Ellis-van Creveld Syndrome Clinical Presentation

Updated: Nov 06, 2017
  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD  more...
  • Print
Presentation

History

Family history may indicate parental consanguinity or previously affected siblings or extended family members.

Next:

Physical

Ellis-van Creveld (EVC) syndrome is inherited as an autosomal recessive condition with variable expression. This variable phenotype affects multiple organs, with the clinical tetrad of EVC syndrome consisting 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)
    • Progressive distal limb shortening, symmetrically affecting the forearms and lower legs
  • Polydactyly (consistent clinical finding)
    • Typically, bilateral and postaxial
    • Unilateral polydactyly (of hands and/or feet) has been reported.
    • In most cases, postaxial polydactyly is observed in the hands; polydactyly of the feet has been reported in 10% of cases.
  • Hidrotic ectodermal dysplasia (observed in as many as 93% of cases)
    • Nails are hypoplastic, dystrophic, and friable or can be completely absent. 
    • Tooth involvement may include neonatal teeth, partial anodontia, small teeth, and delayed eruption.
      • Enamel hypoplasia may result in abnormally shaped teeth (conical teeth). 
    • Hair may occasionally be sparse.
  • Congenital cardiac anomalies
    • Heart defects occur in 50-60% of patients; the most common cardiac anomaly is a common atrium (40%). [15]
    • Review of the cardiac phenotype in patients with EVC 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. [16]
    • The severity of the patient's congenital cardiac anomaly may lead to a shortened life expectancy. [17]

Other anomalies may also be present.

  • Musculoskeletal anomalies include low-set shoulders, a narrow thorax frequently leading to respiratory difficulties, valgus deformity ("knock-knees"), lumbar lordosis, broad hands and feet, and brachydactyly.
  • EVC 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 hypodontia. [18, 3]
    • 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)
      • Serrated lower alveolar ridge
      • Teeth may be prematurely erupted at birth or exfoliate prematurely.
  • Genitourinary and renal anomalies include hypospadias, epispadias, hypoplastic penis, cryptorchidism, vulvar atresia, focal renal tubular dilation in medullary region, nephrocalcinosis, renal agenesis, and megaureters.
  • Occasionally, central nervous system (CNS) anomalies (ie, Dandy-Walker anomaly) or intellectual impairments are present.

Clinical manifestations in heterozygous carriers [3]

  • Polydactyly has been reported in relatives of four unrelated EVC syndrome families. [19, 20]
  • A father of a child with EVC syndrome with finger and teeth abnormalities has been reported, as have several other reports of phenotypic heterozygous manifestations. [21]
  • Weyers acrofacial/acrodental dysostosis, an autosomal dominant disorder described in 1952, is characterized by variable skeletal and facial features. This condition has been found to be associated with EVC and EVC2 mutations, confirming that Weyers dysostosis represents the heterozygous expression of the mutation that causes EVC syndrome. [22, 23, 24, 25]
Previous
Next:

Causes

Ellis-van Creveld (EVC) syndrome has an autosomal recessive inheritance; consequently, there is a Mendelian risk of 25% for its occurrence in subsequent pregnancies. The EVC gene has been mapped to the short arm of chromosome 4, band 16.2 (4p16.2) through linkage analysis of nine interrelated Amish pedigrees and three unrelated families from Mexico, Ecuador, and Brazil. [26] A 992–amino acid protein encoded by the EVC gene has a leucine zipper motif, 3 nuclear localization signals, and a transmembrane domain. [27]

Mutations in EVC have been described in Amish and Brazilian pedigrees of EVC syndrome but have accounted for only a small proportion of affected cases, thereby suggesting that EVC syndrome is a heterogeneous disease. [28] More recently, mutations in a second gene, EVC2, were described in an Ashkenazi Jewish child with EVC syndrome. [29]  EVC2 is immediately adjacent to EVC (also referred to as EVC1) and has the same gene locus, 4p16.2. The EVC protein was shown to localize to the base of the primary cilium of chondrocytes, and defective hedgehog (Hh) signalling was observed in proliferating chondrocytes of EVC-null mice. The phenotype of EVC syndrome is indistinguishable between the genotypes EVC and EVC2.

EVC syndrome is considered to be a ciliopathy. [30]  Skeletal conditions also identified in the ciliopathy group [31] are (1) the short rib-polydactyly (SRP) group, which, along with EVC syndrome includes asphyxiating thoracic dystrophy (Jeune syndrome); (2) Sensenbrenner syndrome and its fetal variant; and (3) Weyers acrofacial/acrodental dysostosis. [32]  Heterozygous mutations in EVC or EVC2 cause Weyers dysostosis, an allelic disorder that is inherited as autosomal dominant. [22, 23, 24]

A report by Ginns et al suggested that having the EVC gene helps to protect patients against bipolar affective disorder. The investigators pointed out that even though several Old Order Amish families have shown a high prevalence of EVC syndrome and bipolar disorder type 1, the two conditions have not been diagnosed together in the same individual. Moreover, since homozygous Amish EVC mutations disrupt sonic hedgehog (Shh) protein signaling, the investigators suggested that the protein is in some way associated with bipolar disorder type 1. [33]

Previous