Bardet-Biedl syndrome (ORPHA:110)
A rare genetic multisystem disorder characterized by the variable association of retinal dystrophy, obesity, polydactyly, genitourinary and kidney anomalies, learning disability and hypogonadism, with a wide spectrum of other minor manifestations.
Epidemiology
In the USA, the prevalence is estimated at 1/100,000. Whilst epidemiological data is limited in Europe, a prevalence of 1/59,000 has been estimated in Denmark and 1/45,000-66,000 in the Reunion Island, France (due to a founder effect).
Clinical description
The clinical manifestations are highly variable, even within affected families. Post-axial polydactyly, sometimes associated with brachydactyly and/or syndactyly, is a common congenital feature. Other manifestations develop gradually over the first decade of life. Rapid weight gain is often described in early childhood, with obesity/overweight present in over 90% of individuals after 5 years of age; it is often difficult to treat and is associated with the metabolic syndrome in adults. Rod-cone or choroidal dystrophy causes decreased visual acuity, night blindness, photophobia and loss of central and color vision by late childhood/early adulthood. Other ocular manifestations include strabismus, cataracts, and astigmatism. Kidney and urinary tract abnormalities are common and may lead a progressive decline of kidney function: stage II-V chronic kidney disease (CKD) is described in 30 to over 40% of affected individuals. Developmental delay, cognitive deficit and behavioral disorders (autism, psychosis) are frequent features. Hypogonadism is often reported, especially in males. Minor signs include diabetes mellitus, heart (valvular stenoses, patent ductus arteriosus, cardiomyopathy), gastrointestinal tract (Hirschsprung disease), central nervous system (clumsiness, ataxia), liver (fibrosis, biliary cirrhosis, portal hypertension), and dentition (dental crowding, hypodontia, malocclusion, enamel hypoplasia) abnormalities. Subtle and inconsistent dysmorphic features (brachycephaly, macrocephaly, hypertelorism, midface hypoplasia, retrognathia) have also been reported. Anosmia or hyposmia may also be found as well as bilateral sensorineural hearing loss.
Etiology
Bardet-Biedl syndrome (BBS) is a ciliopathy associated with abnormalities in proteins involved in the development and function of primary cilia. Pathogenic or likely pathogenic variants in at least 24 different genes have been associated with BBS to date. Depending on the population origin, BBS1 (11q13.2) and BBS10 (12q21.2) are the most frequent genes, respectively accounting for ~23% and 15% of genotyped BBS patients.
Diagnostic methods
The diagnosis of BBS is based on the clinical manifestations (at least four major clinical signs or 3 major and 2 minor clinical signs) and can be confirmed by molecular genetic testing of the causative genes in more than 80% of patients. Visual manifestations are often the first sign leading to diagnosis in patients with no polydactyly; polydactyly and kidney anomalies (hyperechoic or multicystic kidneys) can be antenatal presenting signs.
Differential diagnosis
Main differential diagnoses include Alström syndrome, McKusick-Kaufman syndrome, Joubert syndrome, Jeune syndrome, Sensenbrenner syndrome and Senior-Løken syndrome.
Antenatal diagnosis
Genetic prenatal testing for BBS is possible in families with an identified gene mutation.
Genetic counseling
BBS is inherited in an autosomal recessive manner. Oligogenic inheritance has also been reported is some affected families. Genetic counseling should be provided to affected families.
Management and treatment
Multidisciplinary management and treatment is required. Most manifestations are treated following standard practice for the general population (obesity, learning disability, kidney anomalies). Setmelanotide was approved for hunger control in genetically confirmed Bardet-Biedl syndrome patients. Genital abnormalities and polydactyly may be treated with surgery.
Prognosis
Chronic kidney disease is considered the main cause of morbidity and mortality; its severity varies among patients but may potentially lead to end-stage kidney disease requiring dialysis or transplantation. Progressive vision loss due to retinal dystrophy, together with moderate intellectual deficit (when present), behavioral anomalies, hypomimia and obesity will affect the social life of these patients.

                            Last update: 
                            September 2021


                            - Expert reviewer(s): 
                            Dr Jean MULLER | ERN-EYE* - Pr Miriam ZACCHIA | ERKNet*


                                * European Reference Network