AUTHOR INFORMATION

Section 1 of 12

Authored by Harold Chen, MD, MS, FAAP, FACMG, Chief, Professor, Department of Pediatrics, Section of Perinatal Genetics, Louisiana State University Medical Center

Coauthored by Ayala Laufer-Cahana, MD, Fellow, Department of Pediatrics, Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia

Harold Chen, MD, MS, FAAP, FACMG, is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, American Society of Human Genetics, and Teratology Society

Edited by 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; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Harold Chen, MD, MS, FAAP, FACMG
Editor's Email:	Michael Fasullo, PhD

eMedicine Journal, April 24 2006, VOLUME 7, Number 4

INTRODUCTION

Section 2 of 12

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 they 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:

• In the US: 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. 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

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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:

• 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 is observed in the hands in most cases but in the feet in only 10% of cases.
  
  
  
  • Ectodermal dysplasia (observed in up to 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.
  
  
  
  • Cardiac anomalies
    • Heart defects occur in 50-60% of patients; the most common anomaly is a common atrium (40%).

    • Other cardiac anomalies include AV canal, ventricular septal defect, atrial septal defect, and patent ductus arteriosus.

    • The cardiac anomaly is the major cause of shortened life expectancy.
  
  
  
• 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
    • A fusion of the anterior portion of the upper lip to the maxillary gingival margin resulting in 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.
  
  
  
  • Occasional CNS anomalies or mental retardation
  
  
  

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. 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. 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.

DIFFERENTIALS

Section 4 of 12

Other Problems to be Considered:

Other short rib polydactyly syndromes
Asphyxiating thoracic dystrophy (Jeune syndrome)
Polydactyly and hypodontia (described in Weyers acrodental dysostosis, which is allelic with EVC and in trisomy 13)

WORKUP

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Lab Studies:

• Gene testing for mutational analysis may be developed now that the EVC gene has been identified (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)
  
  
  
• Chest radiograph, ECG, echocardiogram (to evaluate cardiac anatomy)



• Head MRI (brain anomalies infrequent)



• Renal ultrasound (renal anomalies infrequent)

Other Tests:

• Histopathology - 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 the childhood



• Consider eye examination to exclude eye anomalies, which have been infrequently described.
  

TREATMENT

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Medical Care: Care for respiratory distress, recurrent respiratory infections, and cardiac failure is supportive.

• Dental care in childhood


• • 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
  
  
  
• 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.

MEDICATION

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Specific drug therapy currently is not a component of the standard of care for Ellis–van Creveld syndrome. Treat systemic sequelae as needed (see Treatment).

FOLLOW-UP

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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 exists, 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
    Tel: 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.
  
  
  

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Failure to identify anomalies on prenatal ultrasound



• 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 is used to visualize a narrow chest, postaxial polydactyly, short limbs especially of middle and distal segments, and a single atrium. Fetal echocardiography is used in conjunction for delineating 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.
  
  
  

TEST QUESTIONS

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CME Question 1: Which of the following physical features is not a characteristic in patients with Ellis–van Creveld syndrome?

A: Disproportionately short stature
B: Hypoplastic nails
C: Preaxial polydactyly
D: Dental abnormalities
E: Small thorax

The correct answer is C: Postaxial (ulnar side) polydactyly is a feature. Preaxial (radial side) polydactyly is not a feature seen in patients with Ellis–-van Creveld syndrome.

CME Question 2: In which of the following populations is Ellis–-van Creveld syndrome found more commonly?

A: Jewish persons of Ashkenazi descent
B: Persons of English and Scottish descent
C: Persons of Old Order Amish descent
D: Parents with advanced age at delivery
E: Equally common in all ethnic groups

The correct answer is C: In the general population, incidence of Ellis–-van Creveld syndrome is 1 case per 60,000 live births. In the Old Order Amish, frequency is estimated at 5 cases per 1000 live births. The frequency of carriers in this population is as high as 13%.

Pearl Question 1 (T/F): Following the birth of a child with Ellis–-van Creveld syndrome, the risk that future children born to this couple will have the syndrome is 25%.

The correct answer is True: Both parents are probably carriers of a mutation in the gene for Ellis–-van Creveld syndrome. The gene for Ellis–-van Creveld syndrome is inherited in an autosomal recessive pattern.

Pearl Question 2 (T/F): Prenatal diagnosis is possible in fetuses with Ellis–-van Creveld syndrome.

The correct answer is True: Skeletal and cardiac anomalies can be seen on prenatal ultrasound images. Recent identification of the gene will make mutational analysis possible in the fetus.

Pearl Question 3 (T/F): The most important factors for determining the prognosis of a newborn with Ellis–-van Creveld syndrome are the final predicted height and hand anomalies.

The correct answer is False: The presence and nature of a heart defect and the severity of thoracic dysplasia are the most important factors determining prognosis, since these are the leading causes of death in patients with Ellis–-van Creveld syndrome.

Pearl Question 4 (T/F): The incidence of heart defects in patients with Ellis–-van Creveld syndrome is 20-30%.

The correct answer is False: Incidence is approximately 50-60%. The most common heart defect is a common atrium.

PICTURES

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Caption: Picture 1. Newborn with Ellis–van Creveld syndrome. Note the narrow chest.
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Caption: Picture 2. Natal teeth and lip tie.
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Caption: Picture 3. Postaxial polydactyly.
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Caption: Picture 4. Newborn with Ellis–van Creveld syndrome. Note the narrow chest and disproportionate dwarfism.
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BIBLIOGRAPHY

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• Arya L, Mendiratta V, Sharma RC, Solanki RS: Ellis-van Creveld Syndrome: a report of two cases. Pediatr Dermatol 2001 Nov-Dec; 18(6): 485-9[Medline].
• Cahuana A, Palma C, Gonzáles W, Gean E: Oral manifestations in Ellis-van Creveld syndrome: report of five cases. Pediatr Dent 2004 May-Jun; 26(3): 277-82[Medline].
• Chen H: Ellis-van Creveld syndrome. In: Atlas of Genetic Diagnosis and Counseling. Humana Press; 2006:350-354.
• Dugoff L, Thieme G, Hobbins JC: First trimester prenatal diagnosis of chondroectodermal dysplasia (Ellis-van Creveld syndrome) with ultrasound. Ultrasound Obstet Gynecol 2001 Jan; 17(1): 86-8[Medline].
• Galdzicka M, Patnala S, Hirshman MG, et al: A new gene, EVC2, is mutated in Ellis-van Creveld syndrome. Mol Genet Metab 2002 Dec; 77(4): 291-5[Medline].
• 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 1997 Dec; 61(6): 1405-12[Medline].
• 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 1996 Nov; 98(5): 572-5[Medline].
• Jones KL: Chondroectodermal dysplasia. In: Smith's Recognizable Patterns of Human Malformation. 5th ed. WB Saunders Co; 1997:374-5.
• Mahoney MJ, Hobbins JC: Prenatal diagnosis of chondroectodermal dysplasia (Ellis-van Creveld syndrome) with fetoscopy and ultrasound. N Engl J Med 1977 Aug 4; 297(5): 258-60[Medline].
• McKusick VA, EgelandJA, Eldridge R: Dwarfism in the Amish. I. The Ellis van Creveld syndrome. Bull Johns Hopkins Hosp 1964 Oct; 115: 306-36[Medline].
• McKusick VA: Ellis-van Creveld syndrome and the Amish. Nat Genet 2000 Mar; 24(3): 203-4[Medline].
• Polymeropoulos MH, Ide SE, Wright M, et al: The gene for the Ellis-van Creveld syndrome is located on chromosome 4p16. Genomics 1996 Jul 1; 35(1): 1-5[Medline].
• Qureshi F, Jacques SM, Evans MI, et al: Skeletal histopathology in fetuses with chondroectodermal dysplasia (Ellis-van Creveld syndrome). Am J Med Genet 1993 Feb 15; 45(4): 471-6[Medline].
• Rosemberg S, Carneiro PC, Zerbini MC, Gonzalez CH: Brief clinical report: chondroectodermal dysplasia (Ellis-van Creveld) with anomalies of CNS and urinary tract. Am J Med Genet 1983 Jun; 15(2): 291-5[Medline].
• 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 2000 Mar; 24(3): 283-6[Medline].
• Sergi C, Voigtländer T, Zoubaa S, et al: Ellis-van Creveld syndrome: a generalized dysplasia of enchondral ossification. Pediatr Radiol 2001 Apr; 31(4): 289-93[Medline].
• Tongsong T, Chanprapaph P: Prenatal sonographic diagnosis of ellis-van creveld syndrome. J Clin Ultrasound 2000 Jan; 28(1): 38-41[Medline].
• Torrente I, Mangino M, De Luca A, et al: First-trimester prenatal diagnosis of Ellis-van Creveld syndrome using linked microsatellite markers. Prenat Diagn 1998 May; 18(5): 504-6[Medline].
• Zangwill KM, Boal DK, Ladda RL: Dandy-Walker malformation in Ellis-van Creveld syndrome. Am J Med Genet 1988 Sep; 31(1): 123-9[Medline].

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