Surgery may also be a point of concern for patients with BBS. General anaesthesia 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 anaesthesia. Anaesthetic 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 children approach puperty:
- hormone levels should be monitored to determine whether hormone replacement therapy is needed
- it should not be assumed that people affected by the disease are infertile, so it is advisable to seek advice on contraception
What are the prospects?
What will happen to my child in the future?
Once the diagnosis has been made, tests are likely to be carried out to detect other possible changes associated with this syndrome and further treatment will be established.
Regular check-ups/tests will monitor general health, kidney function, sex hormone levels, glucose tolerance/prevalence of diabetes and common concomitant lipid disorders are indicated throughout life. The frequency of testing will depend on the abnormalities found as well as their stage of development. These checks will be carried out more frequently during periods of intense growth, i.e., early childhood or adolescence, or in case of identified problems. The frequency of ophthalmic check-ups will depend on the progression of the retinal dystrophy.
In adolescence or early adulthood, it may be very beneficial for many patients to find a support group, psychological help, or contact with people affected by the same disease.
It is important to perpetuate a habit of an active lifestyle. This can improve cell insulin sensitivity/counteract excessive weight gain and its related disorders including diabetes or fatty liver disease. An active lifestyle, as demonstrated in recent studies, also improves cognitive function, learning and memory in patients with BBS.
Please note:
Disease documentation and test results
For rare and complex diseases like BBS, it is worthwhile collecting all the results of medical examinations and regularly documenting data such as body weight, growth, and blood pressure.
Such data collection and monitoring can be very helpful in assessing the course of the disease, making a diagnosis, and planning further research and specialist care.
In many countries, BBS patient surveys are maintained. Participation allows for better understanding of the disease and the development of new strategies for the diagnosis and treatment of the disease.
SUPPORTIVE CARE
In case of questions or requests for support, do not hesitate to talk to your family paediatrician or paediatric nephrologist. In many countries there are BBS patient support groups. BBS is a rare disease and still insufficiently studied.T he exchange of information and one‘s own experiences can be very helpful for many patients and their families. As part of the activities of these groups and foundations, meetings, lectures as well as holiday camps are organised. Find the link to BBS patients organi-sations here.
If you have any other questions or need for support, do not hesitate to tell your GP or paediatric nephrologist.
GLOSSARY
Being diagnosed with a chronical medical condition can feel difficult, but understanding your or your child's condition is the first step to taking control of its symptoms. Some of these common terms might be mentioned by the doctors. Here's what they mean:
CKD (Chronic Kidney Disease) | A progressive and irreversible damage to the kidneys which, over the course of months or years can lead to kidney (renal) failure. There is no cure for CKD, but there are treatments that can significantly slow the progression of the disease if started early. |
Creatinine | A normal body waste product. Sometimes the level of creatinine in your urine is checked and used to determine how well your kidneys are filtering waste from your blood. |
Crohn’s Disease | A type of inflammatory bowel disease (IBD), autoimmunological disorder, occurring not rarely in BBS pts. It causes inflammation of your digestive tract, which can lead to abdominal pain, severe diarrhoea, fatigue, weight loss and malnutrition. |
Dialysis | The process of artificially removing waste and excess fluid from your blood. There are two main kinds of dialysis-haemodialysis and peritoneal dialysis. With haemodialysis, your blood is filtered by an external machine called a dialyser. Peritoneal dialysis works by passing dialysis solution into your abdomen through a catheter to filter your blood in your body. |
ESRD (End-Stage Renal Disease) | The final stage and most severe form of kidney disease. It signifies that your kidneys have failed, and at this point dialysis or a kidney transplant is needed. |
GFR (Glomerular Filtration Rate) | The rate at which your kidneys (specifically the glomeruli in them) filter waste from your blood. The test for it is called estimated glomerular filtration rate test eGFR. |
Hirschsprungs 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. This disorders was observed in BBS patients. |
Insulin | Is a hormone produced by the pancreas that regulates the transport of glucose (sugar) to cells and its use for energy production. The secretion is known to be stimulated by the production of glucose. |
Insulinresistance | Body’s cells do not respond adequately to insulin stimulation, and as a result glucose don`t penetrate into the cells. |
Nycturia | Purposeful urination at night, after waking from sleep; typically caused by nocturnal urine volumen. |
Polydipsia | Is an excessive thirst. People with this condition tend to drink too much, may never feel sated and end up consuming much more water than they should. |
Polyuria | Is excessive or an abnormally large production or output of urine (>than 3L over 24h in adults). |
Renoprotection | Measures taken to prevent damage to the kidney from any cause, minimise adverse effects – especially due to oxidative stress – on renal vasculature. |
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https://rarediseases.org/rare-diseases/bardet-biedl-syndrome/