Simpson–Golabi–Behmel Syndrome Type 1 and Hepatoblastoma in a Patient With a Novel Exon 2–4 Duplication of the GPC3 Gene

Abstract

Mutations in the gene encoding glypican (GPC) 3 appear to be responsible for most cases of Simpson-Golabi-Behmel syndrome type 1. Duplication of the GPC4 gene has also been associated to this syndrome; however, no duplications involving GPC3 have been related. We describe a family that harbors a novel exon 2-4 duplication event leading to a truncating germline mutation of the GPC3 gene that, to our knowledge, has not been previously reported. GPC3 transcripts that carry this duplication bear non-functional proteins making its pathogenic role highly probable. The absence of a functional GPC3 may alter the normal differentiation of embryonal mesodermal tissues predisposing to the development of embryonal tumors, as the index case studied who developed a hepatoblastoma at age 9 months.

Duplication of exon 2 of the GPC3 gene in a case of Simpson‐Golabi‐Behmel syndrome

“…In the May issue of the Journal, Mateos et al [2013] reported a case of Simpson-Golabi-Behmel syndrome (SGBS), with a novel mutation of the GPC3 gene consisting of a duplication of exons 2-4 which causes a frameshift leading to a protein truncated of its last 183 amino-acids including the C-terminus. This report pinpointed that duplication of the GPC3 gene had not been reported before.…”

A patient with a unique frameshift mutation in GPC3, causing Simpson–Golabi–Behmel syndrome, presenting with craniosynostosis, penoscrotal hypospadias, and a large prostatic utricle

“…Endocrine abnormalities seen with SGBS include neonatal hypoglycemia due to pancreatic hyperplasia of the islets of Langerhans and newborn bone age advancement [Neri et al, ; Chen et al, ; Baujat et al, ]. As with other overgrowth syndromes, patients with SGBS are at increased risk for certain tumors, including Wilms tumor, hepatoblastoma, hepatocellular carcinoma, gonadoblastoma, and neuroblastoma [Behmel et al, ; Golabi and Rosen, ; Neri et al, ; Mateos et al, ]. Recently a case of SGBS with medulloblastoma has been reported [Thomas et al, ].…”

Glypican4 promotes cardiac specification and differentiation by attenuating canonical Wnt and Bmp signaling

“…In vitro, the Wnt-promoting factor R-spondin 3 was shown to interact with Syndecans and Glypican3 (Ohkawara et al, 2011), suggesting a complex interaction of heparan sulphate proteoglycans and Wnt signaling components at the cell membrane. Interestingly, human SGBS patients have a tendency to develop pre-and postnatal tumors, such as Wilm's tumor, hepatoblastomas, neuroblastomas and gonadoblastomas (Golabi et al, 1993;Rodríguez-Criado et al, 2005;Thomas et al, 2012;Mateos et al, 2013). The development of these tumors has been brought into correlation with a misregulation of canonical Wnt signaling (Honecker et al, 2004;Lapunzina, 2005;Liu et al, 2008;Armengol et al, 2011), indicating that the lack of glypicans might result in a misregulation of canonical Wnt signaling in SGBS patients.…”