Dandy-Walker malformation in Ellis-van Creveld syndrome

We report on 2 Old Order Amish patients with Ellis-van Creveld (EvC) syndrome and the Dandy-Walker malformation; a similar case is noted in the literature. Pedigree analysis of our patients documents extensive inbreeding in successive generations. Considering the rarity of EvC syndrome and Dandy-Walker malformation as isolated malformations, the appearance of both in our 2 patients plus the patient in the literature suggests that Dandy-Walker malformation may be a manifestation in the EvC syndrome. However, in this isolate the coincidental occurrence of 2 rare recessive traits cannot be excluded.     

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.     

Molecular and clinical analysis of Ellis-van Creveld syndrome in the United Arab Emirates

Background  

Ellis-van Creveld (EvC) syndrome is an autosomal recessive chondrodysplastic condition with clinical manifestations that include short-limbs and ribs, postaxial polydactyly and dysplastic nails and teeth. In about two thirds of patients, mutations in either EVC or EVC2 genes have been found to be the underlying cause.     

Two cases of Ellis-van Creveld syndrome in a small island population.

Two individuals showing features typical of the autosomal recessive Ellis-van Creveld syndrome have been diagnosed in a population of 1340 individuals living on a small island off the west coast of Scotland. Clinical features and family relationships of the affected individuals are described.     

Ellis-van Creveld syndrome: report of 15 cases in an inbred kindred.

An inbred kindred with 15 cases of the autosomal recessive Ellis-van Creveld syndrome is reported. The ages of the 12 living affected varied between 3 and 82 years. The main characteristics include polydactyly of the hands and feet and several other skeletal anomalies, oral manifestations, and malformations of the heart in 50% of the living affected.     

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.     

Duplication 17q mosaicism: an infant with features of Ellis-van Creveld syndrome.

We describe an infant with multiple dysmorphic features who is mosaic for duplication 17q21.1----qter, owing to a direct tandem duplication. He is the first case with mosaicism for a 17q duplication to be reported. His features are strikingly suggestive of Ellis-van Creveld syndrome.     

Novel and recurrent EVC and EVC2 mutations in Ellis-van Creveld syndrome and Weyers acrofacial dyostosis

Ellis van Creveld syndrome and Weyers acrofacial dysostosis are allelic disorders caused by mutations in EVC or EVC2 genes. We illustrate the results of direct analysis of whole EVC and EVC2 genes' coding regions in 32 unrelated families with clinical diagnosis of Ellis van Creveld syndrome and in 2 families with Weyers acrofacial dysostosis. We identified mutations in 27/32 (84%) cases with Ellis van Creveld syndrome and 2/2 cases with Weyers acrofacial dysostosis. Of the Ellis van Creveld syndrome cases, 20/27 (74%) had a mutation in EVC and 7/27 (26%) in EVC2 genes. The two subjects with Weyers acrofacial dysostosis had a heterozygous mutation in the last exon of EVC2. In total, we detected 25 independent EVC and 11 independent EVC2 mutations. Nineteen EVC mutations (19/25, 76%) and 4 EVC2 mutations (4/11, 36%) were novel. Also one EVC2 gene mutation found in Weyers acrofacial dysostosis was novel. In 5 unrelated cases with a clinical diagnosis of Ellis van Creveld syndrome, we did not find any mutation in either EVC or EVC2 genes. Current findings expand the Ellis van Creveld syndrome and Weyers acrofacial dysostosis mutation spectra, and provide further evidence that the last exon of EVC2 gene is a hot spot for Weyers acrofacial dysostosis mutations. Accordingly, EVC2 exon 22 should be analyzed with priority by mutation screening in individuals with a suspected diagnosis of Weyers acrofacial dysostosis.     

Correction of knee deformity in patients with Ellis-van Creveld syndrome: A case report and review of the literature

Ellis-van Creveld Syndrome (EVC) is a rare autosomal recessive disorder. In 1940 Richard W. Ellis and Simon van Creveld first reported on a rare skeletal dysplasia, which to emphasize the main clinical characteristics, was termed "chondro-ectodermal dysplasia". The ectodermal involvement includes the skin, hair and nails while the chondrodysplastic characteristics involve the cartilage and bones, primarily in the forearms and lower legs. For the orthopaedic surgeon progressive valgus knee deformity accompanied by patella dislocation is the main problem in EVC. This study reports a ten year follow-up after a primarily failed operative therapy of knee deformity due to incomplete correction and the surgical technique utilized to correct the residual external torsional deformity and dislocation of the patella in a 19 year old girl who presented with the typical clinical features of Ellis-van Creveld Syndrome.     

Chondroectodermal dysplasia (Ellis-van Creveld) with anomalies of CNS and urinary tract

We report on a 19-month-old girl with chondroectodermal dysplasia (Ellis-van Creveld) and other previously undescribed visceral and central nervous system anomalies. These anomalies include cerebral heterotopias, renal agenesis, and congenital megaureter.     

Two novel heterozygous mutations of EVC2 cause a mild phenotype of Ellis-van Creveld syndrome in a Chinese family

Ellis–van Creveld syndrome (EvC, chondroectodermal dysplasia; OMIM 225500) is an autosomal recessive skeletal dysplasia with associated multisystem involvement. The syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails, and abnormal teeth. Congenital heart defects occur in 50–60% of cases. In this study, we report EvC in a 6‐year‐old Chinese girl with hypodontia and polydactyly, mild short stature, and abnormalities of the knee joints. No signs of short ribs, narrow thorax, or congenital heart defects were found in this patient. The EvC phenotype shares some similarity with Weyers acrofacial dysostosis (Weyer; OMIM 193530), an autosomal dominant disorder clinically characterized by mild short stature, postaxial polydactyly, nail dystrophy, and dysplastic teeth. Mutations in EVC or EVC2 are associated with both EvC syndrome and Weyers acrodental dysostosis, but the two conditions differ in the severity of the phenotype and their pattern of inheritance. In this study, two novel heterozygous EVC2 mutations, IVS5‐2A > G and c.2653C > T (Arg885X), were identified in the patient. The IVS5‐2A > G mutation was inherited from the patient's mother and the c.2653C > T from her father. Her parents have no phenotypic symptoms similar to those of the patient. These findings extend the mutation spectrum of this malformation syndrome and provide the possibility of prenatal diagnosis for future offspring in this family. © 2011 Wiley‐Liss, Inc.     

Short limbed dwarfism,genital hypoplasia,sparse hair,and vertebral anomalies: a variant of Ellis-van Creveld syndrome?

A male newborn with acromesomelic short limbed dwarfism, genital hypoplasia, and vertebral anomalies is reported. As the child had an important number of clinical and radiological symptoms seen in patients with Ellis-van Creveld syndrome, we raise the question of whether he may represent a variant example of this syndrome despite the absence of cardinal symptoms such as postaxial polydactyly and ectodermal changes (nail hypoplasia).     

Expression of the Ellis-van Creveld (Evc) gene in the rat tibial growth plate

Ellis-van Creveld (EvC) syndrome is an autosomal recessive chondrodysplasia characterized by short limbs, postaxial polydactyly, natal teeth, and dysplastic nails. The Ellis-van Creveld (EVC) gene, which is mutated in patients with EvC syndrome, has been identified by positional cloning. However, the physiological roles of the EVC gene have not been elucidated. Histopathological analyses of EvC syndrome have shown disturbed chondrocytic phenotypes during cartilage development. We therefore postulated that the EVC gene is a critical factor for chondrocytes during endochondral ossification. The present study focuses on the relationship between the Evc gene and chondrocytes, and examines Evc gene expression in the rat tibial growth plate at the mRNA and protein levels. Evc mRNA in tibial epiphyseal cartilage was expressed at postnatal day (P) 1, P28, and P56 by RT-PCR. Immunohistochemical analyses localized the Evc protein mainly in prehypertrophic and hypertrophic chondrocytes of the epiphyseal growth plate in the tibia during the embryonic and postnatal periods. Evc mRNA was also detected in prehypertrophic and hypertrophic chondrocytes by in situ hybridization. These results indicate that the Evc gene functions mainly in the prehypertrophic and hypertrophic chondrocytes of the epiphyseal growth plate. The data presented here are important for future studies of the underlying mechanism of chondrodysplasia in EvC syndrome.     

Exclusion of the Ellis-van Creveld region on chromosome 4p16 in some families with asphyxiating thoracic dystrophy and short-rib polydactyly syndromes

Ellis-van Creveld syndrome (EVC) is a relatively rare, usually non-lethal, autosomal recessive skeletal dysplasia characterized by short stature, polydactyly, cardiac and renal anomalies. Linkage analysis has localized the disease gene to chromosome 4p16, with the markers at loci D4S827 and D4S3135 defining the centromeric and telomeric limits of the linked interval, respectively. There has been long-term speculation that asphyxiating thoracic dystrophy (ATD) and the short-rib polydactyly syndromes (SRP) represent the severe end of the EVC disease spectrum. We performed linkage analysis using markers from the EVC region in seven families manifesting either ATD or SRP type III. In two of the families, one segregating ATD and one SRP kindred, linkage of the phenotype to the EVC region was excluded. In the other five families linkage of the phenotype to the EVC region could not be excluded, but the families were too small for linkage to the region to be established. The exclusion of the EVC region in ATD and SRP III families suggests that locus heterogeneity exists within the short-rib dysplasia (with and without polydactyly) group of disorders.     

Spurious dyserythropoiesis.

We documented the occurrence and severity of dyserythropoiesis as an artifact of storage in bone marrow aspirates collected in EDTA. Bone marrow samples were obtained from 7 patients without myelodysplasia. Specimens were stored at room (20 degrees C-24 degrees C) or refrigerated (1 degrees C-6 degrees C) temperature and examined for dyserythropoiesis at 0, 1, 2, and 3 days. Initial specimens showed few dyserythropoietic abnormalities; nuclear aberrations occurred in 1.07%+/-0.06% (mean +/- SEM) of the erythroid population. At room temperature, dyserythropoietic changes increased significantly with each day of storage. Nuclear and cytoplasmic alterations occurred; the former are diagnostically more important in the diagnosis of myelodysplastic syndromes. Cytoplasmic changes were more extensive than nuclear abnormalities. The mean +/- SEM percentage of erythroblasts with cytoplasmic vacuoles increased with each day of storage: day 0, 1.1%+/-0.2%; day 1, 22.1%+/-1.8%; day 2, 29.4%+/-2.0%; day 3, 35.6%+/-1.9%. Nuclear shape changes increased to 6.21%+/-1.12%, 11.36%+/-1.12%, and 12.85%+/-1.20% on days 1, 2, and 3, respectively. After 1 day of storage, sufficient dysplastic changes occur to cause difficulty in the diagnosis of a myelodysplastic syndrome. Changes are inhibited significantly by refrigerated storage.     

Long interspersed nuclear element-1 (LINE1)-mediated deletion of EVC, EVC2, C4orf6, and STK32B 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.