Bardet-Biedl Syndrome (BBS) is an autosomal recessive disorder associated with primary cilia dysfunction, presenting with retinal degeneration and morbid obesity, amongst other clinical features. There is no disease-modifying therapy available for BBS. BBS affects between one in 70,000 and one in 100,000 in Europe and North America, with up to five times that prevalence in certain populations including the Middle East. BBS1 is the most commonly mutated gene found in BBS, with the missense BBS1 M390R mutation, the most common allele observed.
People with BBS are commonly affected by learning difficulties with poor educational attainment.3
People with BBS commonly have behavioral problems ranging from outbursts of frustration and obsessive-compulsive behavior patterns to autism and anxiety and depression.3
The majority of people with BBS suffer developmental delay.3
Children showed a delay in walking by one year and speaking by two years and boys can be slow in passing through puberty.3,10
Many affected individuals suffer from a degree of clumsiness or signs of ataxia and poor coordination.3
Rod cone dystrophy causes night blindness in children progressing to legal blindness in most people by early adulthood.3
Electroretinography may reveal changes to photoreceptors in children within the first two years, although significant changes are rarely visible before age five.3
People with BBS experience a reduced sense of smell or the inability to smell.3
Overcrowded teeth and/or a high-arched palate are most common; however, misaligned teeth (malocclusion), missing teeth (hypodontia), small roots or thin enamel also occurs.3
People with BBS experience speech delay and children often do not develop intelligible speech before the age of four.3
Speech is often high-pitched and nasal sounding. Speech difficulties may be complicated by hearing loss.3
People with BBS are born with additional digits outside their little fingers or toes. This may be the only obvious sign of the disorder at birth.3
People with BBS often have short/webbed fingers or toes.3
Cardiac abnormalities observed in people with BBS are highly variable.
Congenital heart disease includes atrial septal defect (ASD) or ventricular septal defect (VSD), a hole in the wall between the two upper or lower chambers, respectively, or left ventricular hypertrophy (LVH), the thickening of the heart’s muscular walls.3
Hypertension is a feature of BBS which puts additional strain on the heart and could increase the risk of heart attack, heart failure and sudden cardiac death.4
People with BBS report significantly increased levels of triglycerides and cholesterol which can lead to fat deposits and clogging of blood vessels.5
Renal abnormalities or malformations affect people with BBS and can be life-threatening due to the development of chronic kidney disease (CKD) which may progress to end-stage disease in some.3,9
People with BBS develop obesity, often due to feelings of extreme hunger.3,5 Babies with a normal birth weight often develop obesity by 12 months and development of type 2 diabetes is common.3,8
Low levels of sex hormones delay puberty or prevent genitalia from developing in people with BBS, causing infertility in men and genital malformations in women.3
Children with ciliopathic symptoms generally experience a “rare disease odyssey” where patients report having waited five to 30 years for the correct diagnosis, with the initial diagnosis being incorrect in 40% of cases.1,11
Earlier diagnoses reduce stress for children and their caregivers and enable BBS-induced medical conditions to be managed more effectively early.2,12
For example, children can potentially receive interdisciplinary streamlined care where seven specialists can be seen in a single visit and those with speech delays are responsive to speech therapy.3
Diagnostic criteria published by Prof. Phil Beales can be used to diagnose BBS before genetic testing has been completed or if genetic testing does not reveal a mutation in a gene known to cause BBS.3
A minimum of four primary or three primary and two secondary features are required for a clinical diagnosis of BBS.3
Primary Features |
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Rod-cone Dystrophy
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Polydactyly
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Obesity
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Genital Anomalies
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Learning Difficulties
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Secondary Features |
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Speech Delay
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Developmental Delay
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Diabetes Mellitus
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Dental Anomalies
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Congenital Heart Disease
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Brachydactyly/Syndactyly
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Ataxia/Poor Coordination
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Anosmia/Hyposmia
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Use this decision tree to assess people with suspected BBS who do not fulfill the diagnostic criteria for BBS outlined above.3
If the full BBS phenotype is not expressed, are there at least two primary BBS features present based on the diagnostic criteria above?
Is your patient an adult or a child?
Phenotype may still be evolving
See full assessment criteria under management
Discuss with a clinical geneticist if a BBS diagnosis is likely
Differential diagnosis:
Assess whether your patient has one of these conditions:
Use this decision tree to help confirm a suspected BBS diagnosis and to manage people with clinically diagnosed BBS.3
Does your patient have at least four primary or three primary and two secondary features from the diagnostic criteria above?
Disease management
Confirm a possible diagnosis
Assessment
Annual assessment
At least once and more often if required
If required
While diagnostic criteria for BBS may seem straightforward, children with learning disabilities and weight management challenges who aren’t born with a congenital abnormality may be difficult to diagnose until vision loss symptoms present.13 Genetic testing can help confirm a BBS diagnosis in people with specific BBS mutations.13
Increased genetic testing, prenatal testing and newborn screening can facilitate earlier diagnoses, reducing stress for children and their caregivers and enabling BBS-induced medical conditions to be managed more effectively early.2,12
Since BBS is not currently included on newborn screening panels and genetic tests are not widely available,13 a referral to a clinical geneticist is recommended to confirm a BBS diagnosis.
A UK-registered charity providing support, information and advocacy services to those living with BBS, their families and carers.
Visit SiteA US non-profit organisation that connects families and shares information on research, treatment and therapies for BBS.
Visit SiteAn integrated health system in Wisconsin, US with a BBS multidisciplinary clinic for people with BBS that accepts self-referrals. The Clinical Registry Investigating Bardet-Biedl Syndrome (CRIBBS) includes participants from 40 countries.
Visit SiteThe mission of Race Against Blindness is to advance therapies for pediatric inherited retinal diseases.
Visit Site1EURORDIS 2007. 2Forsythe E, et al. Front Pediatr. 2018;6:23. 3Forsythe E, et al. Eur J Hum Genet. 2013;21:8–13. 4Thadchanamoorthy V, et al. Cureus 2021;13:e12617. 5Mujahid S, et al. J Clin Endocrinol Metab. 2018;103:1834–41. 6Waters AM, et al. Pediatr Nephrol. 2011;26:1039–56. 7Suspitsin EN, Imyanitov EN. Mol Syndromol 2016;7:62–71. 8Tobin JL, et al. Pediatr Nephrol. 2007;22:926–36. 9Forsythe E, et al. J Am Soc Nephrol. 2017;28:963–70. 10Beales PL, et al. J Med Genet 1999;36:437–446. 11Policy Innovation Research Unit. 2015. 12Ashkinadze E, et al. Clin Genet. 2013;83:553–9. 13NORD. BBS. 2017.
Medical History:
Diagnosed with echogenic kidneys during routine 20-week antenatal scan.
Amniocentesis revealed BBS1 gene mutations.
Delivered at 39 weeks, normal birth weight.
Poor feeding; admitted to NICU for 3 days.
Bilateral polydactyly (please confirm that each limb means both upper and lower limbs).
Clubbed feet- improved with physio.
Post-delivery USS- bilateral, multiple renal cysts with normal renal function.
Enlarged bladder and small phallus.
Delayed development milestones noted at 2 months- not smiling, rolling over, unable to sit unaided and unable to crawl.
Today:
Weight 99th centile.
Constantly hungry requiring feeding every 3 hours.
Child presents with moonface, anteverted nostrils, and squint with high arched palate.
Beales Criteria fulfilled- polydactyly, obesity, renal cystic disease, hypogonadism, and developmental delay.
Family History:
7-year-old brother with hearing difficulties, recurrent chest infections, polydactyly right hand, and learning difficulties.
BBS Management:
Referred by paeds to geneticist to specialist BBS clinic.
Currently monitored for further complications of condition e.g. renal failure, endocrine insufficiency.
Parental counselling has been given to ensure that they are aware of likelihood of vision loss during teenage years.
Genetic counselling also given for future autosomal recessive condition and 1 in 4 chance of recurrent BBS child. Advised that prenatal genetic testing for BBS1 can be offered for future pregnancies.
Medical History:
Uneventful pregnancy and delivery.
Bilateral polydactyly on upper and lower limbs.
At birth- enlarged abdomen secondary to hydrometrocolpos (enlarged fluid filled uterus). Immediate surgery undertaken.
Noted to have missed all developmental milestones including sitting, smiling, standing, and walking.
Today:
From 9 months increased weight gain and currently at 99th centile for age.
Constantly hungry and from age of 6 developed rare form of epilepsy requiring several anti-epileptic medications to control frequency and duration of seizures. She needs to wear head protection during the day.
Unable to engage in conversation nor learn sign language.
Unable to maintain continence.
From age of 5 early vision loss noted particularly evident in low light.
Referred by optician to paediatric ophthalmologist at 8 years of age and diagnosed with retinitis pigmentosa. BBS was considered as a differential diagnosis.
Routine blood tests showed chronic renal failure and renal USS showed a smaller left kidney, and bilateral renal cysts.
Raised cholesterol, hyperinsulinemia, and hyperglycaemia all noted. Commenced on anti-diabetic medications.
Genetic testing undertaken and 2 mutations in BBS1 gene noted.
Family History:
No family history of note. Both parents are first cousins.
BBS Management:
Symptoms progressing, no improvement in cognition, but renal function stable (CKD stage 4) under close supervision from nephrologist.
Vision worsening with significant peripheral visual field loss. She continues to be cared for by the dedicated BBS multi-disciplinary team in partnership with her primary care physician paying special attention to her renal function and metabolic disease status and raised lipids. Her parents are keen for her to be considered for gene therapy in future.
32-year-old female who had worked as a supermarket checkout assistant. Recently made redundant following increasing difficulty seeing money being handed to her. Diagnosed with BBS at age of 30 by clinical geneticist. Genetic test showed mutation of BBS1 gene.
Medical History:
At birth 3 weeks spent on SCBU for feeding and breathing problems.
Aged 2, diagnosed with Hirschsprung’s disease requiring large bowel resection. Persistent constipation.
Wearing glasses from a young age. But had noticed progressive vision deterioration and diagnosed with retinitis pigmentosa at age of 28.
Recurrent UTIs and 3 hospital admissions with pyelonephritis.
Today:
Polydipsia, drinking up to 4 litres of water per day, and polyuria. Diagnosed with Diabetes insipidus.
Constantly hungry and persistent weight gain since infancy, currently weighing 18stone (114kg), BMI 44.
Family History:
One sister (37yr) married with two children, both are well. Two brothers, one has horseshoe kidney but no polydactyly or signs of BBS. Both parents alive and well without any family history of note.
BBS Management:
Treated with metformin, insulin, liraglutide, being assessed for bariatric surgery. However due to her inability to lose any weight, she is unable to meet the criteria needed to be eligible for surgical intervention.
The diagnosis of BBS1 has been of significant relief to the patient as this has given her an underlying reason for her multiple health problems. She recently became pregnant (father unavailable for carrier testing) and was offered prenatal screening at 12 weeks gestation. The fetus was found to be a carrier of a single BBS1 mutation.