Objective IGF2 is a paternally expressed growth-promoting gene. Here, we report five cases with IGF2 mutations and review IGF2 mutation-positive patients described in the literature. We also compare clinical features between patients with IGF2 mutations and those with H19/IGF2:IG-DMR epimutations. Results We recruited five cases with IGF2 mutations: case 1 with a splice site mutation (c.–6–1G>C) leading to skipping of exon 2 and cases 2–5 with different missense mutations (p.(Cys70Tyr), p.(Cys71Arg), p.(Cys33Ser), and p.(Cys45Ser)) affecting cysteine residues involved in the S-S bindings. All the mutations resided on the paternally inherited allele, and the mutation of case 5 was present in a mosaic condition. Clinical assessment revealed Silver–Russell syndrome (SRS) phenotype with Netchine–Harbison scores of ≥5/6 in all the apparently nonmosaic 14 patients with IGF2 mutations (cases 1–4 described in this study and 10 patients reported in the literature). Furthermore, compared with H19/IGF2:IG-DMR epimutations, IGF2 mutations were associated with low frequency of hemihypoplasia, high frequency of feeding difficulty and/or reduced body mass index, and mild degree of relative macrocephaly, together with occasional development of severe limb malformations, high frequency of cardiovascular anomalies and developmental delay, and low serum IGF-II values. Conclusions This study indicates that IGF2 mutations constitute a rare but important cause of SRS. Furthermore, while both IGF2 mutations and H19/IGF2:IG-DMR epimutations lead to SRS, a certain degree of phenotypic difference is observed between the two groups, probably due to the different IGF2 expression pattern in target tissues.

Background Insulin and insulin-like growth factor (IGF) signaling plays an important role in prenatal and postnatal growth and glucose metabolism. Both smallfor-gestational age (SGA) and preterm infants have abnormal growth and glucose metabolism. However, the underlying mechanism remains unknown. Recently, we showed that term SGA infants have abnormal insulin/ IGF signaling in cord blood. In this study, we examined whether preterm infants show similar aberrations in cord blood insulin/IGF signaling. Methods A total of 41 preterm cord blood samples were collected. Blood glucose, insulin, IGF-1, and C-peptide concentrations were measured, and mRNA expression of IGF1R, INSR, IRS1, IRS2, and SLC2A4 (i.e., GLUT4) was analyzed by quantitative reversetranscription PCR. Results This study included 34 appropriate-forgestational age (AGA) and 7 SGA preterm neonates. No hyperinsulinemia or any differences in IGF1R or INSR mRNA expression were detected between the two groups. However, GLUT4 mRNA levels were increased in preterm SGA. Moreover, the expression level in hypoglycemic preterm SGA was significantly higher than that in hypoglycemic preterm AGA. IRS2 mRNA expression did not show a statistically significant difference between preterm SGA and AGA neonates. Conclusion SGA preterm birth does not induce hyperinsulinemia; however, it modifies insulin/IGF signaling components such as GLUT4 in umbilical cord blood. Our study suggests that prematurity or adaptation to malnutrition alters the insulin/IGF signaling pathway.

We describe a case of posthumously diagnosed MIRAGE syndrome (Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital problems, and Enteropathy) in a girl with a new pathogenic SAMD9 variant (p.F437S), who was initially considered to have familial dysautonomia (FD)-like disease due to increased levels of catecholamine metabolites. Functional analyses of F437S-SAMD9 were performed, showing characteristics of disease-causing variants. This new SAMD9 variant (p.F437S) also causes MIRAGE syndrome.

Mitochondria are essential organelles for maintaining intracellular homeostasis. Their dysfunction can directly or indirectly affect cell functioning and is linked to multiple diseases. Donation of exogenous mitochondria is potentially a viable therapeutic strategy. For this, selecting appropriate donors of exogenous mitochondria is critical. We previously demonstrated that ultra-purified bone marrow-derived mesenchymal stem cells (RECs) have better stem cell properties and homogeneity than conventionally cultured bone marrow-derived mesenchymal stem cells. Here, we explored the effect of contact and noncontact systems on three possible mitochondrial transfer mechanisms involving tunneling nanotubes, connexin 43 (Cx43)-mediated gap junction channels (GJCs), and extracellular vesicles (Evs). We show that Evs and Cx43-GJCs provide the main mechanism for mitochondrial transfer from RECs. Through these two critical mitochondrial transfer pathways, RECs could transfer a greater number of mitochondria into mitochondria-deficient (ρ0) cells and could significantly restore mitochondrial functional parameters. Furthermore, we analyzed the effect of exosomes (EXO) on the rate of mitochondrial transfer from RECs and recovery of mitochondrial function. REC-derived EXO appeared to promote mitochondrial transfer and slightly improve the recovery of mtDNA content and oxidative phosphorylation in ρ0 cells. Thus, ultrapure, homogenous, and safe stem cell RECs could provide a potential therapeutic tool for diseases associated with mitochondrial dysfunction.