Clinical characteristics.

Ellis-van Creveld (EVC) syndrome is characterized by postaxial polydactyly of the hands, disproportionate short stature with short limbs, dystrophic and/or hypoplastic nails, dental and oral manifestations, congenital heart disease, and radiologic abnormalities (narrow chest, short ribs, short tubular bones, bulbous ends of the proximal ulnae and distal radii, carpal and metacarpal fusions, cone-shaped epiphyses of phalanges, small iliac crests, acetabular spur projections [trident ilia], and lateral slanting of the tibial plateau). Other less common and more variable features include postaxial polydactyly of the feet, upper lip defect, and developmental delay.

Diagnosis/testing.

The diagnosis of EVC syndrome is established in a proband with characteristic clinical and radiographic findings and biallelic pathogenic variants in DYNC2H1, DYNC2LI1, EVC, EVC2, GLI, SMO, or WDR35 or a heterozygous pathogenic variant in PRKACA or PRKACB identified by molecular genetic testing.

Management.

Treatment of manifestations: Surgical amputation for polydactyly if desired; surgical correction of genu valgum as needed; physical therapy as needed; mechanical ventilation may be required in the neonatal period in those with severe restrictive lung disease; orthodontic and/or surgical treatment of dental anomalies; standard treatment for congenital heart disease; developmental services as needed; surgical correction of genital urinary malformations as needed; standard treatment for hearing loss.

Surveillance: Monitor growth at least annually throughout childhood; orthopedic evaluation with radiographic assessment as needed; physical and rehabilitation medicine evaluation as needed; assessment for manifestations of respiratory failure and/or restrictive lung disease as needed; monitor for dental eruption, overcrowding, and dental morphology annually throughout childhood; echocardiogram as needed; monitor developmental progress and educational needs at each visit until adulthood; hearing evaluation as needed if hearing loss is present.

Pregnancy management: Cesarean delivery is recommended in pregnant women with EVC syndrome who have pelvic/hip abnormalities.

Genetic counseling.

EVC syndrome caused by pathogenic variants in DYNC2H1, DYNC2LI1, EVC, EVC2, GLI, SMO, or WDR35 is inherited in an autosomal recessive manner. EVC syndrome caused by pathogenic variants in PRKACA or PRKACB (accounting for 2% of affected individuals) is inherited in an autosomal dominant manner.

Autosomal recessive inheritance: If both parents are known to be heterozygous for an EVC syndrome-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the EVC syndrome-related pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.

Suggestive Findings

EVC syndrome should be suspected in probands with a combination of the following clinical and imaging findings and family history.

Clinical findings

• Bilateral postaxial polydactyly of the hands (see Figure 1B-C) with or without postaxial polydactyly of the feet
• Limb shortening (prenatal or postnatal)
• Disproportionate short stature (prenatal or postnatal onset)
• Dystrophic and/or hypoplastic nails (See Figure 1B-E.)
• Dental and oral anomalies (hypodontia, delayed eruption of teeth, frenulum abnormalities)
• Congenital heart defects (atrial septal defect, ventricular septal defect, single atrium, atrioventricular canal)

Figure 1.

Clinical and radiographic images of a male child with Ellis-van Creveld (EVC) syndrome A. Dysmorphic features at age 19 months with short broad nose and partial upper lip defect in the midline.

Imaging findings (See Figure 1F-K.)

• Narrow chest with short ribs
• Short and thickened tubular bones
• Bulbous ends of the proximal ulnae and distal radii
• Carpal and metacarpal fusions (typically capitate and hamate)
• Cone-shaped epiphyses of phalanges
• Small iliac crests
• Acetabular spur projections (trident ilia)
• Lateral slanting of the tibial plateau

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of EVC syndrome is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in DYNC2H1, DYNC2LI1, EVC, EVC2, GLI, SMO, or WDR35 or a heterozygous pathogenic (or likely pathogenic) variant in PRKACA or PRKACB identified by molecular genetic testing.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Ellis-van Creveld (EVC) syndrome is characterized by postaxial polydactyly of the hands, disproportionate short stature, features of ectodermal dysplasia, congenital heart disease, and radiologic abnormalities (such as short ribs and short tubular bones) [Da Silva et al 2023]. Other less common and more variable features include postaxial polydactyly of the feet, nonspecific dysmorphic facial features, and developmental delay. To date, approximately 250 individuals with EVC syndrome have been identified with pathogenic variants in one of the genes listed in Table 1 [Aubert-Mucca et al 2023, Da Silva et al 2023]. The following description of the phenotypic features associated with this condition is based on these reports.

Growth deficiency. Disproportionate short stature is common in individuals with EVC syndrome. About one third of individuals manifest growth deficiency in the perinatal setting, with shortened long bones evident on prenatal ultrasound, as well as short stature and/or limb shortening at birth [Da Silva et al 2023]. Most children present with growth failure and consequent short stature. Body segments are disproportionate, with a long, narrow thorax, usually accompanied by shortening of all four limbs. Limb segments are typically affected, with increasing severity from proximal to distal (rhizomelia > mesomelia > acromelia) [Baujat & Le Merrer 2007]. Adult height is most often below the midparental height and ranges between 109 and 152 cm.

Musculoskeletal manifestations. The most common feature in individuals with EVC syndrome is bilateral postaxial polydactyly of the hands (see Figure 1B-C and Figure 1F-G) [Da Silva et al 2023]. Almost all individuals have hexadactyly of each hand, although a smaller subset have heptadactyly (seven digits) on each hand. Postaxial polydactyly of the feet is less common and is almost always bilateral. Polydactyly can sometimes be identified on prenatal ultrasound.

The thorax is usually long and narrow due to underdevelopment of the rib cage / short ribs, which may lead to lung hypoplasia during development or restrictive lung disease after birth. However, respiratory insufficiency is rarely severe [Huber & Cormier-Daire 2012]. Less commonly, pectus carinatum can be observed.

Other common skeletal abnormalities include shortening of long bones, brachydactyly (see Figure 1B-C and Figure 1F-I), carpal and metacarpal fusions (see Figure 1G), and genu valgum (due to a delay in ossification of the lateral tibial metaphysis) (see Figure 1K) [Handa et al 2020, Da Silva et al 2023]. The ulnae and radii usually have a distinct appearance due to the presence of abnormally bulbous ends. Bone age is usually delayed [Baujat & Le Merrer 2007]. Clinodactyly and syndactyly have also been reported.

The skull and spine are usually normal [Handa et al 2020]. Muscle strength is also normal.

Dental and oral manifestations. Anomalies of the teeth are frequent and varied. The most common findings are delayed eruption and hypodontia. Some individuals have natal teeth or early eruption of the primary dentition during the first two months of life and dental dysmorphism (e.g., cone-shaped teeth). Less frequent findings include enamel hypoplasia, dental transposition, and taurodontism [Peña-Cardelles et al 2019]. Frenulum anomalies, with multiple frenula and adhesions, are also common [Da Silva et al 2023].

Nail dystrophy. Nails are usually hypoplastic, and all nails show at least mild dystrophy, including discoloration, brittleness, pitting, ingrown nails, and deep-set nails (see Figure 1B-E).

Congenital heart defects are relatively frequent and can be detected prenatally. When present, they almost always include an atrial septal defect that can be isolated or coexist with other malformations. Ventricular septal defects, single atrium, and left superior vena cava are also rather common. Just under half of individuals with congenital heart defects develop some degree of heart failure [Hills et al 2011]. Other types of malformations (e.g., hypoplastic left ventricle, pulmonary valve stenosis/atresia, aortic coarctation) are rare [Hills et al 2011].

Craniofacial features are variable and nonspecific, and there is no specific facial gestalt for EVC syndrome. Upper lip defects (see Figure 1A) frequently manifest with partial cleft lip (without cleft palate); disruption of the superior gingivolabial groove due to adhesions is frequently seen with the lip defect. Additional reported facial features described in less than one in four individuals include hypertelorism, short broad nose (see Figure 1A), long philtrum, and postnatal microcephaly [Da Silva et al 2023].

Development. Intellectual disability is not typical of EVC syndrome. Individuals usually exhibit normal intelligence. A small percentage of individuals exhibit developmental delay and/or intellectual disability that is mostly mild or moderate [Öztürk et al 2021, Zaka et al 2021, Qian et al 2022]. Motor skills are most often affected, which may be secondary to the musculoskeletal abnormalities.

Other. Other rare features (described in <5% of individuals with EVC syndrome) include:

• Genitourinary abnormalities (epispadias, hypospadias, cryptorchidism, hydrometrocolpos, kidney malformations, kidney cysts)
• Central nervous system malformations (Dandy-Walker malformation, corpus callosum hypoplasia, cerebellar hypoplasia)
• Sensorineural deafness

Phenotype Correlations by Gene

EVC2. A detailed assessment showed increased frequency of some manifestations in individuals with EVC2-related EVC syndrome compared to those with pathogenic variants in EVC [Da Silva et al 2023], but the phenotype in those with EVC-related EVC syndrome is most often clinically indistinguishable from that of EVC2-related EVC syndrome. Individuals with biallelic EVC2 pathogenic variants have increased shortening and thickening of the tubular bones and lower weight than individuals with EVC pathogenic variants. This suggests (but does not confirm) increased severity for EVC2-related EVC syndrome.

DYNC2H1, DYNC2LI1, GLI1, PRKACA, PRKACB, SMO, and WDR35. EVC syndrome due to pathogenic variants in DYNC2H1, DYNC2LI1, GLI1, PRKACA, PRKACB, SMO, or WDR35 are rare, so phenotype correlations by gene cannot be definitively established. However, postaxial polydactyly of the feet seems to be more common (and present in most individuals) with DYNC2H1-, DYNC2LI1-, GLI1-, SMO-, and WDR35-related EVC syndrome [Caparrós-Martín et al 2015, Palencia-Campos et al 2017, Niceta et al 2018, Aubert-Mucca et al 2023, Piceci-Sparascio et al 2023].

Genotype-Phenotype Correlations

EVC syndrome caused by large intragenic deletions or duplications affecting EVC and/or EVC2 are associated with more atypical clinical presentations, with a decrease in the proportion of musculoskeletal findings and an increase in the frequency of dysmorphic features [Da Silva et al 2023].

EVC

• Missense variants are associated with decreased frequency of common skeletal findings (e.g., shortening and thickening of tubular bones, small iliac crest).
• The coding region of EVC partially overlaps with the coding region of CRMP1. Individuals with pathogenic variants affecting the coding region shared between EVC and CRMP1 have an increased incidence of musculoskeletal and ectodermal dysplasia features compared to those with pathogenic variants only within the coding region of EVC. Therefore, CRMP1 has been suggested as a modifier of severity in individuals with EVC-related EVC syndrome [Da Silva et al 2023].

No definitive genotype-phenotype correlations have been identified for DYNC2H1-, DYNC2LI1-, GLI1-, PRKACA-, PRKACB-, SMO-, or WDR35-related EVC syndrome.

Nomenclature

In the 2023 revised Nosology of Genetic Skeletal Disorders [Unger et al 2023], EVC syndrome is included in Group 10, "Skeletal disorders caused by abnormalities of cilia or ciliary signaling," and referred to as "chondroectodermal dysplasia (Ellis-van Creveld)" followed by the involved gene – e.g., chondroectodermal dysplasia (Ellis-van Creveld), EVC2-related.

Prevalence

The exact prevalence of EVC syndrome is unknown. To date, there have been approximately 250 individuals reported with EVC syndrome and confirmed pathogenic variants identified in one of the genes listed in Table 1.

EVC syndrome may have an increased prevalence in individuals of Amish descent, as there is a founder EVC variant (c.1886+5G>T) in the Amish population of Lancaster County, Pennsylvania [McKusick 2000].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with EVC syndrome, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive treatment to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 6).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In pregnant women with EVC syndrome who have pelvic/hip abnormalities, cesarean delivery is recommended.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Ellis-van Creveld (EVC) syndrome caused by pathogenic variants in DYNC2H1, DYNC2LI1, EVC, EVC2, GLI, SMO, or WDR35 is inherited in an autosomal recessive manner.

EVC syndrome caused by pathogenic variants in PRKACA or PRKACB (accounting for 2% of affected individuals) is inherited in an autosomal dominant manner [Palencia-Campos et al 2020, Aubert-Mucca et al 2023]. Autosomal dominant inheritance is not discussed further in this section.

Risk to Family Members (Autosomal Recessive Inheritance)

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an EVC syndrome-related pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an EVC syndrome-related pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are usually asymptomatic and are not at risk of developing EVC syndrome. However, a small number of heterozygous variants (typically EVC2 truncating variants in exon 22) have been associated with Weyers acrofacial dysostosis (see Table 3) [Da Silva et al 2023].

Sibs of a proband

• If both parents are known to be heterozygous for a pathogenic variant in one of the genes listed in Table 1, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Heterozygotes (carriers) are usually asymptomatic and are not at risk of developing EVC syndrome. However, a small number of heterozygous variants (typically EVC2 truncating variants in exon 22) have been associated with Weyers acrofacial dysostosis (see Table 3) [Da Silva et al 2023].

Offspring of a proband. Unless an affected individual's reproductive partner also has EVC syndrome or is heterozygous for an EVC syndrome-related pathogenic variant, offspring will be obligate heterozygotes (carriers) for an EVC syndrome-related pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a pathogenic variant of one of the genes listed in Table 1.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the EVC syndrome-related pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing for the reproductive partners of known carriers should be considered, particularly if both partners are of the same ancestry. An EVC founder variant has been identified in individuals of Amish ancestry (see Table 9).

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the EVC syndrome-related pathogenic variants have been identified in a family member with autosomal recessive EVC syndrome, prenatal and preimplantation genetic testing are possible.

Fetal ultrasound examination. In a fetus not already known to be at risk for EVC syndrome based on family history, the identification on fetal ultrasound examination of the following features may prompt consideration of gene-targeted testing for known EVC syndrome-related genes: shortening of long bones, polydactyly, thoracic narrowing, and congenital heart disease (typically endocardial cushion defects) (see Diagnosis) [Chen et al 2012]. Other findings that may be observed on ultrasound examination of an affected fetus include severe upper lip defects and genitourinary and central nervous system malformations (though the latter two features are rarely reported in EVC syndrome).

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

EVC and EVC2 encode membrane proteins that form a complex in the basal body of primary cilia [Ruiz-Perez et al 2007]. They have an essential function as mediators of hedgehog signaling in primary cilia, which is one of the fundamental drivers of the development of the orofacial region, the endochondral plate of the axial skeleton, and cardiac morphogenesis [Louie et al 2020].

SMO encodes a transcription factor that is activated upon hedgehog binding, leading to the production of GLI proteins (such as that encoded by GLI1) [Tukachinsky et al 2010]. SMO also interacts with the EVC-EVC2 complex, which allows translocation of the GLI proteins to the tip of the primary cilia, which are the distal effectors of hedgehog signaling, modulating proliferation and differentiation of developing tissues [Louie et al 2020].

WDR35 encodes a protein that coats Golgi vesicles, functioning as a signal for transport into the primary cilia, affecting both assembly and cargo transport. Its disruption has been shown to impair the recruitment of EVC and SMO to the primary cilia [Caparrós-Martín et al 2015]. Similarly, DYNC2H1 and DYNC2LI1 encode for subunits of dynein-2, which has a key role in the transport of cargo to the primary cilia [Niceta et al 2018].

PRKACA and PRKACB encode subunits of the enzyme protein kinase A (PKA). PKA is an intracellular mediator of G protein-coupled receptors (GPCR) that is activated by increases in intracellular cAMP. In primary cilia PKA constitutively represses GLI proteins and, therefore, hedgehog signaling [Palencia-Campos et al 2020]. SMO activation upon hedgehog binding leads to removal of the cilia GPCR and, consequently, to PKA inactivation.

Mechanism of disease causation. The mechanism of disease for EVC and EVC2 is loss of function [Zhang et al 2016, Louie et al 2020]. Despite functioning together as a protein complex, they are nonredundant, and the loss of one protein is sufficient to impair the function of the complex. Less data is available regarding the mechanism of disease causation for the other genes associated with Ellis-van Creveld (EVC) syndrome. However, considering the mechanism of EVC and EVC2, as well as the known function of the other genes, it is likely that loss of function is the mechanism in DYNC2H1-, DYNC2LI1-, GLI1-, SMO-, and WDR35-related EVC syndrome. PRKACA- and PRKACB-related EVC syndrome may be due to gain of function, as causal variants have been shown to lead to PKA activity elevation due to increased cAMP sensitivity and, therefore, hedgehog signaling inhibition [Palencia-Campos et al 2020]. This is also in line with the autosomal dominant mode of inheritance for both genes.

Author Notes

Jorge Diogo Da Silva, Nataliya Tkachenko, and Ana Rita Soares are actively involved in clinical research regarding individuals with Ellis-van Creveld (EVC) syndrome. They would be happy to communicate with persons who have any questions regarding diagnosis of EVC syndrome or other considerations.

The authors are also interested in hearing from clinicians treating families affected by EVC syndrome in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact Dr Jorge Diogo Da Silva ([email protected]) to inquire about the above subjects, or about the review of EVC or EVC2 variants of uncertain significance.

Acknowledgments

The authors would like to acknowledge Dr Catarina Martins Silva for her valuable help regarding the photographic records of the individual with EVC syndrome presented in Figure 1.

Revision History

• 26 October 2023 (sw) Review posted live
• 5 July 2023 (jds) Original submission

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