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PubMed1996

Prenatal diagnosis of asphyxiating thoracic dysplasia (Jeune syndrome).

Asphyxiating thoracic dysplasia (ATD), or Jeune syndrome, is an uncommon autosomal recessive skeletal disorder characterized by a small thorax, varying degrees of rhizomelic brachymelia, polydactyly, pelvic abnormalities, and renal anomalies. We describe prenatal sonographic examinations in the third trimester of a fetus with abnormal small thorax, short limbs, polyhydramnios, and absence of fetal respiratory movements. At 36 weeks gestation, the fetal biparietal diameter was 93 mm, compatible with 37 weeks; the long-bone lengths measured < 5th percentile; the thoracic circumference (TC) measured 230 mm (< 5th percentile); the abdominal circumference (AC) measured 286 mm (25th percentile), and the TC/AC ratio was 0.80 (lower limit of normal). Our case shows that, although a discrepancy between gestational age and TC is prominent, TC/AC ratio may reach lower limit of normal in cases of fetal ATD, when fetal growth is compromised.

Adult↗
PubMed1999

[Orofaciodigital syndrome--a new variant? Psychiatric, neurologic and neuroradiological findings].

Oral-facial-digital (OFD) syndromes are a heterogeneous group of inherited syndromes that have in common anomalies of the face (median cleft lip), the tongue (bifid or lobulated tongue with harmartomas), and the digits (brachydactyly, polydactyly, syndactyly). Due to more or less subtle clinical features, at least seven causally different entities can be identified: 1) OFDS I; 2) OFDS II (Mohr syndrome); 3) OFDS III; 4) OFDS with tibial anomalies (OFDS IV); 5) OFDS V (Thurston syndrome); 6) OFDS VI (Váradi syndrome); and 7) OFDS VII (Whelan syndrome). The neuro-psychiatric clinical observations and MRI findings of a 40 year old woman with a OFD syndrome are described. The observed findings (leukoaraiosis, epilepsy, major depression) in combination with a proven OFD syndrome possibly reflect a new type of OFD syndrome.

Adult↗
PubMedDate not supplied

[Mesomelic dysplasia: presentation of a case and literature of Werner's syndrome].

The extremely rare Werner syndrome (tibial hemimelia, foot polydactyly, triphalangeal thumbs) is represented by an own case: a 21 year old female has been treated since her birth in the orthopedic department of Homburg/Saar university clinic. First, during several operative sessions, there was the correction of the bilateral completely webbed fingers and the resection of the supernumerary toes. Because of tibial hypoplasia there was need of bilateral operative club-foot-correction, too. Presentation of the course over 20 years with clinical and roentgenological late results. In several publications we find different classifications of the collective name, tibial hemimelia'; the symptom-triade congenital tibia-defect/foot-polydactyly/triphalangeal thumb was of special interest.

Adolescent↗
PubMedDate not supplied

[The triphalangeal thumb].

A theory about formal aetiology of triphalangeal thumb is emphasized. All teratological grades of triphalangism of the thumb associated with preaxial polydactyly or reduction abnormality of the thumb are to be submitted to our diagram of thumb malformations.

Fingers↗
PubMed1988

The spectrum of renal disease in Laurence-Moon-Biedl syndrome.

To determine the nature, extent, and severity of renal involvement in Laurence-Moon-Biedl syndrome (obesity, mental retardation, polydactyly, hypogonadism, and pigmented retinal dystrophy), we evaluated 20 of 30 patients with the disorder identified from ophthalmologic records in Newfoundland. The mean age was 31 years, and seven were male. All 20 patients had structural or functional abnormalities of the kidneys or both. Three had end-stage renal disease, with two requiring maintenance hemodialysis. The remaining 17 patients had normal serum creatinine values and estimated creatinine clearances. Half the subjects had hypertension. Fourteen of 17 patients could not concentrate urine above 750 mOsm per kilogram of body weight even after vasopressin, whereas all 10 normal controls could. Urinary pH decreased below 5.3 after ammonium chloride administration in all 15 normal controls, but in only 13 of 18 patients. Calyceal clubbing or blunting was evident in 18 of 19 patients studied by intravenous pyelography; 13 patients had calyceal cysts or diverticula. Seventeen of 19 patients had lobulated renal outlines of the fetal type. Four patients had diffuse renal cortical loss, but only two of these had renal insufficiency. We conclude that Laurence-Moon-Biedl syndrome includes the presence of renal abnormalities.

Adolescent↗
PubMed2003

Multiple recurrent and de novo odontogenic keratocysts associated with oral-facial-digital syndrome.

In 1954, Papillon-Leage and Psaume were the first to describe the clinical characteristics of oral-facial-digital syndrome (OFDS). On the basis of their clinical features and the inheritance pattern, 2 variants were initially distinguished, namely OFDS type I (Papillon-Leage and Psaume) and OFDS type II, or Mohr syndrome. At present, 11 types of OFDS have been discovered. OFDS represents a heterogeneous group of disorders characterized by oral manifestations including oral frenula, cleft or lobulated tongue, high arched palate, cleft lip and/or palate, facial anomalies, and digital abnormalities such as syndactyly, polydactyly, brachydactyly, and clinodactyly. Depending on the type of OFDS, abnormalities may be present in other organs, such as the brain and heart. We report a patient with OFDS in whom multiple recurrent and de novo keratocysts were found. Although multiple keratocysts are commonly found in Gorlin-Goltz nevoid basal cell carcinoma syndrome, a relationship between OFDS and multiple keratocysts has not been described.

Child↗
PubMed2004

Bardet-Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assembly.

The functions of the proteins encoded by the Bardet-Biedl syndrome (BBS) genes are unknown. Mutations in these genes lead to the pleiotropic human disorder BBS, which is characterized by obesity, retinopathy, polydactyly, renal and cardiac malformations, learning disabilities, and hypogenitalism. Secondary features include diabetes mellitus and hypertension. Recently, it has been suggested that the BBS phenotypes are the result of a lack of cilia formation or function. In this study, we show that mice lacking the Bbs4 protein have major components of the human phenotype, including obesity and retinal degeneration. We show that Bbs4-null mice develop both motile and primary cilia, demonstrating that Bbs4 is not required for global cilia formation. Interestingly, male Bbs4-null mice do not form spermatozoa flagella, and BBS4 retinopathy involves apoptotic death of photoreceptors, the primary ciliated cells of the retina. These mutation data demonstrate a connection between the function of a BBS protein and cilia. To further evaluate an association between cilia and BBS, we performed homology comparisons of BBS proteins in model organisms and find that BBS proteins are specifically conserved in ciliated organisms.

Animals↗
PubMed2004

Bbs2-null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsin.

Bardet-Biedl syndrome (BBS) is a heterogeneous, pleiotropic human disorder characterized by obesity, retinopathy, polydactyly, renal and cardiac malformations, learning disabilities, hypogenitalism, and an increased incidence of diabetes and hypertension. No information is available regarding the specific function of BBS2. We show that mice lacking Bbs2 gene expression have major components of the human phenotype, including obesity and retinopathy. In addition, these mice have phenotypes associated with cilia dysfunction, including retinopathy, renal cysts, male infertility, and a deficit in olfaction. With the exception of male infertility, these phenotypes are not caused by a complete absence of cilia. We demonstrate that BBS2 retinopathy involves normal retina development followed by apoptotic death of photoreceptors, the primary ciliated cells of the retina. Photoreceptor cell death is preceded by mislocalization of rhodopsin, indicating a defect in transport. We also demonstrate that Bbs2(-/-) mice and a second BBS mouse model, Bbs4(-/-), have a defect in social function. The evaluation of Bbs2(-/-) mice indicates additional phenotypes that should be evaluated in human patients, including deficits in social interaction and infertility.

Animals↗
PubMed2006

Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11).

The identification of mutations in genes that cause human diseases has largely been accomplished through the use of positional cloning, which relies on linkage mapping. In studies of rare diseases, the resolution of linkage mapping is limited by the number of available meioses and informative marker density. One recent advance is the development of high-density SNP microarrays for genotyping. The SNP arrays overcome low marker informativity by using a large number of markers to achieve greater coverage at finer resolution. We used SNP microarray genotyping for homozygosity mapping in a small consanguineous Israeli Bedouin family with autosomal recessive Bardet-Biedl syndrome (BBS; obesity, pigmentary retinopathy, polydactyly, hypogonadism, renal and cardiac abnormalities, and cognitive impairment) in which previous linkage studies using short tandem repeat polymorphisms failed to identify a disease locus. SNP genotyping revealed a homozygous candidate region. Mutation analysis in the region of homozygosity identified a conserved homozygous missense mutation in the TRIM32 gene, a gene coding for an E3 ubiquitin ligase. Functional analysis of this gene in zebrafish and expression correlation analyses among other BBS genes in an expression quantitative trait loci data set demonstrate that TRIM32 is a BBS gene. This study shows the value of high-density SNP genotyping for homozygosity mapping and the use of expression correlation data for evaluation of candidate genes and identifies the proteasome degradation pathway as a pathway involved in BBS.

Animals↗
PubMed1997

Regulation of number and size of digits by posterior Hox genes: a dose-dependent mechanism with potential evolutionary implications.

The proper development of digits, in tetrapods, requires the activity of several genes of the HoxA and HoxD homeobox gene complexes. By using a variety of loss-of-function alleles involving the five Hox genes that have been described to affect digit patterning, we report here that the group 11, 12, and 13 genes control both the size and number of murine digits in a dose-dependent fashion, rather than through a Hox code involving differential qualitative functions. A similar dose-response is observed in the morphogenesis of the penian bone, the baculum, which further suggests that digits and external genitalia share this genetic control mechanism. A progressive reduction in the dose of Hox gene products led first to ectrodactyly, then to olygodactyly and adactyly. Interestingly, this transition between the pentadactyl to the adactyl formula went through a step of polydactyly. We propose that in the distal appendage of polydactylous short-digited ancestral tetrapods, such as Acanthostega, the HoxA complex was predominantly active. Subsequent recruitment of the HoxD complex contributed to both reductions in digit number and increase in digit length. Thus, transition through a polydactylous limb before reaching and stabilizing the pentadactyl pattern may have relied, at least in part, on asynchronous and independent changes in the regulation of HoxA and HoxD gene complexes.

Alleles↗
PubMed2004

A soluble form of fibroblast growth factor receptor 2 (FGFR2) with S252W mutation acts as an efficient inhibitor for the enhanced osteoblastic differentiation caused by FGFR2 activation in Apert syndrome.

Apert syndrome is an autosomal dominant disease characterized by craniosynostosis and bony syndactyly associated with point mutations (S252W and P253R) in the fibroblast growth factor receptor (FGFR) 2 that cause FGFR2 activation. Here we investigated the role of the S252W mutation of FGFR2 on osteoblastic differentiation. Osteoblastic cells derived from digital bone in two Apert patients with the S252W mutation showed more prominent alkaline phosphatase activity, osteocalcin and osteopontin mRNA expression, and mineralized nodule formation compared with the control osteoblastic cells derived from two independent non-syndromic polydactyly patients. Stable clones of the human MG63 osteosarcoma cells (MG63-Ap and MG63-IIIc) overexpressing a splice variant form of FGFR2 with or without the S252W mutation (FGFR2IIIcS252W and FGFR2IIIc) showed a higher RUNX2 mRNA expression than parental MG63 cells. Furthermore MG63-Ap exhibited a higher osteopontin mRNA expression than did MG63-IIIc. The enhanced osteoblastic marker gene expression and mineralized nodule formation of the MG63-Ap was inhibited by the conditioned medium from the COS-1 cells overexpressing the soluble FGFR2IIIcS252W. Furthermore the FGF2-induced osteogenic response in the mouse calvarial organ culture system was blocked by the soluble FGFR2IIIcS252W. These results show that the S252W mutation in the FGFR2 gene enhances the osteoblast phenotype in human osteoblasts and that a soluble FGFR2 with the S252W mutation controls osteoblast differentiation induced by the S252W mutation through a dominant negative effect on FGFR2 signaling in Apert syndrome.

Acrocephalosyndactylia↗
PubMed2005

Hoxd13 and Hoxa13 directly control the expression of the EphA7 Ephrin tyrosine kinase receptor in developing limbs.

Hoxa and Hoxd genes, related to the Drosophila Abd-B gene, display regionally restricted expression patterns and are necessary for the formation of the limb skeletal elements. Hox genes encode transcription factors, which are supposed to control the expression of a series of downstream target genes, whose nature has remained largely elusive. Several genes were identified that are differentially expressed in relation to Hox gene activity; few studies, however, explored their direct regulation by Hox proteins. Ephrin tyrosine kinase receptors and ephrins have been proposed as Hox targets, and recently, evidence was gained for their role in limb development. The expression of the EphA7 gene in developing limbs was shown to correlate with the expression of Hoxa13 and Hoxd13; however, its direct regulation by these genes has never been assessed. We have characterized the EphA7 promoter region and show that it contains multiple binding sites for paralog group 13 Hox proteins. We found that one of these sites is bound in vivo by HOXA13 and HOXD13 and by endogenous Hoxd13 in developing mouse limbs. Moreover, we show that HOXD13 and HOXA13 activate transcription from the EphA7 promoter and that a mutation of the HOXA13/HOXD13 binding site was sufficient to abolish activation. Conversely, the HOXD13(147L) mutation, identified in patients displaying a novel brachydactyly-polydactyly syndrome, does not bind to in vivo, and fails to transactivate the EphA7 promoter. These results establish that EphA7 is a direct downstream target of Hoxd13 and Hoxa13 during limb development, thus providing further insight into the regulatory networks that control limb patterning.

Amino Acid Sequence↗
PubMed2000

Unusual congenital deformities of the lower limb in two calves.

Congenital deformities of the lower limb were observed in 2 calves from different properties. One was a newborn Holstein-Friesian bull calf with polydactyly and polypodia of the right fore-limb. The other was an 8-month-old Friesian/Jersey crossbred heifer calf, which had a mirror image duplication of the plantar/palmar half of the distal portion of the digits. The abnormalities in the second calf have not previously been described in cattle. This paper presents details of the clinical, radiological and necropsy findings in these 2 calves.

Journal Article↗
PubMed2004

Triallelic inheritance: a bridge between Mendelian and multifactorial traits.

The increasing identification of disease genes is revealing a growing number of traits that fail to conform to traditional Mendelian paradigms, thereby creating new challenges to both genetic investigators and clinicians. Bardet-Biedl syndrome (BBS) is one such disorder that has helped to define 'oligogenic' inheritance, a term that implies that some diseases are not inherited as simple single-gene Mendelian disorders and yet are not classic complex traits, but rather fit a model in which mutations in a small number of genes may interact genetically to manifest the phenotype. BBS is a pleiotropic disorder characterized by postnatal obesity, post-axial polydactyly, and progressive retinal dystrophy. Eight BBS loci have been identified to date and six of these genes have been cloned. Mutation analysis of these BBS genes in a cohort of patients has led to the description of the novel phenomenon of 'triallelic inheritance', wherein families were identified in which three mutations from genes at two different BBS loci segregate with expression of the disease. Modeling the cooperative ability of alleles of different genes at distinct loci to give rise to a particular phenotype will facilitate the understanding of complex multifactorial and polygenic traits.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Cloning and characterization of a splice variant of human Bardet-Biedl syndrome 4 gene (BBS4).

Bardet-Biedl syndrome (BBS) is a heterogeneous multisystemic disorder characterized primarily by five cardinal features of retinal degeneration, obesity, polydactyly, hypogenitalism and mental retardation. To date, six distinct BBS loci that have been identified on different chromosomes. BBS4 gene is mapped to 15q22.2-23, which when mutated can cause BBS4. Its protein shows strong homology to O-linked N-acetylglucosamine (O-GlcNAc) transferase. Here we report a splice variant of BBS4, which is 2556 bp in length and has an open reading frame coding a predicted 527 amino-acids protein. RT-PCR shows that the cDNA is widely expressed while it has higher expression levels in pancreas, liver and prostate.

Alternative Splicing↗
PubMed1984

Ethylenethiourea-induced hindpaw deformities in mice and effects of metabolic modifiers on their occurrence.

Time-mated Swiss-Webster mice were pretreated in separate experiments with phenobarbital (60 mg/kg X d sc on d 7-10 of pregnancy), SKF-525A (40 mg/kg ip on d 12 of pregnancy) or 3-methylcholanthrene (20 mg/kg X d on d 10-12 of pregnancy). On the d 12 of pregnancy (1 h after SKF-525A or 3-methylcholanthrene treatment), one group each of pretreated mice was given a single oral dose of 1600, 2000, or 2400 mg/kg of ethylenethiourea (ETU) as a 5% concentrate in a 1.5% aqueous gelatin solution, which as a vehicle was given to other pretreated groups. The respective volume doses were 3.2, 4.0, or 4.8 ml/100 g body weight with the controls given 4.8 ml/100 g body weight of vehicle alone. Maternal toxicity was observed in all groups given ETU, whether pretreated with metabolic modifiers or not. In the three experiments, treatment with ETU alone reduced fetal weight by 15% at 2400 mg/kg and 8% with the remaining 2 doses, and increased the incidence of resorptions (19-62% with the 2400 mg/kg dose, 8-59% at 2000 mg/kg, and 7-32% at the 1600 mg/kg dose). The significant defects with incidence ranges in three experiments were: hindpaw ectrodactyly, 2-6% at 1600 mg/kg, 4-20% at 2000, and 20-29% at 2400 mg/kg; and hindpaw syndactyle, 3% at 16 mg/kg, 6-14% at 2000, and 2-12% at 2400 mg/kg doses. Minor incidences of cleft palate and hindpaw polydactyly were also observed. Phenobarbital pretreatment did not change the ETU-induced maternal or fetal effects. SKF-525A enhanced the resorptions and reduced the litter-size but had no effect on fetal malformations. The 3-methylcholanthrene pretreatment reduced the ETU-induced incidences of hindpaw ectrodactyly, hindpaw syndactyly, and cleft palate at the 2000 and 2400 mg/kg doses. Previous studies with rats and hamsters revealed that SKF-525A enhanced the ETU-induced fetal malformations but phenobarbital and 3-methyl-cholanthrene had no effect in these two species.

Abnormalities, Drug-Induced↗
PubMed1999

Assignment of the locus for hydrolethalus syndrome to a highly restricted region on 11q23-25.

Hydrolethalus syndrome is a recessively inherited lethal malformation syndrome characterized by hydrocephaly with absent midline structures of the brain, micrognathia, polydactyly, and several other abnormalities, mostly in the midline structures. Hydrolethalus syndrome was described in 1981 in Finland, where the incidence is 1:20,000. Only a few cases have been reported elsewhere, and the pathogenesis has remained unknown. Here we report the assignment of the hydrolethalus syndrome locus to chromosome 11q23-25 in Finnish families. The initial genome scan was performed using DNA samples from only 15 affected individuals. In the next step, the hydrolethalus syndrome locus was assigned to an 8.5-cM interval between markers D11S4144 and D11S1351 by linkage analysis in eight families. Finally, the critical locus could be restricted by linkage disequilibrium and haplotype analyses to a 0.5-1-cM region between markers D11S933 and D11S934. Genealogical studies performed in 40 families affected by hydrolethalus revealed no regional clustering, suggesting a relatively early introduction of the disease mutation into the Finnish population and the spreading of the mutation with the inhabitation of the late-settlement area.

Abnormalities, Multiple↗