GPC3 mutation analysis in a spectrum of patients with overgrowth expands the phenotype of Simpson-Golabi-Behmel syndrome

• Published in: American journal of medical genetics 2001-08, Vol.102 (2), p.161-168
• Main Authors: Li, Madeline, Shuman, Cheryl, Fei, Yan Ling, Cutiongco, Eva, Bender, H.A., Stevens, C., Wilkins-Haug, L., Day-Salvatore, D., Yong, S.L., Geraghty, M.T., Squire, Jeremy, Weksberg, Rosanna
• Format: Article
• Language: English
• Subjects: Abnormalities, Multiple - genetics; Abnormalities, Multiple - pathology; Biological and medical sciences; Blotting, Southern; Diseases of the osteoarticular system; DNA - genetics; Face - abnormalities; Family Health; Female; Gene Deletion; Genetic Linkage; Glypicans; Growth Disorders - genetics; Heparan Sulfate Proteoglycans - genetics; hepatoblastoma; Humans; Male; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; Mutation; PCR analysis; Pedigree; Perlman syndrome; Phenotype; Sotos syndrome; Syndrome; Wiedemann-Beckwith syndrome; X Chromosome - genetics
• ISSN: 0148-7299; 1096-8628
• DOI: 10.1002/1096-8628(20010801)102:2<161::AID-AJMG1453>3.0.CO;2-O

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. © 2001 Wiley‐Liss, Inc.