Clinical and genetic epidemiology of Bardet-Biedl syndrome in Newfoundland: a 22-year prospective, population-based, cohort study

Abstract

Bardet-Biedl syndrome (BBS) and Laurence-Moon syndrome (LMS) have a similar phenotype, which includes retinal dystrophy, obesity, and hypogenitalism. They are differentiated by the presence of spasticity and the absence of polydactyly in LMS. The aims of this study were to describe the epidemiology of BBS and LMS, further define the phenotype, and examine genotype-phenotype correlation. The study involved 46 patients (26 males, 20 females) from 26 families, with a median age of 44 years (range 1-68 years). Assessments were performed in 1986, 1993, and 2001 and included neurological assessments, anthropometric measurements, and clinical photographs to assess dysmorphic features. The phenotype was highly variable within and between families. Impaired co-ordination and ataxia occurred in 86% (18/21). Thirty percent (14/46) met criteria for psychiatric illness; other medical problems included cholecystectomy in 37% (17/46) and asthma in 28% (13/46). Dysmorphic features included brachycephaly, large ears, and short, narrow palpebral fissures. There was no apparent correlation of clinical or dysmorphic features with genotype. Two patients were diagnosed clinically as LMS but both had mutations in a BBS gene. The features in this population do not support the notion that BBS and LMS are distinct. The lack of a genotype-phenotype correlation implies that BBS proteins interact and are necessary for the development of many organs.

Fig. 1

Pedigrees of Newfoundland Bardet–Biedl syndrome patients.

Fig. 2

Median age in years (and 95% confidence intervals) to onset of major clinical endpoints in BBS by genotype group.

Fig. 3

a: Polydactyly by genotype group in Bardet–Biedl syndrome; (b) maximum body mass index by genotype group in Bardet–Biedl syndrome.

Fig. 4

Diadochokinetic speech tests in Bardet–Biedl syndrome.

Fig. 5

Craniofacial features of three unrelated male Newfoundland BBS patients, showing frontal balding (all), bitemporal narrowing (a, c), short narrow palpebral fissures (a, c), ptosis (d), long smooth philtrum (c, d), thin upper lip (all), small mouth (c), downturned mouth (a, d). Lateral view (b) shows brachycephaly and long ears. Patients (a, b and d) have mutations in the MKKS/BBS6 gene, patient (c) links to the BBS5 locus.

Fig. 6

Facial features of four unrelated BBS Newfoundland patients showing asymmetric, expressionless facies, bitemporal narrowing, short narrow palpebral fissures, long shallow philtrum (b), small downturned mouth and thin upper lip (a, b, and d). Patient (a) has a mutation in the BBS1 gene, patients (b) and (c) have mutations in the MKKS/BBS6 gene, and patient (d) shows linkage to the BBS5 locus.