What is Bardet-Biedl syndrome?

Bardet-Biedl Syndrome

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterized by retinal dystrophy, obesity, post-axial polydactyly, renal dysfunction, learning difficulties, and hypogonadism that requires early diagnosis and multidisciplinary management to prevent morbidity and mortality. 1

Clinical Characteristics

BBS presents with a constellation of primary and secondary features:

Primary Features

• Retinal dystrophy (rod-cone dystrophy) leading to night blindness and progressive vision loss
• Obesity (central) often developing in early childhood
• Post-axial polydactyly (extra digits on hands/feet)
• Renal abnormalities (structural malformations and progressive dysfunction)
• Learning difficulties/cognitive impairment
• Hypogonadism (particularly in males)

Secondary Features

• Hepatic fibrosis
• Speech disorders
• Developmental delay
• Dental anomalies
• Cardiovascular abnormalities
• Diabetes mellitus
• Hearing loss (less common)

Genetics and Pathophysiology

BBS is a ciliopathy - a disorder affecting the primary cilia, which are antenna-like structures on most cells that play crucial roles in cell signaling and development. At least 25 genes (BBS1-BBS25) have been identified, with mutations in BBS1 being most common in North America and Europe 1, 2. These genes encode proteins involved in cilia biogenesis and function, explaining the pleiotropic effects observed in BBS.

Diagnostic Approach

The diagnosis of BBS is based on clinical findings and can be confirmed by genetic testing:

1. Clinical Diagnosis: Requires the presence of either:

   • Four primary features, or
   • Three primary features plus two secondary features

2. Genetic Testing:

   • Recommended for all patients with suspected BBS
   • Gene panel testing can identify causative mutations in approximately 80% of patients 1
   • Large rearrangements should be confirmed by a second method (e.g., multiplex ligation-dependent probe amplification)

Age-Specific Presentations

Prenatal/Neonatal

• Polyhydramnios (excessive amniotic fluid)
• Polydactyly may be noted at birth

Infancy/Early Childhood

• Failure to thrive initially, followed by obesity development
• Developmental delay
• Renal abnormalities may be detected in the first year of life 3

Later Childhood/Adolescence

• Progressive vision loss (night blindness progressing to tunnel vision)
• Worsening obesity
• Learning difficulties become more apparent
• Delayed puberty

Adulthood

• Complete vision loss may occur
• Hypertension (35% of adults) 1
• Progressive renal dysfunction (42% of adults have CKD) 3
• Metabolic complications (diabetes, hyperlipidemia)

Management

Management requires a multidisciplinary approach focusing on:

Ophthalmologic Care

• Regular ophthalmologic evaluations
• Visual aids and rehabilitation
• Vitamin A supplementation may be considered 4

Renal Management

• Regular monitoring of renal function
• Ultrasound to detect structural abnormalities
• Blood pressure control (hypertension correlates with CKD progression) 3
• Management of CKD according to stage

Metabolic Management

• Weight management strategies
• Screening for diabetes and dyslipidemia
• Setmelanotide (IMCIVREE) has been FDA-approved for obesity management in BBS patients aged 6 years and older 5
  • In clinical trials, 61.3% of patients achieved ≥5% BMI decrease and 38.7% achieved ≥10% BMI decrease after 52 weeks 5
  • Common adverse effects include skin hyperpigmentation (63%), injection site reactions (51%), nausea (26%), and vomiting (19%) 5

Developmental/Cognitive Support

• Special education services
• Speech therapy when needed
• Psychological support

Other Considerations

• Genetic counseling for families
• Screening for hearing loss
• Dental care
• Endocrine evaluation for hypogonadism

Prognosis and Long-term Outcomes

The prognosis varies depending on:

1. Genotype: BBS1 mutations are associated with less severe renal disease compared to BBS10 mutations 3
2. Mutation Type: Two missense mutations generally cause less severe CKD than two truncating mutations 3
3. Renal Function: Renal disease is a major determinant of morbidity and mortality
4. Comorbidities: Obesity, diabetes, and hypertension can worsen outcomes

Key Monitoring Parameters

• Annual ophthalmologic examination
• Regular renal function tests (creatinine, eGFR, urinalysis)
• Blood pressure monitoring
• Growth charts in children
• Developmental assessments
• Screening for metabolic complications

Pitfalls and Caveats

1. Diagnostic Delay: Due to the rarity of BBS and the gradual appearance of symptoms, diagnosis is often delayed.

2. Phenotypic Variability: Significant variation in presentation exists, even within families with the same mutation.

3. Medication Considerations:

   • NSAIDs should be used cautiously due to potential renal effects
   • Setmelanotide requires monitoring for skin hyperpigmentation and development of new melanocytic nevi 5

4. Overlapping Phenotypes: BBS shares features with other ciliopathies, making differential diagnosis challenging.

5. Renal Disease Progression: Regular monitoring is essential as renal function can deteriorate rapidly in some patients.

Early diagnosis, comprehensive management, and regular monitoring are essential to improve quality of life and prevent complications in patients with Bardet-Biedl syndrome.