The endocrine phenotype in Silver-Russell syndrome is defined by the underlying epigenetic alteration

Context: Around 50% of children with Silver-Russell syndrome (SRS) carry a hypomethylation of the imprinting control region 1 at the IGF2/H19 locus on 11p15, the functional significance of which is unknown. Objective: We aimed to compare the genotype in SRS with the endocrine phenotype. Design: The retrospective study included all SRS children who were treated during the last 18 yr at our hospital and for comparison a cohort of GH treated nonsyndromic short children born small for gestational age (SGA). Patients: The 61 patients with SRS included were defined by the presence of intrauterine growth retardation, lack of catch-up growth, and at least two of the criteria: typical face, relative macrocephaly, and skeletal asymmetry. Routine karyotype and GH secretion was normal in all children studied. A subgroup of 53 patients was treated with GH. Materials and Methods: Genomic DNA was available from 44 children. Multiplex ligation probe-dependent amplification analysis was performed to detect hypomethylation at the imprinting control region1 on 11p15. Uniparental disomy of chromosome7(UPD7) was analyzed by short tandem repeats typing. Serum levels of GH, IGF-I, and IGF-binding protein (IGFBP)-3 were measured by RIA. Results: Epimutations at 11p15 were found in 19 of 44, UPD7 in five of 44, and small structural aberrations of the short arm of chromosome 11 in two of 44 children. Of 44 cases, 18 were negative for any genetic defect known (41%). The most severe phenotype was found in children with 11p15-SRS. Children with UPD7-SRS had a significantly higher birth length (P < 0.004) but lost height SD score (SDS) postpartum, whereas children with 11p15-SRS showed no change in height SDS. IGF-I and IGFBP-3 serum levels were inadequately high in 11p15-SRS at -0.02 SDS (1.07, SD) and +1.38 SDS (1.01), compared with the low levels in UPD7-SRS and in the cohort of 58 nonsyndromic SGA children (P < 0.0009). During GH therapy, IGFBP-3 serum levels increased above normal values in 11p15-SRS (P < 10(-4)), whereas IGF-I increase was moderate. There was a trend toward more height gain in children with UPD7 than in those with 11p15 epimutation under GH therapy (+2.5 vs. +1.9 height SDS after 3 yr) (P = 0.08). Conclusions: Children with SRS and an 11p15 epimutation have IGFBP-3 excess and show endocrine characteristics suggesting IGF-I insensitivity, whereas children with SRS and UPD7 were not different from nonsyndromic short children born SGA. This phenotype- genotype correlation implicates divergent endocrine mechanisms of growth failure in SRS.