Clinical phenotype and molecular genetic analysis of 24 cases of Beckwith-Wiedemann syndrome
Highlight box
Key findings
• In this study, we analyzed a small cohort of Beckwith-Wiedemann syndrome (BWS) patients with short stature in China.
• The clinical manifestations of BWS include macroglossia, lateralized overgrowth, omphalocele, hypoglycemia, visceromegaly, renal anomalies, and auricular malformations.
What is known and what is new?
• BWS is a genetic disorder characterized by various clinical features.
• The findings identified a high prevalence of uniparental disomy (UPD) in the southern Chinese population and highlighted the diagnostic role of chromosomal microarray analysis (CMA) in detecting UPD-related phenotypes in patients with BWS. We report a novel co-occurrence of BWS and a pathogenic DUOX2 gene variant, suggesting a potential previously unrecognized pathophysiological link.
What is the implication, and what should change now?
• Future studies should confirm the observed high UPD prevalence and explore its population-specific basis in Chinese BWS, while further evaluating the diagnostic yield and optimal integration of CMA in the BWS diagnostic workflow. Expanding the cohort size remains crucial to support these aims and enhance diagnostic precision.
Introduction
Background
Beckwith-Wiedemann syndrome (BWS), alternatively referred to as omphalocele-macroglossia-gigantism syndrome, is a congenital overgrowth disorder (1). Beckwith and Wiedemann first reported the condition independently in 1963 and 1964, with a global incidence of approximately 1:10,340 (2). The clinical manifestations of BWS include macroglossia, lateralized overgrowth, omphalocele, hypoglycemia, visceromegaly, renal anomalies, and auricular malformations (3). Furthermore, prior research has shown that BWS individuals are more likely to confer a genetic predisposition to embryonal tumors, including hepatoblastoma and Wilms tumor (4). The most common molecular defect in BWS, a human imprinting condition with phenotypic diversity, is aberrant DNA methylation.
Rationale and knowledge gap
The disorder is mostly caused by genetic and epigenetic changes at chromosome 11p15.5 (5). Currently, most reported cases on BWS in China are individual case reports.
Objective
This research performed a retrospective review of all cases confirmed BWS in a single center in Guangzhou. We analyzed the clinical features and genetic characteristics of BWS pediatric patients, aiming to improve clinical awareness and understanding of the diagnosis, treatment, and prognosis of this disease, while providing guidance for genetic counseling. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-219/rc).
Methods
Study population
Clinical information from pediatric BWS patients treated at Guangzhou Women and Children’s Medical Center, Guangzhou Medical University from March 2014 to March 2024 was examined in retrospect. The inclusion criteria were as follows: (I) clinically diagnosed BWS, with a score of ≥ four based on the European BWS diagnostic criteria (2); (II) molecularly confirmed BWS, with chromosomal microarray analysis (CMA) or methylation testing revealing molecular abnormalities that meet the BWS molecular diagnostic criteria.
Study design
Data collection
This retrospective study collected patient information through review of electronic medical records, including patient’s gender, clinical manifestations, laboratory examinations, and molecular test results. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics review board of Guangzhou Women and Children’s Medical Center [ethics approval No. (2020) 49801]. Informed consent was obtained from all participants’ legal guardians at the medical appointment or registration.
Molecular analysis
Array comparative genomic hybridization (Array-CGH)
Peripheral blood samples (2 mL) were collected from children with suspected BWS in ethylenediaminetetraacetic acid (EDTA)-anticoagulated tubes. Genomic DNA was analyzed using the Affymetrix CytoScan750K array platform to detect copy number variations (CNVs), loss of heterozygosity (LOH), and iso-disomic uniparental disomy (iso-UPD). Detection thresholds for LOH regions were defined as >30%. Data processing and interpretation were performed using ChAS software (GRCh37/hg19 reference genome).
Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA)
MS-MLPA combines multiplex ligation-dependent probe amplification (MLPA) with methylation-specific detection. The SALSA ME030 MLPA Kit (MRC Holland) was utilized to assess CNVs and imprinting center methylation within the BWS/RSS pathogenic locus (11p15.4–p15.5). This method employs methylation-sensitive HhaI restriction enzyme digestion: unmethylated DNA allows probe digestion, abolishing PCR amplification signals, while methylated DNA blocks enzyme activity, enabling probe amplification and electrophoretic detection. DNA isolated from patient peripheral blood underwent hybridization, ligation, PCR amplification, and capillary electrophoresis. Data were analyzed using Coffalyser software.
Clinical features and diagnosis
According to the 2018 European expert guidelines (2), the clinical manifestations of BWS can be categorized into Cardinal features and Suggestive features. Each major clinical feature is assigned two points, while each minor clinical feature is assigned 1 point. A total score of ≥ four points is required for a clinical diagnosis of BWS. The major features include: (I) macroglossia; (II) lateralized overgrowth; (III) omphalocele; (IV) multifocal or bilateral Wilms tumor or nephroblastoma; (V) hyperinsulinemic hypoglycemia (lasting > a week or requiring glucose-elevating medications); (VI) adrenal cortex cytomegaly, placental mesenchymal dysplasia, or pancreatic adenomatosis. Minor criteria include: (I) macrosomia (birth weight >2 SD above the mean); (II) facial naevus simplex; (III) polyhydramnios or placentomegaly; (IV) ear creases/pits; (V) transient hypoglycemia (< a week); (VI) renal enlargement and/or hepatic enlargement, umbilical hernia and/or abdominal muscle separation; and (VII) typical BWS-related tumors (rhabdomyosarcoma, neuroblastoma, hepatoblastoma, unilateral nephroblastoma, pheochromocytoma, or adrenocortical carcinoma).
Statistical analysis
Statistical analysis was performed using SPSS 26.0 (IBM Corp.). Categorical variables were presented as counts (percentages), and continuous variables as median (range). Given the small sample size, Fisher’s exact test was applied to compare proportions between groups, with two-tailed P<0.05 considered statistically significant.
Results
Demographics and clinical phenotypes
A total of 24 BWS patients (16 males, 8 females) were included, with a median diagnosis age of nine months (range: fetal period to 4 years). Macroglossia (95.8%) and lateralized overgrowth (54.2%) were the most prevalent cardinal features, followed by omphalocele (25.0%) and persistent hyper-insulinemic hypoglycemia (8.3%) (Table 1).
Table 1
| Case | Gender | Clinical manifestations | Other manifestations | BWSp score | |
|---|---|---|---|---|---|
| Cardinal features | Suggestive features | ||||
| 1 | Female | Macroglossia, lateralized overgrowth, hyper insulinemic hypoglycemia | Umbilical hernia, hepatoblastoma | Precocious puberty | 8 |
| 2 | Male | Macroglossia | Umbilical hernia | – | 3 |
| 3 | Female | Macroglossia, hyper insulinemic hypoglycemia | – | – | 4 |
| 4 | Female | Macroglossia, lateralized overgrowth | – | Thyroid dysfunction | 4 |
| 5 | Male | Macroglossia, lateralized overgrowth | – | Urachal fistula, inguinal hernia, right testicular hydrocele | 4 |
| 6 | Male | Macroglossia, lateralized overgrowth | Umbilical hernia | – | 5 |
| 7 | Male | Macroglossia, lateralized overgrowth | Bilateral renal enlargement, hepatomegaly | Right renal simple cyst; left renal pelvis separation with full-length ureteral dilation | 5 |
| 8 | Male | Macroglossia, lateralized overgrowth, omphalocele, recurrent hypoglycemia | – | Cryptorchidism | 8 |
| 9 | Male | Macroglossia, lateralized overgrowth, omphalocele | Slightly enlarged left kidney | Cryptorchidism, infantile hepatitis syndrome | 7 |
| 10 | Female | Lateralized overgrowth, recurrent hypoglycemia | Umbilical hernia | – | 5 |
| 11 | Male | Macroglossia | Transient hypoglycemia | – | 3 |
| 12 | Male | Macroglossia, omphalocele | Ear-lobe creases | Cryptorchidism, torticollis | 5 |
| 13 | Female | Macroglossia | Umbilical hernia | IVF baby | 3 |
| 14 | Male | Macroglossia, lateralized overgrowth, omphalocele | – | – | 6 |
| 15 | Male | Macroglossia, recurrent hypoglycemia | – | Cryptorchidism | 4 |
| 16 | Male | Macroglossia | – | IVF baby | 2 |
| 17 | Male | Macroglossia, omphalocele | – | – | 4 |
| 18 | Male | Macroglossia | Transient hypoglycemia, facial naevus flammeus | – | 4 |
| 19 | Female | Macroglossia, omphalocele, lateralized overgrowth | – | – | 5 |
| 20 | Female | Macroglossia, lateralized overgrowth | Transient hypoglycemia | – | 5 |
| 21 | Male | Macroglossia, lateralized overgrowth | – | – | 4 |
| 22 | Male | Macroglossia, omphalocele | Ear creases | – | 5 |
| 23 | Female | Omphalocele, lateralized overgrowth | Transient hypoglycemia | – | 5 |
| 24 | Male | Macroglossia, omphalocele, lateralized overgrowth | – | – | 6 |
BWS, Beckwith-Wiedemann syndrome; BWSp, Beckwith-Wiedemann syndrome spectrum; IVF, in vitro fertilization.
Molecular subtypes
Among 19 patients undergoing MLPA and/or CMA, 57.9% (11/19) showed imprinting control region 2 loss of methylation (IC2 LOM), 5.3% (1/19) imprinting control region 1 gain of methylation (IC1 GOM), and 36.8% (7/19) uniparental disomy (UPD) (Table 2); three patients with normal Array-CGH results exhibited methylation abnormalities on MS-MLPA (Table 3).
Table 2
| Case | Age at diagnosis (months) | CMA | MS-MLPA |
|---|---|---|---|
| 1 | 3 | No abnormality | Mosaic uniparental disomy |
| 2 | 24 | Abnormality in chromosome 11p15.5p13, consistent with BWS alteration | Decreased methylation of KCNQ1OT1 in IC2 region |
| 3 | 1 | – | Decreased methylation of KCNQ1OT1 in IC2 region |
| 4 | 21 | – | Mosaic uniparental disomy |
| 5 | 3 | – | Decreased methylation of KCNQ1OT1 in IC2 region |
| 6 | 4 | A 33.43Mb mosaic uniparental disomy was detected in chromosome 11p15.5p13 segment | – |
| 7 | Fetal period | A >34.2Mb heterozygous loss was detected in chromosome 11p13p15 segment | – |
| 8 | 1 | A 32.76Mb mosaic uniparental disomy was detected in chromosome 11p15.5p13 segment | – |
| 9 | 36 | No abnormality | Methylation abnormality loss in IC2 region |
| 10 | Fetal period† | No abnormality | Abnormal methylation of IC2 region |
| 11 | 4 | – | Decreased methylation of KCNQ1OT1 in IC2 region |
| 12 | 3 | – | Gain methylation levels in the IC1 region |
| 13 | 12 | – | Decreased methylation of KCNQ1OT1 in IC2 region |
| 14 | 10 | – | Mosaic uniparental disomy |
| 15 | 48 | A 47.61Mb mosaic uniparental disomy was detected in the chromosome 11p15.5p11.2 segment | – |
| 16 | 3 | – | Abnormal methylation of IC2 region |
| 17 | 1 | – | Decreased methylation of KCNQ1OT1 in IC2 region |
| 18 | 1 | – | Decreased methylation of KCNQ1OT1 in IC2 region |
| 19 | 5 | – | Decreased methylation of KCNQ1OT1 in IC2 region |
†, fetal period molecular diagnosis was performed on samples obtained amniocentesis sampling. BWS, Beckwith-Wiedemann syndrome; CMA, chromosomal microarray analysis; IC1, imprinting control region 1; IC2, imprinting control region 2; MS-MLPA, multiplex-specific multiplex ligation-dependent probe amplification.
Table 3
| Clinical feature | IC1 GOM (n=1) | IC2 LOM (n=11) | UPD (n=7) | P value |
|---|---|---|---|---|
| Macroglossia | 1 (5.3) | 10 (90.9) | 7 (100.0) | >0.99 |
| Lateralized overgrowth | – | 4 (36.4) | 6 (85.7) | 0.06 |
| Hypoglycemia | – | 4 (36.4) | 3 (42.9) | >0.99 |
| Omphalocele | 1 (5.3) | 2 (18.2) | 2 (28.6) | 0.34 |
| Visceromegaly | – | 1 (9.1) | 2 (28.6) | 0.60 |
| Umbilical hernia | – | 4 (36.4) | 2 (28.6) | >0.99 |
Data are presented as n (%). IC1 GOM, imprinting control region 1 gain of methylation; IC2 LOM, imprinting control region 2 loss of methylation; UPD, uniparental disomy.
Genotype-phenotype correlations
Patients with UPD showed significantly higher prevalence of lateralized overgrowth than the IC2 LOM (85.7% vs. 36.4%, P=0.06). The single hepatoblastoma case occurred in a patient with UPD.
Hepatoblastoma in one case, case 1
The pediatric patient was a gravida 2 para 2 (G2P2), born via cesarean section at 35 weeks of gestation. After birth, the pediatric patient was admitted to the neonatal unit due to hypoglycemia. Physical examination revealed macroglossia, omphalocele, and a 2 cm × 2 cm mass palpated in the abdomen. Despite intravenous fluid supplementation, the patient experienced recurrent hypoglycemia, prompting a fasting-glucagon stimulation test. The results indicated that elevated insulin and C-peptide levels could still be detected during hypoglycemia, suggesting congenital hyperinsulinemia. The pediatric patient was treated with diazoxide, and blood glucose levels were controlled. During follow-up, the patient’s alpha-fetoprotein (AFP) levels gradually increased. Abdominal mass biopsy revealed hepatoblastoma (Figure 1), and the pediatric patients underwent surgical resection followed by regular postoperative chemotherapy.
Discussion
BWS is a clinically heterogeneous overgrowth disorder, is primarily caused by dysregulation of imprinted genes at chromosome 11p15.5 (6). While its global incidence is estimated at 1:10,340 (7), the prevalence in China remains undetermined due to limited population-based studies. This critical region contains two imprinting control centers (IC1 and IC2) governing adjacent gene clusters (8). Paternal methylation at IC1 regulates expression of H19 and IGF2, whereas maternal methylation at IC2 controls KCNQ1OT1 and the key cell cycle inhibitor CDKN1C (9,10). CDKN1C, expressed in both embryonic and postnatal tissues, plays a vital role in constraining cell proliferation (11).
Genetic basis of BWS: ethnic disparities
In BWS spectrum (BWSp), approximately 80% of cases harbor molecular alterations at 11p15, most commonly caused by DNA methylation defects (12). Under normal imprinting, paternal IC1 methylation suppresses H19 and activates IGF2, whereas maternal IC2 methylation represses KCNQ1OT1 and enables CDKN1C expression (13). IC2 LOM on the maternal allele is found in approximately 50% of patients, resulting in de-inhibition of KCNQ1OT1 and downregulation of CDKN1C in the maternal allele. Conversely, 5–10% show IC1 GOM, downregulating maternal H19 and IGF2 expression. When patients inherit both paternal copies of 11p15 without a maternal copy, paternal uniparental disomy (pUPD) occurs, accounting for approximately 20% of cases (14). In this study, we find a high prevalence of UPD (36.8%) in our cohort exceeds rates reported in Spain (10%) (15), broader European (22.7%) (16) and Korea (27.5%) (17). The higher UPD prevalence in our cohort suggests potential ethnic differences in epigenetic regulation, possibly influenced by genetic modifiers or environmental factors.
Clinical phenotypes in our cohort
Consistent with diagnostic criteria (18), our cohort (n=24) exhibited classic BWS manifestations: macroglossia (95.8%), lateralized overgrowth (54.2%), and neonatal hypoglycemia (20.8%) (19). Macroglossia was the predominant initial diagnostic feature (20/24 cases), aligning with its 90% global prevalence (20). Notably, 20 cases in our cohort were diagnosed with “macroglossia” during their initial consultation.
Lateralized overgrowth can occur in all molecular subtypes of BWSp, with segmental paternal(11) uniparental disomy [pat(11)UPD] individuals being more vulnerable, and lower frequency among CDKN1C mutations carriers (21). In our study, lateralized overgrowth occurred in 54.2% (13/24), exceeding general prevalence reports.
Neonatal hypoglycemia occurred in 20.8% (5/24) of our cohort, within the established 30–60% prevalence range for BWSp (22). While typically transient, one patient developed refractory hyperinsulinemia (23). Notably, we identified a case of hypothyroidism with a homozygous DUOX2 mutation—a rare association supported by limited international reports (24); additionally, a currently asymptomatic heterozygous LDLR variant was also detected, warranting longitudinal lipid monitoring. This finding reinforces the need for thyroid surveillance in BWSp patients.
BWSp confers an 8% embryonal tumors risk (25), predominantly Wilms tumor (52%), hepatoblastoma (14%), neuroblastoma (10%), rhabdomyosarcoma (5%), and adrenocortical carcinoma (3%). Tumor risk varies among BWSp molecular subgroups (26): IC1 GOM (28%), segmental pat(11)UPD (16%), CDKN1C variants (6.9%), and IC2 LOM (2.6%). Tumor spectra differ significantly—IC1 GOM patients primarily develop Wilms tumor, while pat(11)UPD carriers risk all subtypes. In our cohort of 24 patients, one hepatoblastoma case emerged in a patient with visceral enlargement (case 1), visceromegaly was radiologically confirmed in 3/24 cases (all under surveillance). Therefore, when visceral enlargement is observed in pediatric patients, long-term monitoring of tumor markers and imaging surveillance may be required for follow-up.
Cryptorchidism occurred in 16.7% (4/24) of male patients. Current evidence suggests association with 11p15.5 UPD or pathogenic CDKN1C variants (27), potentially mediated through placental hCG secretion defects affecting testicular descent via fetal leydig cell LH/HCG receptor (28).
Molecular diagnostics
First-line molecular testing for BWS patients involves DNA methylation analysis, as abnormalities commonly affect IC1 GOM, IC2 LOM, pUPD, and CNVs (29). The most widely used diagnostic technique at the moment is MS-MLPA (30), which simultaneously assesses CNVs and 11p15 methylation status with high specificity and reproducibility. However, the size or number of CNVs cannot be conclusively determined by MS-MLPA. CMA primarily includes single nucleotide polymorphism (SNP) analysis and CGH, which detect CNVs with resolutions down to a few kilobases (31). When CNVs are found, CMA may be used to ascertain the precise amount and type of deletions or duplications. SNP microarray is the most sensitive technique for detecting UPD and related mosaicism, while SNP probes can detect variations at single-nucleotide positions. Comparative genomic hybridization (GCH) can detect deletions or duplications as small as a few thousand base pairs, but it cannot detect balanced chromosomal rearrangements, UPD, or low-level mosaicism. In this study, 4 confirmed BWS pediatric patients underwent both Array-CGH and MS-MLPA testing. Three patients showed normal CMA results but abnormal methylation patterns on MLPA, indicating that MLPA has higher sensitivity and specificity for BWS pediatric patient genetic testing.
Conclusions
Given the diverse clinical manifestations of BWS pediatric patients, this study collected clinical data and molecular testing results to jointly confirm BWS diagnoses and analyzed their clinical features and genetic characteristics, aiming to enhance clinicians’ understanding of the diagnosis, treatment, and prognosis of this condition.
Acknowledgments
We would like to thank all the patients and their families.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-219/rc
Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-219/dss
Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-219/prf
Funding: This study was supported by funding from
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-219/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics review board of Guangzhou Women and Children’s Medical Center [ethics approval No. (2020) 49801]. Informed consent was obtained from all participants’ legal guardians at the medical appointment or registration.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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