RARE DISEASE
Ellis Van Creveld syndrome
Ellis Van Creveld syndrome
Ellis Van Creveld syndrome
Synonyms: Chondroectodermal dysplasia, Mesodermic dysplasia
Synonyms: Chondroectodermal dysplasia, Mesodermic dysplasia
Synonyms: Chondroectodermal dysplasia, Mesodermic dysplasia
Drug discovery
41
papers
On emerging therapies
Overview
Ellis Van Creveld syndrome (EVC) is a rare autosomal recessive chondroectodermal dysplasia caused by mutations in EVC or EVC2 genes [1][6][7]. Key features include disproportionate dwarfism, postaxial polydactyly, ectodermal dysplasia (hypoplastic nails/teeth), and cardiac defects (e.g., atrial septal defect) in 50-60% of patients [1][4][7]. Overlaps with Weyers acrofacial dysostosis but includes severe skeletal/visceral involvement [1][2].
Burden
Mortality: 40-50% infant mortality from cardiac/respiratory complications [4][16].
Morbidity: Chronic pain, mobility limitations, and recurrent surgeries for skeletal/orthopedic issues [3][11][20].
Psychosocial impact: Lifelihood challenges due to short stature, requiring adaptive supports and mental health resources [11][16].
Therapies
Surgical: Polydactyly correction, cardiac repair (ASD/VSD closure), and knee alignment surgery for severe genu valgum [3][16][20].
Multidisciplinary care: Dental management (natal teeth/malocclusion), pulmonary support for restrictive lung disease, and growth monitoring [8][11][20].
Genetic counseling: Critical due to autosomal recessive inheritance; prenatal ultrasound detects skeletal/cardiac anomalies [7][12].
Categories: rare bone diseases, rare cardiac malformations, rare developmental anomalies during embryogenesis, rare genetic diseases, rare renal diseases, rare respiratory diseases, rare skin diseases, rare transplant-related disorders
Research Papers
41 drug discovery papers about Ellis Van Creveld syndrome. Recent publications:
41 drug discovery papers about Ellis Van Creveld syndrome. Recent publications:
categories:
Small molecules
proteins
2024-09-01 | Enhanced growth of short stature in Ellis-van Creveld syndrome: A case report of a Saudi child
This case report presents the diagnosis and management of Ellis-van Creveld syndrome (EVC) in a 20-year-old Saudi boy, highlighting the condition’s genetic basis and prevalence in consanguineous communities. The patient exhibited characteristic clinical and radiological features, including below-average height, bilateral postaxial polydactyly, and hypoplastic nails. Diagnosis was confirmed through genetic testing, revealing a nonsense homozygous mutation in the EVC2 gene. Remarkably, the absence of cardiac abnormalities allowed for the successful administration of growth hormone (GH) therapy, which led to a notable increase in height over 2 years, from 108 cm at age 12 to 122 cm at age 14. This case underscores the importance of comprehensive assessment and the potential benefits of GH therapy in EVC patients, particularly those without cardiac defects.
2023-07-27 | 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.
2022-08-01 | Elevated WNT signaling and compromised Hedgehog signaling due to Evc2 loss of function contribute to the abnormal molar patterning
Ellis-van Creveld (EVC) syndrome is an autosomal recessive chondrodysplasia. The affected individuals bear a series of skeleton defects, congenital heart septum anomalies, midfacial defects, and dental defects. Previous studies using Evc or Evc2 mutant mice have characterized the pathological mechanism leading to various types of congenital defects. Some patients with EVC have supernumerary tooth; however, it is not known yet if there are supernumerary tooth formed in Evc or Evc2 mutant mice, and if yes, what is the pathological mechanism associated. In the present study, we used Evc2 mutant mice and analyze the pattern of molars in Evc2 mutant mice at various stages. Our studies demonstrate that Evc2 loss of function within the dental mesenchymal cells leads to abnormal molar patterning, and that the most anterior molar in the Evc2 mutant mandible represents a supernumerary tooth. Finally, we provide evidence supporting the idea that both compromised Hedgehog signaling and elevated WNT signaling due to Evc2 loss of function contributes to the supernumerary tooth formation.
2016-12-27 | Elevated Fibroblast Growth Factor Signaling Is Critical for the Pathogenesis of the Dwarfism in Evc2/Limbin Mutant Mice
Ellis-van Creveld (EvC) syndrome is a skeletal dysplasia, characterized by short limbs, postaxial polydactyly, and dental abnormalities. EvC syndrome is also categorized as a ciliopathy because of ciliary localization of proteins encoded by the two causative genes, EVC and EVC2 (aka LIMBIN). While recent studies demonstrated important roles for EVC/EVC2 in Hedgehog signaling, there is still little known about the pathophysiological mechanisms underlying the skeletal dysplasia features of EvC patients, and in particular why limb development is affected, but not other aspects of organogenesis that also require Hedgehog signaling. In this report, we comprehensively analyze limb skeletogenesis in Evc2 mutant mice and in cell and tissue cultures derived from these mice. Both in vivo and in vitro data demonstrate elevated Fibroblast Growth Factor (FGF) signaling in Evc2 mutant growth plates, in addition to compromised but not abrogated Hedgehog-PTHrP feedback loop. Elevation of FGF signaling, mainly due to increased Fgf18 expression upon inactivation of Evc2 in the perichondrium, critically contributes to the pathogenesis of limb dwarfism. The limb dwarfism phenotype is partially rescued by inactivation of one allele of Fgf18 in the Evc2 mutant mice. Taken together, our data uncover a novel pathogenic mechanism to understand limb dwarfism in patients with Ellis-van Creveld syndrome.
2013-01-11 | Evc regulates a symmetrical response to Shh signaling in molar development.
Tooth morphogenesis involves patterning through the activity of epithelial signaling centers that, among other molecules, secrete Sonic hedgehog (Shh). While it is known that Shh responding cells need intact primary cilia for signal transduction, the roles of individual cilia components for tooth morphogenesis are poorly understood. The clinical features of individuals with Ellis-van Creveld syndrome include various dental anomalies, and we show here that absence of the cilial protein Evc in mice causes various hypo- and hyperplasia defects during molar development. During first molar development, the response to Shh signaling is progressively lost in Evc-deficient embryos and, unexpectedly, the response consistently disappears in a buccal to lingual direction. The important role of Evc for establishing the buccal-lingual axis of the developing first molar is also supported by a displaced activity of the Wnt pathway in Evc mutants. The observed growth abnormalities eventually manifest in first molar microdontia, disruption of molar segmentation and symmetry, root fusions, and delayed differentiation. Analysis of our data indicates that both spatially and temporally disrupted activities of the Shh pathway are the primary cause for the variable dental anomalies seen in patients with Ellis-van Creveld syndrome or Weyers acrodental dysostosis.
small molecules
2021-10-30 | Blocking chondrocyte hypertrophy in conditional Evc knockout mice does not modify osteoarthritis progression
ABSTRACT Background Chondrocytes in osteoarthritic (OA) cartilage acquire a hypertrophic-like phenotype, where Hedgehog (Hh) signaling is pivotal. Hh overexpression causes OA-like cartilage lesions, whereas its downregulation prevents articular destruction in mouse models. Mutations in EVC and EVC2 genes disrupt Hh signaling, and are responsible for the Ellis-van Creveld syndrome skeletal dysplasia. Since Ellis-van Creveld syndrome protein (Evc) deletion is expected to hamper Hh target gene expression we hypothesized that it would also prevent OA progression avoiding chondrocyte hypertrophy. Our aim was to study Evc as a new therapeutic target in OA, and whether Evc deletion restrains chondrocyte hypertrophy and prevents joint damage in an Evc tamoxifen induced knockout ( Evc cKO ) model of OA. Methods OA was induced by surgical knee destabilization in wild-type (WT) and Evc cKO adult mice, and healthy WT mice were used as controls (n=10 knees/group). Hypertrophic markers and Hh genes were measured by qRT-PCR, and metalloproteinases (MMP) levels assessed by western blot. Human OA chondrocytes and cartilage samples were obtained from patients undergoing knee joint replacement surgery. Cyclopamine (CPA) was used for Hh pharmacological inhibition and IL-1β as an inflammatory insult. Results Tamoxifen induced inactivation of Evc inhibited Hh overexpression and partially prevented chondrocyte hypertrophy during OA, although it did not ameliorate cartilage damage in DMM- Evc cKO mice. Hh pathway inhibition did not modify the expression of proinflammatory mediators induced by IL-1 beta in human OA chondrocytes in culture. Hypertrophic – IHH – and inflammatory – COX-2 – markers co-localized in OA cartilage samples. Conclusions Tamoxifen induced inactivation of Evc partially prevented chondrocyte hypertrophy in DMM- Evc cKO mice, but it did not ameliorate cartilage damage. Our results suggest that chondrocyte hypertrophy per se is not a pathogenic event in the progression of OA.
2021-06-25 | IFT20 is critical for early chondrogenesis during endochondral ossification
Abstract Ciliogenic components, such as the family of intraflagellar transport (IFT) proteins, are recognized to play key roles in endochondral ossification, a critical process to form most bones. However, it remains unclear how each IFT protein performs its unique function to regulate endochondral ossification. Here, we show that intraflagellar transport 20 (IFT20) is required for early chondrogenesis. Utilizing three osteo-chondrocyte lineage-specific Cre mice ( Prx1-Cre , Col2-Cre and Aggrecan-CreER T2 ), we deleted Ift20 to examine its function. While chondrocyte-specific Ift20 deletion with Col2-Cre or Aggrecan-CreER T2 drivers did not cause overt skeletal defects, mesoderm-specific Ift20 deletion using Prx1-Cre ( Ift20:Prx1-Cre ) resulted in shortened limb outgrowth. Although primary cilia were not formed in Ift20:Prx1-Cre mice, ciliary Hedgehog signaling was only moderately affected. Interestingly, loss of Ift20 lead to upregulation of Fgf18 expression resulting in ERK1/2 activation and sustained Sox9 expression, thus preventing endochondral ossification. Inhibition of enhanced phospho-ERK1/2 activation partially rescued defective chondrogenesis in Ift20 mutant cells, supporting an important role for FGF signaling. Our findings demonstrate a novel mechanism of IFT20 in early chondrogenesis during endochondral ossification.
2016-02-22 | Dullard/Ctdnep1 regulates endochondral ossification via suppression of TGF-β signaling.
Transforming growth factor (TGF)-β signaling plays critical roles during skeletal development and its excessive signaling causes genetic diseases of connective tissues including Marfan syndrome and acromelic dysplasia. However, the mechanisms underlying prevention of excessive TGF-β signaling in skeletogenesis remain unclear. We previously reported that Dullard/Ctdnep1 encoding a small phosphatase is required for nephron maintenance after birth through suppression of bone morphogenetic protein (BMP) signaling. Unexpectedly, we found that Dullard is involved in suppression of TGF-β signaling during endochondral ossification. Conditional Dullard-deficient mice in the limb and sternum mesenchyme by Prx1-Cre displayed the impaired growth and ossification of skeletal elements leading to postnatal lethality. Dullard was expressed in early cartilage condensations and later in growth plate chondrocytes. The tibia growth plate of newborn Dullard mutant mice showed reduction of the proliferative and hypertrophic chondrocyte layers. The sternum showed deformity of cartilage primordia and delayed hypertrophy. Micromass culture experiments revealed that Dullard deficiency enhanced early cartilage condensation and differentiation, but suppressed mineralized hypertrophic chondrocyte differentiation, which was reversed by treatment with TGF-β type I receptor kinase blocker LY-364947. Dullard deficiency induced upregulation of protein levels of both phospho-Smad2/3 and total Smad2/3 in micromass cultures without increase of Smad2/3 mRNA levels, suggesting that Dullard may affect Smad2/3 protein stability. The phospho-Smad2/3 level was also upregulated in perichondrium and hypertrophic chondrocytes in Dullard-deficient embryos. Response to TGF-β signaling was enhanced in Dullard-deficient primary chondrocyte cultures at late, but not early, time point. Moreover, perinatal administration of LY-364947 ameliorated the sternum deformity in vivo. Thus, we identified Dullard as a new negative regulator of TGF-β signaling in endochondral ossification.
2014-07-04 | Epigenetic deregulation of Ellis Van Creveld confers robust Hedgehog signaling in adult T-cell leukemia.
One of the hallmarks of cancer, global gene expression alteration, is closely associated with the development and malignant characteristics associated with adult T‐cell leukemia ( ATL ) as well as other cancers. Here, we show that aberrant overexpression of the Ellis Van Creveld ( EVC ) family is responsible for cellular Hedgehog ( HH ) activation, which provides the pro‐survival ability of ATL cells. Using microarray, quantitative RT ‐ PCR and immunohistochemistry we have demonstrated that EVC is significantly upregulated in ATL and human T‐cell leukemia virus type I ( HTLV ‐1)‐infected cells. Epigenetic marks, including histone H3 acetylation and Lys4 trimethylation, are specifically accumulated at the EVC locus in ATL samples. The HTLV ‐1 Tax participates in the coordination of EVC expression in an epigenetic fashion. The treatment of sh RNA targeting EVC , as well as the transcription factors for HH signaling, diminishes the HH activation and leads to apoptotic death in ATL cell lines. We also showed that a HH signaling inhibitor, GANT 61, induces strong apoptosis in the established ATL cell lines and patient‐derived primary ATL cells. Therefore, our data indicate that HH activation is involved in the regulation of leukemic cell survival. The epigenetically deregulated EVC appears to play an important role for HH activation. The possible use of EVC as a specific cell marker and a novel drug target for HTLV ‐1‐infected T‐cells is implicated by these findings. The HH inhibitors are suggested as drug candidates for ATL therapy. Our findings also suggest chromatin rearrangement associated with active histone markers in ATL .
2012-09-18 | Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2
Hedgehog (Hh) signaling plays pivotal roles in embryonic development and adult tissue homeostasis in species ranging from Drosophila to mammals. The Hh signal is transduced by Smoothened (Smo), a seven-transmembrane protein related to G protein coupled receptors. Despite a conserved mechanism by which Hh activates Smo in Drosophila and mammals, how mammalian Hh signal is transduced from Smo to the Gli transcription factors is poorly understood. Here, we provide evidence that two ciliary proteins, Evc and Evc2, the products of human disease genes responsible for the Ellis-van Creveld syndrome, act downstream of Smo to transduce the Hh signal. We found that loss of Evc/Evc2 does not affect Sonic Hedgehog-induced Smo phosphorylation and ciliary localization but impedes Hh pathway activation mediated by constitutively active forms of Smo. Evc/Evc2 are dispensable for the constitutive Gli activity in Sufu−/− cells, suggesting that Evc/Evc2 act upstream of Sufu to promote Gli activation. Furthermore, we demonstrated that Hh stimulates binding of Evc/Evc2 to Smo depending on phosphorylation of the Smo C-terminal intracellular tail and that the binding is abolished in Kif3a−/− cilium-deficient cells. We propose that Hh activates Smo by inducing its phosphorylation, which recruits Evc/Evc2 to activate Gli proteins by antagonizing Sufu in the primary cilia.
gene therapies
2026-03-05 | Genetic analysis of children with suspected immunodeficiency: mimickers of inborn errors of immunity.
Inborn errors of immunity (IEI) comprise a heterogeneous group of disorders with diverse clinical manifestations. In this study, we aimed to evaluate genetic findings in patients with suspected IEI and to assess the contribution of next-generation sequencing (NGS) in identifying both IEI-related and non-IEI-related genetic variants. Between January 2020 and January 2025, 91 pediatric patients (0-18 years) referred for suspected IEI were retrospectively analyzed. Demographic data, clinical features, immunological profiles, and genetic results were reviewed, including single-gene sequencing, fluorescence in situ hybridization (FISH), targeted gene panels (TGP), and whole-exome sequencing (WES). Patients analyzed by NGS were classified into three categories according to detected variants: IEI-related, non-IEI-related, and undetected disease-causing variant. A total of 79 patients underwent NGS-based genetic testing. The mean age was 4.37 ± 5.09 years. WES was performed in 40 patients (50.6%) and TGP in 39 (49.4%). Pathogenic variants linked to IEI-related were detected in 28 patients (35.4%), whereas non-IEI-related pathogenic variants were identified in 12 (15.2%). The remaining 39 patients (49.4%) had undetected disease-causing variants. The diagnoses of patients carrying pathogenic variants unrelated to IEI included primary ciliary dyskinesia, Ellis-van Creveld syndrome, desmoglein-1 deficiency, and others. Conclusion: Our study highlights the importance of genetic testing in the differential diagnosis of IEI and provides evidence supporting its role in identifying mixed IEI phenotypes. Comprehensive interpretation of genetic results within a multidisciplinary clinical framework is essential for accurate diagnosis, appropriate management, and effective genetic counseling.
2025-10-01 | Ellis–van Creveld Syndrome with Common Atrium: A Clinically Diagnosed Case Report with Literature Review
Ellis-van Creveld (EVC) syndrome is a rare, autosomal recessive disorder defined by a classic tetrad of features: chondroectodermal dysplasia causing disproportionate short stature, postaxial polydactyly, ectodermal defects affecting the nails and teeth, and congenital heart disease. The most significant cause of morbidity and mortality is the associated cardiac anomaly, most commonly a large atrial septal defect resulting in a functional common atrium. Early and accurate diagnosis is critical for managing cardiovascular risk and implementing appropriate long-term care. We report the case of a 12-year-old female from Pakistan, with a weight of 26 kg (BMI 18.8 kg/m²), who presented with a classic EVC phenotype. Clinical examination revealed short-limb dwarfism, bilateral postaxial polydactyly of all four limbs, genu valgum, and ectodermal dysplasia. Her parents were non-consanguineous. Cardiovascular evaluation confirmed a common atrium via echocardiography, with corresponding ECG findings of right axis deviation and an incomplete right bundle branch block. Based on this distinct constellation of clinical and imaging evidence, a clinical diagnosis was made, as molecular genetic testing was not available. This case confirms the importance of recognizing the distinct clinical phenotype of Ellis-van Creveld syndrome. In settings where molecular diagnostics are unavailable, a confident diagnosis can be made through thorough clinical assessment. Prompt identification is paramount for initiating multidisciplinary management, thereby improving the patient's long-term health and quality of life, with the patient currently awaiting surgical repair of her cardiac defect and referral for orthopedic and dental care.
2019-04-11 | Down-regulated WDR35 contributes to fetal anomaly via regulation of osteogenic differentiation.
Autosomal recessive disorder is closely correlated with congenital fetal malformation. The mutation of WDR35 may lead to short rib-polydactyly syndrome (SRP), asphyxiating thoracic dystrophy (ATD, Jeune syndrome) and Ellis van Creveld syndrome. The purpose of this study is to investigate the role of WDR35 in fetal anomaly. The fetuses presented malformation with abnormal head shape, cardiac dilatation, pericardial effusion, and non-displayed left pulmonary artery and left lung. After the detection of genomic DNA (gDNA) in amniotic fluid cells (AFC), chromosomal rearrangement was found in arr[hg19] 2p25.3p23.3. It was revealed through multiple PCR-DHPLC that MYCN, WDR35, LPIN1, ODC1, KLF11 and NBAS contained duplicated copy numbers in 2p25.3p23.3. AF-MSCs were mostly positive for CD44, CD105, negative for CD34 and CD14. Western Blot test showed that WDR35-encoded protein was decreased in the patients' AFC compared to that in normal pregnant women. In the patients' amniotic fluid-derived mesenchymal stem cells (AF-MSCs), WDR35 overexpression could repair cilia formation, and the overexpression of WDR35 or Gli2 could significantly enhance ALP activity and expressions of osteogenic differentiation marker genes, including RUNXE2, OCN, BSP and ALP. However, WDR35 silencing in C3H10T1/2 cells could remarkably inhibit cilia formation and osteogenic differentiation. This inhibitory effect could be attenuated by Gli2 overexpression. The results demonstrated that copy number variation (CNV) of WDR35 may lead to skeletal dysplasia and fetal anomaly, and that down-regulated WDR35 may damage the cilia formation and sequentially indirectly regulate Gli signal, which would eventually result in negative regulation of osteogenic differentiation.
2016-04-28 | Specific variants in WDR35 cause a distinctive form of Ellis-van Creveld syndrome by disrupting the recruitment of the EvC complex and SMO into the cilium.
Most patients with Ellis-van Creveld syndrome (EvC) are identified with pathogenic changes in EVC or EVC2, however further genetic heterogeneity has been suggested. In this report we describe pathogenic splicing variants in WDR35, encoding retrograde intraflagellar transport protein 121 (IFT121), in three families with a clinical diagnosis of EvC but having a distinctive phenotype. To understand why WDR35 variants result in EvC, we analysed EVC, EVC2 and Smoothened (SMO) in IFT-A deficient cells. We found that the three proteins failed to localize to Wdr35(-/-) cilia, but not to the cilium of the IFT retrograde motor mutant Dync2h1(-/-), indicating that IFT121 is specifically required for their entry into the ciliary compartment. Furthermore expression of Wdr35 disease cDNAs in Wdr35(-/-) fibroblasts revealed that the newly identified variants lead to Hedgehog signalling defects resembling those of Evc(-/-) and Evc2(-/-) mutants. Together our data indicate that splicing variants in WDR35, and possibly in other IFT-A components, underlie a number of EvC cases by disrupting targeting of both the EvC complex and SMO to cilia.
cell therapies
2021-12-28 | Ellis-Van-Creveld Syndrome and Congenital Cardiac Anomaly: Common Atrium with Atrioventricular Canal Septal Defect
Background: Children presenting with physical features of chondro-ectodermal dysplasia (Ellis-Van Creveld syndrome) such as skeletal and joint abnormalities often have concomitant congenital cardiac anomalies. Presence of cardiorespiratory symptoms in children with Ellis-Van Craved syndrome warrants a thorough cardiologic evaluation to recognize and treat underlying congenital heart anomaly. Aim: A child with physical stigmata of Ellis-Van-Creveld syndrome is evaluated to detect an associated congenital cardiac anomaly and accomplish successful repair of the underlying cardiac lesion to reduce the cardiac related morbidity and improve the patient survival. Case Presentation: Ten years old boy with chondroectodermal dysplasia (dental anomalies, genu valgum and other skeletal abnormalities) presented with dyspnea and cyanosis. Cardiac evaluation by 2D echo revealed an atrioventricular (AV) canal septal defect with AV valve regurgitation and a common atrium. Angiocardiography showed a goose neck deformity of the left ventricular outflow tract. The Qp/Qs was 3.4: 1, with systemic arterial oxygen desaturation (SaO2 of 0.7) and O2 saturation in the common atrium was 0.7. The pulmonary venous connections to the common atrium were anomalous. Atriotomy on cardiopulmonary bypass and on a cardioplegic arrest discerned a partial AV canal septal defect with a common bridging leaflet, clefts in septal leaflets of tricuspid and mitral vlalves, an incompletely closed interventricular communication, and a common atrium with highly anomalous pulmonary venous insertions well anterior (8 cm) to vena caval orifices. Intracardiac repair was performed with two patches of Goertex to partition the common atrium into the pulmonary and systemic venous chambers after repair of the partial AV canal septal defect. Patient required only a temporary afterload reduction with enalapril; otherwise patient had an uneventful postoperative course. At a 2-year follow-up, the child was well without AV valve regurgitation and had normal biventricular function. Conclusion: A child with Ellis-Van-Creveld syndrome with skeletal abnormalities and dental anomalies had manifested with cardio-respiratory symptoms. Preoperative cardiac and intraoperative evaluation showed a common atrium with severely anomalous pulmonary venous connection and partial AV canal septal defect. Successful biventricular repair was accomplished by repairing the partial AV canal septal defect and partitioning the common atrium into left and right atrium by a complex atrial routing technique with two patches of Gore-Tex. On a follow-up at 2 years, the patient had adequate biventricular function without AV valve regurgitation. 114264
proteins
2024-09-01 | Enhanced growth of short stature in Ellis-van Creveld syndrome: A case report of a Saudi child
This case report presents the diagnosis and management of Ellis-van Creveld syndrome (EVC) in a 20-year-old Saudi boy, highlighting the condition’s genetic basis and prevalence in consanguineous communities. The patient exhibited characteristic clinical and radiological features, including below-average height, bilateral postaxial polydactyly, and hypoplastic nails. Diagnosis was confirmed through genetic testing, revealing a nonsense homozygous mutation in the EVC2 gene. Remarkably, the absence of cardiac abnormalities allowed for the successful administration of growth hormone (GH) therapy, which led to a notable increase in height over 2 years, from 108 cm at age 12 to 122 cm at age 14. This case underscores the importance of comprehensive assessment and the potential benefits of GH therapy in EVC patients, particularly those without cardiac defects.
2023-07-27 | 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.
2022-08-01 | Elevated WNT signaling and compromised Hedgehog signaling due to Evc2 loss of function contribute to the abnormal molar patterning
Ellis-van Creveld (EVC) syndrome is an autosomal recessive chondrodysplasia. The affected individuals bear a series of skeleton defects, congenital heart septum anomalies, midfacial defects, and dental defects. Previous studies using Evc or Evc2 mutant mice have characterized the pathological mechanism leading to various types of congenital defects. Some patients with EVC have supernumerary tooth; however, it is not known yet if there are supernumerary tooth formed in Evc or Evc2 mutant mice, and if yes, what is the pathological mechanism associated. In the present study, we used Evc2 mutant mice and analyze the pattern of molars in Evc2 mutant mice at various stages. Our studies demonstrate that Evc2 loss of function within the dental mesenchymal cells leads to abnormal molar patterning, and that the most anterior molar in the Evc2 mutant mandible represents a supernumerary tooth. Finally, we provide evidence supporting the idea that both compromised Hedgehog signaling and elevated WNT signaling due to Evc2 loss of function contributes to the supernumerary tooth formation.
2016-12-27 | Elevated Fibroblast Growth Factor Signaling Is Critical for the Pathogenesis of the Dwarfism in Evc2/Limbin Mutant Mice
Ellis-van Creveld (EvC) syndrome is a skeletal dysplasia, characterized by short limbs, postaxial polydactyly, and dental abnormalities. EvC syndrome is also categorized as a ciliopathy because of ciliary localization of proteins encoded by the two causative genes, EVC and EVC2 (aka LIMBIN). While recent studies demonstrated important roles for EVC/EVC2 in Hedgehog signaling, there is still little known about the pathophysiological mechanisms underlying the skeletal dysplasia features of EvC patients, and in particular why limb development is affected, but not other aspects of organogenesis that also require Hedgehog signaling. In this report, we comprehensively analyze limb skeletogenesis in Evc2 mutant mice and in cell and tissue cultures derived from these mice. Both in vivo and in vitro data demonstrate elevated Fibroblast Growth Factor (FGF) signaling in Evc2 mutant growth plates, in addition to compromised but not abrogated Hedgehog-PTHrP feedback loop. Elevation of FGF signaling, mainly due to increased Fgf18 expression upon inactivation of Evc2 in the perichondrium, critically contributes to the pathogenesis of limb dwarfism. The limb dwarfism phenotype is partially rescued by inactivation of one allele of Fgf18 in the Evc2 mutant mice. Taken together, our data uncover a novel pathogenic mechanism to understand limb dwarfism in patients with Ellis-van Creveld syndrome.
2013-01-11 | Evc regulates a symmetrical response to Shh signaling in molar development.
Tooth morphogenesis involves patterning through the activity of epithelial signaling centers that, among other molecules, secrete Sonic hedgehog (Shh). While it is known that Shh responding cells need intact primary cilia for signal transduction, the roles of individual cilia components for tooth morphogenesis are poorly understood. The clinical features of individuals with Ellis-van Creveld syndrome include various dental anomalies, and we show here that absence of the cilial protein Evc in mice causes various hypo- and hyperplasia defects during molar development. During first molar development, the response to Shh signaling is progressively lost in Evc-deficient embryos and, unexpectedly, the response consistently disappears in a buccal to lingual direction. The important role of Evc for establishing the buccal-lingual axis of the developing first molar is also supported by a displaced activity of the Wnt pathway in Evc mutants. The observed growth abnormalities eventually manifest in first molar microdontia, disruption of molar segmentation and symmetry, root fusions, and delayed differentiation. Analysis of our data indicates that both spatially and temporally disrupted activities of the Shh pathway are the primary cause for the variable dental anomalies seen in patients with Ellis-van Creveld syndrome or Weyers acrodental dysostosis.
small molecules
2021-10-30 | Blocking chondrocyte hypertrophy in conditional Evc knockout mice does not modify osteoarthritis progression
ABSTRACT Background Chondrocytes in osteoarthritic (OA) cartilage acquire a hypertrophic-like phenotype, where Hedgehog (Hh) signaling is pivotal. Hh overexpression causes OA-like cartilage lesions, whereas its downregulation prevents articular destruction in mouse models. Mutations in EVC and EVC2 genes disrupt Hh signaling, and are responsible for the Ellis-van Creveld syndrome skeletal dysplasia. Since Ellis-van Creveld syndrome protein (Evc) deletion is expected to hamper Hh target gene expression we hypothesized that it would also prevent OA progression avoiding chondrocyte hypertrophy. Our aim was to study Evc as a new therapeutic target in OA, and whether Evc deletion restrains chondrocyte hypertrophy and prevents joint damage in an Evc tamoxifen induced knockout ( Evc cKO ) model of OA. Methods OA was induced by surgical knee destabilization in wild-type (WT) and Evc cKO adult mice, and healthy WT mice were used as controls (n=10 knees/group). Hypertrophic markers and Hh genes were measured by qRT-PCR, and metalloproteinases (MMP) levels assessed by western blot. Human OA chondrocytes and cartilage samples were obtained from patients undergoing knee joint replacement surgery. Cyclopamine (CPA) was used for Hh pharmacological inhibition and IL-1β as an inflammatory insult. Results Tamoxifen induced inactivation of Evc inhibited Hh overexpression and partially prevented chondrocyte hypertrophy during OA, although it did not ameliorate cartilage damage in DMM- Evc cKO mice. Hh pathway inhibition did not modify the expression of proinflammatory mediators induced by IL-1 beta in human OA chondrocytes in culture. Hypertrophic – IHH – and inflammatory – COX-2 – markers co-localized in OA cartilage samples. Conclusions Tamoxifen induced inactivation of Evc partially prevented chondrocyte hypertrophy in DMM- Evc cKO mice, but it did not ameliorate cartilage damage. Our results suggest that chondrocyte hypertrophy per se is not a pathogenic event in the progression of OA.
2021-06-25 | IFT20 is critical for early chondrogenesis during endochondral ossification
Abstract Ciliogenic components, such as the family of intraflagellar transport (IFT) proteins, are recognized to play key roles in endochondral ossification, a critical process to form most bones. However, it remains unclear how each IFT protein performs its unique function to regulate endochondral ossification. Here, we show that intraflagellar transport 20 (IFT20) is required for early chondrogenesis. Utilizing three osteo-chondrocyte lineage-specific Cre mice ( Prx1-Cre , Col2-Cre and Aggrecan-CreER T2 ), we deleted Ift20 to examine its function. While chondrocyte-specific Ift20 deletion with Col2-Cre or Aggrecan-CreER T2 drivers did not cause overt skeletal defects, mesoderm-specific Ift20 deletion using Prx1-Cre ( Ift20:Prx1-Cre ) resulted in shortened limb outgrowth. Although primary cilia were not formed in Ift20:Prx1-Cre mice, ciliary Hedgehog signaling was only moderately affected. Interestingly, loss of Ift20 lead to upregulation of Fgf18 expression resulting in ERK1/2 activation and sustained Sox9 expression, thus preventing endochondral ossification. Inhibition of enhanced phospho-ERK1/2 activation partially rescued defective chondrogenesis in Ift20 mutant cells, supporting an important role for FGF signaling. Our findings demonstrate a novel mechanism of IFT20 in early chondrogenesis during endochondral ossification.
2016-02-22 | Dullard/Ctdnep1 regulates endochondral ossification via suppression of TGF-β signaling.
Transforming growth factor (TGF)-β signaling plays critical roles during skeletal development and its excessive signaling causes genetic diseases of connective tissues including Marfan syndrome and acromelic dysplasia. However, the mechanisms underlying prevention of excessive TGF-β signaling in skeletogenesis remain unclear. We previously reported that Dullard/Ctdnep1 encoding a small phosphatase is required for nephron maintenance after birth through suppression of bone morphogenetic protein (BMP) signaling. Unexpectedly, we found that Dullard is involved in suppression of TGF-β signaling during endochondral ossification. Conditional Dullard-deficient mice in the limb and sternum mesenchyme by Prx1-Cre displayed the impaired growth and ossification of skeletal elements leading to postnatal lethality. Dullard was expressed in early cartilage condensations and later in growth plate chondrocytes. The tibia growth plate of newborn Dullard mutant mice showed reduction of the proliferative and hypertrophic chondrocyte layers. The sternum showed deformity of cartilage primordia and delayed hypertrophy. Micromass culture experiments revealed that Dullard deficiency enhanced early cartilage condensation and differentiation, but suppressed mineralized hypertrophic chondrocyte differentiation, which was reversed by treatment with TGF-β type I receptor kinase blocker LY-364947. Dullard deficiency induced upregulation of protein levels of both phospho-Smad2/3 and total Smad2/3 in micromass cultures without increase of Smad2/3 mRNA levels, suggesting that Dullard may affect Smad2/3 protein stability. The phospho-Smad2/3 level was also upregulated in perichondrium and hypertrophic chondrocytes in Dullard-deficient embryos. Response to TGF-β signaling was enhanced in Dullard-deficient primary chondrocyte cultures at late, but not early, time point. Moreover, perinatal administration of LY-364947 ameliorated the sternum deformity in vivo. Thus, we identified Dullard as a new negative regulator of TGF-β signaling in endochondral ossification.
2014-07-04 | Epigenetic deregulation of Ellis Van Creveld confers robust Hedgehog signaling in adult T-cell leukemia.
One of the hallmarks of cancer, global gene expression alteration, is closely associated with the development and malignant characteristics associated with adult T‐cell leukemia ( ATL ) as well as other cancers. Here, we show that aberrant overexpression of the Ellis Van Creveld ( EVC ) family is responsible for cellular Hedgehog ( HH ) activation, which provides the pro‐survival ability of ATL cells. Using microarray, quantitative RT ‐ PCR and immunohistochemistry we have demonstrated that EVC is significantly upregulated in ATL and human T‐cell leukemia virus type I ( HTLV ‐1)‐infected cells. Epigenetic marks, including histone H3 acetylation and Lys4 trimethylation, are specifically accumulated at the EVC locus in ATL samples. The HTLV ‐1 Tax participates in the coordination of EVC expression in an epigenetic fashion. The treatment of sh RNA targeting EVC , as well as the transcription factors for HH signaling, diminishes the HH activation and leads to apoptotic death in ATL cell lines. We also showed that a HH signaling inhibitor, GANT 61, induces strong apoptosis in the established ATL cell lines and patient‐derived primary ATL cells. Therefore, our data indicate that HH activation is involved in the regulation of leukemic cell survival. The epigenetically deregulated EVC appears to play an important role for HH activation. The possible use of EVC as a specific cell marker and a novel drug target for HTLV ‐1‐infected T‐cells is implicated by these findings. The HH inhibitors are suggested as drug candidates for ATL therapy. Our findings also suggest chromatin rearrangement associated with active histone markers in ATL .
2012-09-18 | Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2
Hedgehog (Hh) signaling plays pivotal roles in embryonic development and adult tissue homeostasis in species ranging from Drosophila to mammals. The Hh signal is transduced by Smoothened (Smo), a seven-transmembrane protein related to G protein coupled receptors. Despite a conserved mechanism by which Hh activates Smo in Drosophila and mammals, how mammalian Hh signal is transduced from Smo to the Gli transcription factors is poorly understood. Here, we provide evidence that two ciliary proteins, Evc and Evc2, the products of human disease genes responsible for the Ellis-van Creveld syndrome, act downstream of Smo to transduce the Hh signal. We found that loss of Evc/Evc2 does not affect Sonic Hedgehog-induced Smo phosphorylation and ciliary localization but impedes Hh pathway activation mediated by constitutively active forms of Smo. Evc/Evc2 are dispensable for the constitutive Gli activity in Sufu−/− cells, suggesting that Evc/Evc2 act upstream of Sufu to promote Gli activation. Furthermore, we demonstrated that Hh stimulates binding of Evc/Evc2 to Smo depending on phosphorylation of the Smo C-terminal intracellular tail and that the binding is abolished in Kif3a−/− cilium-deficient cells. We propose that Hh activates Smo by inducing its phosphorylation, which recruits Evc/Evc2 to activate Gli proteins by antagonizing Sufu in the primary cilia.
gene therapies
2026-03-05 | Genetic analysis of children with suspected immunodeficiency: mimickers of inborn errors of immunity.
Inborn errors of immunity (IEI) comprise a heterogeneous group of disorders with diverse clinical manifestations. In this study, we aimed to evaluate genetic findings in patients with suspected IEI and to assess the contribution of next-generation sequencing (NGS) in identifying both IEI-related and non-IEI-related genetic variants. Between January 2020 and January 2025, 91 pediatric patients (0-18 years) referred for suspected IEI were retrospectively analyzed. Demographic data, clinical features, immunological profiles, and genetic results were reviewed, including single-gene sequencing, fluorescence in situ hybridization (FISH), targeted gene panels (TGP), and whole-exome sequencing (WES). Patients analyzed by NGS were classified into three categories according to detected variants: IEI-related, non-IEI-related, and undetected disease-causing variant. A total of 79 patients underwent NGS-based genetic testing. The mean age was 4.37 ± 5.09 years. WES was performed in 40 patients (50.6%) and TGP in 39 (49.4%). Pathogenic variants linked to IEI-related were detected in 28 patients (35.4%), whereas non-IEI-related pathogenic variants were identified in 12 (15.2%). The remaining 39 patients (49.4%) had undetected disease-causing variants. The diagnoses of patients carrying pathogenic variants unrelated to IEI included primary ciliary dyskinesia, Ellis-van Creveld syndrome, desmoglein-1 deficiency, and others. Conclusion: Our study highlights the importance of genetic testing in the differential diagnosis of IEI and provides evidence supporting its role in identifying mixed IEI phenotypes. Comprehensive interpretation of genetic results within a multidisciplinary clinical framework is essential for accurate diagnosis, appropriate management, and effective genetic counseling.
2025-10-01 | Ellis–van Creveld Syndrome with Common Atrium: A Clinically Diagnosed Case Report with Literature Review
Ellis-van Creveld (EVC) syndrome is a rare, autosomal recessive disorder defined by a classic tetrad of features: chondroectodermal dysplasia causing disproportionate short stature, postaxial polydactyly, ectodermal defects affecting the nails and teeth, and congenital heart disease. The most significant cause of morbidity and mortality is the associated cardiac anomaly, most commonly a large atrial septal defect resulting in a functional common atrium. Early and accurate diagnosis is critical for managing cardiovascular risk and implementing appropriate long-term care. We report the case of a 12-year-old female from Pakistan, with a weight of 26 kg (BMI 18.8 kg/m²), who presented with a classic EVC phenotype. Clinical examination revealed short-limb dwarfism, bilateral postaxial polydactyly of all four limbs, genu valgum, and ectodermal dysplasia. Her parents were non-consanguineous. Cardiovascular evaluation confirmed a common atrium via echocardiography, with corresponding ECG findings of right axis deviation and an incomplete right bundle branch block. Based on this distinct constellation of clinical and imaging evidence, a clinical diagnosis was made, as molecular genetic testing was not available. This case confirms the importance of recognizing the distinct clinical phenotype of Ellis-van Creveld syndrome. In settings where molecular diagnostics are unavailable, a confident diagnosis can be made through thorough clinical assessment. Prompt identification is paramount for initiating multidisciplinary management, thereby improving the patient's long-term health and quality of life, with the patient currently awaiting surgical repair of her cardiac defect and referral for orthopedic and dental care.
2019-04-11 | Down-regulated WDR35 contributes to fetal anomaly via regulation of osteogenic differentiation.
Autosomal recessive disorder is closely correlated with congenital fetal malformation. The mutation of WDR35 may lead to short rib-polydactyly syndrome (SRP), asphyxiating thoracic dystrophy (ATD, Jeune syndrome) and Ellis van Creveld syndrome. The purpose of this study is to investigate the role of WDR35 in fetal anomaly. The fetuses presented malformation with abnormal head shape, cardiac dilatation, pericardial effusion, and non-displayed left pulmonary artery and left lung. After the detection of genomic DNA (gDNA) in amniotic fluid cells (AFC), chromosomal rearrangement was found in arr[hg19] 2p25.3p23.3. It was revealed through multiple PCR-DHPLC that MYCN, WDR35, LPIN1, ODC1, KLF11 and NBAS contained duplicated copy numbers in 2p25.3p23.3. AF-MSCs were mostly positive for CD44, CD105, negative for CD34 and CD14. Western Blot test showed that WDR35-encoded protein was decreased in the patients' AFC compared to that in normal pregnant women. In the patients' amniotic fluid-derived mesenchymal stem cells (AF-MSCs), WDR35 overexpression could repair cilia formation, and the overexpression of WDR35 or Gli2 could significantly enhance ALP activity and expressions of osteogenic differentiation marker genes, including RUNXE2, OCN, BSP and ALP. However, WDR35 silencing in C3H10T1/2 cells could remarkably inhibit cilia formation and osteogenic differentiation. This inhibitory effect could be attenuated by Gli2 overexpression. The results demonstrated that copy number variation (CNV) of WDR35 may lead to skeletal dysplasia and fetal anomaly, and that down-regulated WDR35 may damage the cilia formation and sequentially indirectly regulate Gli signal, which would eventually result in negative regulation of osteogenic differentiation.
2016-04-28 | Specific variants in WDR35 cause a distinctive form of Ellis-van Creveld syndrome by disrupting the recruitment of the EvC complex and SMO into the cilium.
Most patients with Ellis-van Creveld syndrome (EvC) are identified with pathogenic changes in EVC or EVC2, however further genetic heterogeneity has been suggested. In this report we describe pathogenic splicing variants in WDR35, encoding retrograde intraflagellar transport protein 121 (IFT121), in three families with a clinical diagnosis of EvC but having a distinctive phenotype. To understand why WDR35 variants result in EvC, we analysed EVC, EVC2 and Smoothened (SMO) in IFT-A deficient cells. We found that the three proteins failed to localize to Wdr35(-/-) cilia, but not to the cilium of the IFT retrograde motor mutant Dync2h1(-/-), indicating that IFT121 is specifically required for their entry into the ciliary compartment. Furthermore expression of Wdr35 disease cDNAs in Wdr35(-/-) fibroblasts revealed that the newly identified variants lead to Hedgehog signalling defects resembling those of Evc(-/-) and Evc2(-/-) mutants. Together our data indicate that splicing variants in WDR35, and possibly in other IFT-A components, underlie a number of EvC cases by disrupting targeting of both the EvC complex and SMO to cilia.
cell therapies
2021-12-28 | Ellis-Van-Creveld Syndrome and Congenital Cardiac Anomaly: Common Atrium with Atrioventricular Canal Septal Defect
Background: Children presenting with physical features of chondro-ectodermal dysplasia (Ellis-Van Creveld syndrome) such as skeletal and joint abnormalities often have concomitant congenital cardiac anomalies. Presence of cardiorespiratory symptoms in children with Ellis-Van Craved syndrome warrants a thorough cardiologic evaluation to recognize and treat underlying congenital heart anomaly. Aim: A child with physical stigmata of Ellis-Van-Creveld syndrome is evaluated to detect an associated congenital cardiac anomaly and accomplish successful repair of the underlying cardiac lesion to reduce the cardiac related morbidity and improve the patient survival. Case Presentation: Ten years old boy with chondroectodermal dysplasia (dental anomalies, genu valgum and other skeletal abnormalities) presented with dyspnea and cyanosis. Cardiac evaluation by 2D echo revealed an atrioventricular (AV) canal septal defect with AV valve regurgitation and a common atrium. Angiocardiography showed a goose neck deformity of the left ventricular outflow tract. The Qp/Qs was 3.4: 1, with systemic arterial oxygen desaturation (SaO2 of 0.7) and O2 saturation in the common atrium was 0.7. The pulmonary venous connections to the common atrium were anomalous. Atriotomy on cardiopulmonary bypass and on a cardioplegic arrest discerned a partial AV canal septal defect with a common bridging leaflet, clefts in septal leaflets of tricuspid and mitral vlalves, an incompletely closed interventricular communication, and a common atrium with highly anomalous pulmonary venous insertions well anterior (8 cm) to vena caval orifices. Intracardiac repair was performed with two patches of Goertex to partition the common atrium into the pulmonary and systemic venous chambers after repair of the partial AV canal septal defect. Patient required only a temporary afterload reduction with enalapril; otherwise patient had an uneventful postoperative course. At a 2-year follow-up, the child was well without AV valve regurgitation and had normal biventricular function. Conclusion: A child with Ellis-Van-Creveld syndrome with skeletal abnormalities and dental anomalies had manifested with cardio-respiratory symptoms. Preoperative cardiac and intraoperative evaluation showed a common atrium with severely anomalous pulmonary venous connection and partial AV canal septal defect. Successful biventricular repair was accomplished by repairing the partial AV canal septal defect and partitioning the common atrium into left and right atrium by a complex atrial routing technique with two patches of Gore-Tex. On a follow-up at 2 years, the patient had adequate biventricular function without AV valve regurgitation. 114264
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