Inherited Heart Disease

Ellis-van Creveld Syndrome

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. Note the narrow chest.

Postaxial polydactyly

Natal teeth and lip tie.

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).
• 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 & Age

• Frequency of Ellis–van Creveld syndrome is equal in males and females.
• 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.
  • 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
    • Heart defects occur in 50-60% of patients; the most common anomaly is a common atrium (40%).
    • Other cardiac anomalies include atrioventricular canal, ventricular septal defect, atrial spetal 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 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 hypospedias, 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 carriers
  • Polydactyly has been reported in relatives of 4 unrelated Ellis–van Creveld syndrome families.
  • 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.
  • 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.

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.

Prognosis

• Approximately 50% of patients with Ellis–van Creveld (EVC) syndrome 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.
• End-organ involvement may include the following:
  • Renal involvement including nephrotic syndrome, nephronophthisis, and renal failure
  • Hepatic involvement, including a congenital paucity of bile ducts that leads to progressive fibrosis and hepatic failure
  • Hematologic involvement ranges from myelodysplastic changes with dyserythropoiesis to acute leukemia.

Treatment

Medical Care

• The management of Ellis–van Creveld (EVC) syndrome is multidisciplinary.
• Care for respiratory distress, recurrent respiratory infections, and cardiac failure is supportive.
• Dental care in childhood includes the following:
  • Neonatal teeth should be removed because they may impair feeding.
  • Prevention of caries includes dietary counseling, plaque control, and oral hygiene instruction.
  • Crown or composite build-ups for microdonts may be indicated.
  • Partial dentures can maintain space and improve mastication, esthetics, and speech due to congenitally missing teeth.
  • Orthodontic treatment is needed for bone deformity, especially knee valgus with depression of the lateral tibial plateau and dislocation of the patella.
• For dental care during adulthood, implants and prosthetic rehabilitation are required to replace congenitally missing teeth.
• Short stature is considered resulting of chondrodysplasia of the legs and the possible treatment with growth hormone is considered ineffective, unless the patient is also deficient in growth hormone.

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.
• Perioperative morbidity may result from difficulties with airway management and pulmonary abnormalities.¹⁵
  • Although these concerns are less common than congenital heart disease, abnormalities leading to difficulties in airway management include cleft lip and plate orodental malformations.
  • Frenulae, or fusions between the inner upper lip and gum, as well as maxillary or mandibular deformities, may lead to difficulties in bag-valve-mask ventilation and should be identified during the preoperative evaluation.
  • Dental abnormalities, such as peg teeth or natal teeth, may be more prone to dislodgement during airway instrumentation.
  • A single report describes a patient with Ellis–van Creveld syndrome who presented with congenital stridor related to a cyst involving the neck and airway.

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

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

Differential Diagnoses

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.

Workup

Laboratory Studies

• Sequencing of EVC and EVC2 identified mutations in two thirds of patients with Ellis-van Creveld (EVC) syndrome.
• Gene testing for mutational analysis of EVC and EVC2 is not currently available clinically.

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, and 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.