CASE REPORT
A 10-year-old Turkish girl with short stature and polydactyly was
referred to our clinic. She was the second child and was born at
40th week of pregnancy, delivered by C/S with 4,000 gr
weight at birth. Birth weight was 4,000 g (75th centile) with a length
of 48 cm (25th centile) and a head circumference of 35 cm (10th
centile). Apgar’s score was calculated to be normal. She had neonatal
jaundice on day 8 of life, and treated with phototherapy for 2–3 days.
Her parents were first degree cousins. The family history revealed that
the patient’s sister died after birth and seemingly featured similar
clinical presentation. She had a history of atrial septal defect (ASD)
surgeries, when she was 1.5 years and 4 years old. The patient’s
developmental milestones were delayed, she started walking from the age
of 4 and she started to speech from the age of 3. At 10 year of age,
some dysmorphic features were detected, including high forehead, wide
nasal bridge, short philtrum, disproportionate shortness of extremities,
postaxial polydactyly and brachydactyly in hands and bilateral
shortening of the 4th and 5thmetatarsal bones, syndactyly between 2nd and
3rd toes, dystrophic hand and toe nails, hypodontia
and early dental decay. She had genu valgum deformity with inability to
full extension in knee and dislocated patellae, causing a limited
walking distance and restriction of movements (Fig. 1).
The main physical findings were height 111 cm
(<3rd centile) her weight was 19 kg
(<3rd centile) and her head circumference
was 50 cm (<3rd centile). Further evaluation
revealed that she had previously operated ASD, mitral regurgitation,
tricuspid regurgitation and dilatation in right cardiac cavities in
echocardiography (ECO). Vision and hearing examination were normal. The
patient’s complete blood count was normal. The systemic examination was
otherwise unremarkable. Cytogenetic analysis revealed a normal 46,XX
karyotype. No additional abnormalities were detected. Her parents and
sister were apparently healthy.
The clinical diagnosis was EvC syndrome. A signed informed consent was
obtained from her family prior to genetic testing. Venous blood was
sampled from the proband, and was sent to the Medical Genetic Laboratory
of Haseki Education and Research Hospital in Turkey. Subsequently,
genomic DNA was extracted from peripheral blood leukocytes by the help
of standard protocols. Then, entire coding exons and their flanking
regions of the EVC and EVC2 genes were screened using
targeted next-generation sequencing (MiSeq) approach.
DNA sequence analysis of the EVC gene was normal, while DNA
sequence analysis of the complete coding region of the EVC2 gene
(NM_147127.5) showed homozygous for c.3533_3546del, p.Glu1178Glyfs*82
in exon 20 (Figure 2 by the DECIPHER). This EVC2 gene
variation has not been reported before. Using an in-silico prediction
tool, MutationTaster (mutationtaster.org), we identified this variation
as a disease-causing predisposition factor. According to the American
College of Medical Genetics and Genomics (ACMG) sequence variant
classification guideline, the variant was classified as pathogenic. This
variant was not present in healthy control population databases (gnomAD,
1000 Genomes Project) and also had not been reported in disease mutation
databases (Clinvar, Human Gene Mutation Database). This is both
frameshift and pathogenic variation, thereby confirming the clinical
diagnosis of EVC syndrome. This is both frameshift and pathogenic
variation, thereby confirming the clinical diagnosis of EVC syndrome.