ESPE Abstracts

Introduction: Silver-Russell syndrome (SRS) is a rare, well-defined genetic disease characterized by intrauterine and postnatal growth retardation, short stature, triangular face, relative macrocephaly and body asymmetry. The most common molecular pathologies are loss of methylation (50%) of the imprinting center in the p15.5 region of the paternal 11th chromosome and maternal uniparental disomy of the 7th chromosome (5-10%). The IGF2 (insulin-like growth factor 2, MIM#147470) gene located in the imprinting center in the 11p15.5 region and expressed only from the paternal allele has a critical importance in the pathophysiology of SRS due to its varying expressions. Although SRS is often associated with epigenetic changes, IGF2 gene variants in the paternal allele can rarely be identified in the etiology. Here we present a case with SRS3(MIM#616489) with a novel variant in the IGF2 gene.

Case: A 3.6 years old male who was born at term with 2500 gr (-2 SD) was evaluated for short stature. His mother and father were from the same village. His height was -3.39SDS, body weight was -2.28SDS, BMI was 0.57SDS, head circumference was -0.88SDS. He had relative macrocephaly, prominent forehead, prominent ears, long eyelashes, midface hypoplasia, slightly elongated filtrum, microstomy, and thin lips. Extremity diameters were symmetrical, there was no hand-foot anomaly. The target height was 168.5 cm (-1.24SDS)(Mothers’&Fathers’ height SDS:-0.95/-1.56SDS). Peak growth hormone responses to L-dopa&clonidine were found as 2.79/7.21ng/ml, respectively. His bone age was 2 years. Pituitary MRI, ecocardiography, abdominal USG and bone survey were normal. Heterozygous variant of c.518dupC (P.Glu174ArgfsTer50) was detected in the IGF2 gene (NM_000612.6) with SRS1 sequencing panel. The variant was determined to be of paternal origin by Sanger sequencing analysis and it was planned to expand the segregation study to the upper generations. His growth rate was found 3.6 cm /year in the follow-up period. The growth hormone treatment (dose of 0.3mg/kg/week) was started at the age of 6.3 years. With the growth hormone treatment, his growth velocity was measured by 4.4 cm in the first three months of treatment.

Conclusion: Although SRS is a clinically diagnosable disease with a well-known follow-up, the etiology cannot be determined in 30-40% of patients with SRS phenotype. Paternally inherited IGF2 variants have been reported to be associated with the disease in only a few case reports. We think that experience should be increased in order to understand the formation mechanisms of the disease and possible phenotypic differences in subtypes arising from different mechanisms.

Keywords: Short stature, IGF2 gene, Silver-Rusell syndrome