The Diagnostic Value of IGF-2 and the IGF/IGFBP-3 System in Silver-Russell Syndrome

Abstract

Background/Aims: Recently, we have described a family of 4 members presenting with intrauterine and postnatal growth failure, low IGF-2 levels, and signs of Silver-Russell syndrome (SRS) who carried a genomic IGF2 mutation. Here, we assess the value of IGF-2 in relation to SRS. Methods: We collected data from 48 SRS children and 48 short children born small for gestational age (SGA) seen at our center. The SRS children were 4.6 ± 2.0 years of age, and the SGA children were 4.8 ± 1.8 years of age. All patients were prepubertal and growth hormone naive. An 11p15 ICR1 loss of methylation (11p15LOM) was present in 22, maternal uniparental disomy of chromosome 7 (upd(7)mat) in 7, and IGF2 genomic mutation (IGF2mut) in 3 patients. Growth factors were measured by in-house radioimmunoassays. Results: The median IGF-2 standard deviation scores (SDSs) were: IGF2mut –1.75, upd(7)mat –1.69, nonsyndromic SGA –1.52, 11p15LOM –0.61, and clinical (tested negative) –0.55. The median IGF-2:IGF-1 concentration ratio was 2.57 in IGF2mut compared to 5.44 in 11p15LOM (p = 0.036), 7.84 in clinical, and 7.98 in upd(7)mat. Upd(7)mat patients had significantly lower IGF-1 and IGFBP-3 SDSs than patients with 11p15LOM (p ≤ 0.002). Conclusion: Serum IGF-2 in combination with IGF-1 and IGFBP-3 can add to the clinical signs of SRS patients and help to perform targeted genetic testing. Further studies are needed.

Prenatal correction of IGF2 to rescue the growth phenotypes in mouse models of Beckwith-Wiedemann and Silver-Russell syndromes

“…Reduced IGF2 RNA levels in human SRS fibroblasts (Gicquel et al, 2005) and epimutation positive fetuses and placentas (Yamazawa et al, 2008) support the insulator model in humans. Reduced IGF2 protein levels in SRS children (Begemann et al, 2015;Binder et al, 2017) suggest the involvement of IGF2 misregulation in SRS.…”

Downregulation of miR-637 promotes vascular smooth muscle cell proliferation and migration via regulation of insulin-like growth factor-2

“…Insulin-like growth factor 2 (IGF-2) is a protein hormone that has a verified and pivotal role in various human diseases [17]. For instance, it has a diagnostic value in Silver-Russell syndrome and is closely related to the catch-up growth of low-birthweight infants [18,19]. Accumulating evidence confirms that IGF-2 can facilitate atherosclerosis by accelerating the proliferation and migration of VSMCs [20,21].…”