eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Ellis-van Creveld Syndrome

Author: Harold Chen, MD, MS, FAAP, FACMG, Professor, Departments of Pediatrics, Obstetrics and Gynecology, and Pathology, Director of Genetic Laboratory Services, Louisiana State University Medical Center
Contributor Information and Disclosures

Updated: Jun 30, 2009

Introduction

Background

  • Richard W.B. Ellis of Edinburgh and Simon van Creveld of Amsterdam first described Ellis–van Creveld (EVC) syndrome. They met in a train compartment while traveling to a pediatrics conference in England in the late 1930s and discovered that each had a patient with the syndrome. In 1940, Ellis and van Creveld (Ellis and van Creveld, 1940) formally described the syndrome that would bear their names, although they termed it chondroectodermal dysplasia.
  • Disproportionate dwarfism, postaxial polydactyly, ectodermal dysplasia, a small chest, and a high frequency of congenital heart defects characterize this autosomal recessive syndrome, which has increased incidence among persons of Old Order Amish descent.

    Newborn with Ellis–van Creveld syndrome. No...

    Newborn with Ellis–van Creveld syndrome. Note the narrow chest.

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    Newborn with Ellis–van Creveld syndrome. No...

    Newborn with Ellis–van Creveld syndrome. Note the narrow chest.



    Postaxial polydactyly.

    Postaxial polydactyly.

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    Postaxial polydactyly.

    Postaxial polydactyly.



    Newborn with Ellis–van Creveld syndrome. Not...

    Newborn with Ellis–van Creveld syndrome. Note the narrow chest and disproportionate dwarfism.

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    Newborn with Ellis–van Creveld syndrome. Not...

    Newborn with Ellis–van Creveld syndrome. Note the narrow chest and disproportionate dwarfism.



    Natal teeth and lip tie.

    Natal teeth and lip tie.

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    Natal teeth and lip tie.

    Natal teeth and lip tie.

Pathophysiology

  • Pathophysiology is unknown; however, recent identification of the EVC gene should lead to a better understanding.1
  • Histopathologic examination of fetuses with Ellis–van Creveld syndrome revealed that the cartilage of long bones showed chondrocyte disorganization in the physeal growth zone. Variable chondrocyte disorganization was seen in the central physeal growth zone of the vertebrae.

Frequency

United States

  • In the general population, the frequency is 1 case per 60,000 live births.
  • Among persons from the Old Order Amish, the incidence is estimated at 5 cases per 1000 live births.2
  • The frequency of carriers in this population may be as high as 13%.

Mortality/Morbidity

  • Thoracic dysplasia leads to respiratory insufficiency and cardiac anomalies lead to death in infancy in 50% of patients.
  • Patients who survive infancy have a normal life expectancy.

Race

  • The highest frequency of Ellis–van Creveld syndrome is seen in one particular inbred population, the Old Order Amish community in Lancaster County, Pennsylvania, where the largest pedigree has been described (52 cases in 30 sibships).2
  • Among the Amish, the abnormal gene can be traced to the immigrants Samuel King and his wife, whose identity is not known.
  • No other ethnic group has a high incidence of Ellis–van Creveld syndrome.

Sex

  • Frequency of Ellis–van Creveld syndrome is equal in males and females.

Age

  • In patients with Ellis–van Creveld syndrome, physical findings, such as disproportionate extremities, small stature, polydactyly, cardiac defects, and minor dysmorphic features, are seen at birth.

Clinical

History

  • In the prenatal period, intrauterine growth retardation, skeletal malformations, and cardiac defects can be depicted on ultrasound images in fetuses with Ellis–van Creveld (EVC) syndrome.
  • Family history may include parental consanguinity or previously affected siblings or family members.
  • Neonatal history may include small size at birth, slow growth, and skeletal anomalies are the initial symptoms. Natal teeth may be present.
  • Heart disease may be manifested as failure to thrive, cyanosis, shortness of breath, cardiac murmur, or other signs suggestive of heart failure.
  • Developmentally, most patients have had intelligence in the normal range. Occasionally, patients present with associated brain malformations and developmental delay.

Physical

  • The variable phenotype affects multiple organs.
  • A clinical tetrad of Ellis–van Creveld syndrome consists of chondrodystrophy, polydactyly, ectodermal dysplasia, and cardiac anomalies.3
    • Chondrodystrophy (the most common feature affecting the tubular bones)
      • Disproportionate dwarfism (small stature of prenatal onset; average adult height, 109-155 cm)
      • Progressive distal limb shortening, symmetrically affecting the forearms and lower legs
    • Polydactyly (constant findings)
      • Bilateral and postaxial
      • Polydactyly, observed in the hands in most cases but in the feet in 10% of cases
    • Hidrotic ectodermal dysplasia (observed in as many as 93% of cases)
      • Nails are hypoplastic, dystrophic, and friable. Nails can be completely absent in some cases.
      • Tooth involvement may include neonatal teeth, partial anodontia, small teeth, and delayed eruption. Enamel hypoplasia may result in abnormally shaped teeth with frequent malocclusion.
      • Hair may occasionally be sparse.
    • Congenital cardiac anomalies
  • Other anomalies may also be present.
    • Musculoskeletal anomalies include low-set shoulders, a narrow thorax frequently leading to respiratory difficulties, knock knees, lumbar lordosis, broad hands and feet, and sausage-shaped fingers.
    • Oral lesions include the following:
      • A fusion of the anterior portion of the upper lip to the maxillary gingival margin, resulting in an absence of mucobuccal fold and the upper lip to present a slight V-notch in the middle
      • Short upper lip, bound by frenula to alveolar ridge (lip tie)
      • Often serrated lower alveolar ridge
      • Teeth may be prematurely erupted at birth or exfoliate prematurely
    • Occasional genitourinary anomalies include hypospadias, epispadias, hypoplastic penis, cryptorchidism, vulvar atresia, focal renal tubular dilation in medullary region, nephrocalcinosis, renal agenesis, and megaureters.
    • Occasionally, CNS anomalies or mental retardation are present.
  • Clinical manifestations in heterozygous carriers3
    • Polydactyly has been reported in relatives of 4 unrelated Ellis–van Creveld syndrome families.5,6
    • A father of a child with Ellis–van Creveld syndrome who had finger and teeth abnormalities has been reported, as have several other reports of symptomatic heterozygous manifestations.7
    • The Weyers acrofacial dysostosis, an autosomal dominant disorder described in 1952, is characterized by variable extremities and facial features. This condition has been found to be associated with EVC and EVC2 mutations that have confirmed that Weyers dysostosis represents the heterozygous expression of the mutation that causes Ellis–van Creveld syndrome.8,9,10

Causes

  • Ellis–van Creveld syndrome has an autosomal recessive inheritance.
  • The EVC gene has been mapped to chromosome band 4p16 using linkage analysis of 9 interrelated Amish pedigrees and 3 unrelated families from Mexico, Ecuador, and Brazil.11 A 992 amino acid protein encoded by this gene is predicted to contain a leucine zipper domain, 3 putative nuclear localization signals, and a putative transmembrane domain.
  • Mutations in the EVC gene were identified in patients with Ellis–van Creveld syndrome.
  • Ellis–van Creveld syndrome is also caused by mutations in a second gene, called EVC2, that gives rise to the same phenotype of the syndrome.12
  • Patients with Weyers acrodental dysostosis were also found to have mutations in the gene, which confirms that Ellis–van Creveld syndrome and Weyers dysostosis are allelic.8,9,10

More on Ellis-van Creveld Syndrome

Overview: Ellis-van Creveld Syndrome
Differential Diagnoses & Workup: Ellis-van Creveld Syndrome
Treatment & Medication: Ellis-van Creveld Syndrome
Follow-up: Ellis-van Creveld Syndrome
Multimedia: Ellis-van Creveld Syndrome
References
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References

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  2. McKusick VA. Ellis-van Creveld syndrome and the Amish. Nat Genet. Mar 2000;24(3):203-4. [Medline].

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  6. Goldblatt J, Minutillo C, Pemberton PJ, Hurst J. Ellis-van Creveld syndrome in a Western Australian aboriginal community. Postaxial polydactyly as a heterozygous manifestation?. Med J Aust. Aug 17 1992;157(4):271-2. [Medline].

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  8. Ruiz-Perez VL, Ide SE, Strom TM, et al. Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis. Nat Genet. Mar 2000;24(3):283-6. [Medline].

  9. Ruiz-Perez VL, Ide SE, Strom TM, et al. Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis. Nature Genet. 2000;24:283-286.

  10. Ye X, Song G, Fan M, Shi L, Jabs EW, Huang S. A novel heterozygous deletion in the EVC2 gene causes Weyers acrofacial dysostosis. Hum Genet. Mar 2006;119(1-2):199-205. [Medline].

  11. Howard TD, Guttmacher AE, McKinnon W, et al. Autosomal dominant postaxial polydactyly, nail dystrophy, and dental abnormalities map to chromosome 4p16, in the region containing the Ellis-van Creveld syndrome locus. Am J Hum Genet. Dec 1997;61(6):1405-12. [Medline].

  12. Galdzicka M, Patnala S, Hirshman MG, et al. A new gene, EVC2, is mutated in Ellis-van Creveld syndrome. Mol Genet Metab. Dec 2002;77(4):291-5. [Medline].

  13. Shibata T, Kawabata H, Yasui N, et al. Correction of knee deformity in patients with Ellisvan Creveld syndrome. J Pediatr Orthop B. 1999;8:282-284.

  14. Pirazzoli P, Mazzanti L, Mandini M, Cau M, Ravagli L, Cacciari E. GH-deficiency in Ellis-van-Crefeld Syndrome: response to remplacementtherapy. Growth Abnormalities. 1989;56:391-3.

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  18. Digoy GP, Greenberg M, Magit A. Congenital stridor secondary to an upper airway cyst in a patient with Ellis-van Creveld syndrome. Int J Pediatr Otorhinolaryngol. Oct 2005;69(10):1433-5. [Medline].

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  20. Moudgil A, Bagga A, Kamil ES, et al. Nephronophthisis associated with Ellis-van Creveld syndrome. Pediatr Nephrol. Jan 1998;12(1):20-2. [Medline].

  21. Datta V, Chaturvedi P. Ellis-Van Creveld syndrome associated with nodular sclerosing Hodgkin's disease and nephrotic syndrome. Indian J Pediatr. Dec 2000;67(12):929-30. [Medline].

  22. Black D, Reutter J, Johnson M, Fair J, Woosley J, Gerber D. Liver transplantation in Ellis-van Creveld syndrome: a case report. Pediatr Transplant. Jun 2002;6(3):255-9. [Medline].

  23. Miller DR, Newstead GJ, Young LW. Perinatal leukemia with a possible variant of the Ellis-van Greveld syndrome. J Pediatr. Feb 1969;74(2):300-3. [Medline].

  24. Scurlock D, Ostler D, Nguyen A, Wahed A. Ellis-van Creveld syndrome and dyserythropoiesis. Arch Pathol Lab Med. May 2005;129(5):680-2. [Medline].

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  27. Venkat-Raman N, Sebire NJ, Murphy KW, Carvalho JS, Hall CM. Increased first-trimester fetal nuchal translucency thickness in association with chondroectodermal dysplasia (Ellis-Van Creveld syndrome). Ultrasound Obstet Gynecol. Apr 2005;25(4):412-4. [Medline].

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  33. Galdzicka M, Patnala S, Hirshman MG, Cai JF, Nitowsky H, Egeland JA. A new gene, EVC2, is mutated in Ellis-van Creveld syndrome. Mol Genet Metab. Dec 2002;77(4):291-5. [Medline].

  34. Ide SE, Ortiz de Luna RI, Francomano CA, Polymeropoulos MH. Exclusion of the MSX1 homeobox gene as the gene for the Ellis van Creveld syndrome in the Amish. Hum Genet. Nov 1996;98(5):572-5. [Medline].

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  41. Qureshi F, Jacques SM, Evans MI, et al. Skeletal histopathology in fetuses with chondroectodermal dysplasia (Ellis-van Creveld syndrome). Am J Med Genet. Feb 15 1993;45(4):471-6. [Medline].

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  44. Tompson SW, Ruiz-Perez VL, Wright MJ, Goodship JA. Ellis-van Creveld syndrome resulting from segmental uniparental disomy of chromosome 4. J Med Genet. Jun 2001;38(6):E18. [Medline].

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Further Reading

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Keywords

Ellis-van Creveld syndrome, EVC syndrome, chondroectodermal dysplasia, disproportionate dwarfism, postaxial polydactyly, ectodermal dysplasia, common atrium, small chest, congenital heart defects, thoracic dysplasia, skeletal malformations, cardiac murmur, heart failure, hypoplastic nails, dystrophic nails, anodontia, enamel hypoplasia, atrioventricular canal, ventricular septal defect, atrial septal defect, patent ductus arteriosus, hypospadias, epispadias, hypoplastic penis, cryptorchidism, vulvar atresia, focal renal tubular dilation in medullary region, nephrocalcinosis, renal agenesis, megaureters, respiratory insufficiency, treatment, diagnosis

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Contributor Information and Disclosures

Author

Harold Chen, MD, MS, FAAP, FACMG, Professor, Departments of Pediatrics, Obstetrics and Gynecology, and Pathology, Director of Genetic Laboratory Services, Louisiana State University Medical Center
Harold Chen, MD, MS, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Human Genetics, and Teratology Society
Disclosure: Nothing to disclose.

Medical Editor

Michael Fasullo, PhD, Senior Scientist, Ordway Research Institute; Associate Professor, State University of New York at Albany; Adjunct Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College
Michael Fasullo, PhD is a member of the following medical societies: Radiation Research Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia
David Flannery, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics and American College of Medical Genetics
Disclosure: Nothing to disclose.

CME Editor

Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine
Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine
Disclosure: Baxter Honoraria Consulting

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

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