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Purpose: To describe a case of choroidal neovascularization in a young patient with genetically-proven Bardet-Biedl syndrome., Methods: Case description with fundus and anatomical photography and optical coherence tomography., Patients: Single patient case description., Results: Fundus photography and optical coherence tomography reveal the presence of previously-active choroidal neovascularization. Anatomical, historical, and genetic evidence confirm Bardet-Biedl syndrome in this individual., Discussion: Choroidal neovascularization accompanying this syndrome has not been reported. Herein we describe the first published description of choroidal neovascularization in an individual with genetically-proven Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterised by retinal dystrophy, obesity, post-axial polydactyly, renal dysfunction, learning difficulties and hypogonadism. Many associated minor features can be helpful in making a diagnosis and are important in the clinical management of BBS. The diagnosis is based on clinical findings and can be confirmed by sequencing of known disease-causing genes in 80% of patients. BBS genes encode proteins that localise to the cilia and basal body and are involved in cilia biogenesis and function. Mutations lead to defective cilia accounting in part for the pleiotropic effects observed in BBS. We provide an overview of BBS including the clinical findings, current understanding of cilia biology, and a practical approach to diagnosis, genetic counselling and up-to-date management.

Background: Bardet-Biedl syndrome (BBS) is a genetic disorder with obesity as one of the major phenotypic criterion, which is proposed to be of neuroendocrine origin. Therefore, disturbances in appetite-regulating hormones have been considered as causative factors. Acyl ghrelin is an orexigenic hormone, whereas its desacylated form, obestatin, and leptin have the opposite functions. Ghrelin is negatively regulated in relation to nutritional status. The aim of this study was to evaluate the impact of hormone alterations on obesity development in BBS patients., Methods: Total and acylated ghrelin, obestatin, leptin and adiponectin were measured in eight children with BBS. The results were analyzed in relation to auxological parameters [body mass index (BMI), height]., Results: The mean BMI was significantly increased in BBS patients compared to the controls. Plasma levels of acylated ghrelin, total ghrelin and obestatin were slightly elevated in BBS patients compared to controls, as was the acyl/total ghrelin ratio. Leptin levels were significantly elevated in BBS patients., Conclusion: BBS patients lack the negative regulatory mechanisms of appetite-regulating hormones with respect to nutritional status and exhibit resistance to anorexigenic leptin. This results in a shift towards the orexigenic effects of this self-regulating system. These alterations may in part be responsible for the disturbed appetite regulation in BBS patients.

Objective: To investigate the involvement of the Bardet-Biedl syndrome (BBS) gene BBS1 p.M390R variant in nonsyndromic autosomal recessive retinitis pigmentosa (RP)., Methods: Homozygosity mapping of a patient with isolated RP was followed by BBS1 sequence analysis. We performed restriction fragment length polymorphism analysis of the p.M390R allele in 2007 patients with isolated RP or autosomal recessive RP and in 1824 ethnically matched controls. Patients with 2 BBS1 variants underwent extensive clinical and ophthalmologic assessment., Results: In an RP proband who did not fulfill the clinical criteria for BBS, we identified a large homozygous region encompassing the BBS1 gene, which carried the p.M390R variant. In addition, this variant was detected homozygously in 10 RP patients and 1 control, compound heterozygously in 3 patients, and heterozygously in 5 patients and 6 controls. The 14 patients with 2 BBS1 variants showed the entire clinical spectrum, from nonsyndromic RP to full-blown BBS. In 8 of 14 patients, visual acuity was significantly reduced. In patients with electroretinographic responses, a rod-cone pattern of photoreceptor degeneration was observed., Conclusions: Variants in BBS1 are significantly associated with nonsyndromic autosomal recessive RP and relatively mild forms of BBS. As exemplified in this study by the identification of a homozygous p.M390R variant in a control individual and in unaffected parents of BBS patients in other studies, cis - or trans -acting modifiers may influence the disease phenotype., Clinical Relevance: It is important to monitor patients with an early diagnosis of mild BBS phenotypes for possible life-threatening conditions.

Purpose: To assess for SDCCAG8 mutations in Bardet-Biedl syndrome (BBS) subjects with renal involvement and no polydactyly, and to describe phenotypic characteristics of SDCCAG8-related disease., Material and Methods: Five patients (from 4 pedigrees) with clinical diagnosis of BBS, who had retinal and renal involvement and no polydactyly, were assessed. Sequence analysis of SDCCAG8 was undertaken and a detailed clinical review of an affected sibship was performed., Results: A sibship of East Indian origin who carried a putative clinical diagnosis of BBS had compound heterozygous mutations in SDCCAG8 (p.Thr482LysfsX12/p.Asp543AlafsX24). The renal involvement was early and required transplant in both cases. Both were short statured and had asthma since childhood. The younger sister also had non-alcoholic fatty liver disease. Visual acuity and central fields were preserved in the teenage years in both patients. The optical coherence tomography showed preservation of the retinal lamination at the fovea; fundus autofluorescence demonstrated a perifoveal ring of hyperfluorescence as commonly observed in other forms of retinitis pigmentosa. Full-field electroretinogram revealed rod function to be more severely affected than cone function in both cases., Conclusion: Our results and prior literature suggest that SDCCAG8 could play an important role in presumed BBS patients affected with severe kidney disease and absent polydactyly. This report enhances the phenotypic description of SDCCAG8-related disease.

Cilia are antenna-like organelles found on the surface of most cells. They transduce molecular signals and facilitate interactions between cells and their environment. Ciliary dysfunction has been shown to underlie a broad range of overlapping, clinically and genetically heterogeneous phenotypes, collectively termed ciliopathies. Literally, all organs can be affected. Frequent cilia-related manifestations are (poly)cystic kidney disease, retinal degeneration, situs inversus, cardiac defects, polydactyly, other skeletal abnormalities, and defects of the central and peripheral nervous system, occurring either isolated or as part of syndromes. Characterization of ciliopathies and the decisive role of primary cilia in signal transduction and cell division provides novel insights into tumorigenesis, mental retardation, and other common causes of morbidity and mortality, including diabetes mellitus and obesity. New technologies ("Next generation sequencing/NGS") have considerably improved genetic research and diagnostics by allowing simultaneous investigation of all disease genes at reduced costs and lower turn-around times. This is undoubtedly a result of the dynamic development in the field of human genetics and deserves increased attention in genetic counselling and the management of affected families.

Background: Bardet-Biedl syndrome (BBS) is a pleiotropic recessive disorder that belongs to the rapidly growing family of ciliopathies. It shares phenotypic traits with other ciliopathies, such as Alström syndrome (ALMS), nephronophthisis (NPHP) or Joubert syndrome. BBS mutations have been detected in 16 different genes (BBS1-BBS16) without clear genotype-to-phenotype correlation. This extensive genetic heterogeneity is a major concern for molecular diagnosis and genetic counselling. While various strategies have been recently proposed to optimise mutation detection, they either fail to detect mutations in a majority of patients or are time consuming and costly., Method: We tested a targeted exon-capture strategy coupled with multiplexing and high-throughput sequencing on 52 patients: 14 with known mutations as proof-of-principle and 38 with no previously detected mutation. Thirty genes were targeted in total including the 16 BBS genes, the 12 known NPHP genes, the single ALMS gene ALMS1 and the proposed modifier CCDC28B., Results: This strategy allowed the reliable detection of causative mutations (including homozygous/heterozygous exon deletions) in 68% of BBS patients without previous molecular diagnosis and in all proof-of-principle samples. Three probands carried homozygous truncating mutations in ALMS1 confirming the major phenotypic overlap between both disorders. The efficiency of detecting mutations in patients was positively correlated with their compliance with the classical BBS phenotype (mutations were identified in 81% of 'classical' BBS patients) suggesting that only a few true BBS genes remain to be identified. We illustrate some interpretation problems encountered due to the multiplicity of identified variants., Conclusion: This strategy is highly efficient and cost effective for diseases with high genetic heterogeneity, and guarantees a quality of coverage in coding sequences of target genes suited for diagnosis purposes.

The Bardet-Biedl syndrome (BBS) is a human genetic disorder with an array of clinical features affecting many body systems. BBS is a pleiotropic disorder with mostly monogenic causes. It is also considered a primary ciliopathy syndrome. It is characterised by obesity, pigmentary retinopathy, polydactyly, mental deficiency and hypogonadism and recently a sixth feature, renal disease, has also been described. Since none of the diverse symptoms of BBS by itself is diagnostic of the disorder and many of the symptoms only become apparent over time, diagnosis of the BBS is often delayed until about 9 years of age when visual problems first appear.

Introduction: Early onset retinal degeneration associated with obesity can present a diagnostic challenge in paediatric ophthalmology practice. Clinical overlap between Bardet-Biedl syndrome (BBS) and Alström syndrome has been described, although the two entities are genetically distinct. To date, 16 genes are known to be associated with BBS (BBS1-16) and only one gene has been identified for Alström syndrome (ALMS1)., Materials and Methods: In collaboration with the French National Center for Sequencing (CNS, Evry), all coding exons and flanking introns were sequenced for 27 ciliopathy genes (BBS1-12, MGC1203, TTC21b, AHI1, NPHP2-8 (NPHP6=BBS14), MKS1(BBS13), MKS3, C2ORF86, SDCCAG8, ALMS1) in 96 patients referred with a clinical diagnosis of BBS. ALMS1 gene analysis included sequencing of all coding exons., Results: BBS known gene mutations were found in 44 patients (36 with two mutations and 8 heterozygous). ALMS1 mutations were found in four cases. The rate of ALMS1 mutations among patients suspected of having BBS was 4.2%., Discussion: Clinically, all four patients presented early-onset severe retinal degeneration with congenital nystagmus associated with obesity. The difficult early differential diagnosis between the two syndromes is outlined. One mutation had already been reported (c.11310delAGAG/p.R3770fsX) and three were novel (c.2293C > T/p.Q765X, c.6823insA/p.R2275fsX, c.9046delA/p.N3016fsX)., Conclusions: Ciliopathy genes sequencing can be very helpful in providing a timely diagnosis in this group of patients, hence appropriate genetic counselling for families and adequate medical follow-up for affected children.

Bardet-Biedl syndrome (BBS) is a multisystemic developmental disorder diagnosed on the basis of the presence of obesity, retinal defects, polydactyly, hypogonadism, renal dysfunction, and learning disabilities. The syndrome is genetically heterogeneous with 14 BBS genes identified to date. Since the cloning of the first gene in 2000, a combination of genetic, in vitro, and in vivo studies have highlighted ciliary dysfunction as a primary cause of BBS pathology. Pleiotropy of ciliopathy phenotypes and complex genetic interactions between causal and modifying alleles of ciliary genes contribute to phenotypic variability. In particular, kidney disease in BBS is clinically heterogeneous, but is now recognized as a cardinal feature and a major cause of mortality in BBS.

Disorders within the "ciliopathy" spectrum include Joubert (JS), Bardet-Biedl syndromes (BBS), and nephronophthisis (NPHP). Although mutations in single ciliopathy genes can lead to these different syndromes between families, there have been no reports of phenotypic discordance within a single family. We report on two consanguineous families with discordant ciliopathies in sibling. In Ciliopathy-672, the older child displayed dialysis-dependent NPHP whereas the younger displayed the pathognomonic molar tooth MRI sign (MTS) of JS. A second branch displayed two additional children with NPHP. In Ciliopathy-1491, the oldest child displayed classical features of BBS whereas the two younger children displayed the MTS. Importantly, the children with BBS and NPHP lacked MTS, whereas children with JS lacked obesity or NPHP, and the child with BBS lacked MTS and NPHP. Features common to all three disorders included intellectual disability, postaxial polydactyly, and visual reduction. The variable phenotypic expressivity in this family suggests that genetic modifiers may determine specific clinical features within the ciliopathy spectrum., (Copyright © 2011 Wiley Periodicals, Inc.)

Laurance Moon Bardet Biedl (LMBB) syndrome is a rare disorder characterised by retinitis pigmentosa, hexadactyly, obesity, mental retardation and hypogonadism. In the present case report the patient presented with the features of Laurence Moon Bardet Biedl syndrome in association with dyslipoproteinaemia.

Background: Bardet-Biedl syndrome (BBS) is a heterogeneous human disorder inherited in an autosomal recessive pattern, and characterized by the primary findings of obesity, polydactyly, hypogonadism, and learning and behavioural problems. BBS mouse models have a neuroanatomical phenotype consisting of third and lateral ventriculomegaly, thinning of the cerebral cortex, and reduction in the size of the corpus striatum and hippocampus. These abnormalities raise the question of whether humans with BBS have a characteristic morphologic brain phenotype. Further, although behavioral, developmental, neurological and motor defects have been noted in patients with BBS, to date, there are limited reports of brain findings in BBS. The present study represents the largest systematic evaluation for the presence of structural brain malformations and/or progressive changes, which may contribute to these functional problems., Methods: A case-control study of 21 patients, most aged 13-35 years, except for 2 patients aged 4 and 8 years, who were diagnosed with BBS by clinical criteria and genetic analysis of known BBS genes, and were evaluated by qualitative and volumetric brain MRI scans. Healthy controls were matched 3:1 by age, sex and race. Statistical analysis was performed using SAS language with SAS STAT procedures., Results: All 21 patients with BBS were found to have statistically significant region- and tissue-specific patterns of brain abnormalities. There was 1) normal intracranial volume; 2) reduced white matter in all regions of the brain, but most in the occipital region; 3) preserved gray matter volume, with increased cerebral cortex volume in only the occipital lobe; 4) reduced gray matter in the subcortical regions of the brain, including the caudate, putamen and thalamus, but not in the cerebellum; and 5) increased cerebrospinal fluid volume., Conclusions: There are distinct and characteristic abnormalities in tissue- and region- specific volumes of the brain in patients with BBS, which parallel the findings, described in BBS mutant mouse models. Some of these brain abnormalities may be progressive and associated with the reported neurological and behavioral problems. Further future correlation of these MRI scan findings with detailed neurologic and neuropsychological exams together with genotype data will provide better understanding of the pathophysiology of BBS.

Purpose: Bardet-Biedl syndrome (BBS) is genetically heterogeneous with 15 BBS genes currently identified, accounting for approximately 70% of cases. The aim of our study was to define further the spectrum of BBS mutations in a cohort of 44 European-derived American, 8 Tunisian, 1 Arabic, and 2 Pakistani families (55 families in total) with BBS., Methods: A total of 142 exons of the first 12 BBS-causing genes were screened by dideoxy sequencing. Cases in which no mutations were found were then screened for BBS13, BBS14, BBS15, RPGRIP1L, CC2D2A, NPHP3, TMEM67, and INPP5E., Results: Forty-three mutations, including 8 frameshift mutations, 10 nonsense mutations, 4 splice site mutations, 1 deletion, and 20 potentially or probably pathogenic missense variations, were identified in 46 of the 55 families studied (84%). Of these, 21 (2 frameshift mutations, 4 nonsense mutations, 4 splice site mutations, 1 deletion, and 10 missense variations) were novel. The molecular genetic findings raised the possibility of triallelic inheritance in 7 Caucasian families, 1 Arabian family, and 1 Tunisian patient. No mutations were detected for BBS4, BBS11, BBS13, BBS14, BBS15, RPGRIP1L, CC2D2A, NPHP3, TMEM67, or INPP5E., Conclusions: This mutational analysis extends the spectrum of known BBS mutations. Identification of 21 novel mutations highlights the genetic heterogeneity of this disorder. Differences in European and Tunisian patients, including the high frequency of the M390R mutation in Europeans, emphasize the population specificity of BBS mutations with potential diagnostic implications. The existence of some BBS cases without mutations in any currently identified BBS genes suggests further genetic heterogeneity.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder with a wide spectrum of clinical manifestations. BBS is predominantly characterized by dysmorphic distal extremities, obesity, structural abnormalities or functional impairment of the kidney, rod cone dystrophy, and varying degrees of mental retardation. Hypogenitalism is also present, only in males, and in all cases, facial similarities. We present herein two sisters with BBS, one of whom also had cerebellar vermis hypoplasia and cerebral and cerebellar atrophy, and both of whom had ocular abnormalities in the form of epicanthus and telecanthus and metabolic syndrome. It should also be emphasized that the occurrence of cerebellar involvement such as cerebellar vermis hypoplasia and cerebellar atrophy in BBS is very unusual. The association of abnormalities in brain development and other facial features in children with BBS is not seen frequently; thus, these abnormalities should be searched carefully.

Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinal degeneration, obesity, polydactyly, renal abnormalities, and cognitive impairment for which 15 causative genes have been identified. Here we present the results of a mutational analysis of our multiethnic cohort of 83 families (105 cases); 75.9% of them have their mutations identified including 26 novel changes. Comprehensive phenotyping of these patients demonstrate that the spectrum of clinical features is greater than expected and overlapped with the features of other ciliopathies; specifically Alström and McKusick-Kauffman syndromes.

Given the genetic basis of their disease, children with major chromosomal abnormalities including Bardet-Biedl syndrome (BBS) are generally considered to have a guarded prognosis with persistence or progression of disease manifestations. Although various therapeutic interventions are commonly used to control signs and symptoms of illness, parents of BBS children are usually cautioned against hoping for sustained improvement. A case of a 21-month-old girl, diagnosed with BBS, manifesting signs of worsening visual impairment, obesity, irascible and disordered behaviour, as well as developmental delay, is presented. After initial evaluation suggested specific biochemical deficiencies, nutritional status correction was undertaken and the patient's signs and symptoms subsequently resolved over the course of several months. To the authors' knowledge, this is the first case report of sustained resolution of all disease manifestations in the face of previously deteriorating health in a young child with this major chromosomal abnormality. It appears that biochemical imbalances and insufficiencies resulting from abnormal metabolism and excretion are potentially amenable to extraordinary dietary supplementation, with partial or complete resolution of clinical abnormalities. It is recommended that all children with chromosomal abnormalities have biochemical and nutritional status evaluation with correction of disordered biochemistry as is possible., (© 2010 John Wiley & Sons A/S.)

A 24-year-old primigravid women with no remarkable history and antenatal follow-up was referred to our clinic with the diagnosis of fetal megacystis. Ultrasound examination revealed an oval shaped hypoechoic cystic mass measuring 80×55×50 mm occupying the fetal pelvis in a female fetus. The fluid inside the cyst was heterogeneous giving a two level appearance. A normal looking urinary bladder was visualised separately which was located in normal position. Further sonographic evaluation revealed postaxial polydactyly in both hands. The fetal echocardiography and amniotic fluid index was normal. An obstetrical MRI was done for the suspicion of a hydrometrocolpos and confirmed the diagnosis. The infant was delivered by vaginal route at term. Physical examination of neonate confirmed postaxial polydactyly in hands. After birth a cystoscopy performed by the paediatric surgeons revealed a urogenital sinus and vaginal atresia. A catheter was placed in the uterine cavity to drain it. Nine months later the baby went on a 'vaginal pull through' operation to reconstruct the vagina and the urethra. The baby is now 3 years old and doing well.

Hydrometrocolpos and polydactyly diagnosed in the prenatal period or early childhood may raise diagnostic dilemmas especially in distinguishing McKusick-Kaufman syndrome (MKKS) and the Bardet-Biedl syndrome (BBS). These two conditions can initially overlap. With time, the additional features of BBS appearing in childhood, such as retinitis pigmentosa, obesity, learning disabilities and progressive renal dysfunction allow clear differentiation between BBS and MKKS. Genotype overlap also exists, as mutations in the MKKS-BBS6 gene are found in both syndromes. We report 7 patients diagnosed in the neonatal period with hydrometrocolpos and polydactyly who carry mutations in various BBS genes (BBS6, BBS2, BBS10, BBS8 and BBS12), stressing the importance of wide BBS genotyping in patients with this clinical association for diagnosis, prognosis and genetic counselling., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Background: The syndrome of Bardet-Biedl is definite clinically by the association of obesity, polydactyly, pigmentary retinopathy, hypogonadism and backwardness., Aim: To study the epidemiologic, clinical, biological, genetic, therapeutic and evolutionary characteristic of our patients., Methods: We carried out a retrospective study concerning 11 hospitalized children and/or follow-ups with the service of pediatry of the CHU Hédi Chaker of Sfax for syndrome of Bardet-Biedl during a period of 21 years (1987-2007)., Results: The obesity was constant among all patients, polydactyly was found in 9 cases, the fall of night vision in 7 cases. The hypogonadism was constant among all our boys. The bottom of eye was practised among 9 patients, it showed a pigmentary aspect of retinopathy among 8 patients. The electroretinogram was done in 10 patients, it showed a pigmentary retinopathy in all the cases. The radiological exploration of the urinary tract made it possible to identify morphological anomalies in 3 cases. The genetic study concerned the families of one of our patients and it allowed the identification of a new gene BBS8 at one of the families. Treatment was only symptomatic. After 6 years an average retreat, we noted an aggravation of obesity (9cas) and visual deficit (7cas). Only one patient evolved to the chronic renal insufficiency., Conclusion: The syndrome of Bardet-Biedl is a hereditary disease characterized by a genetic heterogeneity. The diversity of the systemic attacks defining this syndrome is a source of several handicaps: blindness, backwardness and obesity. The forecast is conditioned by the renal attack of or the interest of an early tracking and genetic council.

Purpose: Bardet-Biedl syndrome is a pleiotropic multiple anomaly syndrome inherited in an autosomal recessive pattern. It is now known that this disorder has locus heterogeneity, with causative mutations identified in as many as 14 genes. The aim of this study was to derive locus-specific recurrence risk estimates for family members of a proband affected with Bardet-Biedl syndrome., Methods: Mutation data from 187 probands affected with Bardet-Biedl syndrome were used. The authors counted the relative proportion of families with mutations at each of 10 loci and estimated locus-specific carrier rates for mutations using Hardy-Weinberg principles and an aggregate population frequency of 1/100,000 for the phenotype. Locus-specific recurrence risks were calculated for relatives of an affected proband., Results: Locus-specific carrier frequencies range from 1/250 to 1/2200, and the risks for an offspring of the sibling of an affected individual range from 1/1,500 to 1/13,000. The estimate of this risk derived under a locus homogeneity model is 1/960., Conclusion: Variation of recurrence risks of this magnitude may have implications for genetic counseling of families with affected individuals, in particular about prenatal testing and other reproductive options. Similar analyses to determine locus-specific carrier frequencies for other phenotypes with significant locus heterogeneity may yield similarly relevant results.

Background: Bardet-Biedl syndrome is a pleiotropic disorder with 14 BBS genes identified. BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, and BBS9 form a complex called the BBSome, which is believed to recruit Rab8(GTP) to the primary cilium and promote ciliogenesis. The second group, the chaperonin-like proteins BBS6, BBS10, and BBS12, have been defined as a vertebrate-specific branch of the type II chaperonin superfamily. These may play a role in the regulation of BBSome assembly., Methods and Results: Using sequence analysis, the role of BBS6, 10 and 12 was assessed in the patient population comprising 93 cases from 74 families. Systemic and ocular phenotypes were defined. In the study, chaperonin-like BBS gene mutations accounted for the disease in approximately 36.5% of BBS families. A total of 38 different non-polymorphic exonic sequence variants were identified in 40.5% of BBS families (41.9% cases), of which 26 were novel (68%). Six cases had mutations present in more than one chaperonin-like BBS gene. One case with four mutations in BBS10 had a phenotype of overall greater severity. The phenotypes observed were beyond the classic BBS phenotype as they overlapped with characteristics of MKKS (congenital heart defect, vaginal atresia, hydrometrocolpos, cryptorchidism), as well as Alström syndrome (diabetes, hearing loss, liver abnormalities, endocrine anomalies, cardiomyopathy)., Conclusions: While overlap between the MKKS and BBS phenotypes has previously been reported for cases with BBS6 mutations, we also observed MKKS phenotypes involving BBS10 and BBS12 and Alström-like phenotypes associated with mutations in BBS1, BBS2, BBS6, BBS7, BBS9, BBS10 and BBS12 for the first time.

Bardet-Biedl syndrome (BBS) is a ciliopathy with pleiotropic effect that manifests primarily as renal insufficiency, polydactyly, retinal dystrophy and obesity. The current phenotype-genotype correlation is insufficient to predict the likely causative mutation that makes sequencing of all 14 BBS genes an often necessary but highly complicated way to identify the underlying genetic defect in affected patients. In this study, homozygosity mapping is shown as a robust approach that is highly suited for genetically heterogeneous autosomal recessive disorders in populations in which consanguinity is prevalent. This approach allowed us to quickly identify seven novel mutations in seven families with BBS. Some of these mutations would have been missed by unguided routine sequencing, which suggests that missed mutations in known BBS genes could be more common than previously thought. This study, the largest to date on Saudi BBS families, also revealed interesting phenotypic aspects of BBS, including the first report of non-syndromic retinitis pigmentosa as a novel BBS phenotype.

Bardet-Biedl syndrome (BBS), an emblematic disease in the rapidly evolving field of ciliopathies, is characterized by pleiotropic clinical features and extensive genetic heterogeneity. To date, 14 BBS genes have been identified, 3 of which have been found mutated only in a single BBS family each (BBS11/TRIM32, BBS13/MKS1 and BBS14/MKS4/NPHP6). Previous reports of systematic mutation detection in large cohorts of BBS families (n > 90) have dealt only with a single gene, or at most small subsets of the known BBS genes. Here we report extensive analysis of a cohort of 174 BBS families for 12/14 genes, leading to the identification of 28 novel mutations. Two pathogenic mutations in a single gene have been found in 117 families, and a single heterozygous mutation in 17 families (of which 8 involve the BBS1 recurrent mutation, M390R). We confirm that BBS1 and BBS10 are the most frequently mutated genes, followed by BBS12. No mutations have been found in BBS11/TRIM32, the identification of which as a BBS gene only relies on a single missense mutation in a single consanguineous family. While a third variant allele has been observed in a few families, they are in most cases missenses of uncertain pathogenicity, contrasting with the type of mutations observed as two alleles in a single gene. We discuss the various strategies for diagnostic mutation detection, including homozygosity mapping and targeted arrays for the detection of previously reported mutations.

Bardet-Biedl syndrome (BBS) is a rare genetic disorder characterized by a wide range of phenotypic variability and associated with the development of life-threatening obesity. Birth weight tends to be normal, but rapid weight gain begins after the first year, probably due to polyphagia rather than abnormalities in energy metabolism. A morbidly obese 16-year-old male patient with BBS was referred to our institution, after nonsurgical methods of weight control had failed, for surgical treatment of his obesity. His preoperative body mass index (BMI) was 52.28 kg/m(2) (height, 1.84 m; weight, 177 kg) and was above the 99th centile for age and gender. The patient underwent laparoscopic Roux-en-Y gastric bypass (RYGBP). The postoperative period was uneventful. Three and a half years after the operation, the patient's weight has decreased to 118 kg (BMI, 34.85 kg/m(2)), while significant improvement in his hypertension, hyperuricemia, and mobility has been noted. In our BBS patient, RYGBP proved to be safe and effective; nevertheless, longer follow-up is required to evaluate the weight loss durability and to assess the lasting beneficial effect of surgical intervention on genetically determined co-morbidities.

The combined occurrence of diabetes mellitus (DM) and retinitis pigmentosa (RP) is rare. It has been reported in the form of four different syndromes that are inherited in an autosomal recessive fashion. We describe two cases of DM and RP occurring together. The first case was a 35-year-old male who presented with insulin-treated diabetes, obesity, hypertension, polydactyly, normal cognitive functions, an ataxic gait, blindness secondary to RP, dyslipidemia, impaired renal function, and multiple renal cysts. He was diagnosed clinically as having Bardet-Biedl syndrome. The second case was a 34-year-old male who presented with insulin-resistant diabetes, hypertension, blindness secondary to RP, deafness, normal cognitive functions, primary infertility, renal, and liver impairment. He was diagnosed clinically as having Alström syndrome. Because of overlapping clinical manifestations and the cost and time involved in genetic studies, clinical criteria can be used for diagnosis and as a guide for genetic mapping in these patients.

Ubiquitous in nature, cilia and flagella comprise nearly identical structures with similar functions. The most obvious example of the latter is motility: driving movement of the organism or particle flow across the epithelial surface in fixed structures. In vertebrates, such motile cilia are evident in the respiratory epithelia, ependyma, and oviducts. For over a century, non-motile cilia have been observed on the surface of most vertebrate cells but until recently their function has eluded us. Gathering evidence now points to critical roles for the mono-cilium in sensing the extracellular environment, and perturbation of this function gives rise to a predictable panoply of clinical problems. We review the common clinical phenotypes associated with ciliopathies and interrogate Online Mendelian Inheritance in Man (OMIM) to compile a comprehensive list of putative disorders in which ciliary dysfunction may play a role., (Copyright 2009 Wiley-Liss, Inc.)

A 4-year old boy was referred for evaluation of renal failure, posterior urethral valve (PUV) and urinary tract infection. His parents added complaints of polyuria, polydipsia, enuresis, shortness of stature, and inappropriate obesity. Serum blood urea nitrogen and creatinine levels were 45 and 3.5 mg/dL, respectively. Urine culture was positive for Pseudomonas aeruginosa, and abdominal ultrasound revealed bilateral small kidneys. The patient's history included mild to moderate mental retardation and postaxial polydactyly of both lower limbs amputated two years ago. The combination of mental retardation, obesity, postaxial polydactyly, and bilateral renal hypoplasia were compatible with the diagnosis Bardet-Biedl syndrome (BBS). The combination of PUV and BBS is a rare condition that caused this early onset of renal failure and inappropriate obesity guided us to the diagnosis.

A young boy of 9 years hailing from Fulpur, Mymensingh was admitted in the department of Ophthalmology, Mymensingh Medical College Hospital, Mymensingh, Bangladesh on the 26th November, 2007 with the complaints of dimness of vision of both the eyes and night blindness since birth. The boy suffered poor mental performances with delayed mild stone development. He was apathetic looking and below average IQ with short stature. Visual acuity of this patient recorded 6/60 both the eyes with nystagmus. Fundus examination revealed waxy disc atrophy, arteriolar attenuation and retinal degeneration both the eyes. He had polydactilism, trunkal obesity, hypogenitalism. On the basis of history, clinical examination and relevant investigations the patient was diagnosed as Bardet-Biedl Syndrome.

A 14 year old Bangladeshi boy presented with obesity, reduced vision, mental retardation, hypogonadism, delayed development and learning difficulty. On examination, he had polydactyly, moon face, bilateral gynaecomastia, small penis and undescended testes. Retinitis pigmentosa was found on fundoscopy. With typical features, he was diagnosed as a case of Laurence-Moon-Bardet-Biedl syndrome. It is a rare autosomal recessive disorder with mutation in 6 loci identified so far. It is commonly found in communities with high inter-family marriage. Clinical features appear early in childhood and diagnosis is usually done by puberty. Prominent features include rod-cone dystrophy leading to blindness, postaxial polydactyly, central obesity, learning disability, hypogonadism in males and renal dysfunction. Relatives with a single affected gene may have obesity, hypertension, diabetes and renal disease. There is increased risk of renal cell carcinoma. There is no definite treatment. Early diagnosis and symptomatic, supportive and rehabilitative measures can reduce the disability. These include dietary modification, oral hypoglycaemic drugs, testosterone supplement etc. Relatives of the patient should be screened for renal abnormality.

Bardet-Biedl syndrome (BBS) is a ciliopathy causing multivisceral abnormalities. Its prevalence in Europe is from 1/125,000 to 1/175,000. This disorder is defined by a combination of clinical signs: obesity, pigmentary retinopathy, post-axial polydactyly, polycystic kidneys, hypogenitalism, and learning disabilities, many of which appearing after several years of evolution. Individual clinical phenotype is highly variable. Most signs are present in a majority of patients but only pigmentary retinopathy is constant after infancy. There are many other associated minor clinical signs including diabetes, blood hypertension, congenital cardiopathy or Hirschsprung disease. This broad clinical spectrum is associated to a great genetic heterogeneity, with mainly an autosomal recessive transmission and, sometimes cases of oligogenism. To date, mutations in 12 different genes (BBS1 to BBS12) are responsible for this phenotype. These genes code for proteins involved in the development and function of primary cilia. Absent or non functional BBS proteins affect cilia in certain organs such as kidney or eye. However, some symptoms are still not clearly related to cilia dysfunction. BB syndrome has to be recognized because a molecular diagnosis is possible and will lead to familial genetic counseling and possibly prenatal diagnosis. Patients with BBS will need a multidisciplinary medical care. The renal abnormalities are the main life-threatening features because they can lead to end-stage renal failure and renal transplantation. Retinal dystrophy leading to progressive vision loss, moderate mental retardation, and obesity will affect social life of these patients.

A case diagnosed as Bardet-Biedl syndrome with polydactyly and hypertension has been presented here. Bardet-Biedl syndrome is an autosomal recessive disorder, which includes renal dystrophy, dystrophic extremities (often polydactyly), obesity, hypogenitalism, renal disease, and mental retardation. It was first described by John Z. Laurence and Robert Moon. The basic components of the syndrome were established by George Bardet in 1920 and Arthur Biedl in 1922. Although it is still referred to as Laurence-Moon-Bardet-Biedl in some reports, it has recently acquired the name Bardet-Biedl syndrome. Patients were generally lost due to renal insufficiency at young ages.

Laurence-Moon-Bardet-Biedl syndrome is a rare, genetically heterogeneous, autosomal recessive inherited disorder with wide variability in expression. We report a case of Laurence-Moon-Bardet-Biedl syndrome with typical phenotype in conjunction with nonalcoholic steatohepatitis. The diagnosis had been missed until the patient presented at our hospital.

Background: To report the clinical findings in two brothers presenting with a pigmentary retinopathy and post-axial polydactyly, who were found to have a mutation in the BBS1 gene, confirming a diagnosis of Bardet-Biedl syndrome (BBS)., Materials and Methods: Documentation of the clinical history, electrophysiological investigations, clinical examination and ocular findings of two brothers born to non-consanguineous white parents, with careful delineation of their clinical phenotypes. Screening of the BBS 1 gene on chromosome 11q13 by PCR-amplified exon alterations followed by direct sequencing was carried out to identify pathogenic mutations., Results: Although both probands had polydactyly and the characteristic ocular signs of BBS on both ophthalmological examination and electro-retinography, neither of them had dysmorphic facial features, obesity, hypogonadism, cognitive impairment, or renal anomalies. The first proband did have mild learning difficulties, although this did not restrict him in activities of daily living. Both probands were homozygous positive for the presence of a c.1169T > G (p.Met390Arg) mutation in BBS1., Conclusion: Although neither proband fulfilled the typical criteria for BBS, this diagnosis was confirmed on mutation analysis. These cases serve to highlight the degree of clinical variability observed in BBS which may be under-diagnosed in patients with milder phenotypes.

Hirschsprung's disease (HSCR) is a developmental disorder characterized by the absence of enteric neurons in distal segments of the gut. Though HSCR is isolated (nonsyndromic) in most cases, its association with chromosomal aberrations, some congenital anomalies, and a few syndromes has been documented. We report the association of HSCR with Bardet-Biedl syndrome in 2 siblings born to consanguineous Saudi Arabian parents. Both cases were diagnosed during the neonatal period. The first patient had the severe variety of the disease with aganglionosis involving the entire colon and terminal ileum. He died of postoperative complications. The second child had a limited short segment variety of HSCR. For social reasons, the surgical intervention was done only at 5 years of age with no documented complications.

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous autosomal recessive disorder characterized by progressive retinal dystrophy, polydactyly, obesity, hypogonadism, mental retardation, and renal dysfunction. Other manifestations include diabetes mellitus, heart disease, hepatic fibrosis, neurological features, and multiple pigmented nevi. To date, twelve BBS genes have been cloned (BBS1-BBS12). Herein we discussed a patient with BBS who had multiple pigmented nevi.

Fraser syndrome is an autosomal recessive disorder characterized by cryptophthalmos and cutaneous syndactyly. We present a case of Fraser syndrome with bilateral cryptophthalmos and other common features of Fraser syndrome including syndactyly (hands and feet bilaterally), ambiguous genitalia with clitoromegaly, vaginal atresia, and unilateral renal agenesis. We also present the major and minor diagnostic criteria for Fraser syndrome and the frequency of associated malformations.

Obesity has become an increasingly prevalent public health problem and results of the complex interaction of genetic and environmental factors. The study of rare syndromic forms of obesity enables progress in identifying molecular and physiological mechanisms, underlying the development of adiposity, food intake and energy expenditure. The identified role of the hypothalamic leptin-melanocortin pathway as major in monogenic forms of obesity, has led to the recognition of new genes controlling energy homeostasis and new pharmacological targets.

Purpose: To determine whether retinal dysfunction in obligate carriers of the Bardet-Biedl syndrome (BBS) could be observed in local electroretinographic responses obtained with the multifocal electroretinogram (mfERG)., Methods: Six obligate carriers of the BBS were examined for the study. Examination of each carrier included an ocular examination and mfERG testing of one eye. For the mfERG, we used a 103-scaled hexagonal stimulus array that subtended a retinal area of approximately 40 degrees in diameter. The amplitudes and implicit times in each location for the mfERG were compared with the corresponding values determined for a group of 34 normally sighted, age-similar control subjects., Results: Mapping of 103 local electroretinographic response amplitudes within a central 40 degrees area with the mfERG showed regions of reduced mfERG amplitudes in three of six carriers. Implicit time measurements in the 6 carriers were all normal except for those locations associated with abnormal amplitude reductions in 3 of the carriers. When present, retinal dysfunction was evident in the presence of a normal-appearing fundus., Conclusions: Multifocal ERG testing can demonstrate areas of retinal dysfunction in carriers of the BBS. This test may therefore be useful for identifying some heterozygous carriers of this disease.

Bardet-Biedl Syndrome (BBS) is a multisystemic disorder diagnosed on the basis of a combination of primary and secondary clinical features that include retinal dystrophy, obesity, polydactyly, cognitive dysfunction, and renal malformations. We report a unique case of BBS in a 13-year old girl of African-American descent who presented with retinitis pigmentosa, obesity, polydactyly, learning disabilities, precocious puberty, hypertension, renal cysts, and Hirschprung disease. Further evaluation revealed a history of precocious puberty, which is antithetical to the common manifestations of BBS, while neuroimaging was suggestive of periventricular leukomalacia and neuro-electrophysiologic studies revealed diffuse cerebral disturbance, which may contribute to her neurological abnormalities. The patient was also diagnosed with hydrometrocolpos, a finding typical of McKusick-Kaufman Syndrome (MKKS) but infrequent in other disorders. This observation, together with recent findings in some mouse models of BBS, raises the question of whether hydrometrocolpos should be considered as an additional diagnostic criterion for BBS to be used in females in parallel to the criterion of hypogonadism in males, thereby improving diagnostic sensitivity.

Duane's retraction syndrome (DRS) includes changes in palpebral fissure width along with restriction of ocular motility. Bardet Biedl syndrome (BBS) includes presence of retinitis pigmentosa (RP) with obesity, mental retardation, polydactyly and renal abnormalities. We report a case of rare association of DRS with BBS in a seven-year-old child. The ocular motility examination revealed left DRS with esotropia. Fundus examination revealed findings characteristic of an atypical retinitis pigmentosa. The electro-retinogram waveforms were extinguished both for rods and cones. He was diagnosed as a case of BBS on the basis of the ophthalmological findings plus association with the systemic features of obesity, polydactyly, hypogonadism, mental retardation and renal abnormalities. This case gives further evidence of the fact that BBS may be associated with abnormalities of eye movements.

Imperforate hymen is most commonly an isolated finding and usually remains asymptomatic until puberty. Rarely, symptoms of imperforate hymen manifest antenatally as well as in the neonatal period, requiring surgical correction for life-threatening consequences. We report a 5-day-old infant with a large hydrometrocolpos causing severe renal compromise and abdominal ascites, successfully surgically treated in the neonatal period. Associated polydactyly suggested McKusick-Kaufman syndrome.

Bardet-Biedl Syndrome (BBS) is a rare genetic disorder. It is considered to develop as a result of ciliary dysfunction. There are some clues about splenic expression of ciliary dysfunction. Therefore, splenic anomalies may be expected in BBS. We, here, describe a first case of BBS associated with splenic lobulations.