DISCUSSION
EVC is characterized by short stature, chondrodystrophy, thoracic hypoplasia, postaxial polydactyly, abnormalities in dental structures with varying severity such as peg-shaped teeth, natal teeth and abnormalities in enamel, multiple frenulum, dysplastic nails, congenital heart anomalies and sparse hair. A narrow thorax due to the shortness of ribs may result in severe postnatal respiratory distress. Heart defects are present in 60% of cases. The presence of cardiac disease is the main determinant of life expantancy. Mental and cognitive retardation is not expected in this disease4,5. The estimated prevalence of EvC is 1-7/1,000,000 in non-Amish population. Clinical manifestations are variable among patients and not all patients exhibit whole cardinal signs1,11.
Disproportionate short stature, polydactyly and brachydactyly in hands, shortness of extremities, genu, bilateral shortening of 4th and 5th metatarsal bones, dystrophic nails in hand and toes, hypodontia and cardiac defects were observed in our patient. Peg shaped teeth and multiple frenulum were not observe in proband. She had dislocated patellae and genu valgum deformity, causing a limited walking distance. Clinically, her ortopedic disability progress more rapidly than what is expected. While mesomelic shortness is commonly reported in EvC syndrome, few cases with rhizomelia were also reported12,13. Our patient had both distal and proximal shortness with distal limb shortness being more prominent.
EvC syndrome is mostly related to the EVC and EVC2 gene mutations. The clinical presentation of EvC patients with variations inEVC and EVC2 genes is indistinguishable. EVC and EVC2 play role in endochondral growth and skeletal development. EVC and EVC2 are co-localize in the EvC Zone and EVC2 is essential for the localization of EVC at the base of primary cilia14. They encode ciliar basal body proteins15. Thus, EvC is also defined as primary ciliopathy.
Various types of ciliopathies are caused by defects in cilia structure or function6. Among the ciliopathy diseases, while the structure of the cilia is normal in EvC, Hedgehog and Fibroblast growth factor (FGF) signaling pathways are impaired10,14. Reduced Hedgehog signaling and increased FGF signaling at the growth plaque was reported in Evc2 mutant mice10. The Hehgehog signaling starts the association of Evc2 with Smoothened (Smo). Smo-Evc2 signaling complex at the EvC zone is essential for Hh signal transmission14,16.
Homozygous mutations in the EVC and EVC2 g enes cause the EvC syndrome while heterozygous mutations cause the Weyers acrofacial dysostosis (WAD, OMIM 193530) that shows a similar phenotype as in EvC syndrome3,6. Weyers acrofacial dysostosis is a milder disease compared to EvC syndrome. In general, congenital heart disease is not found in WAD patients. Although many cases with EvC syndrome have been reported up to date, few cases of Weyers acrofacial dysostosis are present in the literature. Variants in both the EVC andEVC2 gene have been reported in WAD. It is usually detected in the last exon of the EVC2 . It is suggested that the last exon of the EVC2 gene may serve as a hotspot for WAD mutations3 .
The EVC2 gene is located on the 4p16.2 chromosome, has 22 exons and encodes a single-pass type I transmembrane protein. Gene expression occurs in many different organs including heart, placenta, lung, liver and skeletal muscles. According to the Human Gene Mutation Database (HGMD), 82 variations have been identified so far for the EVC2 . Majority of the mutations reported are nonsense mutation. Many EvC patients with EVC gene mutations were reported in Turkish population, previously. To our knowledge, there is three case of a Turkish EvC patient with EVC2 mutation reported in the literature17