Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow in Fetal and Perinatal Skeletal Dysplasias, 2012
Other conditions with mesoaxial polydactyly : oral-facial-digital syndrome type 6: autosomal recessive condition, with hypertelorism, median cleft lip and palate, lingual cleft with nodules, teeth abnormalities, multiple frenula, midline brain malformation (absence of olfactory bulbs and tracts, semilobar holoprosencephaly, absence or dysgenesis of the cerebellar vermis, corpus callosum, hypothalamus and pituitary gland), retinal dystrophy, congenital heart defects, renal agenesis, short stature, mental retardation. McKusick-Kaufman syndrome: triad of hydrometrocolpos or male genital malformations, postaxial or mesoaxial polydactyly, and cardiac malformations. Caused by recessive mutations in the gene MKKS; more frequent in the Amish population. Some overlap with Bardet-Biedl syndrome. Chondroectodermal dysplasia (Ellis-van Creveld) (p. 167).
Etiology and Prevalence of Obesity
Claude Bouchard in The Genetics of Obesity, 2020
The Lawrence-Moon and Bardet-Biedl syndromes are often considered together, but probably represent distinct entities. In 1866, Laurence and Moon described four patients with retinal degeneration of the pigment cells, mental retardation, hypogenitalism, and a neurologic defect characterized as spastic paraplegia, but without obesity or digital anomalies. Obesity was present in two, spastic paraplegia in one, and ataxia in two patients. Nearly 60 years later Bardet described a syndrome consisting of retinitis pigmentosa, obesity, and polydactyly, and 2 years later Biedl independently described two cases with additional findings of genital hypoplasia, mental retardation, and anal atresia. There have subsequently been more than 500 cases which fit into this group of syndromes.13 Although often lumped together, the Bardet-Biedl and Lawrence-Moon syndromes differ in a number of important ways and should be considered as separate entities. Both are inherited as autosomal recessive traits. Pigmentary retinopathy is present in the Lawrence-Moon syndrome, but tapetoretinal degeneration occurs in the Bardet-Biedl syndrome. Spastic paraplegia is present in the Lawrence-Moon syndrome, but does not occur in the Bardet-Biedl syndrome. Obesity, which is an almost uniform feature of the Bardet-Biedl syndrome, is uncommon in the Lawrence-Moon syndrome. In addition, the Bardet-Biedl syndrome may be associated with congenital heart disease and nephropathy, which has been reported to be as high as 71% in one autopsy series.14
The Human Genome Project and Its Impact on Understanding Developmental Disabilities
Merlin G. Butler, F. John Meaney in Genetics of Developmental Disabilities, 2019
The availability of thousands of markers mapped to the human genome led not only to an increased rate of identification of genes that cause developmental disabilities, but also revealed the complexity of human disease. Positional cloning efforts have demonstrated concepts such as genetic heterogeneity (i.e., different mutations causing the same trait or pattern of traits (phenotype), locus heterogeneity (i.e., more than one mutated gene causing the same phenotype), allelic heterogeneity (i.e., more than one mutation within a gene causing the same phenotype), pleiotropy (i.e., one mutated gene having multiple phenotypes), and even digenic inheritance (i.e., the necessity of mutations at two loci causing a specific phenotype). All of these concepts are exemplified by the study of one disease, Bardet-Biedl syndrome (BBS). BBS is characterized primarily by mental retardation, obesity, pigmentary retinopathy, polydactyly, renal malformations, and hypogenitalism (10). The multiple, seemingly unrelated, effects in multiple organ systems due to one altered gene demonstrate pleiotropy. Some of the phenotypic features are common to many disorders and may make accurate diagnosis in early childhood difficult even for the experienced clinician. Early efforts at positional cloning showed linkage to chromosomes 3, 11, 15, 16 (11-14). By 2000, 10 years after the start of the HGP, six loci had been mapped (15-17). Careful assessment of the involved pedigrees showed that despite the significant variation of phenotypic features (expressivity) within the families used for linkage, the characteristic features were present across studies involving different chromosomes, demonstrating locus heterogeneity. All of the mapped loci fit an autosomal recessive pattern of inheritance. Two mutations at the given locus being evaluated in a particular family or genetic isolate segregated with the phenotype.
Novel compound heterozygous pathogenic BBS5 variants in Filipino siblings with Bardet-Biedl syndrome (BBS)
Published in Ophthalmic Genetics, 2020
Aramis B. Torrefranca, Alvina Pauline D. Santiago, Michelle D. Lingao, Marie Julianne C. Racoma
Based on the constellation of clinical features a clinical diagnosis of Bardet-Biedl syndrome (BBS) was made. This prompted additional investigations. Orthopedic evaluation showed polydactyly of the extremities (see Figure 2). Obesity work-up included a lipid profile revealing dyslipidemia. Transrectal, kidney and urinary bladder ultrasonography were non-pathologic.
An evaluation of setmelanotide injection for chronic weight management in adult and pediatric patients with obesity due to Bardet–Biedl syndrome
Published in Expert Opinion on Pharmacotherapy, 2023
Julia Lazareva, Sheila M. Brady, Jack A. Yanovski
Bardet–Biedl Syndrome is a rare genetic disease. The large number of participants required for a randomized control trial design to establish efficacy at 1y is not considered feasible for BBS [43,44]. Therefore, only short-term placebo-controlled data and longer-term uncontrolled efficacy data are available.
Bardet-Biedl syndrome-7 (BBS7) shows treatment potential and a cone-rod dystrophy phenotype that recapitulates the non-human primate model
Published in Ophthalmic Genetics, 2021
Tomas S. Aleman, Erin C. O’Neil, Keli O’Connor, Yu You Jiang, Isabella A. Aleman, Jean Bennett, Jessica I. W. Morgan, Brian W. Toussaint
SD-OCT imaging was used to explore the underlying structural abnormalities in cross-section (Figure 1b). P1 showed obvious foveal and juxtafoveal thinning of the photoreceptor outer nuclear layer (ONL), including the photoreceptor axons. At the foveal center there is approximation of the inner segment ellipsoid band (EZ) to the apical retinal pigmented epithelium and Bruch’s membrane (RPE/BrM) signals, likely from shortening and/or loss of photoreceptor outer segments (Figure 1b) (40,57–63). While the EZ and outer limiting membrane (OLM) are visible at the foveal center, the EZ becomes undiscernible in the juxtafoveal region (<0.75 mm of eccentricity), where the OLM abuts the apical RPE (Figure 1b, between yellow arrows) (64,65). This segment corresponds to the area of hypoautofluorescence on SW-FAF and NIR-FAF that is slightly eccentric toward the nasal side of the fovea (Figure 1a). With increasing eccentricity into the parafovea and pericentral retina, the retinal lamination regains a normal appearance with the exception for the existence of a darker than usual band separating the EZ signal from the signal originating from the tip or distal photoreceptor outer segments as they interdigitate with the apical RPE, conventionally known as the interdigitation zone (IZ) band (60,63). The foveal center in P2 appears to be normal in thickness and the only visible abnormality is the loss of the IZ signal with approximation of the EZ to the apical RPE with an intervening hyporreflective signal. In the juxtafovea there is a brief interruption of the EZ band (Figure 2b, between yellow arrows). The association of polydactyly, obesity, endocrine abnormalities and an outer retinal degeneration was suggestive of Bardet-Biedl syndrome. Genetic testing by Next Generation Sequencing identified two novel variants in the BBS7 gene segregating in a compound heterozygous state with the phenotype in both patients: p.Val266Glu:c.797 T > A, maternally inherited, predicted to be damaging by both Polyphen-2 and REVEL, and c.1781_1783delCAT, an in-frame deletion of p.Ser594, inherited from their father. Both patients were negative for mutations in BBS1, BBS2, BBS4, BBS5, BBS9, BBS10, BBS12, and ALSM1 genes (Molecular Vision Laboratories, Panel v1). The involvement of other BBS variants was not pursued.
Related Knowledge Centers
- Ciliopathy
- Cone Dystrophy
- Dystrophy
- Hypogonadism
- Kidney Failure
- Genetic Disorder
- Pleiotropy
- Polydactyly
- Abdominal Obesity
- Expressivity