Phenotypic Spectrum of Simpson–Golabi–Behmel Syndrome in a Series of 42 Cases With a Mutation in GPC3 and Review of the Literature

Abstract

Simpson-Golabi-Behmel syndrome (SGBS) is a rare X-linked multiple congenital abnormality/intellectual disability syndrome characterized by pre- and post-natal overgrowth, distinctive craniofacial features, macrocephaly, variable congenital malformations, organomegaly, increased risk of tumor and mild/moderate intellectual deficiency. In 1996, Glypican 3 (GPC3) was identified as the major gene causing SGBS but the mutation detection rate was only 28-70%, suggesting either genetic heterogeneity or that some patients could have alternative diagnoses. This was particularly suggested by some reports of atypical cases with more severe prognoses. In the family reported by Golabi and Rosen, a duplication of GPC4 was recently identified, suggesting that GPC4 could be the second gene for SGBS but no point mutations within GPC4 have yet been reported. In the genetics laboratory in Tours Hospital, GPC3 molecular testing over more than a decade has detected pathogenic mutations in only 8.7% of individuals with SGBS. In addition, GPC4 mutations have not been identified thus raising the question of frequent misdiagnosis. In order to better delineate the phenotypic spectrum of SGBS caused by GPC3 mutations, and to try to define specific clinical criteria for GPC3 molecular testing, we reviewed the clinical features of all male cases with a GPC3 mutation identified in the two molecular laboratories providing this test in France (Tours and Paris). We present here the results of the analysis of 42 patients belonging to 31 families and including five fetuses and three deceased neonates.

Two Consecutive Pregnancies with Simpson-Golabi-Behmel Syndrome Type 1: Case Report and Review of Published Prenatal Cases

“…Several authors have reported certain features on prenatal ultrasound that can facilitate SGB syndrome diagnosis before birth [Chen et al, 1993;Yamashita et al, 1995;Enns et al, 1998;Weichert et al, 2011;Garavelli et al, 2012;Cottereau et al, 2013;Kehrer et al, 2016;Magini et al, 2016;Mujezinović et al, 2016;Støve et al, 2017;Zimmermann and Stanek, 2017]. Table 1 summarizes the described prenatal findings from previously published cases and our cases.…”

“…However, how often preterm birth occurs in pregnancies with SGB syndrome is not clearly reported. The largest review with prenatal series of SGB syndrome to date reported a high proportion of preterm births (13/42, 31%); most of the cases were moderately premature [Cottereau et al, 2013]. Four pregnancies in that series were terminated in the late second trimester; therefore, the true incidence of preterm birth could be even higher.…”

“…We only chose the articles clearly describing SGB type 1 prenatal features. We also included a review on SGB syndrome, in which the incidence of prenatal symptoms was estimated [Cottereau et al, 2013]. As a result, 57 cases of prenatally detected SGB syndrome were found and calculations of the incidence of prenatal symptoms were made, together with our own 3 cases.…”

A Clinical Review of Generalized Overgrowth Syndromes in the Era of Massively Parallel Sequencing

“…Intellectual disability can be mild to severe. The condition is X-linked involving mutations in GPC3 [Neri et al, 1998;Li et al, 2001;Sakazume et al, 2007;Cottereau et al, 2013]. GPC4 duplication detected by MLPA has been reported in 2 individuals from one family with a clinical diagnosis of SGB syndrome [Cottereau et al, 2013].…”

“…Recent data suggests the tumor frequency could be lower as 1/34 patients developed Wilms tumor and 1/34 patients developed leukemia [Cottereau et al, 2013].…”