Simpson–Golabi–Behmel syndrome: a prenatal diagnosis in a foetus with GPC3 and GPC4 gene microduplications

To the Editor: Mutations and genomic rearrangements involving the GPC3 gene lead to an X-linked overgrowth syndrome called Simpson–Golabi–Behmel type I (SGBS1) (1). One case of a GPC4 duplication linked to SGBS1 has been reported in the literature (2); however, no point mutations or deletions have been described so far. We present a male foetus and his mother with two microduplications involving the GPC3 and GPC4 genes. The foetus presented with a full-blown SGBS1 with severe brain malformations, whereas the mother was diagnosed with the Wilms’ tumour as a toddler. To our knowledge, this is the first report of a SGBS1 carrier with Wilms’ tumour. Our patient was a 28 year old primigravida, who had undergone a unilateral nephrectomy at 18 months of age because of the Wilms’ tumour, had no other medical problems and was of normal stature and intelligence. In her pregnancy, the second trimester scan detected foetal overgrowth, polyhydramnios, an enlarged placenta and an abnormal development of the central nervous system. At 24 weeks 6 days gestation, she gave birth to a boy weighing 1235 g with the head circumference of 27 cm (>99th percentile) who died a few minutes later. A foetal examination showed macrosomy, hypertelorism, short nose, broad nasal bridge, macrostomia, macroglossia (Fig. 1c), and 13 ribs on the left side (Fig. 1d). Hepatomegaly, nephromegaly, thymic hyperplasia, ventricular septal defect (VSD), complete agenesis of the corpus callosum, cerebellar hypoplasia, dilatation of lateral ventricles, and histological abnormalities of renal tissue were noted at autopsy. Molecular karyotyping of the amniotic fluid revealed a male karyotype with two maternally inherited interstitial microduplications at Xq26.2. Larger microduplication encompasses four genes: HS6ST2, USP26, TFDP3, and GPC4. Smaller microduplication is located within the GPC3 gene and contains exons 6 and 7 of its longest transcript (Fig. 1a). Both duplications were confirmed by the multiplex ligation-dependent probe amplification (Fig. 1b). The mother had a skewed chromosome X inactivation pattern (retaining approximately 12% of non-shared human androgen receptor (HUMARA) gene allele) (Fig. 1b). HS6ST2 and TFDP3 have been associated with various tumours in the literature, but never with the Wilms’ tumour. At present, there is also no indication that rearrangements of USP26 and TFDP3 cause brain malformations. HS6ST2 is expressed in the brain and believed to play a role in embryonic development. 3-O-sulphated heparan sulphates produced by a similar sulfotransferase, HS3ST2, have been reported to act as molecular chaperones allowing the abnormal phosphorylation of tau in Alzheimer’s disease (3). Considering that the structure of this gene is disrupted by the larger duplication in our case, its potential pathological effect on brain development cannot be ruled out. Glypicans are involved in signalling pathways associated with cell division and growth regulation (1). The loss of functional GPC3 probably leads to hyperactivation of Hedgehog signalling which could explain overgrowth and increased tumour risk seen in SGBS1 (4). GPC4 gene presumably has a similar biological role to GPC3 (2). Mapping of GPC3 and GPC4 showed that these two genes are tandemly arrayed. Because SGBS1 patients have variable clinical features, it was proposed that GPC3-GPC4 gene cluster might be reciprocally expressed, whereby loss of GPC3 function leads to loss of GPC4 function, which could, in turn, lead to a more severe clinical presentation in some SGBS1 patients. Thus, screening for mutations in both genes was proposed in SGBS patients, especially in cases where no mutations in GPC3 gene were detected (5). In silico prediction showed that duplication of exons 6 and 7 of the GPC3 gene disrupts its transcription and causes loss of functional protein, thereby causing the SGBS1 phenotype in the foetus. However, it does not fully explain the mother’s Wilms’ tumour, which has never been reported in GPC3 mutation carriers and the brain malformations in the foetus, which are rare in this syndrome (6, 7). Considering the close association of GPC4 with GPC3, it remains possible that the duplication of GPC4 contributed to the development of these two features. Even if GPC4 is not important in SGBS1 pathogenesis, the larger duplication could further disrupt the expression of GPC3 as it flanks its 3′ end (5). Also, aberrant expression of the other three genes, encompassed by the larger duplication, could alter the phenotypic presentation in the foetus and its mother. Our findings also raise the important question whether carriers of SGBS1 are at an increased risk of certain malignancies. Further studies of tissue expression of GPC3, GPC4, and the other three genes involved are