Major Features
Cone-rod dystrophy. Early macular involvement typically presents first with night blindness, followed by progressive peripheral vision loss, diminution of color discrimination, and overall loss of visual acuity [Weihbrecht et al 2017]. These symptoms are often what brings individuals to medical attention and obtain the diagnosis of BBS, usually in the first decade of life.
Electroretinography (ERG) is more likely to show significant findings after age five years.
Individuals often become legally blind by the second to third decade of life.
Retinal disease is the most penetrant feature in BBS, affecting up to 100% of individuals in some studies [Denniston et al 2014].
Central (truncal) obesity develops in the first year of life; birth weight is usually normal. Other features commonly associated with obesity are considered minor features in BBS. Mean body mass index has been reported to be 35.7±8.0 kg/m2 [Mujahid et al 2018].
Postaxial polydactyly are additional digits usually found on the ulnar side of the hand and/or fibular side of the foot. Mesoaxial polydactyly is also reported in individuals with pathogenic variants in LZTFL1 (BBS17) [Schaefer et al 2014].
Cognitive impairment. Historical reports describing significant intellectual disability as a prominent feature did not account for visual impairments.
Kerr et al [2016] evaluated the cognitive, adaptive, and behavioral function of 24 individuals with molecularly confirmed BBS and visual acuity ≥20/400. Visual fields and visual acuity were not significantly correlated with verbal comprehension index or any of the other cognitive measures. While only 20%-25% of individuals met criteria for a diagnosis of intellectual disability, mean intellectual functioning of all participants was 1.5 SD below the mean. Individuals also had impairments in verbal fluency (22%-44%), perceptual reasoning (53%), attention capacity (69%), and functional independence (74%). Features associated with autism spectrum disorders were present in 77%.
Hypogonadism and genitourinary malformations. Hypogonadism with delay in onset of secondary sexual characteristics may not be apparent until puberty.
Males can have micropenis and/or small-volume testes. Cryptorchidism is present in 9% of males with BBS. On endocrinologic assessment in one study, 19.5% of males were hypogonadal [Mujahid et al 2018].
Females can have anatomic anomalies including hypoplastic or duplex uterus, hypoplastic fallopian tubes and/or ovaries, septate vagina, partial or complete vaginal atresia, absent vaginal and/or urethral orifice, hydrocolpos or hydrometrocolpos, persistent urogenital sinus, and vesico-vaginal fistula [Deveault et al 2011].
Infertility is common, but both sexes are known to have been able to have biological children.
Kidney disease. The renal phenotype of BBS is highly variable and can include structural anomalies, hydronephrosis and vesicoureteral reflux, and progressive renal parenchymal disease that is commonly associated with urinary concentration defects (symptoms of polyuria and polydipsia) [Putoux et al 2012].
Structural kidney disease includes developmental anomalies such as horseshoe, ectopic, duplex, or absent kidneys; or dysplastic cystic disease ranging from single unilateral to multiple bilateral cysts.
Urologic complications including neurogenic bladder and bladder outflow obstruction have been reported in 5%-10% of adults [Forsythe et al 2017].
Chronic kidney disease (CKD) is a major contributor of morbidity and mortality in individuals with BBS. In a recent study, CKD was present in 31% of children and 42% of adults; 6% of children and 8% of adults developed end-stage kidney disease requiring dialysis and/or transplantation [Forsythe et al 2017].
In the majority of children with BBS with advanced (Stage 4-5) chronic kidney disease, the initial diagnosis of renal disease was made within the first year of life and almost all were diagnosed by age five years [Forsythe et al 2017].
Comorbidities including hypertension (present in about one third of individuals with BBS) and type 2 diabetes mellitus (T2DM) may affect progression of CKD.
Favorable long-term outcomes of renal transplantation have been reported [Haws et al 2016].
Minor Features
Neurodevelopmental abnormalities. Ataxia and poor coordination with mild hypertonia of all four extremities has been described in individuals with BBS, but correlation with brain changes on MRI needs to be better characterized.
Seizures and/or epilepsy (as defined by the International League Against Epilepsy) were reported in individuals in the Clinical Registry Investigating Bardet-Biedl Syndrome (CRIBBS) database, but the majority had resolution before adulthood [Unpublished data].
Speech abnormalities including receptive and expressive speech delay, articulation defects, and nasal and/or breathy speech quality are also observed, and likely multifactorial as a result of hearing issues, oral/dental abnormalities, and primary underlying neurologic issues.
The behavioral and psychiatric abnormalities, including obsessive compulsive behavior, anxiety and mood disorder, that have been observed are also likely multifactorial.
Because of the aforementioned, developmental delay in all domains (i.e., gross motor, fine motor, speech/language) is common in children with BBS; most children do eventually attain major developmental milestones (e.g., walking, talking).
Dysmorphic craniofacial features observed in individuals with BBS include brachycephaly, macrocephaly, and narrow forehead; short, narrow, and downslanted palpebral fissures; deep and widely set eyes; large ears; long and smooth philtrum; depressed nasal bridge; malar flattening; and retrognathia. These features can be subtle and are inconsistent among the population of individuals with BBS [Forsythe & Beales 2013]. A systematic review of the incidence of dysmorphic craniofacial features has not been performed.
Anosmia/hyposmia is likely underreported. While defects in olfactory cilia are thought to be responsible, the olfactory bulb has an abnormal appearance on brain MRIs of individuals with BBS [Braun et al 2016].
Oral/dental abnormalities. Primary anomalies can include hypodontia or microdontia, dental crowding, short roots and taurodontism, posterior crossbite, enamel hypoplasia, and high-arched palate.
Potential secondary oral complications that can result from the other clinical manifestations of BBS (e.g., visual impairment, obesity, cognitive defects, renal disease, mouth breathing, incompetent lips, anosmia) include poor oral hygiene, periodontal disease, dental caries, drug-induced gingival hyperplasia, xerostomia, altered taste, and speech disturbances [Panny et al 2017].
Cardiovascular and other thoraco-abdominal abnormalities. In a retrospective study of individuals in the CRIBBS database, a small percentage (1.6%) of individuals were found to have thoraco-abdominal abnormalities, namely, laterality defects [Olson et al 2019]. This percentage reflects a 170-fold higher prevalence compared to the general population, but is lower than that found in disorders of motile cilia, such as primary ciliary dyskinesia.
Laterality defects can range from situs inversus totalis to various features of heterotaxy (i.e., midline abdominal organs, asplenia, or polysplenia).
Congenital heart defects associated with laterality defects, including atrioventricular septal defects and vascular anomalies (i.e., bilateral persistent superior vena cava, interrupted inferior vena cava, and hemiazygos continuation) were also reported in the individuals with laterality defects in the CRIBBS database, but at a much lower rate than historically reported including in the meta-analysis by Niederlova et al [2019], which found an incidence of unspecified heart anomalies in 29% of individuals.
Dilated cardiomyopathy has been reported rarely in individuals with BBS, but exclusion of other genetic causes of these individuals' cardiomyopathy was not performed [Yadav et al 2013].
Gastrointestinal abnormalities. Hirschsprung disease and anatomic anomalies of the gastrointestinal tract (bifid epiglottis, laryngeal and esophageal webs, bowel atresia, imperforate anus) were identified in a small percentage of individuals in the CRIBBS database [Unpublished data].
Inflammatory bowel disease and celiac disease were also more prevalent in individuals with BBS compared to the general population.
Liver disease includes bile duct abnormalities with cystic dilatation, and periportal fibrosis and non-alcoholic fatty liver disease (NAFLD), thought to partially be a secondary effect of obesity [Branfield Day et al 2016].
Endocrine/metabolic abnormalities. Comorbidities of obesity, including hyperlipidemia (usually hypertriglyceridemia), insulin resistance, and elevated fasting plasma glucose with or without T2DM, are common. In addition, polycystic ovarian syndrome is common in females.
T2DM may be controlled by diet but often requires medications including insulin.
Subclinical hypothyroidism has also been reported; the clinical significance is unknown [Mujahid et al 2018].
Other Features (Not Part of the Clinical Diagnostic Criteria)
Dermatologic abnormalities. In one study, cutaneous dermatoses were present in all individuals and included seborrheic dermatitis (in 19.3%), keratosis pilaris (80.6%), and skin changes associated with obesity (e.g., striae, hidradenitis supportiva, acanthosis nigricans) [Haws et al 2019].
Subclinical sensorineural hearing loss is detected on audiometry testing in adults. Conductive hearing loss can occur in childhood as a result of recurrent otitis media. Hearing loss was reported in 17%-21% of individuals with BBS [Forsythe & Beales 2013].
Musculoskeletal abnormalities. Compared to the general population, individuals in the CRIBBS database had higher rates of: scoliosis (in 16%; usually not requiring surgery), leg length discrepancy (9.6%), club foot (1.8%; typically requiring surgery), Blount disease (0.9%), and joint laxity (27.6%) [CRIBBS database, unpublished data].
