Laurence-Moon-Biedl Syndrome

Laurence-Moon-Biedl Syndrome (LMBS), also known as Bardet-Biedl Syndrome (BBS), is a rare, autosomal recessive genetic disorder characterized by a complex array of clinical features affecting multiple organ systems. It is named after the physicians who first described the condition: John Laurence, Robert Moon, Georges Bardet, and Arthur Biedl.

Key Points:

• Incidence: Varies by population, ranging from 1 in 13,500 to 1 in 160,000 live births
• Inheritance: Autosomal recessive
• Genes involved: At least 21 genes identified (BBS1-BBS21)
• Primary features: Retinal dystrophy, obesity, polydactyly, cognitive impairment, hypogonadism, and renal abnormalities

Note: The terms Laurence-Moon Syndrome and Bardet-Biedl Syndrome were once thought to be distinct entities but are now generally considered to be part of the same clinical spectrum.

Clinical Features

Laurence-Moon-Biedl Syndrome presents with a wide range of clinical features, which can vary in severity and combination among affected individuals:

Primary Features:

1. Retinal Dystrophy:
   • Progressive rod-cone dystrophy leading to vision loss
   • Night blindness, peripheral vision loss, and eventual central vision loss
   • Onset typically in first decade of life
2. Obesity:
   • Typically begins in early childhood
   • Truncal obesity with increased risk of metabolic syndrome
3. Polydactyly:
   • Most commonly postaxial (extra digit on the ulnar side of hands or fibular side of feet)
   • Present in about 60-80% of cases
4. Cognitive Impairment:
   • Ranges from mild learning difficulties to moderate intellectual disability
   • Speech and language delays are common
5. Hypogonadism:
   • More pronounced in males
   • Delayed puberty, undescended testes, small penis in males
   • Menstrual irregularities, hypoplastic fallopian tubes in females
6. Renal Abnormalities:
   • Structural abnormalities (e.g., calyceal clubbing, fetal lobulation)
   • Functional abnormalities (e.g., reduced concentrating ability)
   • Can progress to chronic kidney disease

Secondary Features:

• Hepatic fibrosis
• Diabetes mellitus
• Congenital heart defects
• Dental abnormalities
• Anosmia or hyposmia
• Behavioral problems
• Brachydactyly or syndactyly
• Developmental delay
• Speech disorders
• Ataxia or poor coordination
• Facial dysmorphism (deep-set eyes, hypertelorism, midface hypoplasia)

Diagnosis

Diagnosis of Laurence-Moon-Biedl Syndrome is based on clinical criteria and can be confirmed by genetic testing:

Clinical Diagnostic Criteria:

Beales et al. (1999) proposed the following criteria:

• Major features (4 primary or 3 primary + 2 secondary required):
  1. Rod-cone dystrophy
  2. Polydactyly
  3. Obesity
  4. Learning disabilities
  5. Hypogonadism in males
  6. Renal anomalies
• Minor features:
  • Speech disorder/delay
  • Strabismus/cataracts/astigmatism
  • Brachydactyly/syndactyly
  • Developmental delay
  • Polyuria/polydipsia (nephrogenic diabetes insipidus)
  • Ataxia/poor coordination/imbalance
  • Mild spasticity (especially lower limbs)
  • Diabetes mellitus
  • Dental crowding/hypodontia/small roots/high arched palate
  • Left ventricular hypertrophy/congenital heart disease
  • Hepatic fibrosis

Genetic Testing:

• Molecular genetic testing of known BBS genes
• Next-generation sequencing panels including all known BBS genes
• Whole exome or genome sequencing in cases where targeted testing is negative

Differential Diagnosis:

Consider other syndromes with overlapping features:

• Alström syndrome
• McKusick-Kaufman syndrome
• Prader-Willi syndrome
• Cohen syndrome

Management

Management of Laurence-Moon-Biedl Syndrome requires a multidisciplinary approach and is primarily supportive:

Ophthalmological Management:

• Regular ophthalmological examinations
• Low vision aids and adaptive technologies
• Genetic counseling regarding prognosis of vision loss

Obesity and Metabolic Issues:

• Dietary management and exercise programs
• Monitoring for complications of obesity (diabetes, hypertension)
• Consideration of bariatric surgery in severe cases

Renal Management:

• Regular monitoring of renal function
• Management of chronic kidney disease if present
• Consideration of renal transplantation in end-stage renal disease

Endocrine Management:

• Hormone replacement therapy for hypogonadism
• Management of diabetes mellitus if present

Developmental and Cognitive Support:

• Early intervention programs
• Special education support
• Speech and language therapy

Other Management Aspects:

• Cardiac evaluation and management of any heart defects
• Dental care and orthodontic interventions as needed
• Psychological support for patients and families
• Genetic counseling for family planning

Surveillance:

• Annual ophthalmologic examination
• Annual renal function tests and ultrasound
• Regular monitoring of blood pressure, lipid profile, and glucose tolerance
• Regular developmental and educational assessments

Genetics

Laurence-Moon-Biedl Syndrome is genetically heterogeneous:

Inheritance Pattern:

• Primarily autosomal recessive
• Rare cases of triallelic inheritance reported (three mutations in two different BBS genes required for phenotypic expression)

Known Genes:

• At least 21 genes identified (BBS1-BBS21)
• Most common genes: BBS1, BBS10, BBS12
• All known BBS proteins localize to the centrosome and/or basal body of cilia

Molecular Pathogenesis:

• BBS is considered a ciliopathy (dysfunction of cellular cilia)
• Defects in cilia structure or function affect multiple organ systems
• Impaired intracellular transport and cell signaling

Genetic Testing Strategies:

• Multi-gene panel testing including all known BBS genes
• Whole exome sequencing if panel testing is negative
• Deletion/duplication analysis

Genotype-Phenotype Correlations:

• Generally poor correlation between specific genes and phenotypic features
• Some trends observed:
  • BBS1 mutations associated with milder retinal phenotype
  • BBS10 mutations associated with more severe renal disease