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

Abstract

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.

Glypican-3 is overexpressed in lung squamous cell carcinoma, but not in adenocarcinoma

“…9 In addition to visceral and skeletal abnormalities, SimpsonGolabi-Behmel patients have increased incidence of embryonal tumors (Wilms' tumor, neuroblastoma and hepatoblastoma). 8,10 This combination of findings suggested that glypican-3 has an inhibitory effect on cell proliferation and could function as a tumor-suppressor gene. 11 Indeed, few tumors, including ovarian carcinoma, 12 mesothelioma 13 and breast carcinoma, 2,14 show lower glypican-3 expression relative to normal tissue.…”

Expression profiles of congenital renal dysplasia reveal new insights into renal development and disease

“…For example, we found genes/gene families involved in UB branching and growth, such as BMP7 [19,20]; UB elongation and epithelial maturation, such as Pod1, HSPG, and MDK; and renin and extracellular matrix/matrix protease genes that participate in epithelial formation and vascular patterning [21,22] were decreased in RD. Expression of a number of genes implicated in human syndromes with abnormal renal phenotype (SALL1, GPC3, AGTR2, WNT5A, and renin) was also decreased in RD kidney samples [23][24][25][26][27]. Decreased expression of these genes in the kidneys in RD in our study reiterates their importance in normal kidney development and suggests their loss may contribute to pathogenesis of RD, not only in heritable human disorders but also in patients with sporadic congenital RD.…”

Expression of glypican 3 in hepatoblastoma: an immunohistochemical study of 65 cases

“…Currently, data suggest that GPC3 is involved in signaling pathways by direct or indirect interactions with Wnts, Hedgehogs, and bone morphogenetic proteins [12,[23][24][25][26][27][28]. GPC3 appears to have a role in morphogenesis, as it has stage-and tissue-specific expression in fetal development.…”

“…In SGB syndrome, 10% to 20% of patients described have an embryonal malignancy, including hepatoblastoma, neuroblastoma, gonadoblastoma, Wilms tumor, and hepatocellular carcinoma [4][5][6]. GPC3 exon deletions have been found in patients with SGB syndrome with embryonal malignancies, but the effect on the GPC3 protein expression and function is unknown [23,24]. As well, the GPC3 gene mutation status in sporadic hepatoblastoma has not been well studied.…”