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