Ellis-Van Creveld Syndrome

A number sign (#) is used with this entry because Ellis-van Creveld syndrome (EVC) is caused by homozygous or compound heterozygous mutation in the EVC gene (604831) on chromosome 4p16.

Ellis-van Creveld syndrome can also be caused by mutation in a nonhomologous gene, EVC2 (607261), located close to the EVC gene in a head-to-head configuration.

Mutations in the EVC and EVC2 genes also cause Weyers acrofacial dysostosis (WAD; 193530), an allelic disorder showing autosomal dominant inheritance.

Description

Ellis-van Creveld syndrome is an autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly, and dysplastic nails and teeth. Congenital cardiac defects, most commonly a defect of primary atrial septation producing a common atrium, occur in 60% of affected individuals (summary by Ruiz-Perez et al., 2000).

The clinical features of the Ellis-van Creveld syndrome appear to be identical regardless of whether the disorder is caused by mutation in the EVC gene (604831) or in the EVC2 gene (607261) (Ruiz-Perez et al., 2003, Galdzicka et al., 2002).

Clinical Features

The largest pedigree with EVC was that observed by McKusick et al. (1964) in an inbred religious isolate, the Old Order Amish, in Lancaster County, Pennsylvania. Almost as many persons were known in this one kindred as had been reported in all the medical literature up to that time. Features are dwarfism with most striking shortening in the distal part of the extremities, polydactyly, fusion of the hamate and capitate bones of the wrist, dystrophy of the fingernails, change in the upper lip variously called 'partial hare-lip,' 'lip-tie,' etc., and cardiac malformation, usually a septal defect and often single atrium. Teeth may already be erupted at birth ('natal teeth;' 187050) and exfoliate prematurely.

From observations in the large Amish kindred, McKusick et al. (1964) concluded that there are no heterozygous manifestations of EVC. However, Fryns (1991) noted the occurrence of unilateral postaxial polydactyly type A (complete extra finger and extra metacarpal) in one parent and one otherwise normal brother of 2 unrelated newborn infants with EVC. Goldblatt et al. (1992) described EVC in a Western Australian Aboriginal community in which 2 relatives were observed to have isolated postaxial polydactyly of the feet. They advanced this as evidence of heterozygous manifestation. In the 2 families reported by Goldblatt et al. (1992), each with 1 case of EVC, the postaxial polydactyly of the feet occurred in a first cousin and a first cousin once removed of the proband in 1 family only.

Engle and Ehlers (1969) described a case of EVC syndrome with unilateral polydactyly. The left hand and the right foot had an extra digit. A second child with EVC had been born in this family; polydactyly of the hands was bilateral (Engle, 1976).

Blackburn and Belliveau (1971) reported 2 sibs EVC with single atrium and hypoplastic left heart syndrome.

Onat (1994) described a patient with single atrium and postaxial hexodactyly. Since the patient had no additional anomalies, all known syndromes, including the EVC combination of malformations, were excluded and it was proposed that the association represented a previously undescribed syndrome. Digilio et al. (1995) described 2 children with this combination and referred to 2 children previously reported in an abstract. They raised the possibility that Ellis-van Creveld syndrome and single atrium/polydactyly syndrome may be related, possibly due to allelic mutations. The parents of one of the children reported by Digilio et al. (1995) were consanguineous, and the father, like the daughter, had postaxial polydactyly of the left hand and both feet, partial atrial ventricular canal with single atrium, and agenesis of the upper lateral incisors bilaterally with enamel abnormalities. His height was 165 cm. The father and daughter were later found to have a mutation in the EVC gene (604831.0005) (Ruiz-Perez et al., 2000).

Spranger and Tariverdian (1995) described a 13-month-old girl with apparently typical EVC whose 32-year-old father had some features that they suggested might be heterozygous manifestations. He had disproportionate short stature (162 cm). Polydactyly was not present either clinically or by x-ray examination. Hands and feet were broad and square with short fingers and toes. He could not make a tight fist. He had dysplastic finger- and toenails, which never needed to be cut and were quite typical of those of EVC. The teeth were conical in shape with side spaces. The father had previously been thought to have Weyers acrodental dysostosis. Spranger and Tariverdian (1995) reviewed other reports of possible heterozygous manifestations.

Howard et al. (1997) studied a 4-generation family with features of Weyers acrofacial dysostosis in which the proband had a more severe phenotype, resembling Ellis-van Creveld syndrome. Weyers acrofacial dysostosis is an autosomal dominant condition with dental anomalies, nail dystrophy, postaxial polydactyly, and mild short stature. EVC is a similar condition, with autosomal recessive inheritance and the additional features of disproportionate dwarfism, thoracic dysplasia, and congenital heart disease.

Mostafa et al. (2005) reported 6 cases of EVC in 3 Egyptian families. All of the families were consanguineous. Father to son or daughter transmission was observed in 2 of the families, thus demonstrating pseudodominant inheritance. None of the presumed heterozygotes in these families exhibited abnormalities of the body, limbs, or orodental structures. Bifid tip of the tongue was found in all affected individuals. Mostafa et al. (2005) suggested that midline orodental anomalies should be sought in cases of EVC and Weyers acrofacial dysostosis, and that their presence or absence might be a differentiating feature between the 2 disorders.

Diagnosis

Prenatal Diagnosis

Mahoney and Hobbins (1977) proposed fetoscopy and ultrasound as methods of prenatal diagnosis. Qureshi et al. (1993) described the skeletal histopathology in 3 fetuses with EVC. The diagnosis had been made in each of these cases on the basis of ultrasonography, and the pregnancies were terminated at 22 to 23 weeks.

Population Genetics

D'Asdia et al. (2013) stated that the incidence of Ellis-van Creveld syndrome is estimated at 1 in 60,000, whereas it is as high as 5 in 1000 in the Old Order Amish community of Lancaster County, Pa.

Mapping

In studies of 9 interrelated Amish pedigrees and 2 unrelated families from Mexico and Ecuador, Francomano et al. (1995) demonstrated linkage of the EVC gene to the distal short arm of chromosome 4 in an area proximal to the FGFR3 gene (134934), which is mutant in achondroplasia (100800) and hypochondroplasia (146000). The maximum lod score was 4.65 at theta = 0.05 for marker D4S431.

Polymeropoulos et al. (1996) reported the results of linkage analysis in 9 interrelated Amish pedigrees and 3 unrelated families from Mexico, Ecuador, and Brazil. Their analysis revealed linkage of the Ellis-van Creveld phenotype to genetic markers on the short arm of chromosome 4p with no evidence of heterogeneity. Polymeropoulos et al. (1996) reported that multipoint analysis places the gene between D4S3007 and D4S431, whereas haplotype analysis sublocalizes the gene in the interval between D4S2957 and D4S827.

By linkage and haplotype analysis in a 4-generation family with features of Weyers acrofacial dysostosis in which the proband had a more severe phenotype resembling Ellis-van Creveld syndrome, Howard et al. (1997) determined that the disease locus resided on 4p16, distal to the genetic marker D4S3007 and within a 17-cM region flanking the genetic locus D4S2366. This region includes the EVC locus, which had previously been mapped within a 3-cM region between genetic markers D4S2957 and D4S827. The authors concluded that either the genes for the condition in the family of Howard et al. (1997) and for EVC are near one another or these 2 conditions are allelic. The data also raised the possibility that Weyers acrofacial dysostosis is a heterozygous expression of the mutation that, in homozygous form, causes the autosomal recessive disorder EVC.

Exclusion Studies

Polymeropoulos et al. (1996) suggested that the HMX1 gene (142992) is most likely located in the 12-cM interval between D4S394 and D4S2362, excluding it as a candidate gene for Ellis-van Creveld syndrome. Ide et al. (1996) excluded the MSX1 gene (142983) as a candidate gene for this disorder in the Amish.

Molecular Genetics

By positional cloning, Ruiz-Perez et al. (2000) identified a novel gene, EVC (604831), that is mutated in individuals with Ellis-van Creveld syndrome. They identified a splice-donor change in an Amish pedigree (604831.0001), and 6 truncating mutations and a single amino acid deletion in 7 pedigrees (see, e.g., 604831.0002-604831.0004). The heterozygous carriers of these mutations did not manifest features of EVC.

Ruiz-Perez et al. (2000) found 2 heterozygous missense mutations associated with a phenotype, one in a man with Weyers acrodental dysostosis (604831.0006) and another in a father and his daughter, who both had the heart defect characteristic of EVC and polydactyly, but not short stature (604831.0005). Ruiz-Perez et al. (2000) suggested that EVC and Weyers acrodental dysostosis are allelic conditions.

In a patient with Ellis-van Creveld syndrome of Ashkenazi Jewish origin, Galdzicka et al. (2002) identified 2 homozygous mutations in the EVC2 gene; see 607261.0007.

In a patient with Ellis-van Creveld syndrome in a consanguineous Gypsy pedigree, Ruiz-Perez et al. (2003) identified a frameshift mutation in the EVC2 gene (607261.0001). They found 4 other truncating mutations and a missense change.

Tompson et al. (2007) analyzed the EVC and EVC2 genes in 65 unrelated individuals with EVC syndrome, 19 of whom came from consanguineous families. Mutations in the EVC gene were identified in 20 patients (17 homozygotes and 3 compound heterozygotes); mutations in the EVC2 gene were identified in 25 patients (17 homozygotes, 5 compound heterozygotes, and 3 in whom only 1 mutation was identified). The majority of the mutations introduced a premature termination codon. The authors noted that no mutations were found in either gene in 20 (31%) cases and suggested that there may be further genetic heterogeneity.

In a 6-year-old Chinese girl with mild Ellis-van Creveld syndrome, Shen et al. (2011) identified compound heterozygosity for a splice site and a missense mutation in the EVC2 gene (607621.0010-607621.0011). The patient had mild short stature, postaxial polydactyly, dysplastic nails, abnormal teeth, and genus valgum; features not present in this patient included short ribs, narrow thorax, or cardiac defects. Her unaffected parents were each heterozygous for 1 of the mutations; neither mutation was found in 200 control chromosomes. Shen et al. (2011) noted that all 3 Weyers acrofacial dysostosis-associated mutations reported to date were located in exon 22 of EVC2, whereas this patient's mutations were in IVS5 and exon 15.

History

The disorder that now goes by the name of Ellis-van Creveld syndrome was described by Richard W. B. Ellis (1902-1966) of Edinburgh and Simon van Creveld (1895-1971) of Amsterdam. Each had a patient with this syndrome, as they had discovered when they met in the same train compartment on the way to a pediatrics conference in England in the late 1930s. A third patient had been referred to by L. Emmett Holt, Jr. and Rustin McIntosh in a textbook of pediatrics (Holt and McIntosh, 1933) and was included in full in the paper by Ellis and van Creveld (1940).

McKusick (2000) provided perspective on the classic study of dwarfism, including Ellis-van Creveld syndrome, in the Lancaster County Amish.

Christian et al. (1980) reported the unusual case of an infant with both Ellis-van Creveld and Dandy-Walker syndromes and with homozygosity for an unusually long heterochromatic segment of the long arm of chromosome 9 (9qh+). The 18-year-old mother was mentally retarded, the product of a first-cousin mating, and less than 4 feet tall. Although thelarche and menarche occurred on schedule, she developed no pubic or axillary hair. The authors suggested that she may have had a previously unknown recessive disorder. The mating that resulted in the offspring with EVC and Dandy-Walker syndromes was presumably incestuous. Her father and 2 of her brothers, like the 18-year-old mother, had the 9qh+.

Zangwill et al. (1988) described hydrocephalus and the Dandy-Walker anomaly in EVC.

Rosemberg et al. (1983) reported the fatal case of a 19-month-old daughter of consanguineous parents who in addition to cardiac defects, including single atrium, had cerebral heteropias, left renal agenesis, and right megaureter. Serotkin et al. (1988) found features suggesting EVC in an infant who was mosaic for duplication 17q21.1-qter, owing to a direct tandem duplication. The child had bilateral polydactyly of the feet but not of the hands, dysplastic nails, and lip-tie. His gums had scalloped edges, and 2 neonatal teeth were evident.

Because of an observation of the radiologic features characteristic of Jeune syndrome (208500) and EVC in a Japanese boy with a de novo del(12)(p11.21p12.2) chromosomal aberration, Nagai et al. (1995) suggested that the EVC locus is situated on 12p.

EVC and McKusick-Kaufman (MKKS; 236700) syndromes are clinically similar, recessively inherited disorders sharing postaxial polydactyly of the hands and feet and a distinct congenital heart defect. Distinguishing characteristics are the osteochondrodysplasia and ectodermal anomalies in EVC syndrome, and hydrometrocolpos in MKKS. Hydrometrocolpos had been described in the Ellis-van Creveld syndrome by Akoun and Bagard (1956). Digilio et al. (1997) studied 2 sisters presenting with apparent EVC, 1 of whom also had hydrometrocolpos. Digilio et al. (2004) restudied the sisters and excluded linkage to either 4p (where EVC maps) or 20p (where MKKS maps). The sisters were later found to have short-rib thoracic dysplasia-15 with polydactyly (SRTD15; 617088).

Nomenclature

'Six-fingered dwarfism' was an alternative designation used for this condition when it was being studied in the Amish (McKusick et al., 1964) and may have served a useful function in defining this then little known condition for the medical profession, as well as the lay public. The term, however, has been found offensive by some, apparently not because of 'dwarfism,' but because of the reference to the polydactyly, which is seen as a 'freakish' labeling. For this reason, 6-fingered dwarfism has been removed as an alternative name for this entry. This leaves Ellis-van Creveld syndrome with its felicitous abbreviation, EVC, as the only satisfactory designation. Chondroectodermal dysplasia and mesoectodermal dysplasia do not well define the entity and are not satisfactory for general usage, either medical or lay.