Weyers Acrofacial Dysostosis
A number sign (#) is used with this entry because of evidence that Weyers acrofacial dysostosis (WAD) is caused by heterozygous mutation in the EVC2 gene (607261). There is also evidence that WAD is caused by heterozygous mutation in the EVC gene (604831); one such patient has been reported.
Mutations in the EVC and EVC2 genes cause Ellis-van Creveld syndrome (225500), an allelic disorder with autosomal recessive inheritance.
DescriptionWeyers acrofacial dysostosis is an autosomal dominant condition with dental anomalies, nail dystrophy, postaxial polydactyly, and mild short stature. Ellis-van Creveld syndrome is a similar disorder, with autosomal recessive inheritance and the additional features of disproportionate dwarfism, thoracic dysplasia, and congenital heart disease (summary by Howard et al., 1997).
Clinical FeaturesUnder the designation acrofacial dysostosis, Weyers (1952) described a syndrome of postaxial polydactyly with anomalies of the lower jaw, dentition and oral vestibule, and proposed autosomal dominant inheritance. Weyers (1956) was aware of similarities to the Ellis-van Creveld syndrome.
Roubicek and Spranger (1984) reported an affected 4-generation family. Lower and upper incisors were abnormal in shape and number. Additional findings were prominent ear antihelices, hypoplastic and dysplastic nails, and mild shortness of stature. Inheritance was dominant (no male-to-male transmission was observed) with variable expression. To differentiate it from other acrofacial dysostoses, they suggested naming the condition acrodental dysostosis.
Curry and Hall (1979) described a large Spanish-Mexican family in which several members had an autosomal dominant syndrome of postaxial polydactyly, conical teeth, nail dysplasia, and short limbs. Shapiro et al. (1984) reported a similar, isolated case in a 16-year-old male of Cherokee, Irish and German extraction. His father and mother, who were not related, were 32 and 26 years of age, respectively, at his birth. Roubicek and Spranger (1984) concluded that patients reported by Curry and Hall (1979) and Shapiro et al. (1984) had Weyers acrofacial dysostosis.
Turnpenny (1995) examined a family with features that suggested some overlap between this disorder and Pallister-Hall syndrome (PHS; 146510). This family had a mother and son affected with fourth finger duplication and nail and dental dysplasia. The mother had gelastic epilepsy (a form characterized by laughter) and the son had imperforate anus. The absence of MRI findings of hypothalamic hamartomas in these patients argued against Pallister-Hall syndrome but gelastic epilepsy has been associated with hypothalamic lesions, suggesting a functional if not anatomic lesion of this area.
MappingHoward 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. By linkage and haplotype analysis, Howard et al. (1997) determined that the disease locus in this pedigree resided on 4p16 in a region that includes the EVC locus. The authors concluded that the genes for the condition in the family of Howard et al. (1997) and for EVC are near one another or that 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.
Molecular GeneticsMutations in the EVC2 Gene
Ye et al. (2006) identified a heterozygous 1-bp deletion in exon 22 of the EVC2 gene (3793delC; 607261.0009) in affected members of a Chinese family with autosomal dominant Weyers acrofacial dysostosis spanning 5 generations. The findings confirmed that the disorder is allelic to Ellis-van Creveld syndrome.
Valencia et al. (2009) performed direct analysis of the EVC and EVC2 genes in 3 patients with Weyers acrofacial dysostosis and identified a heterozygous mutation in the EVC2 gene in all: the previously identified 3793delC mutation, and 2 novel mutations that occurred at the same nucleotide position, 3979T-G (607261.0012) and 3979T-A (607261.0013), both of which resulted in truncation of the protein at leu1266. All 3 mutations were tightly clustered at the 3-prime end of exon 22, indicating a mutation hotspot for this disorder. In vitro studies in NIH3T3 cells showed that the Hedgehog signaling pathway is fully active in cells mimicking EVC syndrome mutations but is impaired in cells mimicking WAD mutations. This finding was in keeping with the manifestation of an affected phenotype in individuals heterozygous for WAD-related mutations but not in individuals heterozygous for EVC syndrome-related mutations.
D'Asdia et al. (2013) performed direct analysis of the EVC and EVC2 genes in 2 patients with Weyers acrofacial dysostosis and identified a heterozygous mutation in exon 22 of the EVC2 gene in both: the previously identified 3793delC mutation and a novel truncating mutation (G1269X; 607261.0014).
Mutation in the EVC Gene
Ruiz-Perez et al. (2000) determined that a child with EVC, whose father had Weyers acrodental dysostosis (Spranger and Tariverdian, 1995), was a compound heterozygote with a missense mutation in the EVC gene inherited from her father (S307P; 604831.0006) and a 1-nucleotide deletion inherited from her mother (604832.0007).
D'Asdia et al. (2013) reported a patient (patient 6) with classic EVC who had the S307P mutation and another mutation in the EVC gene; his father was heterozygous for S307P and was clinically unaffected. The authors stated that although S307P is a recurrent mutation in EVC, no other mutation carrier besides the father reported by Ruiz-Perez et al. (2000) had been reported to be affected. D'Asdia et al. (2013) suggested that the clinical outcome of heterozygotes may be influenced by the genetic background of each individual carrier.
NomenclatureConfusion has been generated by the use of the Weyers eponym with this disorder and with Weyers ulnar ray oligodactyly syndrome (602418), as well as with the Weyers oculovertebral syndrome. The use of the term Weyers syndrome (without further qualification) should be discontinued for this reason (Biesecker, 1995).