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.