IGF-I and IGF Binding Protein-3 Generation Tests and Response to Growth Hormone in Children with Silver-Russell Syndrome

Silver-Russell syndrome (SRS) was first described in 1953 by Silver et al. [1]and in 1954 by Russell [2]. Ten percent of the cases are due to maternal chromosome 7 disomy (mUPD7) suggesting a genomic "imprinting" [3, 4]. In 2005 Gicquel et al. [5] identified an epimutation (loss of methylation) of the central telomeric imprinting center region 1 (ICR1) on chromosome 11p15 in various patients with typical SRS clinical characteristics. Other authors subsequently confirmed the presence of these mutations with a high frequency (20–63.8%) in patients with SRS [6]. This region is associated with the regulation of many genes, such as tumor suppressor genes (H19) and the IGF-2 gene. Hypermethylation in this region is associated with Beckwith-Wiedemann syndrome characterized by excessive growth and/or asymmetry. Hypomethylation in the H19/IGF2 region could lead to asymmetry and fetal growth retardation as seen in SRS [7]. SRS and Beckwith-Wiedemann syndrome are currently considered two diseases caused by opposite epigenetic alteration in the same chromosomal region (11p15) thus leading to different growth disorders [8–10]. This epigenetic defect can be involved in syndromic intrauterine growth retardation [5, 11]. The diagnosis is clinical and requires at least 3 of the following criteria: (1) birth weight 2 SDS or more below the mean for gestational age (GA), (2) short stature (height more than 2 SDS below the mean for children of the same age and gender) at the time of the diagnosis, (3) characteristic appearance (triangular face, small mandible, low ear implantation, down turned corners of the mouth, proeminent forehead), (4) clinodactyly of the 5th finger, and (5) body asymmetry [12]. The incidence of SRS is 1 in 50.000 to 100.000 newborns [13], and it can be as high as 1？:？3000 with a male predominance [14]. SRS diagnosis although easily recognizable in extreme cases can be difficult in more subtle situations, especially in the absence of body asymmetry. In their review