Ellis-van Creveld Syndrome

The pathophysiology of Ellis-van Creveld (EVC) syndrome is unknown; however, a better understanding may be achieved now that the genes EVC (MIM #604831) and EVC2 (MIM #607261) have been identified.[1]

Histopathologic examination of fetuses diagnosed with EVC syndrome revealed that in the long bones of patients with this condition, chondrocyte disorganization exists in the cartilage's physeal growth zone. In addition, variable chondrocyte disorganization was seen in the central physeal growth zone of the vertebrae.

Frequency

Ellis-van Creveld (EVC) syndrome is a rare disease.  As of 2007, only about 150 cases had been reported since the syndrome's description in the medical literature by Ellis and van Creveld.[4]  In the world population, the frequency of EVC syndrome is 1 per 60,000 to 1 per 200,000 newborns.

Among persons from the Old Order Amish in Lancaster, Pa, however, the incidence is estimated to be 1 case per 200 livebirths.[5]  The frequency of carriers in this population may be as high as 13%.

Mortality/Morbidity

Neonatal phenotypic findings include disproportionate small stature and noted increased severity, with progression from the proximal to distal parts of the limbs; shortening of the middle and distal phalanges; polydactyly affecting the hands (unilateral or bilateral) and, sometimes, feet; and hidrotic ectodermal dysplasia primarily affecting the nails, hair, and teeth. Dental problems are frequent, and natal teeth may be present.[6]

In the neonatal period, the leading causes of death are cardiac anomalies and thoracic dysplasia (with a narrow chest wall), with the latter causing severe respiratory compromise. Approximately 50% of patients with Ellis-van Creveld (EVC) syndrome die in early infancy as a consequence of cardiorespiratory problems.

Congenital cardiac malformations occur in 50-60% of cases and include a number of possible defects, such as a single atrium, patent ductus, defects of the mitral and tricuspid valves, ventricular septal defects (VSD), atrial septal defects (ASD), and hypoplastic left heart syndrome.[4] Significant heart disease may manifest as cardiac murmur, along with failure to thrive, cyanosis, shortness of breath, or other cardinal signs of heart failure.

Limitation of hand function, such as the inability to form a clenched fist, is frequently observed.

Potential end-organ system impact may include the following[7] :

• Renal diagnoses include nephrotic syndrome, nephronophthisis, and renal failure[8, 9, 10]

• Hepatic abnormalities, such as a congenital paucity of bile ducts, can lead to progressive fibrosis and hepatic failure[8, 11]

• Hematologic/oncologic impact can range from myelodysplastic changes with dyserythropoiesis to acute leukemia[12, 13]

Patients who survive infancy with non–life-threatening pulmonary or cardiac conditions are expected to have a normal life span.

Race

The highest frequency of Ellis-van Creveld (EVC) syndrome has been noted in one particular inbred population, the Old Order Amish community in Lancaster County, Pa, where, as based on research by McKusick, the largest pedigree has been described (52 cases in 30 sibships).[5]  This very high incidence (1 in 200) is due to a founder effect. The Old Order Amish population in Lancaster stems from the 1742 immigration of about 200 Europeans, with the abnormal gene having been traced back to one immigrant couple, Samuel King and his wife. 

The incidence of EVC syndrome also appears to be more common in the native aboriginal population of Western Australia.

Sex

The frequency of Ellis-van Creveld (EVC) syndrome is equal in males and females. The EVC gene is located on autosome #4 and not on the sex chromosomes; hence, the occurrence is independent of the affected patient's sex.

Age

Clinical findings, such as disproportionate extremities, narrow thorax, polydactyly, cardiac defects, and hidrotic ectodermal dysplasia affecting the nails, hair and teeth, are observed and diagnosable at birth.

A poor prognosis is declared in the neonatal period. Congenital cardiac anomalies and thoracic dysplasia (with a narrow chest wall) causing severe respiratory compromise are leading causes of death at this time.

Patients who survive infancy with non–life-threatening pulmonary or cardiac conditions are expected to have a normal life span. Final adult skeletal height has been difficult to predict. Publications have cited an adult height range of 119 cm (3'11") to 161 cm (5'3").[14]

Developmentally, most patients have normal intelligence.[4] Case reports have cited patients with associated brain malformations (Dandy-Walker anomaly, hydrocephalus, cerebral heterotopias) and developmental delay.[15]

The following organizations may provide helpful information for patients and their families:

Little People of America, Inc.

617 Broadway #518

Sonoma, CA 95476

Toll free: (888) LPA-2001 or (888) 572-2001

Direct: (714) 368-3689

Fax: (707) 721-1896

E-mail: info@lpaonline.org

Website: http://www.lpaonline.org/

 

Genetic and Rare Diseases Information Center (GARD), of the National Institutes of Health

PO Box 8126

Gaithersburg, Md 20898-8126

Toll free: (888) 205-2311

Fax: (301) 251-4911

Website: https://rarediseases.info.nih.gov

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

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.[4]

• 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%).[16]

  • 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.[17]

  • The severity of the patient's congenital cardiac anomaly may lead to a shortened life expectancy.[18]

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.[19, 4]

  • 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[4]

• Polydactyly has been reported in relatives of four unrelated EVC syndrome families.[20, 21]

• 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.[22]

• 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.[23, 24, 25, 26]

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.[27] A 992–amino acid protein encoded by the EVC gene has a leucine zipper motif, 3 nuclear localization signals, and a transmembrane domain.[28]

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.[29] More recently, mutations in a second gene, EVC2, were described in an Ashkenazi Jewish child with EVC syndrome.[30]  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.[31]  Skeletal conditions also identified in the ciliopathy group[32] 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.[33]  Heterozygous mutations in EVC or EVC2 cause Weyers dysostosis, an allelic disorder that is inherited as autosomal dominant.[23, 24, 25]

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.[34]

Another gene, WDR35, has also been implicated in Ellis-van Creveld syndrome (EVS). A study by Hu et al found evidence that skeletal dysplasia and fetal anomalies may result from WDR35 copy-number variation, while down-regulation of the gene may adversely affect cilia formation and, through indirect regulation of Gli protein signaling, cause osteogenic differentiation to be negatively regulated.[35, 36]

In about 66% of patients diagnosed with Ellis-van Creveld (EVC) syndrome, EVC and EVC2 mutations can be identified via sequencing analysis.[1]

Gene testing for mutational analysis of EVC and EVC2 is available clinically by sequence analysis of the entire coding region, deletion/duplication analysis, and linkage analysis (for up-to-date information on gene testing, see Gene Tests).

A radiographic skeletal survey can define skeletal anomalies. Expected findings in patients with Ellis-van Creveld (EVC) syndrome include the following:

• Retarded bone maturation

• Acromesomelia (relative shortening of the distal and middle segments of the limbs) - Found to be most prominent in the hands, where the distal and middle phalanges are shorter than the proximal phalanx

• Postaxial polydactyly (polydactyly on the ulnar side of the hand)

• Multiple varieties of carpal fusion - Fusion of the hamate and capitate bones of the wrist; fusion of the 5th and 6th metacarpals

• Small iliac crests and sciatic notches (may be revealed on pelvic radiographs)

• Valgus deformity of the knee[3]

• Fibula disproportionately smaller than the tibia

• Thorax (short ribs, narrow chest wall)

• Additional findings - Cubitus valgus, hypoplastic cubitus, supernumerary carpal bone center, clinodactyly of the fifth finger

Chest radiography, electrocardiography, and echocardiography (to evaluate cardiac anatomy) are indicated. Head magnetic resonance imaging (MRI) can be used to reveal structural brain anomalies, while renal ultrasonography can be employed to diagnose renal anomalies.

Prenatal imaging

Ultrasonographic images can detect abnormalities after the 18th week of gestation, including intrauterine growth retardation, skeletal malformations (narrow thorax, marked shortening of the long bones, hexadactyly of the hands and feet), and cardiac defects. These ultrasonographic findings lead to diagnostic discussion of short rib-polydactyly syndromes with the expectant parents.[4] In addition, increased first-trimester fetal nuchal translucency thickness has been reported as early as the 13th week of gestation.[38]    

Consider ocular examination, as eye anomalies (ie, strabismus) have been described.

Using 235 observations of 101 patients with Ellis-van Creveld (EVC) syndrome (49 males, 52 females), Verbeek et al developed growth charts for males and females, aged 0-20 years.[39] The growth charts are useful in the continuity of care of patients with EVC syndrome. Most importantly, early detection of and treatment for growth hormone deficiency, known to occur in EVC syndrome patients, can be facilitated. The growth charts, shown below, reveal that 98% of patients with EVC syndrome will exhibit lower height by age 10 years, when compared with unaffected children.

Histologic findings include the following:

• Disorganization of chondrocytes in the physeal growth zone of the long bones and vertebrae

• Retardation of physeal growth zones in childhood

 

The medical 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, and if they loosen, they can be a choking hazard
• Prevention of caries includes dietary counseling, plaque control, and oral hygiene instruction
• Crown or composite build-ups for microdont/microdontia may be indicated
• Partial dentures can maintain space and improve mastication, esthetics, and speech due to congenitally missing teeth
• For dental care during adulthood, implants and prosthetic rehabilitation are required to replace congenitally missing teeth
• It is important to address the need for prophylactic antibiotic coverage given the high incidence of congenital cardiac defects in patients with EVC syndrome

Short stature is considered to result from chondrodysplasia of the legs, and treatment with growth hormone is considered ineffective, unless the patient is also deficient in growth hormone.[40, 4]

Orthopedic procedures correct polydactyly and other orthopedic malformations. Bone deformity, such as knee valgus with lateral tibial plateau depression and patella dislocation, requires ongoing orthopedic follow-up and care.[4]  

A retrospective study by Weiner et al indicated that surgery can successfully correct genu valgum in Ellis-van Creveld (EVC) syndrome. The study, which involved 23 limbs (13 patients), found that operative treatment (a combination of radical soft tissue release, patellar realignment, and bony osteotomy) reduced valgus deformity of the knee to 10° or less in all patients, with all but four limbs having maintained the correction to 20° of deformity or less at follow-up (average 5 years).[41]

Cardiac surgery may be needed to correct cardiac anomalies. Management of congenital cardiac malformations in EVC syndrome is associated with substantial mortality. In particular, the respiratory system appears to be central with respect to postoperative outcome.[42]

Thoracic expansion has been attempted in some patients. Urologic surgery is required if epispadias, cryptorchidism, or both are present.

Perioperative morbidity

Perioperative morbidity may result from difficulties with airway management and pulmonary abnormalities.[7] Although these concerns are less common than congenital heart disease, abnormalities leading to difficulties in airway management include cleft lip and palate and orodental malformations.[43, 44]  Dental abnormalities, such as peg or natal teeth, may be more prone to dislodgement during airway instrumentation.

Frenula, 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.

A case report describes a patient with EVC syndrome who presented with congenital stridor related to a cyst involving the neck and airway.[45]

See the list below:

• Clinical geneticist/genetic counselor

• Cardiologist

• Pulmonologist

• Orthopedist

• Nephrologist

• Urologist

• Physical and occupational therapist

• Dentist/orthodontist

• Psychologist (to assist with emotional support and address adaptive needs)

• Developmental pediatrician (if developmental delay is present)

• Pediatric neurologist (if developmental delay is present)

No special diet is required unless cardiac failure and/or renal compromise indicate the need for dietary restrictions.

Activities may be limited secondary to cardiorespiratory status or skeletal limitations.

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