Clinical and molecular features of children with Beckwith-Wiedemann syndrome in China: a single-center retrospective cohort study

Beckwith-Wiedemann syndrome (BWS, OMIM#130650), first reported by Beckwith JB and Wiedemann HR in the 1960s, is a rare genetic overgrowth disorder with variable clinical features and cancer predisposition [1‐3]. The estimated incidence of BWS is 1 in 10,000 live births [4]. The clinical manifestations of BWS include macroglossia, macrosomia, abdominal wall defects, hemihyperplasia, enlarged abdominal organs, ear anomalies, facial nevus flammeus, and nephroureteral malformations. In addition, an increased risk of developing embryonal tumors during early childhood was reported in patients with BWS, such as Wilms’ tumor and hepatoblastoma [1, 5].

BWS is caused mainly by molecular alterations affecting imprinted gene expression located within the chromosome 11p15.5 region [1, 2]. The imprinting cluster of chromosome 11p15.5 harbors two imprinting domains, IGF2/H19 and CDKN1C/KCNQ1/KCNQ1OT1, which are controlled by H19-associated imprinting center 1 (IC1) and KCNQ1OT1-associated IC2, respectively [6]. It has been demonstrated that an epigenetic or genetic defect affecting imprinted genes in chromosome region 11p15 could be observed in the majority of BWS patients, and DNA methylation abnormalities are the most commonly detected molecular defects [7, 8]. Gain of methylation at H19/IGF2:IG differentially methylated region (DMR; IC1 GOM), loss of methylation at KCNQ1OT1:TSS (DMR; IC2 LOM), paternal uniparental isodisomy (pUPD11), CDKN1C loss of function mutations, and chromosome abnormalities altering copy number or structure of 11p15.5 were identified in reported BWS patients [4, 7‐9].

Various clinical phenotypes and genotypes have been well-described in European and North American BWS patients [1]. However, there are only limited reports of the clinical features and molecular etiology of BWS patients from mainland, China. In this study, we conduct a single-center retrospective study to characterize the clinical features and genetic defects of patients with clinical suspicion of BWS in Shanghai, China.

Clinical features and molecular etiology in European and North American BWS patients have been well-studied in the literature. Although the typical clinical manifestations of BWS are macroglossia, macrosomia, abdominal wall defects, and an increased risk of embryonal tumors, a growing body of evidence indicates that not all BWS patients display all of these phenotypic features [1]. Increasing BWS patients in the absence of cardinal features were confirmed by the identification of molecular defects in the 11p15.5 region [12, 13]. Thus, both clinical features and molecular testing are important for the clinical diagnosis and management of BWS.

In the current study, we conducted a single-center retrospective cohort study to characterize the clinical features and molecular defects of clinical suspicion BWS patients in a tertiary children’s care center in Shanghai, China. We showed that the most common cardinal features and suggestive features in clinically diagnosed BWS patients in our cohort were macroglossia (71.4%) and lateralized overgrowth (33.3%), umbilical hernia and/or diastasis recti (65.0%) and ear creases or pits (61.9%), respectively, which were comparable with two previous studies of BWS in the Chinese population [14, 15]. A study [14] of 47 Chinese patients with clinical suspicion of BWS, conducted in Taiwan, showed that the most common major clinical features of clinically diagnosed patients were abdominal wall defects, macroglossia and pre- or postnatal overgrowth, and the most common minor features were ear creases or pits and facial nevus flammeus [14]. A retrospective tertiary-wide study [15] performed in Hong Kong with 27 molecularly confirmed BWS reported that the most common clinical features were macrosomia and macroglossia (70.4%) and abdominal wall defects (70.4%). Since BWS patients present with a wide range of clinical features, a recent study investigated whether clinical presentation varied across BWS patients of different race/ethnicity populations [9]. It was shown that the incidences of macroglossia and exomphalos were higher in BWS patients of European/North American populations than Asian populations, while the incidences of umbilical hernia, organomegaly, and lateralized overgrowth were lower in European/North American populations than Asian populations [9]. The incidences of major clinical features of clinically diagnosed BWS patients in our studied cohort were comparable with previously reported Asian BWS patients [9]. Although an increased risk of developing embryonal tumors during early childhood was reported in patients with BWS [1, 5], BWS-related embryonal tumors were not observed in this cohort. In addition, ART was reported as a risk factor for BWS [16], and one female patient with a BWS score of 6 was conceived by ART in our study.

To date, only a small number of genetically confirmed BWS cases have been reported from mainland, China. In 2013, we reported the first two epigenetically confirmed cases with BWS in Shanghai, China: a female patient with IC2 LOM and a male patient with IC1 GOM [17]. Wang Q. et al. reported two Chinese cases with BWS caused by de novo paternal origin duplication of chromosome 11p15.5 in Shenzhen, China, including one patient diagnosed by prenatal analysis on cord blood [18]. It was shown that IC2 LOM (50–60%) and IC1 GOM (5–10%) in the chromosome 11p15 region occurs in the majority of BWS patients with a known molecular defect [5]. The MS-MLPA test was performed to detect the methylation status of the IC2 and IC1 genes in the chromosome 11p15 region in all patients with clinical suspicion of BWS in this study. Seven clinically diagnosed cases and 3 suspected BWS cases were identified with IC2 LOM, 5 clinically diagnosed BWS children were identified with IC1 GOM, and 1 clinically diagnosed BWS children were identified with pUPD11. A lower incidence of IC2 LOM and a higher incidence of IC1 GOM were observed in our studied cohort than previously reported European/North American and Asian BWS patients [9], which may due to the small size of study cohort. It was shown that 50% of clinically diagnosed BWS patients were identified with IC2 LOM, and 4% with IC1 GOM were identified in Taiwanese BWS patients [14]. Furthermore, molecular studies of Chinese BWS patients in Hong Kong showed that 48.1% of the BWS cases were caused by IC2 LOM, and 11.1% were caused by IC1 GOM [15]. The female patient conceived by ART was identified with IC2 LOM, which was consistent with previous studies [15, 19]. Both CDKN1C mutation and pUPD11 were also observed in previous studies of Chinese BWS patients [14, 15]. Unfortunately, CDKN1C loss of function mutation test was not performed in this cohort at the initial genetic testing, and the parents of the patients refused further genetic testing during the follow-up. Nevertheless, it is important to include CDKN1C mutation test to investigate the molecular etiology of BWS children in our future works.

Several limitations exist in the present study. Firstly, this report describes a single-center retrospective study with a limited number of subjects. Secondly, microsatellite analysis was not performed to further confirm the pUPD11 case identified by MS-MLPA. Thirdly, CDKN1C loss of function mutations test was not performed in this study cohort. It is important to include CDKN1C mutation test and microsatellite analysis to characterize the genotypes of Chinese BWS children in our future works.

Our study was the first to describe the clinical features and molecular defects of a cohort of 31 clinical suspicion BWS patients in mainland China. Given the large Chinese population and limited reported cases, further studies are needed to investigate the clinical features and genetic mechanisms vary between Chinese population and other well-studied populations.