Bardet–Biedl syndrome (BBS) is primarily characterized by early-onset retinal dystrophy that is typically a rod–cone dystrophy but may present initially as a maculopathy. Other features include truncal obesity, postaxial polydactyly ( Fig. 19.1), renal abnormalities, hypogonadism, and learning difficulties. Birth weight is typically normal in these patients, but weight gain starts within the first year. Most patients do not present with all findings. BBS is considered a clinically and genetically heterogeneous ciliopathy, with significant intra- and interfamilial phenotypic variability. Prevalence ranges from 1:100,000 to 1:160,000, although in populations with known consanguinity, frequency may be as high as 1:13,000.

Retinal involvement occurs in more than 90% of patients with BBS. Most patients present a rod–cone pattern, but sometimes have a cone–rod pattern. Initial examination may be normal, but rarely maculopathy can be seen in late childhood. Most individuals with BBS present with nyctalopia and abnormal visual fields by the age of 10 years. At the end of the second decade of life, they usually present with a central island of vision. After that, macular involvement progresses, and visual acuity falls into legal blindness, which affects up to 75% of patients with BBS. Other ophthalmic findings may include nystagmus, strabismus, refractive errors, and cataract.

Renal malformations and renal dysfunction that lead to end-stage renal disease are seen in approximately 50 to 80% of affected patients. Up to 45% of individuals with BBS have structural renal abnormalities, including cysts, scarring, agenesis, or dysplasia.

Many patients with BBS are delayed in reaching developmental milestones including speech delay, motor skills, and psychosocial skills. Approximately one-third of children with BBS also show behavioral or psychiatric disorders. Some patients may have ataxia, mild hypertonia, or anosmia. A minority of patients have severe intellectual disability. Structural brain anomalies include ventriculomegaly, cortical thinning, reduced size of the corpus striatum, and hippocampal dysgenesis. Up to 50% of individuals develop a subclinical sensorineural hearing loss.

Polydactyly is seen in up to 80% of cases. Other findings, such as brachydactyly, partial syndactyly, and clinodactyly can be found. Up to half of patients have cardiac anomalies including most commonly valvular stenosis or atrial/ventricular septal defects. BBS patients commonly show hypertension and hyperlipidemia. Liver involvement includes fibrosis, small bile ducts, biliary cirrhosis, portal hypertension, and congenital cystic dilatation of both the intrahepatic and extrahepatic biliary tract. Non–insulin-dependent diabetes mellitus is usually seen in adolescence or early adulthood. Dental crowding, hypodontia, and high-arched palate have also been described. Craniofacial defects include brachycephaly, macrocephaly, narrow forehead, frontal balding, large ears, short and narrow palpebral fissures, a long smooth philtrum, depressed nasal bridge, short nose, midface retrusion, and retrognathia.

19.2 Molecular Genetics

BBS is typically an autosomal recessive (AR) condition. At least 20 genetic subtypes have been described ( Table 19.1). BBS1, BBS10, and BBS8 account for most cases (~23, 20, and 8%, respectively). BBS6, BBS9, BBS12, and BBS13 each represent 5%. Other subtypes are less frequent. Although there are no clear genotype–phenotype correlations, patients with BBS1 seem to have less severe ophthalmologic involvement than those with other genotypes ( Table 19.1).

CCDC28B, MKS1, MKS3, and C2orf86 genes can modify the expression of BBS phenotypes in individuals who have pathogenic variants in other BBS genes. There are reports of unaffected individuals who carry two heterozygous mutations in the same BBS gene, which supports the notion that BBS can be more complex molecularly, requiring three mutant alleles to manifest the phenotype. This is called triallelic inheritance.

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