To study insulin-like growth factor 2 (IGF2) imprinting in BWS (Beckwith-Wiedemann syndrome, an overgrowth syndrome associated with Wilms and other embryonal tumours), we examined allele-specific expression using an Apal polymorphism in the 3' untranslated region of IGF2. Four of six BWS fibroblast strains demonstrated biallelic expression, as did the tongue tissue from one of these patients. Paternal heterodisomy was excluded for all BWS patients with biallelic expression, suggesting strongly that the BWS phenotype in some patients involves disruption of IGF2 imprinting. Constitutional loss of IGF2 imprinting in a subgroup of our BWS patients, and recent reports of loss of imprinting in sporadic Wilms tumour, further strengthens the view that IGF2 overexpression plays an important role in somatic overgrowth and the development of embryonal tumours.

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked overgrowth syndrome caused by deletions in glypican 3 (GPC3). SGBS is characterized by pre- and postnatal overgrowth, a characteristic facial appearance, and a spectrum of congenital malformations which overlaps that of other overgrowth syndromes. We performed GPC3 deletion screening on 80 male patients with somatic overgrowth in the following categories: SGBS (n = 19), possible SGBS (n = 26), including families in which individuals had previously been diagnosed with other overgrowth syndromes, and Wiedemann-Beckwith syndrome (WBS) (n = 35). Using exon-specific PCR and Southern blot analysis, we identified seven GPC3 deletions. In most cases a clear X-linked family history was not present. In two cases, GPC3 deletions were identified in patients belonging to pedigrees published previously as other overgrowth syndromes: one with a diagnosis of Sotos syndrome and the other Perlman syndrome with nephroblastomatosis. A third patient developed hepatoblastoma, a tumor type not previously described in SGBS. No GPC3 deletions were identified among the WBS patients. Direct sequencing of all GPC3 exons in the remaining 13 SGBS patients without GPC3 deletions did not identify any further mutations, raising the possibility of alternative silencing mechanisms and/or other genes in the pathogenesis of SGBS. Our results validate the clinical specificity of the facial appearance, skeletal/hand anomalies, and supernumerary nipples in patients with GPC3 deletions. Our data also suggest that nephroblastomatosis and hepatoblastoma are included in the phenotypic spectrum of GPC3 deletions and SGBS, underscoring the importance of tumor surveillance in these children.