Ellis-van Creveld Syndrome Clinical Presentation

Updated: Apr 21, 2015
  • Author: Harold Chen, MD, MS, FAAP, FACMG; Chief Editor: Maria Descartes, MD  more...
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See the list below:

  • 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.


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
    • Heart defects occur in 50-60% of patients; the most common anomaly is a common atrium (40%).
    • Review of the cardiac phenotype in patients with Ellis–van Creveld syndrome reveals a characteristic pattern of atrioventricular canal defects with systemic and pulmonary venous abnormalities. The frequent association of these abnormalities is strongly reminiscent of the cardiac phenotype found in patients with heterotaxy syndromes. Emerging molecular and developmental studies suggest that EVC and EVC2 proteins may be important for cilia function, which is implicated in the pathogenesis of heterotaxy syndromes. It is speculated that coordinated function between the EVC proteins is required for a cilia-dependent cardiac morphogenesis. [4]
    • The cardiac anomaly is the major cause of shortened life expectancy. [5]

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.
  • Ellis-van Creveld syndrome presents phenotypically diverse oral manifestations of the soft tissues and teeth. These include hyperplastic frenula, absence of mucobuccal fold, serrations of the alveolar ridge, multiple small alveolar notches, partial cleft lip, neonatal teeth, peg-shaped laterals, partial anodontia, conical and microdontic teeth, enamel hypoplasia, and delayed eruption of teeth. [6]
  • 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 carriers [3]

  • Polydactyly has been reported in relatives of 4 unrelated Ellis–van Creveld syndrome families. [7, 8]
  • 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. [9]
  • 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. [10, 11, 12]


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. [13] 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 EVC1 have been described in Amish and Brazilian pedigrees of Ellis–van Creveld syndrome but only accounted for a small proportion of affected cases, thereby suggesting that Ellis–van Creveld syndrome is a heterogeneous disease. [14] More recently, mutations in a second gene, EVC2, have been described in an Ashkenazi child with Ellis–van Creveld syndrome. [15] The Evc protein was shown to localize to the base of the primary cilium of chondrocytes, and defective Ihh signalling was observed in proliferating chondrocytes of Evc-nullmice. Currently, Ellis–van Creveld syndrome is considered to be a ciliopathy. [16]

Skeletal conditions belonging to the ciliopathy group [17] include (1) short rib-polydactyly group, including its oldest examples, asphyxiating thoracic dystrophy (Jeune syndrome) and Ellis–van Creveld syndrome; (2) Sensenbrenner syndrome and its fetal variant; and (3) Weyers acrofacial dysostosis. [18]

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. [10, 11, 12]

A report by Ginns et al suggested that the EVC gene protects against bipolar affective disorder. The investigators pointed out that even though several Old Order Amish families have demonstrated a high prevalence of both Ellis-van Creveld syndrome and bipolar disorder type I, the two conditions have not been found together in the same individual. Moreover, since homozygous Amish EVC mutations disrupt signaling by the sonic hedgehog protein, the investigators suggested that the protein is in some way associated with bipolar affective disorder. [19]