Van Creveld Syndrome Research Articles

Analysis of Ellis van Creveld syndrome gene products: implications for cardiovascular development and disease

Mutations identified in a cohort of patients with atrioventricular septal defects as a part of Ellis van Creveld syndrome (EvC syndrome) led us to study the role of two non-homologous genes, EVC and LBN, in heart development and disease pathogenesis. To address the cause of locus heterogeneity resulting in an indistinguishable heart-hand phenotype, we carried out in situ hybridization and immunofluorescence and identified co-localization of Evc and Lbn mRNA and protein. In the heart, expression was identified to be strongest in the secondary heart field, including both the outflow tract and the dorsal mesenchymal protrusion, but was also found in mesenchymal structures of the atrial septum and the atrioventricular cushions. Finally, we studied the transcriptional hierarchy of EVC and LBN but did not find any evidence of direct transcriptional interregulation between the two. Due to the locus heterogeneity of human mutations predicted to result in a loss of protein function, a bidirectional genomic organization and overlapping expression patterns, we speculate that these proteins function coordinately in cardiac development and that loss of this coordinate function results in the characteristics of EvC syndrome.

Chondroectodermal Dysplasia (Ellis-Van Creveld Syndrome): A case report

Ellis –van Creveld syndrome is a rare autosomal recessive syndrome characterised by several skeletal anomalies, dental anomalies, nail dysplasia, oral mucosal anomalies and congenital cardiac defects. The authors here are reporting a case of Ellis-van Creveld syndrome in a thirteen month old female child presented with history of recurrent lower respiratory tract infections and was diagnosed incidentally as a case of Ellis –van Creveld syndrome

Bronchospasm in a case of Ellis van Creveld syndrome in a patient posted for corrective osteotomy & elizarove surgery

Ellis-van Creveld syndrome (chondroectodermal or mesoectodermal dysplasia) is an autosomal recessive disorder. Initial reported as tetrad of clinical manifestations, including chondrodysplasia, postaxial polydactyly, ectodermal dysplasia, and congenital heart disease (CHD). Other involvement may occur in organs of endodermal origin, such as the pulmonary, renal, gastrointestinal, and central nervous systems. A known case of Ellis van Creveld syndrome was scheduled for elective corrective osteotomy and elizarove surgery. Here with we describe the clinical features of a patient and anaesthetic management of our patient

Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVCgene

BackgroundEllis-van Creveld (EvC) syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth and is inherited in an autosomal recessive pattern. We report a family with complex septal cardiac defects, rhizomelic limb shortening, and polydactyly, without the typical lip, dental, and nail abnormalities of EvC. The phenotype was inherited in an autosomal recessive pattern, with one instance of pseudodominant inheritance.MethodsBecause of the phenotypic overlap with EvC, microsatellite markers were used to test for linkage to the EVC/EVC2 locus. The results did not exclude linkage, so samples were sequenced for mutations.ResultsWe identified a c.1868T>C mutation in EVC, which predicts p.L623P, and was homozygous in affected individuals.ConclusionWe conclude that this EVC mutation is hypomorphic and that such mutations can cause a phenotype of cardiac and limb defects that is less severe than typical EvC. EVC mutation analysis should be considered in patients with cardiac and limb malformations, even if they do not manifest typical EvC syndrome.

Long interspersed nuclear element-1 (LINE1)-mediated deletion ofEVC,EVC2,C4orf6, andSTK32B in Ellis–van Creveld syndrome with borderline intelligence

Previous work has shown Ellis-van Creveld (EvC) patients with mutations either in both alleles of EVC or in both alleles of EVC2. We now report affected individuals with the two genes inactivated on each allele. In a consanguineous pedigree diagnosed with EvC and borderline intelligence, we detected a 520-kb homozygous deletion comprising EVC, EVC2, C4orf6, and STK32B, caused by recombination between long interspersed nuclear element-1 (LINE-1 or L1) elements. Patients homozygous for the deletion are deficient in EVC and EVC2 and have no increase in the severity of the EvC typical features. Similarly deletion carriers demonstrate absence of digenic inheritance in EvC. Further, the phenotype of these patients suggests that the EVC-STK32B deletion also leads to mild mental retardation and reveals that loss of the novel genes C4orf6 and STK32B causes at most mild mental deficit. In an EvC compound heterozygote of different ethnic origin we identified the same LINE-to-LINE rearrangement due to a different recombination event. These findings highlight the importance of L1 repetitive sequences in human genome architecture and disease.

Growth hormone analysis and treatment in Ellis–van Creveld syndrome

Little is known on growth, growth hormone (GH) levels and GH treatment in patients with Ellis-van Creveld syndrome (EvC). The aim of the present study was to assess growth, growth hormone status and the possible effectiveness of GH treatment in literature and in a small series of EvC patients. A review of literature indicated retarded growth for most EvC patients (-2 to -4.5 SDS) and minimal data on GH levels or treatment which did not allow any conclusion. We studied eight EvC patients, seven of whom were treated with GH. Four were GH deficient (GHD) and four were GH sufficient. In all patients treated with GH, first year growth velocity increased. In three of the four GHD and in one GH-sufficient patient a gain in height SDS was noted. In the present small EvC series GHD occurred more often than expected. Patient acquisition through the Growth Hormone Database will have caused a significant bias, but the present results indicate that GH treatment may improve growth in at least some patients with EvC. Therefore we conclude that EvC patients may benefit from being tested for GHD and, if indicated, treated. In addition a prospective study to evaluate GH status and linear growth in patients with EvC as well as the potential effectiveness of GH treatment is warranted.

Chondroectodermal dysplasia (Ellis van Creveld syndrome): A report of three cases with review of literature

Chondroectodermal dysplasia is a rare mesenchymal - ectodermal dysplasia first described in 1940 by Richard W.B. Ellis and Simon van Creveld now known as Ellis van Creveld syndrome. It is also known as Mesvectodermal dysplasia. Majority of cases were characteristically seen in one particular inbred population from the Amish community of Lancaster County, Pennsylvania, U.S.A. The syndrome manifests with several skeletal anomalies, oral mucosal and dental anomalies, congenital cardiac defects and nail dysplasia. Ellis van Creveld syndrome may be differentiated from other chondrodystrophies like achondroplasia, chondroplasia punctata, asphyxiating thorasic dystrophy and Morquio's syndrome. The presence of oral mucosal and dental alterations like notching of the lower alveolar process, fusion of the upper lip with gingival mucosal margin, occasional presence of neonatal teeth, oligodontia and conical shape of anterior teeth will confirm the diagnosis of Ellis van Creveld syndrome and hence its importance to dentists.

Sequencing EVC and EVC2 identifies mutations in two-thirds of Ellis–van Creveld syndrome patients

Ellis-van Creveld syndrome (EvC) is caused by mutations in EVC and EVC2, genes in a divergent orientation separated by only 2.6 kb. We systematically sought mutations in both genes in a panel of 65 affected individuals to assess the proportion of cases resulting from mutations in each gene. We PCR amplified and sequenced the coding exons of both genes. We investigated mutations that could affect splicing by in vitro splicing assays and cDNA analysis. We have identified EVC mutations in 20 cases (31%); in all of these we have detected the mutation on each allele. We have identified EVC2 mutations in 25 cases (38%); in 22 of these we have isolated a mutation on each allele. The majority of the mutations introduce a premature termination codon. We sequenced the region between the two genes in 10 of the 20 cases in which we had not identified a mutation in either gene, revealing only one SNP that was not a common polymorphism. As we have not identified mutations in either gene in 20 cases (31%) it is possible that there is further genetic heterogeneity.

Ellis—van Creveld Syndrome

Ellis—van Creveld syndrome is a rare, singlegene genetic congenital skeletal disorder. It is an autosomal recessive inherited disorder, which means that both parents must carry the gene for the child to be affected. It involves abnormalities of multiple body systems, including teeth, nails, hair, lungs, and liver, and approximately 50% of affected patients will have major heart defects. There is short-limbed dwarfism, with the extremities being disproportionate with the trunk, this being more apparent in the lower limbs. Postaxial polydactyly, or extra digits in the hands, is seen in virtually 100% of those individuals affected with Ellis—van Creveld. Despite the advances in sonography, the prenatal diagnosis of a specific skeletal dysplasia remains very difficult and often can only be made after birth or termination of the pregnancy.

Increased first‐trimester fetal nuchal translucency thickness in association with chondroectodermal dysplasia (Ellis–Van Creveld syndrome)

Increased nuchal translucency thickness (NT) is an established sonographic marker of fetal chromosomal abnormality. Several structural fetal defects and genetic syndromes including a range of skeletal dysplasias have been reported in association with increased NT. We report the first case of fetal Ellis-Van Creveld syndrome presenting as raised fetal NT at 13 weeks' gestation. Ultrasonography at 18 weeks' gestation demonstrated a narrow thorax, marked shortening of the long bones with bowed femora and hexadactyly of hands and feet. Pregnancy was terminated at 23 weeks' gestation. The postmortem radiological examination revealed short and bowed long bones with rounded metaphyses, postaxial polydactyly of hands and feet, short ribs and narrow thorax. The acetabular roofs were horizontal with medial and lateral spurs. This case adds a further type of severe skeletal dysplasia to the list of genetic syndromes which may present as increased fetal NT in the late first trimester.

Ultrasound evaluation of the hips and histological correlations in Ellis van Creveld Syndrome.

Ellis van Creveld Syndrome (EVCs) is a chondroectodermal dysplasia. Its clinical picture includes a meso-acromielic limb dwarfism with normal spine, involvement of the teeth, hair and nails, polydactyly of the hands and feet and heart malformations. Ultrasonography compared with histology were used in the present study to evaluate neo-natal ultrasonographic hip development and acetabular hysto-morphology in EVCs. A flat and abnormal acetabulum with small beta angles and non measurable alfa angles were detected at repeated ultrasonographic evaluations at birth and at four months, with irregular echoes spiking from the inner part of the sockets; the acetabular cavities contained large early ossified proximal femoral epiphyses. Histology was obtained from phal-angeal growth plates of a surgically removed extradigit, stained with alcian blue/PAS and E.E.. The growth plates showed a distorted anatomy with irregular column formation and abnormal distribution of the hypetrophic cells. Ultrasound morphology corresponded to the altered growth plates seen at histology. Early detection of an abnormally early developed proximal femoral ossification centre could be considered a diagnostic feature of the syndrome especially when present in the prenatal period. (Hip International 2004; 14: 39-43).

Ultrasound evaluation of the hips and histological correlations in Ellis van Creveld Syndrome

Ellis van Creveld Syndrome (EVCs) is a chondroectodermal dysplasia. Its clinical picture includes a meso-acromielic limb dwarfism with normal spine, involvement of the teeth, hair and nails, polydactyly of the hands and feet and heart malformations. Ultrasonography compared with histology were used in the present study to evaluate neo-natal ultrasonographic hip development and acetabular hysto-morphology in EVCs. A flat and abnormal acetabulum with small beta angles and non measurable alfa angles were detected at repeated ultrasonographic evaluations at birth and at four months, with irregular echoes spiking from the inner part of the sockets; the acetabular cavities contained large early ossified proximal femoral epiphyses. Histology was obtained from phal-angeal growth plates of a surgically removed extradigit, stained with alcian blue/PAS and E.E.. The growth plates showed a distorted anatomy with irregular column formation and abnormal distribution of the hypetrophic cells. Ultrasound morphology corresponded to the altered growth plates seen at histology. Early detection of an abnormally early developed proximal femoral ossification centre could be considered a diagnostic feature of the syndrome especially when present in the prenatal period. (Hip International 2004; 14: 39-43).

A new gene, EVC2, is mutated in Ellis–van Creveld syndrome

Ellis–van Creveld syndrome (EvC; MIM 225500) is an autosomal recessive chondrodysplastic dwarfism. Thus far, the identified mutations in the EVC gene located on chromosome 4p16 have only accounted for illness in a small proportion of affected individuals. In this report we describe a novel gene, EVC2, that is mutated in an Ashkenazi individual with EvC syndrome. Our findings demonstrate for the first time that the heterogeneity observed in this disorder is not solely the result of mutations in a single gene.

Molecular determinants of atrial and ventricular septal defects and patent ductus arteriosus

Septation defects and patent ductus arteriosus are the most common human cardiovascular malformations (CVMs). Genetic factors play a major part in the origin of these malformations. Recent molecular analyses have shed light on several mendelian forms. In the autosomal dominant Holt-Oram syndrome, both atrial and ventricular septal defects are inherited in association with limb deformity as a result of mutations in the gene encoding the TBX5 transcription factor. Mutations in the NKX2.5 transcription factor gene cause autosomal dominant familial atrial septal defects in association with progressive atrioventricular block as well as complex congenital heart disease. Common atrial syndromes in autosomal dominant Ellis-van Creveld syndrome arise in the context of axial skeletal and limb malformation as a result of mutations in the EVC gene, whose function is unknown. Patent ductus arteriosus occurs in several syndromic forms of congenital heart disease, including Holt-Oram syndrome. Recent analyses of autosomal dominant Char syndrome, which includes, with variable penetrance, patent ductus arteriosus as well as craniofacial and hand malformations, have shown that the syndrome is caused by mutations in the TFAP2B transcription factor gene. Ongoing analyses are poised to determine the contribution of these genes as well as others yet to be identified to common, sporadic forms of congenital heart disease.

Ellis–van Creveld syndrome: examination at 15 weeks' gestation

Ellis–van Creveld syndrome: examination at 15 weeks' gestation

Oral-Facial-Digital syndrome with acromelic short stature

The Oral-Facial-Digital syndromes (OFDS) are a heterogeneous group of disorders having common oral, facial, and digital malformations. Here, we report a consanguineous family with a new variety of OFDS associated with acromelic short stature and genu valgum; the features overlapping with Ellis Van Creveld syndrome. One of the sibs has urinary incontinence and growth hormone deficiency, which has not been reported earlier in any type of OFDS in the literature.

Genomic structure and localization of the human protein phosphatase 2A BRgamma regulatory subunit.

In the course of our analysis of genomic sequence from the human chromosome 4p16.1 region harboring both the Wolfram and Ellis van Creveld syndrome genes we have identified a sequence with high homology (98% at the amino acid level) to the rat cDNA coding for the protein phosphatase 2A BRgamma (PP2ABRgamma) regulatory subunit. Although the human cDNAs for both the BRalpha and BRbeta isoforms have been described previously, the BRgamma subunit has not yet been identified in humans. Here we describe the precise genomic organization and genetic localization of the human PP2ABRgamma gene.

Syndrome of Hexodactily and Single Atrium

I read with interest the letter to the editor by Digilio et al. [1]. Since the syndrome of hexodactily and single atrium that I have described [2] was partly misinterpreted, I take the liberty to explain the situation. In the case that I reported, no chonrodysplastic changes were noted in the pelvis and tubular bones, nor were there any findings related to ectodermal dysplasia (nails, hair, teeth, gums, and labial mucosa), which are the salient features of the Ellis–van Creveld syndrome [3]. The authors want to relate the syndrome that I have described to the Ellis–van Creveld syndrome and they point out as proof the specific occurrence of AV canal defect and/or single atrium in all the reported cases of Ellis–van Creveld syndrome. However, although single atrium and endocardial cushion defects are the most common anomalies, and persisting left superior vena cava, anomalous pulmonary venous drainage, and PDA may accompany these defects in the Ellis–van Creveld syndrome, the incidence is about 65% [3]. I believe that, if no chondroectodermal dysplastic features are present, the combination of postaxial hexodactily with single atrium should not be considered a variable phenotype of the Ellis–van Creveld syndrome.

First-trimester prenatal diagnosis of Ellis–van Creveld syndrome using linked microsatellite markers

We report a personal experience of first-trimester prenatal diagnosis of Ellis-van Creveld (EvC) syndrome based on typing of microsatellite markers flanking the EvC locus. An heterozygous fetus was diagnosed with a diagnostic accuracy of 96 per cent. The DNA prediction was confirmed by ultrasound at 22 weeks of gestation and by clinical evaluation at birth.

Autosomal Dominant Postaxial Polydactyly, Nail Dystrophy, and Dental Abnormalities Map to Chromosome 4p16, in the Region Containing the Ellis–van Creveld Syndrome Locus

We have studied a four-generation family with features of Weyers acrofacial dysostosis, in which the proband has a more severe phenotype, resembling Ellis-van Creveld syndrome. Weyers acrofacial dysostosis is an autosomal dominant condition with dental anomalies, nail dystrophy, postaxial polydactyly, and mild short stature. Ellis-van Creveld syndrome is a similar condition, with autosomal recessive inheritance and the additional features of disproportionate dwarfism, thoracic dysplasia, and congenital heart disease. Linkage and haplotype analysis determined that the disease locus in this pedigree resides on chromosome 4p16, distal to the genetic marker D4S3007 and within a 17-cM region flanking the genetic locus D4S2366. This region includes the Ellis-van Creveld syndrome locus, which previously was reported to map within a 3-cM region between genetic markers D4S2957 and D4S827. Either the genes for the condition in our family and for Ellis-van Creveld syndrome are near one another or these two conditions are allelic with mutations in the same gene. These data also raise the possibility that Weyers acrofacial dysostosis is the heterozygous expression of a mutation that, in homozygous form, causes the autosomal recessive disorder Ellis-van Creveld syndrome.