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Pediatrics: Genetics and Metabolic Disease > Genetics
Ellis-van Creveld Syndrome
Article Last Updated: Nov 6, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Harold Chen, MD, MS, FAAP, FACMG, Professor, Departments of Pediatrics, Obstetrics and Gynecology, Pathology, Director of Perinatal Genetics and Genetic Laboratory Services, Louisiana State University Medical Center; Laboratory Director, Hema-Con Cancer Cytogenetics Laboratory, Gainesville, Florida
Harold Chen is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Human Genetics, and Teratology Society
Coauthor(s):
Ayala Laufer-Cahana, MD, Fellow, Division of Human Genetics and Molecular Biology, Department of Pediatrics, The Children's Hospital of Philadelphia
Editors: Michael Fasullo, PhD, Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; Bruce Buehler, MD, Professor, Department of Pathology and Microbiology, Director, Hattie B Munroe Center for Human Genetics, Chairman, Department of Pediatrics, University of Nebraska Medical Center
Author and Editor Disclosure
Synonyms and related 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
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 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.
Pathophysiology
Pathophysiology is unknown; however, recent identification of the EVC gene should lead to a better understanding. 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. 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).1 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.
History
- In the prenatal period, intrauterine growth retardation, skeletal malformations, and cardiac defects can be depicted on ultrasound images.
- 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.
- 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
- 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.
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.2 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.3
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.
Other Problems to be Considered
Other short rib polydactyly syndromes include the following:
- Saldino-Noonan syndrome, type I
- Majewski syndrome, type II
- Verma-Naumoff syndrome, type III
- Beemer-Langer syndrome, type IV
- Asphyxiating thoracic dystrophy (Jeune syndrome)
Polydactyly and hypodontia have been described in Weyers acrodental dysostosis, which is allelic with EVC and in trisomy 13. Weyers acrodental dysostosis is an autosomal dominant condition that is the heterozygous manifestation of the EVC gene; disproportionate dwarfism, heart defect, and thoracic dysplasia are not present.
Lab Studies
- Sequencing of EVC and EVC2 identified mutations in two thirds of patients with Ellis-van Creveld syndrome.4
- Gene testing for mutational analysis of EVC and EVC2 is not currently available (for up-to-date information on gene testing, see Gene Tests).
Imaging Studies
- A skeletal survey is necessary to define skeletal anomalies. Expected findings include the following:
- Acromesomelia (relative shortening of the distal and middle segment of the limbs) - Most prominent in the hands, where the distal and middle phalanges are shorter than the proximal phalanx
- Polydactyly (ulnar side)
- Multiple varieties of carpal fusion
- Small iliac crests and sciatic notches (may be revealed on pelvic radiographs)
- Valgus deformity of the knee
- Fibula disproportionately smaller than the tibia
- Thorax (short ribs, narrow)
- Retarded bone maturation
- Other findings - Fusion of the hamate and capitate bones of the wrist, cubitus valgus, hypoplastic cubitus, supernumerary carpal bone center, clinodactyly of the 5th finger
- Chest radiography, ECG, echocardiography (to evaluate cardiac anatomy) are indicated.
- Head MRI may infrequently reveal brain anomalies.
- Renal ultrasonography may infrequently reveal renal anomalies.
Other Tests
- Consider eye examination to exclude eye anomalies, which have been infrequently described.
Histologic Findings
- Disorganization of chondrocytes in the physeal growth zone of the long bones and vertebrae in the prenatal period and retardation of physeal growth zones in childhood
Medical Care
- Care for respiratory distress, recurrent respiratory infections, and cardiac failure is supportive.
- Dental care in childhood includes the following:
- Prevention of caries with dietary counseling, plaque control, and oral hygiene instruction
- Crown or composite build-ups for microdonts
- Partial dentures to maintain space and improve mastication, esthetics, and speech because of congenitally missing teeth
- Orthodontic treatment
- For dental care during adulthood, implants and prosthetic rehabilitation are required to replace congenitally missing teeth.
Surgical Care
- Orthopedic procedures correct polydactyly and other orthopedic malformations.
- Cardiac surgery may be needed to correct cardiac anomalies.
- Thoracic expansion has been attempted in some patients.
- Dental care is usually necessary.
- Urologic surgery is required if epispadias, cryptorchidism, or both are present.
Consultations
- Clinical geneticist
- Cardiologist
- Pulmonologist
- Orthopedist
- Urologist
- Physical and occupational therapist
- Dentist
- Psychologist
- Developmental pediatrician (if developmental delay is present)
- Pediatric neurologist (if developmental delay is present)
Diet
No special diet is required unless cardiac failure necessitates dietary restrictions.
Activity
Activities may be limited secondary to cardiorespiratory status or skeletal anomalies.
Specific drug therapy is not currently a component of the standard of care for Ellis–van Creveld syndrome. Treat systemic sequelae as needed (see Treatment).
Prognosis
- Approximately 50% of patients die in early infancy as a consequence of cardiorespiratory problems. Most survivors have intelligence in the normal range.
- Final adult height is 43-60 inches.
- Usually, some limitation of hand function is observed, such as inability to form a clenched fist.
- Dental problems are frequent.
Patient Education
- The following organizations may provide helpful information for patients and their families:
- Ellis-van Creveld Support Group
17 Bridlewood Trail
Honeoye Falls, NY 14472
Telephone: 716-624-8277 or 800-644-6735
email: olesik@juno.com - The National Institutes of Health maintains a Web site for the Office of Rare Diseases.
Medical/Legal Pitfalls
- Failure to identify anomalies on prenatal ultrasonography
- Failure to inform parents of the 25% recurrence risk and offer prenatal diagnosis for future pregnancies
- Failure to fully evaluate the affected patient for cardiac anomalies
Special Concerns
- Genetic counseling
- Recurrence risk to patient's siblings is 25%.
- Recurrence risk to patient's offspring is not increased unless the spouse is a carrier, especially in a consanguineous marriage.
- Prenatal diagnosis
- Fetoscopy may be performed to visualize the fetus with postaxial polydactyly, short distal limbs, and postaxial polydactyly. Fetoscopy is an invasive procedure and is seldom currently used.
- Level II ultrasonography after 18 weeks' gestation is used to reveal a narrow chest, postaxial polydactyly, short limbs (especially of middle and distal segments), and a single atrium. Fetal echocardiography is used in conjunction to delineate fetal cardiac pathologies.
- Molecular genetic testing by amniocentesis or chorion villi biopsy, using linked microsatellite markers flanking the EVC locus, provided the linked markers have been established in the family with a previously affected sibling. Prenatal diagnosis can also be established using mutation analysis of EVC gene from fetal DNA.
| Media file 1:
Newborn with Ellis–van Creveld syndrome. Note the narrow chest. |
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| Media file 4:
Newborn with Ellis–van Creveld syndrome. Note the narrow chest and disproportionate dwarfism. |
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Ellis-van Creveld Syndrome excerpt Article Last Updated: Nov 6, 2007
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