Van Creveld Research Articles

Variants in EFCAB7 underlie nonsyndromic postaxial polydactyly.

Polydactyly is the most common limb malformation that occurs in 1.6-10.6 per one thousand live births, with incidence varying with ancestry. The underlying gene has been identified for many of the ~100 syndromes that include polydactyly. While for the more common form, nonsydromic polydactyly, eleven candidate genes have been reported. We investigated the underlying genetic cause of autosomal recessive nonsyndromic postaxial polydactyly in four consanguineous Pakistani families. Some family members with postaxial polydactyly also present with syndactyly, camptodactyly, or clinodactyly. Analysis of the exome sequence data revealed two novel homozygous frameshift deletions in EFCAB7: [c.830delG;p.(Gly277Valfs*5)]; in three families and [c.1350_1351delGA;p.(Asn451Phefs*2)] in one family. Sanger sequencing confirmed that these variants segregated with postaxial polydactyly, i.e., family members with postaxial polydactyly were found to be homozygous while unaffected members were heterozygous or wild type. EFCAB7 displays expressions in the skeletal muscle and on the cellular level in cilia. IQCE-EFCAB7 and EVC-EVC2 are part of the heterotetramer EvC complex, which is a positive regulator of the Hedgehog (Hh) pathway, that plays a key role in limb formation. Depletion of either EFCAB7 or IQCE inhibits induction of Gli1, a direct Hh target gene. Variants in IQCE and GLI1 have been shown to cause nonsyndromic postaxial polydactyly, while variants in EVC and EVC2 underlie Ellis van Creveld and Weyers syndromes, which include postaxial polydactyly as a phenotype. This is the first report of the involvement of EFCAB7 in human disease etiology.

EVC-EVC2 complex stability and ciliary targeting are regulated by modification with ubiquitin and SUMO.

Ellis van Creveld syndrome and Weyers acrofacial dysostosis are two rare genetic diseases affecting skeletal development. They are both ciliopathies, as they are due to malfunction of primary cilia, microtubule-based plasma membrane protrusions that function as cellular antennae and are required for Hedgehog signaling, a key pathway during skeletal morphogenesis. These ciliopathies are caused by mutations affecting the EVC-EVC2 complex, a transmembrane protein heterodimer that regulates Hedgehog signaling from inside primary cilia. Despite the importance of this complex, the mechanisms underlying its stability, targeting and function are poorly understood. To address this, we characterized the endogenous EVC protein interactome in control and Evc-null cells. This proteomic screen confirmed EVC's main known interactors (EVC2, IQCE, EFCAB7), while revealing new ones, including USP7, a deubiquitinating enzyme involved in Hedgehog signaling. We therefore looked at EVC-EVC2 complex ubiquitination. Such ubiquitination exists but is independent of USP7 (and of USP48, also involved in Hh signaling). We did find, however, that monoubiquitination of EVC-EVC2 cytosolic tails greatly reduces their protein levels. On the other hand, modification of EVC-EVC2 cytosolic tails with the small ubiquitin-related modifier SUMO3 has a different effect, enhancing complex accumulation at the EvC zone, immediately distal to the ciliary transition zone, possibly via increased binding to the EFCAB7-IQCE complex. Lastly, we find that EvC zone targeting of EVC-EVC2 depends on two separate EFCAB7-binding motifs within EVC2's Weyers-deleted peptide. Only one of these motifs had been characterized previously, so we have mapped the second herein. Altogether, our data shed light on EVC-EVC2 complex regulatory mechanisms, with implications for ciliopathies.

Oral manifestations in child patient with Ellis-van Creveld syndrome: case report

Ellis–van Creveld syndrome is an autosomal recessive disorder characterized by a tetrad of disproportionate dwarfism, ectodermal dysplasia, postaxial polydactyly, and congenital heart malformations. In this article, we hereby present a case of a 6-year-old Brazilian boy with Ellis–van Creveld syndrome who presented with a remarkable number of classical oral and dental features and uncommon findings such as taurodontism. Clinical examination revealed multiple enamel hypoplasia, absent vestibular sulcus, alveolar serrations in the maxilla anterior region, missing teeth, conical teeth, lower canine rotation, bilateral posterior crossbite, dental caries, and a nodule. Radiographically were observed teeth agenesis, taurodontism of deciduous and permanent molars, and delayed tooth eruption. Clinical and radiographic findings may be present from birth and the pediatric dentist has a fundamental role in the early diagnosis of Ellis–van Creveld syndrome, as well as oral problems prevention, rehabilitation, and aesthetic interventions.

Report of Ellis–Van Creveld Syndrome: A Chondroectodermal Dysplasia

Report of Ellis–Van Creveld Syndrome: A Chondroectodermal Dysplasia

Severe hydrocephalus in an infant with Ellis–van creveld syndrome: A rare entity

Abstract Ellis–van Creveld (EVC) syndrome is an autosomal recessive condition due to mutation in EVC 1 and EVC 2 genes. The authors report the anesthetic management of EVC syndrome with raised intracranial pressure with concomitant congenital heart disease for emergency cerebrospinal diversion procedure.

Dental Anomalies in Ciliopathies: Lessons from Patients with BBS2, BBS7, and EVC2 Mutations.

To investigate dental anomalies and the molecular etiology of a patient with Ellis-van Creveld syndrome and two patients with Bardet-Biedl syndrome, two examples of ciliopathies. Clinical examination, radiographic evaluation, whole exome sequencing, and Sanger direct sequencing were performed. Patient 1 had Ellis-van Creveld syndrome with delayed dental development or tooth agenesis, and multiple frenula, the feature found only in patients with mutations in ciliary genes. A novel homozygous mutation in EVC2 (c.703G>C; p.Ala235Pro) was identified. Patient 2 had Bardet-Biedl syndrome with a homozygous frameshift mutation (c.389_390delAC; p.Asn130ThrfsTer4) in BBS7. Patient 3 had Bardet-Biedl syndrome and carried a heterozygous mutation (c.389_390delAC; p.Asn130ThrfsTer4) in BBS7 and a homozygous mutation in BBS2 (c.209G>A; p.Ser70Asn). Her clinical findings included global developmental delay, disproportionate short stature, myopia, retinitis pigmentosa, obesity, pyometra with vaginal atresia, bilateral hydronephrosis with ureteropelvic junction obstruction, bilateral genu valgus, post-axial polydactyly feet, and small and thin fingernails and toenails, tooth agenesis, microdontia, taurodontism, and impaired dentin formation. EVC2, BBS2, and BBS7 mutations found in our patients were implicated in malformation syndromes with dental anomalies including tooth agenesis, microdontia, taurodontism, and impaired dentin formation.

Pulmonary Alveolar Microlithiasis in a Patient with Ellis-van Creveld Syndrome.

"Pulmonary Alveolar Microlithiasis in a Patient with Ellis–van Creveld Syndrome." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp. –

Novel large deletion involving EVC and EVC2 in Ellis–van Creveld syndrome

Ellis–van Creveld syndrome is an autosomal recessive skeletal dysplasia that is characterized by thoracic hypoplasia, polydactyly, oral abnormalities, and congenital heart disease. It is caused by pathogenic variants in the EVC or EVC2 genes. We report a case of a newborn with a compound heterozygous variant comprising NM_147127.5: c.1991dup:[p.Lys665Glufs*10] in the EVC2 gene and a novel large deletion involving exon 1 in EVC and exons 1–7 in EVC2.

Role of primary cilia and Hedgehog signaling in craniofacial features of Ellis-van Creveld syndrome.

Ellis-van Creveld syndrome (EvC) is an autosomal recessive genetic disorder involving pathogenic variants of EVC and EVC2 genes and classified as a ciliopathy. The syndrome is caused by mutations in the EVC gene on chromosome 4p16, and EVC2 gene, located close to the EVC gene, in a head-to-head configuration. Regardless of the affliction of EVC or EVC2, the clinical features of Ellis-van Creveld syndrome are similar. Both these genes are expressed in tissues such as, but not limited to, the heart, liver, skeletal muscle, and placenta, while the predominant expression in the craniofacial tissues is that of EVC2. Biallelic mutations of EVC and EVC2 affect Hedgehog signaling and thereby ciliary function, crucial factors in vertebrate development, culminating in the phenotypical features characteristic of EvC. The clinical features of Ellis-van Creveld syndrome are consistent with significant abnormalities in morphogenesis and differentiation of the affected tissues. The robust role of primary cilia in histodifferentiation and morphodifferentiation of oral, perioral, and craniofacial tissues is becoming more evident in the most recent literature. In this review, we give a summary of the mechanistic role of primary cilia in craniofacial development, taking Ellis-van Creveld syndrome as a representative example.

Ellis van Creveld syndrome: An unusual presentation at birth

Ellis Van Creveld, a syndrome comprising of chondrodysplasia, bilateral polydactyly of the hands with skeletal abnormalities, and congenital heart defect is a rare autosomal recessive disease. The prevalence of the disease in the world is 1/6000–20,000 newborns. In the Indian population, it is difficult to estimate the exact prevalence of the disease but, it is mostly seen in the Amish population. The cardinal features are short stature, dysplastic nails and teeth, polydactyly, narrow chest, and heart defects. The crucial differentials are Jeune dystrophy, Weyers syndrome, and McKusick-Kaufman syndrome. Here, we report a neonate, born of a non-consanguineous marriage with a syndromic appearance consisting of a bell-shaped chest, polydactyly, natal teeth, and single atrium. Prognosis is related to respiratory and heart defects in the early neonatal period.

Ellis Van Creveld Syndrome: A Case Report

Ellis Van Creveld Syndrome (EVC) is a infrequent inborn genetic disorder with an x-linked recessive pattern of inheritance. This is recognized by bilateral accessory little finger in upper extremity, short limbs, ectodermal dysplasia affecting teeth and nails, and congenital cardiac defect. The overall prevalence of this disease is 7 in 1000000. In this current case, a 9year old female patient reported with typical general and oral manifestations, which were key diagnostic features of EVC syndrome.

Characteristics of the civil war

In the modern world the problematic of the civil war remains relevant. The transition of the leading countries to post-industrial capitalism does not exclude the threat of wars of this type. The purpose of the article is to identify the conceptual characteristics of civil wars. The methodological basis of the research is based on L. Wittgensteins theory of language games. The first theoretical basis of the study is the definition given by Martin van Creveld: War does not begin when some kill others; it begins when those who kill have risk to be killed. The second theoretical basis of the study is the position put forward by Karl von Clausewitz: War is the continuation of politics by other means. The study revealed that the civil war should be analyzed in two aspects. In the military-strategic aspect the civil war remains a competitive mutual mass physical violence, using both regular and irregular methods of warfare. Whereas in the political aspect, the civil war should be understood as the competitive construction of the state.

Games and War in Early Modern English Literature: From Shakespeare to Swift. Ed. Holly Faith Nelson and Jim Daems.

<i>Games and War in Early Modern English Literature: From Shakespeare to Swift</i>. Ed. Holly Faith Nelson and Jim Daems.

The problem of demarcation of modernity and social reality after modernity philosophical dialogue)

This article discusses the conditions for delimitation of modernity and futureculture, as well as the concept of modernity. Vadim Belyaev claims that what the author refers to as futureculture, in fact does not go beyond the boundaries of modernity; these are rather the processes of promodernity and countermodernity. Vyacheslav Maracha polemicizes with Belyaev&amp;rsquo;s statements. Belyaev substantiates his critical rhetoric, gives characteristics to his interpretation of modernity, and claims that the author did not explain the thesis on the completion of modernity and the establishment of futureculture. The author partially agrees with the criticism and provides additional arguments: characterizes the definition of modernity used by him; distinguishes between the new worldview, semantic reality of culture, and projects of modernity, realization of these projects and objective reality results from implementation of the projects of modernity and responses to new challenges of the time, as well as construction of the social institutions of modernity. The latter statement is illustrated on the example of the formation of state institution, the study by Martin van Creveld &amp;ldquo;The Rise and Fall of the State&amp;rdquo;. The conclusion is made that all plans and fundamental structures of modernity (worldview, semantic reality of culture, projects of modernity, social institutions) can no longer ensure normal flow of modern life, but rather generate problems and social destructions. Objectively, modernity has been reborn and is nearing completion. The author formulates certain ideas and meaning that reveal the formation of the future culture.

Cardiac Defects and Genetic Syndromes: Old Uncertainties and New Insights.

Recent advances in understanding the genetic causes and anatomic subtypes of cardiac defects have revealed new links between genetic etiology, pathogenetic mechanisms and cardiac phenotypes. Although the same genetic background can result in different cardiac phenotypes, and similar phenotypes can be caused by different genetic causes, researchers’ effort to identify specific genotype–phenotype correlations remains crucial. In this review, we report on recent advances in the cardiac pathogenesis of three genetic diseases: Down syndrome, del22q11.2 deletion syndrome and Ellis–Van Creveld syndrome. In these conditions, the frequent and specific association with congenital heart defects and the recent characterization of the underlying molecular events contributing to pathogenesis provide significant examples of genotype–phenotype correlations. Defining these correlations is expected to improve diagnosis and patient stratification, and it has relevant implications for patient management and potential therapeutic options.

New books &amp; media

New books &amp; media

Ellis–van creveld syndrome: A rare autosomal recessive genetic disorder

Ellis–van Creveld syndrome is a rare genetic disorder with autosomal recessive inheritance, mainly affecting the Amish population living in Pennsylvania, USA, with an incidence of 1:244,000 for the general population. This syndrome consists of characteristic features such as bilateral postaxial polydactyly, chondroectodermal dysplasia, congenital heart defects, and hypoplastic nails and teeth. There have been few case reports of this syndrome published mainly in dental literature. We report a case of a 40-year-old male presenting with typical features of this syndrome.

Seeing into the Future: A Short History of Prediction by Martin van Creveld

Seeing into the Future: A Short History of Prediction by Martin van Creveld

Síndrome de Ellis Van Creveld

El síndrome de Ellis van Creveld es un trastorno autosómico recesivo, caracterizado por mutaciones en los genes ECV y ECV2, los cuales son importantes para el desarrollo osteocondral. A nivel mundial, se han reportado aproximadamente 300 casos ,presentándose con mayor frecuencia en poblaciones endogámicas. Se caracteriza por distrofias óseas, displasias ectodérmicas y malformaciones cardíacas.&#x0D; El diagnóstico clínico puede ser confirmado mediante pruebas moleculares. A continuación, se presenta el caso de una paciente diagnosticada con el síndrome, la cual fue evaluada de manera interdisciplinaria. Esta revisión permitió dar a conocer un nuevo caso de la patología, relacionar las manifestaciones clínicas de la paciente con la literatura y describir nuevos hallazgos que pueden correlacionarse con el síndrome.

GENETIC PERSPECTIVE OF THE CONGENITAL HEART DISEASE

GENETIC PERSPECTIVE OF THE CONGENITAL HEART DISEASE