Recent advances in neonatal Beckwith-Wiedemann syndrome: from molecular diagnosis to multidisciplinary management—a narrative review

Introduction

Background

Beckwith-Wiedemann syndrome (BWS) is a rare congenital overgrowth disorder caused by genetic and epigenetic alterations at the imprinted 11p15.5 chromosomal locus, with an estimated incidence of 1 in 10,000–13,700 live births (1). Historically, BWS was considered to present with a classic, predictable triad of symptoms; however, it is now widely recognized as a clinical spectrum characterized by profound phenotypic variability across affected individuals. To address this clinical heterogeneity and standardize diagnostic approaches, the 2018 international consensus guidelines introduced the concept of the Beckwith-Wiedemann spectrum (BWSp) and established a rigorous clinical scoring system based on “cardinal” and “suggestive” features (2). Cardinal features, which are highly specific to the syndrome, include macroglossia, exomphalos (omphalocele), lateralized overgrowth, multifocal and/or bilateral Wilms tumor (WT) or hepatoblastoma (HB), hyperinsulinism lasting more than 1 week, and specific pathological findings such as adrenal cortex cytomegaly. Suggestive features encompass a broader range of overlapping signs, such as birth weight greater than 2 standard deviations, facial nevus simplex, ear creases or pits, transient hypoglycemia, typical BWS facial features, diastasis recti, and umbilical hernia. According to these contemporary guidelines, a definitive clinical diagnosis of classic BWS is established when a patient presents with a clinical score of ≥4, whereas a score of ≥2 provides sufficient clinical justification for comprehensive molecular testing of the 11p15.5 locus. This nuanced phenotypic classification highlights that while some neonates may present with severe, life-threatening manifestations requiring immediate multidisciplinary intervention, others may exhibit only subtle, isolated features, underscoring the absolute necessity for individualized clinical assessment. Beyond the immediate neonatal clinical challenges, BWS is fundamentally recognized as a cancer predisposition syndrome. However, it is crucial to emphasize that the oncologic risk is not uniform across all patients; rather, it is highly heterogeneous and intrinsically tied to the specific underlying (epi)genetic alteration. While the literature frequently cites an “up to 30%” maximum risk for developing embryonal tumors (most commonly WT and HB), this high-risk stratum is exclusively applicable to specific molecular subtypes, namely patients with gain of methylation at IC1 (IC1 GOM) or paternal uniparental disomy of chromosome 11 [pUPD(11)pat]. In stark contrast, individuals with the most common epigenetic defect, loss of methylation at IC2 (IC2 LOM), exhibit a markedly lower tumor incidence (approximately 2.5%). This profound stratification highlights the absolute necessity of molecular subtyping at the time of diagnosis, as it directly dictates prognostic counseling and the implementation of personalized, risk-adapted tumor surveillance protocols during childhood (2-4). The molecular basis of BWS involves dysregulation of two imprinting control regions (ICRs; IC1 and IC2) that govern the expression of key growth-related genes, including H19, IGF2, and CDKN1C (5,6). Common underlying defects include LOM at IC2 (~50% of cases), GOM at IC1, pUPD(11), and CDKN1C mutations, each associated with distinct phenotypic profiles and tumor risks (7,8).

Rationale and knowledge gap

Early recognition and intervention in the neonatal period are critical: untreated hypoglycemia can result in irreversible neurodevelopmental impairment (9), macroglossia may cause life-threatening airway obstruction and feeding difficulties (2), and omphalocele often necessitates complex surgical management and is frequently accompanied by other congenital anomalies (10). Despite significant advances in molecular diagnostics—such as methylation-specific techniques like methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) that enhance detection accuracy even in mosaic cases (11)—translating these insights into routine clinical practice remains challenging. Historically, BWS management struggled with universal screening approaches. However, recent seminal guidelines have successfully established standardized, risk-adapted tumor screening protocols that rigorously account for specific molecular subtypes (12,13). Consequently, the current clinical challenge and knowledge gap have evolved. The primary hurdle is no longer defining the screening intervals, but rather translating these highly optimized oncologic surveillance strategies into seamless, multidisciplinary pediatric care. Effectively integrating these molecular-driven protocols with acute neonatal interventions (such as hypoglycemia and airway management) and long-term developmental monitoring remains complex in routine practice. Furthermore, questions remain regarding whether emerging targeted therapies can mitigate specific BWS-related complications.

Objective

This review aims to synthesize recent evidence on the molecular diagnosis, neonatal clinical challenges, and multidisciplinary management of BWS. By integrating genotype-phenotype correlations, perioperative best practices, and tumor surveillance guidelines, we provide a practical, precision medicine-oriented framework to guide clinicians in improving outcomes for affected neonates (14). Additionally, we highlight unresolved questions and emerging research directions to inform future studies aimed at refining risk stratification, personalizing care, and enhancing quality of life for individuals with BWS (15,16). We present this article in accordance with the Narrative Review reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-793/rc).

Methods

We conducted a literature review on the diagnosis, treatment and progress of BWS. Table 1 summarizes our search strategy. We reviewed the published journal articles from the past 15 years (from 2010 to 2024) that analyzed and discussed the clinical manifestations, diagnosis and latest progress of BSW. We conducted the search using the PubMed database, with the keywords “Beckwith-Wiedemann syndrome”, “Macroglossia”, “Hypoglycemia”, “Genetic diagnosis” and “Perioperative management”.

Molecular pathogenesis and diagnostic advances

Molecular mechanisms at 11p15.5

BWS is driven by genetic and epigenetic dysregulation at the 11p15.5 chromosomal locus, a critical region for genomic imprinting that regulates growth and development (17). This locus contains two ICRs: IC1, regulating H19 and IGF2, and IC2, controlling KCNQ1OT1 and CDKN1C. These regions orchestrate parent-of-origin-specific gene expression, and their disruption leads to the characteristic overgrowth and tumor predisposition of BWS (18).

Role of IC1 (H19/IGF2) and IC2 (KCNQ1OT1/CDKN1C)

IC1 regulates the expression of H19, a long non-coding RNA that suppresses cell proliferation, and IGF2, a growth-promoting gene expressed from the paternal allele (19). Hypermethylation at IC1 (GOM) results in overexpression of IGF2 and silencing of H19, driving excessive growth and increasing tumor risk, particularly for WT (20). IC2 controls KCNQ1OT1, a long non-coding RNA, and CDKN1C, a cyclin-dependent kinase inhibitor expressed from the maternal allele (21). Hypomethylation at IC2 (LOM) reduces CDKN1C expression, contributing to overgrowth and phenotypes like omphalocele (22). The precise interplay between these imprinted gene clusters is paramount for normal fetal development. Specifically, physiological growth relies on a delicate homeostatic balance between growth-promoting signals, primarily driven by the paternally expressed IGF2, and growth-inhibitory signals, predominantly mediated by the maternally expressed CDKN1C (a key negative regulator of the cell cycle). The non-coding RNAs H19 and KCNQ1OT1 act as the epigenetic controllers of these respective domains. When this reciprocal balance is disrupted—either through IGF2 overexpression (e.g., via IC1 GOM or pUPD) or CDKN1C downregulation (e.g., via IC2 LOM or pathogenic variants)—the net result is unopposed cellular proliferation, driving the BWS overgrowth phenotype.

Furthermore, a fundamental mechanism underpinning the profound clinical heterogeneity of BWS is somatic tissue mosaicism. Because the defining epigenetic and genetic errors [particularly IC2 LOM and pUPD(11)pat] frequently occur post-zygotically, the molecular defect is distributed unevenly across different cell lineages and tissues during embryogenesis. Consequently, a patient’s clinical phenotype—which can range from isolated macroglossia to severe lateralized overgrowth and multi-organ tumor predisposition—is directly dictated by which specific tissues harbor the epigenetic defect and the relative cellular burden (proportion of aberrant cells) within those tissues. This mosaic nature also explains why targeted molecular testing in peripheral blood leukocytes may sometimes yield false-negative results, necessitating the sampling of alternative tissues (such as buccal swabs or skin fibroblasts) to confirm a suspected clinical diagnosis.

The primary molecular subtypes of BWS include

• IC2 LOM: occurring in ~50% of cases, IC2 LOM is associated with macroglossia, omphalocele, and a moderate tumor risk (primarily HB) (23).
• IC1 GOM: found in ~5–10% of cases, IC1 GOM is linked to a high risk of WT due to IGF2 overexpression (24).
• Paternal uniparental disomy [pUPD(11)]: present in ~20% of cases, pUPD(11) involves inheritance of two paternal 11p15.5 alleles, leading to IGF2 overexpression and H19 silencing. This subtype is strongly associated with hemihypertrophy and multiple tumors (25).
• CDKN1C mutations: accounting for ~5–10% of cases, these mutations are often familial and linked to variable phenotypes, including macroglossia and low-to-moderate tumor risk (26).

Molecular subtypes correlate with distinct clinical presentations and tumor risks, guiding management strategies. For instance, pUPD(11)pat is strongly associated with lateralized overgrowth (formerly and less accurately termed hemihypertrophy, affecting up to 70% of these cases). This asymmetric growth anomaly can manifest as segmental overgrowth or involve an entire side of the body, reflecting the underlying tissue-specific epigenetic mosaicism. Its presence correlates with a significantly higher risk of embryonal tumors, including WT and HB (up to 30% risk) (27), necessitating vigilant orthopedic and oncologic monitoring. IC2 LOM is more frequently linked to omphalocele and macroglossia but carries a lower tumor risk (~5–10%) (28). IC1 GOM patients have a pronounced risk of WT due to IGF2-driven oncogenesis (29). CDKN1C Pathogenic variants: accounting for ~5–10% of BWS cases, these sequence variants are frequently familial and inherited in an autosomal dominant manner with maternal origin expression. While they are classically linked to variable phenotypes such as macroglossia and abdominal wall defects, their oncologic profile is highly distinct. Crucially, unlike the IC1 GOM or pUPD(11)pat subtypes, the tumor predisposition associated with CDKN1C variants is specifically limited to neuroblastoma, with virtually no elevated risk for WT or HB. This unique (epi)genotype-phenotype correlation underscores the absolute necessity of genetic sequencing in clinically suspected cases that test negative for methylation defects. These correlations highlight the importance of molecular subtyping for risk stratification and personalized care (30). Recent studies also suggest that H19 interacts with microRNAs to modulate cell proliferation, further linking epigenetic dysregulation to tumorigenesis (31), as shown in Figure 1.

Figure 1 Molecular mechanisms of BWS at the 11p15 imprinted region. This schematic diagram illustrates the normal imprinting patterns and gene expression at the 11p15 locus, alongside the major molecular subtypes that lead to BWS. BWS, Beckwith-Wiedemann syndrome.

Clinical diagnosis and scoring systems

To mitigate the diagnostic ambiguity caused by the wide phenotypic variability of the BWSp, it is imperative to utilize standardized, internationally recognized diagnostic criteria rather than relying on subjective clinical gestalt. Therefore, we have comprehensively structured our diagnostic framework strictly based on the consensus scoring system established by the international BWS expert group in 2018 (2). This definitive system abandons ad-hoc classifications and categorizes clinical signs into “cardinal features” (weighted at 2 points each, representing highly specific hallmarks of the syndrome) and “suggestive features” (weighted at 1 point each, representing more common or overlapping signs). A clinical diagnosis of classic BWS requires a score of ≥4, while a score of ≥2 warrants comprehensive molecular testing. The detailed, standardized stratification of these features is explicitly summarized in Table 2.

The presence of these features, particularly in combination, forms the basis for a clinical diagnosis. For example, macroglossia can lead to significant neonatal complications, including airway obstruction and feeding difficulties. Abdominal wall defects, especially omphalocele, may be associated with other congenital malformations and are addressed through standard surgical management approaches (15,20).

To standardize diagnosis and guide molecular testing, clinical scoring systems have been developed, such as the Ibrahim and Brioude scoring systems. These systems assign weighted values to the major and minor manifestations listed in Table 2. They demonstrate good diagnostic efficacy [with reported area under the curve (AUC) values of 0.87 and 0.82, respectively] and are crucial for identifying neonates who warrant molecular investigation (21).

The utility of these scoring systems is particularly high in cases where molecular diagnosis is complex. BWS frequently involves tissue mosaicism, meaning the epigenetic defect (e.g., IC2 LOM) may be present in some tissues (like fibroblasts or kidneys) but absent in others (like peripheral blood leukocytes) (22). This mosaicism can lead to false-negative results if testing is limited to blood samples alone. Therefore, a high clinical suspicion score, even with a negative blood test, justifies further molecular investigation in other tissues (e.g., buccal swabs or skin fibroblasts) to improve diagnostic yield (23). Early clinical identification of key manifestations remains critical, as prompt management of complications like hypoglycemia and airway compromise is essential to prevent long-term morbidity, such as potential neurological damage (24,25).

Molecular diagnostic strategies

A definitive diagnosis of BWS requires molecular confirmation of an 11p15.5 imprinting defect. The diagnostic approach is hierarchical, typically beginning with methylation analysis, which can identify the majority of BWS cases (IC1 GOM, IC2 LOM, and pUPD) (summarized in Table 3). Figure 2 presents the clinical diagnosis and treatment flowchart of BWS.

Figure 2 Clinical diagnostic and management flowchart for BWS. This flowchart outlines a stepwise approach for the diagnosis and initial management of suspected BWS in neonates, integrating clinical assessment with molecular diagnostic strategies, with a particular focus on addressing tissue mosaicism. BWS, Beckwith-Wiedemann syndrome; KOS, Kagami-Ogata syndrome; SRS, Silver-Russell syndrome.

MS-MLPA is a cornerstone technique. It can simultaneously assess methylation status at multiple imprinted loci (IC1 and IC2) and detect copy number variations (CNVs) within the 11p15.5 region (26). Paternal UPD testing, often using microsatellite analysis, is also a critical component, confirming approximately 12.5% of BWS cases (28).

A significant challenge in molecular diagnosis is the high prevalence of tissue mosaicism (22). The epigenetic or genetic alteration may be present in a mosaic state, meaning it is not present in all cells or tissues of the body. This is particularly common for IC2 LOM and pUPD (27). Consequently, testing peripheral blood leukocytes—the most common and accessible sample—may yield a false-negative result if the mosaicism is confined to other tissues (e.g., fibroblasts, liver, or kidneys). Studies have shown that obtaining other tissue samples, such as buccal swabs or skin fibroblasts, for analysis in patients with a high clinical suspicion but negative blood tests can significantly increase the success rate of molecular diagnosis (23,32).

Finally, molecular testing is essential for accurate differential diagnosis. Several other overgrowth syndromes share overlapping clinical features with BWS.

• Kagami-Ogata syndrome (KOS), caused by 14q32 imprinting defects, can also present with fetal gigantism and abdominal wall defects, and should be considered if 11p15.5 testing is negative (30).
• Molecular testing is essential for accurate differential diagnosis, as several other genetic conditions share overlapping clinical features with BWS. When evaluating a neonate with suspected BWS, clinicians must distinguish it from true overgrowth syndromes as well as specific undergrowth disorders that present with confounding asymmetry. For example, KOS, caused by 14q32 imprinting defects, is a true overgrowth disorder that can present with fetal gigantism and abdominal wall defects, requiring careful molecular differentiation if 11p15.5 testing is negative (30). Mutations in the DIS3L2 gene (associated with Perlman syndrome) also cause massive overgrowth and WT susceptibility, mimicking the high-risk BWS phenotype (33,34).
• Conversely, Silver-Russell syndrome/Russell-Silver syndrome (SRS/RSS) must be carefully distinguished from BWS, despite being fundamentally distinct in its growth trajectory. Crucially, unlike the aforementioned overgrowth disorders, SRS is characterized by severe intrauterine and postnatal undergrowth. It warrants critical inclusion in the differential diagnosis primarily because it frequently presents with significant body asymmetry. This relative asymmetry can easily be clinically misidentified as the lateralized overgrowth seen in BWS, especially in the neonatal period. Furthermore, SRS represents the molecular “mirror image” of BWS at the 11p15.5 locus [typically caused by IC1 LOM or maternal UPD(11)], highlighting the complex, biphasic nature of imprinted gene regulation in this region (31,35).
• Placental mesenchymal dysplasia (PMD) can mimic BWS features on prenatal ultrasound, necessitating careful evaluation (36).
• Mutations in other genes, such as DIS3L2 (associated with Perlman syndrome), can also cause overgrowth and WT susceptibility, requiring differentiation from BWS (33,34). A precise molecular diagnosis is therefore crucial not only for confirmation but also for distinguishing BWS from these other phenotypically similar conditions (37).

Differential diagnosis

Molecular testing is essential for accurate differential diagnosis, as several other overgrowth syndromes share overlapping clinical features with BWS.

KOS, caused by 14q32 imprinting defects, can also present with fetal gigantism and abdominal wall defects, and should be considered if 11p15.5 testing is negative (30).

SRS, ironically also associated with 11p15.5 (but typically IC1 LOM), presents with growth restriction, providing a sharp contrast but highlighting the region’s complexity (31,35).

PMD can mimic BWS features on prenatal ultrasound, necessitating careful evaluation (36).

Mutations in other genes, such as DIS3L2 (associated with Perlman syndrome), can also cause overgrowth and WT susceptibility, requiring differentiation from BWS (33,34). A precise molecular diagnosis is therefore crucial not only for confirmation but also for distinguishing BWS from these other phenotypically similar conditions (37). This relative asymmetry can easily be clinically misidentified as the lateralized overgrowth seen in BWS, highlighting the complex, biphasic nature of imprinted gene regulation in this region (31,35). Furthermore, emerging clinical reports emphasize the necessity of broad metabolic screening; for instance, severe cases of BWS presenting with complex metabolic profiles have been documented mimicking the classical form of congenital adrenal hyperplasia (CAH) during newborn screening, further complicating the initial neonatal differential diagnosis (38).

Key neonatal challenges and perioperative management

Management of refractory hypoglycemia

Persistent and often refractory hypoglycemia is one of the most common and urgent clinical challenges in neonates with BWS, occurring in a large subset of patients. This condition is primarily due to hyperinsulinism, analogous to insulinoma-like hypoglycemia, resulting from the dysregulation of the 11p15.5 imprinted genes that control fetal growth and glucose metabolism (1). This hyperinsulinemic state can manifest at birth and persist, leading to a variety of clinical signs, including lethargy, weakness, and feeding difficulties (39). If not identified and managed aggressively, this persistent hypoglycemia can pose a serious threat to the neonate’s central nervous system, potentially leading to significant and permanent neurodevelopmental impairment (40).

Beyond hyperinsulinism, the metabolic profile of BWS neonates can be complex. Patients may also exhibit other metabolic abnormalities, such as insulin resistance, glucose metabolism disorders, abnormal liver function, and disorders of fat metabolism, all of which can increase the frequency and severity of hypoglycemic events (40,41).

Effective management begins with rigorous screening and monitoring, adhering to established principles for neonatal hypoglycemia screening (42). While traditional intermittent fingertip glucose monitoring is standard, it may fail to capture the full extent of glucose variability or detect asymptomatic hypoglycemic events. The application of continuous glucose monitoring (CGM) technology has been shown to be significantly more effective in monitoring hypoglycemia, enabling clinicians to identify excursions promptly, intervene earlier, and adjust management strategies in real-time (43).

The management of BWS-associated hypoglycemia follows a stepwise approach:

• Initial management: this includes frequent feeding schedules (enteral or nasogastric) to provide a constant source of glucose. If oral/enteral feeds are insufficient to maintain euglycemia, intravenous (IV) glucose infusion is necessary to rapidly correct and stabilize blood glucose levels (39).
• Pharmacological therapy: for refractory hypoglycemia that persists despite high-glucose infusions, medical therapy is initiated. The first-line agent is typically diazoxide, which inhibits insulin secretion from pancreatic beta cells. However, diazoxide therapy must be monitored carefully, as it has been associated with severe complications, including necrotizing enterocolitis (NEC) in some cases (41). Other pharmacological agents, such as dexamethasone or tranexamic acid, may also be considered, though their use is also associated with potential side effects, such as edema, hyperglycemia, or abnormal blood clotting (41).
• Surgical intervention: in the most severe and intractable cases where hypoglycemia persists despite maximal medical therapy, a partial pancreatectomy may be considered as a last resort.

The importance of controlling hypoglycemia extends beyond preventing direct neurological injury. Persistent hypoglycemia itself (44), as well as the high-dose therapies used to manage it (41), have been associated with an increased risk of other serious complications, particularly NEC, potentially by exacerbating intestinal ischemia. Therefore, a proactive and multidisciplinary approach to managing hypoglycemia is fundamental to improving both short-term stability and long-term neurodevelopmental outcomes for neonates with BWS (40), as shown in Table 4.

Macroglossia and airway management

• Macroglossia, an enlarged tongue, is one of the most distinctive cardinal features of BWS and is often identified in the neonatal period. Its presence can have profound functional consequences, leading to potential airway obstruction, significant feeding difficulties, and long-term speech development disorders (45). The risk of airway obstruction is particularly high during infancy and presents a significant challenge during anesthetic management (46).
• Given this risk, a thorough preoperative airway assessment is a critical step to ensure patient safety. However, a retrospective cohort study noted that while macroglossia is a hallmark, the actual prevalence of difficult airways recorded during anesthesia may be relatively low (5.3% in one study). Nonetheless, the risk is significantly associated with factors such as age less than 1 year, the presence of macroglossia, and endocrine complications, necessitating vigilant preparation (47).
• Perioperative management strategies must include preparations for a potentially difficult airway. This includes the availability of advanced airway equipment, such as video laryngoscopy, which has been shown to increase intubation success after failed direct laryngoscopy attempts (48). A clear emergency plan for airway management is essential to handle any acute obstruction or intubation difficulties (49).

For neonates with severe macroglossia causing significant airway obstruction, feeding impairment, or speech issues, surgical intervention via tongue reduction (glossectomy) is an effective treatment. Studies have demonstrated that tongue reduction surgery can achieve good results, improving quality of life and long-term functional outcomes (50). Controversy still exists regarding the optimal timing of surgery, but some studies suggest intervention before the patient is 1 year old may reduce complications associated with persistent macroglossia (51). Techniques such as keyhole glossoplasty are considered relatively safe and effective, minimizing postoperative risks while improving facial shape and function (52).

Close postoperative monitoring and support are crucial. Patients may require additional respiratory support, especially if a difficult airway was encountered during anesthesia (53). Postoperative rehabilitation, including speech therapy and swallowing training, is also vital. Many patients show significant improvement in airway symptoms (e.g., reduced sleep apnea) and achieve normal speech development following surgery and subsequent therapy (50), as shown in Table 5.

Management of abdominal wall defects

Abdominal wall defects refer to structural abnormalities where the abdominal wall fails to develop properly. Omphalocele is one of the most common manifestations in BWS, where abdominal organs (such as the intestines and liver) protrude through a defect in the umbilicus, usually covered by a membrane. These can be classified as small or giant omphaloceles, with the latter typically indicating greater risks and more complex management issues.

Some studies have indicated that abdominal wall defects and omphalocele are frequently not isolated events; they are often associated with other localized structural anomalies (e.g., congenital heart defects) or occur as part of complex multi-systemic chromosomal syndromes, such as trisomy 13 and trisomy 18, which frequently feature omphalocele within their broader phenotypic spectrum (12). The presence of such complications not only increases the complexity of perinatal management but also has significant implications for the survival rate and long-term prognosis of newborns. Therefore, early diagnosis and multidisciplinary management are particularly important (54).

Clinical manifestations include a bulge at the umbilicus and exposure of the intestines, with some cases possibly accompanied by intestinal ischemia or necrosis. Early identification of abdominal wall defects is crucial for appropriate perinatal management. Studies have shown that ultrasound examinations during pregnancy can effectively identify omphalocele and guide clinicians in formulating appropriate management strategies to reduce neonatal mortality and the risk of complications (55).

In the postnatal management of neonates, the treatment of abdominal wall defects requires an integration of surgical repair and supportive care.

Small omphaloceles: for small omphaloceles, conservative management can be considered, with the use of new technologies such as negative pressure wound therapy (NPWT) to promote wound healing and reduce the risk of infection.

Giant omphaloceles: for large omphaloceles, surgical intervention is usually necessary, such as using biological materials or synthetic meshes to enhance the repair (56). Recent studies have indicated that staged surgical management of large omphaloceles can improve neonatal prognosis with relatively low surgical risks (57).

Long-term management and prognosis

Embryonal tumor surveillance

A critical component of long-term BWS management is surveillance for embryonal tumors. BWS patients have a significantly increased risk, estimated as high as 30% in some cohorts, of developing tumors during childhood (58). The most common malignancies are WT (nephroblastoma) and HB, though other rare tumors like neuroblastoma and rhabdomyosarcoma have also been reported (58-61).

Crucially, the risk of tumor development is not uniform across all BWS patients; it is strongly correlated with the specific molecular subtype (58). This link mandates a risk-stratified surveillance protocol based on the initial molecular diagnosis (summarized in Table 6).

• High-risk group: patients with IC1 GOM or paternal uniparental disomy [pUPD(11)pat] carry the highest tumor risk (approximately 25–30%). These subtypes are strongly associated with WT (59,62).
• Moderate-risk group: patients with CDKN1C mutations have a moderate risk, primarily for WT.
• Low-risk group: patients with IC2 LOM have a significantly lower tumor risk (approximately 2.5%).

The standard surveillance protocol is designed for the early detection of the two most common tumors:

• HB: HB is a primary concern in the first few years of life (61,63). Historically, surveillance relied heavily on serum alpha-fetoprotein (AFP) measurements every 3 months until age 4 years. However, in accordance with the updated 2024 pediatric cancer predisposition guidelines (12,13), the reliance on AFP is undergoing critical re-evaluation. Because AFP levels are naturally elevated and highly variable in neonates, and given the excellent sensitivity of modern abdominal ultrasound for detecting HB, routine AFP screening is increasingly considered optional or entirely omitted in certain protocols to reduce parental anxiety and avoid unnecessary blood draws, relying instead on high-quality abdominal ultrasounds every 3 months until the 4th birthday.
• WT: WT risk extends later into childhood (59). Previous legacy guidelines recommended abdominal ultrasound screening until age 8 years. However, recent large-scale epidemiological data and the updated 2024 consensus (12) have refined this threshold. It is now definitively recommended to perform comprehensive abdominal ultrasound examinations (focusing on the kidneys) every 3 months from diagnosis until the 7th birthday (age 7 years). BWS-associated WTs have distinct characteristics, including a higher risk of bilateral kidney involvement (59,62), making high-resolution sonography the cornerstone of surveillance for high-risk (epi)genotypes.

Growth, development, and functional rehabilitation

Beyond tumor surveillance, long-term management focuses on addressing the functional and developmental consequences of the BWS phenotype.

Lateralized overgrowth and skeletal abnormalities: lateralized overgrowth—updated in modern nomenclature from the legacy term “hemihypertrophy” to better reflect the true underlying pathophysiology of regional hyperplasia (44)—is a cardinal feature of the BWSp, particularly prevalent in the pUPD(11)pat molecular subtype. This asymmetric growth can manifest in various body segments and lead to significant biomechanical complications, most notably progressive leg length discrepancy (LLD) (64). This asymmetry requires regular physical examinations and imaging evaluations to monitor bone development. Intervention strategies are tiered based on the severity of the discrepancy and include physical therapy, the use of orthoses (e.g., shoe lifts) to improve posture, and, in more significant cases, orthopedic surgical interventions to prevent long-term gait problems and secondary skeletal deformities (65,66).

Speech and swallowing rehabilitation: following glossectomy for macroglossia, the rehabilitation of speech and swallowing functions is crucial. Early intervention with speech therapy and swallowing training has been shown to significantly improve the recovery rate of these functions, helping patients overcome initial speech disorders and promoting their long-term social and communication abilities (67).

Systemic complications: long-term follow-up for other potential complications, such as cardiac lesions (e.g., cardiac hypertrophy, dysfunction), is also a key part of comprehensive management. Regular cardiac ultrasound examinations and monitoring of biochemical indicators are necessary to assess cardiac health status, reinforcing the need for a multidisciplinary collaborative management model to improve quality of life and reduce the risk of long-term complications (68).

Genetic counseling and family support

Genetic counseling plays a crucial role in the management of BWS, providing essential education and support to patients and their families. The significance of the molecular diagnostic result is paramount in this process. With the advancement of genomics, the genetic mechanisms of BWS, primarily involving imprinting abnormalities in the 11p15.5 region, are increasingly clear (69). Genetic testing that identifies the specific pathogenic variant allows for accurate risk assessment and management recommendations.

A key component of counseling is assessing the recurrence risk, which differs dramatically based on the molecular subtype:

• Sporadic epimutations (IC2 LOM, IC1 GOM, pUPD): the vast majority of BWS cases (approximately 85%) are caused by these de novo epimutations. The recurrence risk for future pregnancies is very low (<1%).
• Familial/inherited variants (CDKN1C mutations): approximately 5–10% of BWS cases are caused by pathogenic variants in the CDKN1C gene, which are often inherited from the mother in an autosomal dominant pattern (with expression limited by imprinting) (69). For a mother carrying a CDKN1C mutation, the risk of transmitting it to offspring is 50% for each pregnancy.
• Inherited chromosomal abnormalities: in rare cases, BWS can be caused by inherited duplications or translocations involving 11p15.5, which carry a high recurrence risk.

Given these genetic characteristics, future reproductive risk assessment and recommendations for prenatal diagnosis are vital components of counseling. For families with a known high-risk variant (like a CDKN1C mutation), options for prenatal testing (e.g., amniocentesis or chorionic villus sampling) can provide information for future pregnancies, allowing families to make informed reproductive decisions (70).

Finally, family psychological support and the integration of social resources are extremely important. BWS patients and their families often face significant physical and psychological challenges. Strong family support has been shown to improve a patient’s self-management behaviors, quality of life, and mental health (71). Genetic counseling should include educating family members to help them understand the nature of the disease and its impact, thereby providing emotional support to the patient and reducing psychological burdens (70,71).

Conclusions

BWS represents a highly heterogeneous congenital overgrowth disorder driven by genetic and epigenetic alterations at the 11p15.5 locus, presenting with a wide spectrum of clinical manifestations ranging from macrosomia and macroglossia to embryonal tumor predisposition (72). Historically managed through symptomatic treatment, the care of BWS has evolved significantly with recent advances in molecular diagnostics and multidisciplinary strategies, marking a paradigm shift toward precision medicine (73). This review synthesizes evidence-based approaches to molecular subtyping, neonatal clinical challenges, and long-term surveillance, providing a comprehensive framework to optimize outcomes for affected neonates (74).

The management of BWS hinges on several critical points. First, molecular diagnosis through techniques such as MS-MLPA and uniparental disomy testing enables precise identification of subtypes—IC2 LOM, IC1 GOM, paternal uniparental disomy [pUPD(11)], and CDKN1C mutations—each associated with distinct phenotypic features and tumor risks (75). This subtyping informs tailored interventions, such as intensified tumor screening for pUPD(11) patients or conservative management for IC2 LOM cases with lower risk (76). Second, neonatal challenges, including refractory hypoglycemia, airway obstruction from macroglossia, and abdominal wall defects like omphalocele, require immediate and coordinated care involving endocrinologists, surgeons, and anesthesiologists (77). Advances such as CGM and keyhole glossectomy have improved early outcomes, reducing neurodevelopmental and respiratory complications (78). Third, long-term management emphasizes structured tumor surveillance (e.g., abdominal ultrasound and AFP monitoring) and functional rehabilitation, supported by genetic counseling to address recurrence risks and family support needs (79). This multidisciplinary approach, integrating molecular insights with clinical expertise, underscores the cornerstone of effective BWS care as of 2025 (80).

Despite these advances, significant knowledge gaps remain, highlighting directions for future research. The current tumor screening protocols, while effective for high-risk subtypes, may impose an unnecessary burden on patients with low-risk profiles (e.g., IC2 LOM), prompting the need for optimized, risk-stratified screening schedules (81). Preliminary studies in 2025 suggest that machine learning models analyzing methylation patterns could refine risk prediction, potentially reducing screening frequency for low-risk individuals (82). Additionally, the exploration of targeted therapies, such as IGF2 pathway inhibitors for IC1 GOM-related tumorigenesis or CDKN1C modulators, holds promise but requires clinical trials to establish efficacy and safety (83). Furthermore, long-term data on neurodevelopmental outcomes following early hypoglycemia management and quality-of-life impacts of hemihypertrophy or post-surgical macroglossia remain limited, necessitating longitudinal cohort studies (84). Addressing these gaps through global collaboration and standardized protocols will be essential to advance precision medicine for BWS (85).

In conclusion, the management of BWS has transitioned from a reactive, symptom-based approach to a proactive, molecularly guided strategy, supported by a multidisciplinary team. Key priorities include early molecular diagnosis, prompt neonatal intervention, and diligent long-term monitoring, all tailored to individual molecular profiles. Future efforts should focus on refining screening protocols, developing targeted therapies, and enhancing long-term outcome research to further improve the lives of individuals with BWS and their families.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-793/rc

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References

1. Eggermann T, Perez de Nanclares G, Maher ER, et al. Imprinting disorders: a group of congenital disorders with overlapping patterns of molecular changes affecting imprinted loci. Clin Epigenetics 2015;7:123. [Crossref] [PubMed]
2. Brioude F, Kalish JM, Mussa A, et al. Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol 2018;14:229-49. [Crossref] [PubMed]
3. Mussa A, Russo S, Larizza L, et al. (Epi)genotype-phenotype correlations in Beckwith-Wiedemann syndrome: a paradigm for genomic medicine. Clin Genet 2016;89:403-15. [Crossref] [PubMed]
4. Mussa A, Russo S, De Crescenzo A, et al. (Epi)genotype-phenotype correlations in Beckwith-Wiedemann syndrome. Eur J Hum Genet 2016;24:183-90. [Crossref] [PubMed]
5. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6:e1000097. [Crossref] [PubMed]
6. Shin CH, Lim C, Kim HY, et al. Prospective study of epigenetic alterations responsible for isolated hemihyperplasia/hemihypoplasia and their association with leg length discrepancy. Orphanet J Rare Dis 2021;16:418. [Crossref] [PubMed]
7. Duffy KA, Cielo CM, Cohen JL, et al. Characterization of the Beckwith-Wiedemann spectrum: Diagnosis and management. Am J Med Genet C Semin Med Genet 2019;181:693-708. [Crossref] [PubMed]
8. Duffy KA, Sajorda BJ, Yu AC, et al. Beckwith-Wiedemann syndrome in diverse populations. Am J Med Genet A 2019;179:525-33. [Crossref] [PubMed]
9. Mussa A, Russo S, De Crescenzo A, et al. Prevalence of Beckwith-Wiedemann syndrome in North West of Italy. Am J Med Genet A 2013;161A:2481-6. [Crossref] [PubMed]
10. Mussa A, Di Candia S, Russo S, et al. Recommendations of the Scientific Committee of the Italian Beckwith-Wiedemann Syndrome Association on the diagnosis, management and follow-up of the syndrome. Eur J Med Genet 2016;59:52-64. [Crossref] [PubMed]
11. Luca M, Carli D, Cardaropoli S, et al. Performance Metrics of the Scoring System for the Diagnosis of the Beckwith-Wiedemann Spectrum (BWSp) and Its Correlation with Cancer Development. Cancers (Basel) 2023;15:773. [Crossref] [PubMed]
12. Kalish JM, Becktell KD, Bougeard G, et al. Update on Surveillance for Wilms Tumor and Hepatoblastoma in Beckwith-Wiedemann Syndrome and Other Predisposition Syndromes. Clin Cancer Res 2024;30:5260-9. [Crossref] [PubMed]
13. Kamihara J, Schienda J, McGee RB, et al. Update on Retinoblastoma Predisposition and Surveillance Recommendations for Children. Clin Cancer Res 2025;31:1573-9. [Crossref] [PubMed]
14. Luca F, De Crescenzo A, Mussa A, et al. Validation of Beckwith-Wiedemann Spectrum diagnostic criteria: Insights into molecular diagnosis and tumor screening. Cancers (Basel) 2022;15:773.
15. Bellucca S, Carli D, Gazzin A, et al. Molecular Basis and Diagnostic Approach to Isolated and Syndromic Lateralized Overgrowth in Childhood. J Pediatr 2024;274:114177. [Crossref] [PubMed]
16. Wang KH, Kupa J, Duffy KA, et al. Diagnosis and Management of Beckwith-Wiedemann Syndrome. Front Pediatr 2019;7:562. [Crossref] [PubMed]
17. Mussa A, Carli D, Cardaropoli S, et al. Lateralized and Segmental Overgrowth in Children. Cancers (Basel) 2021;13:6166. [Crossref] [PubMed]
18. Carli D, Resta N, Ferrero GB, et al. Mosaic RASopathies: A review of disorders caused by somatic pathogenic variants in the genes of the RAS/MAPK pathway. Am J Med Genet C Semin Med Genet 2022;190:520-9. [Crossref] [PubMed]
19. Karaca E, Posey JE, Coban Akdemir Z, et al. Phenotypic expansion illuminates multilocus pathogenic variation. Genet Med 2018;20:1528-37. [Crossref] [PubMed]
20. Posey JE, Harel T, Liu P, et al. Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. N Engl J Med 2017;376:21-31. [Crossref] [PubMed]
21. Carli D, Bertola C, Cardaropoli S, et al. Prenatal features in Beckwith-Wiedemann syndrome and indications for prenatal testing. J Med Genet 2021;58:842-9. [Crossref] [PubMed]
22. Carli D, Operti M, Russo S, et al. Clinical and molecular characterization of patients affected by Beckwith-Wiedemann spectrum conceived through assisted reproduction techniques. Clin Genet 2022;102:314-23. [Crossref] [PubMed]
23. Mussa A, Molinatto C, Cerrato F, et al. Assisted Reproductive Techniques and Risk of Beckwith-Wiedemann Syndrome. Pediatrics 2017;140:e20164311. [Crossref] [PubMed]
24. Kopca T, Tulay P. Association of Assisted Reproductive Technology Treatments with Imprinting Disorders. Glob Med Genet 2021;8:1-6. [Crossref] [PubMed]
25. Henningsen AA, Gissler M, Rasmussen S, et al. Imprinting disorders in children born after ART: a Nordic study from the CoNARTaS group. Hum Reprod 2020;35:1178-84. [Crossref] [PubMed]
26. Cortessis VK, Azadian M, Buxbaum J, et al. Comprehensive meta-analysis reveals association between multiple imprinting disorders and conception by assisted reproductive technology. J Assist Reprod Genet 2018;35:943-52. [Crossref] [PubMed]
27. Cohen JL, Duffy KA, Sajorda BJ, et al. Diagnosis and management of the phenotypic spectrum of twins with Beckwith-Wiedemann syndrome. Am J Med Genet A 2019;179:1139-47. [Crossref] [PubMed]
28. Barisic I, Boban L, Akhmedzhanova D, et al. Beckwith Wiedemann syndrome: A population-based study on prevalence, prenatal diagnosis, associated anomalies and survival in Europe. Eur J Med Genet 2018;61:499-507. [Crossref] [PubMed]
29. Baker SW, Ryan E, Kalish JM, et al. Prenatal molecular testing and diagnosis of Beckwith-Wiedemann syndrome. Prenat Diagn 2021;41:817-22. [Crossref] [PubMed]
30. Shieh HF, Estroff JA, Barnewolt CE, et al. Prenatal imaging throughout gestation in Beckwith-Wiedemann syndrome. Prenat Diagn 2019;39:792-5. [Crossref] [PubMed]
31. Shuman C, Kalish JM, Weksberg R. Beckwith-Wiedemann syndrome. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews®. Seattle: University of Washington, Seattle; 1993-2024.
32. Mussa A, Russo S, de Crescenzo A, et al. Fetal growth patterns in Beckwith-Wiedemann syndrome. Clin Genet 2016;90:21-7. [Crossref] [PubMed]
33. Drier Y, Cotton MJ, Williamson KE, et al. An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma. Nat Genet 2016;48:265-272. [Crossref] [PubMed]
34. Ma GC, Chen TH, Wu WJ, et al. Proposal for Practical Approach in Prenatal Diagnosis of Beckwith-Wiedemann Syndrome and Review of the Literature. Diagnostics (Basel) 2022;12:1709. [Crossref] [PubMed]
35. Licata AM, Botzenhart E, Kloth-Stachnau K, et al. Copy Number Variants in the 11p15.5 Associated Imprinting Disorders: An Attempt to Establish a Genotype-Phenotype Correlation. Clin Genet 2026; Epub ahead of print. [Crossref]
36. Beygo J, Russo S, Tannorella P, et al. Prenatal testing for imprinting disorders: A laboratory perspective. Prenat Diagn 2023;43:973-82. [Crossref] [PubMed]
37. Soejima H, Hara S, Ohba T, et al. Placental Mesenchymal Dysplasia and Beckwith-Wiedemann Syndrome. Cancers (Basel) 2022;14:5563. [Crossref] [PubMed]
38. Martins JMES, Braga BL, Sampaio KNF, et al. Beckwith-Wiedemann syndrome mimicking the classical form of congenital adrenal hyperplasia in newborn screening. Arch Endocrinol Metab. 2024;68:e220395. [Crossref] [PubMed]
39. Porter A, Benson CB, Hawley P, et al. Outcome of fetuses with a prenatal ultrasound diagnosis of isolated omphalocele. Prenat Diagn 2009;29:668-73. [Crossref] [PubMed]
40. Boyd PA, Bhattacharjee A, Gould S, et al. Outcome of prenatally diagnosed anterior abdominal wall defects. Arch Dis Child Fetal Neonatal Ed 1998;78:F209-13. [Crossref] [PubMed]
41. George AM, Viswanathan A, Sussman JH, et al. Determinants of Hyperinsulinism Severity in Children with Beckwith-Wiedemann Syndrome. J Clin Endocrinol Metab 2026; Epub ahead of print. [Crossref]
42. Russo S, Calzari L, Mussa A, et al. A multi-method approach to the molecular diagnosis of overt and borderline 11p15.5 defects underlying Silver-Russell and Beckwith-Wiedemann syndromes. Clin Epigenetics 2016;8:23. [Crossref] [PubMed]
43. Koren N, Shust-Barequet S, Weissbach T, et al. Fetal Micro and Macroglossia: Defining Normal Fetal Tongue Size. J Ultrasound Med 2023;42:59-70. [Crossref] [PubMed]
44. Kalish JM, Biesecker LG, Brioude F, et al. Nomenclature and definition in asymmetric regional body overgrowth. Am J Med Genet A 2017;173:1735-8. [Crossref] [PubMed]
45. Baker SW, Duffy KA, Richards-Yutz J, et al. Improved molecular detection of mosaicism in Beckwith-Wiedemann Syndrome. J Med Genet 2021;58:178-84. [Crossref] [PubMed]
46. Mackay DJG, Bliek J, Lombardi MP, et al. Discrepant molecular and clinical diagnoses in Beckwith-Wiedemann and Silver-Russell syndromes. Genet Res (Camb) 2019;101:e3. [Crossref] [PubMed]
47. Yadav S, Madhumita RC, Gupta N, et al. Isolated Lateralized Overgrowth - Phenotypic Spectrum and Molecular Alterations. Indian J Pediatr 2025;92:1049-55. [Crossref] [PubMed]
48. Gazzin A, Reynolds G, Massuras S, et al. Expanding the phenotypic spectrum of PROS: reclassifying isolated lateralised overgrowth. J Med Genet 2025;62:276-80. [Crossref] [PubMed]
49. Gazzin A, Reynolds G, Allegro D, et al. Quantification of Lateralized Overgrowth and Genotype-Driven Tissue Composition. Clin Genet 2025;108:49-57. [Crossref] [PubMed]
50. Klein SD, DeMarchis M, Linn RL, et al. Occurrence of Hepatoblastomas in Patients with Beckwith-Wiedemann Spectrum (BWSp). Cancers (Basel) 2023;15:2548. [Crossref] [PubMed]
51. Sobel Naveh NS, Traxler EM, Duffy KA, et al. Molecular networks of hepatoblastoma predisposition and oncogenesis in Beckwith-Wiedemann syndrome. Hepatol Commun 2022;6:2132-46. [Crossref] [PubMed]
52. Mussa A, Ferrero GB. Screening Hepatoblastoma in Beckwith-Wiedemann Syndrome: A Complex Issue. J Pediatr Hematol Oncol 2015;37:627. [Crossref] [PubMed]
53. Kalish JM, Deardorff MA. Tumor screening in Beckwith-Wiedemann syndrome-To screen or not to screen? Am J Med Genet A 2016;170:2261-4. [Crossref] [PubMed]
54. Mussa A, Duffy KA, Carli D, et al. The effectiveness of Wilms tumor screening in Beckwith-Wiedemann spectrum. J Cancer Res Clin Oncol 2019;145:3115-23. [Crossref] [PubMed]
55. Mussa A, Molinatto C, Baldassarre G, et al. Cancer Risk in Beckwith-Wiedemann Syndrome: A Systematic Review and Meta-Analysis Outlining a Novel (Epi)Genotype Specific Histotype Targeted Screening Protocol. J Pediatr 2016;176:142-149.e1. [Crossref] [PubMed]
56. Cöktü S, Spix C, Kaiser M, et al. Cancer incidence and spectrum among children with genetically confirmed Beckwith-Wiedemann spectrum in Germany: a retrospective cohort study. Br J Cancer 2020;123:619-23. [Crossref] [PubMed]
57. Duffy KA, Hathaway ER, Klein SD, et al. Epigenetic mosaicism and cell burden in Beckwith-Wiedemann syndrome due to loss of methylation at imprinting control region 2. Cold Spring Harb Mol Case Stud 2021;7:a006115. [Crossref] [PubMed]
58. Duffy KA, Getz KD, Hathaway ER, et al. Characteristics Associated with Tumor Development in Individuals Diagnosed with Beckwith-Wiedemann Spectrum: Novel Tumor-(epi)Genotype-Phenotype Associations in the BWSp Population. Genes (Basel) 2021;12:1839. [Crossref] [PubMed]
59. Fiala EM, Ortiz MV, Kennedy JA, et al. 11p15.5 epimutations in children with Wilms tumor and hepatoblastoma detected in peripheral blood. Cancer 2020;126:3114-21. [Crossref] [PubMed]
60. Hol JA, Kuiper RP, van Dijk F, et al. Prevalence of (Epi)genetic Predisposing Factors in a 5-Year Unselected National Wilms Tumor Cohort: A Comprehensive Clinical and Genomic Characterization. J Clin Oncol 2022;40:1892-902. [Crossref] [PubMed]
61. Stoltze UK, Hildonen M, Hansen TVO, et al. Germline (epi)genetics reveals high predisposition in females: a 5-year, nationwide, prospective Wilms tumour cohort. J Med Genet 2023;60:842-9. [Crossref] [PubMed]
62. MacFarland SP, Duffy KA, Bhatti TR, et al. Diagnosis of Beckwith-Wiedemann syndrome in children presenting with Wilms tumor. Pediatr Blood Cancer 2018;65:e27296. [Crossref] [PubMed]
63. Maas SM, Vansenne F, Kadouch DJ, et al. Phenotype, cancer risk, and surveillance in Beckwith-Wiedemann syndrome depending on molecular genetic subgroups. Am J Med Genet A 2016;170:2248-60. [Crossref] [PubMed]
64. Mackay DJG, Gazdagh G, Monk D, et al. Multi-locus imprinting disturbance (MLID): interim joint statement for clinical and molecular diagnosis. Clin Epigenetics 2024;16:99. [Crossref] [PubMed]
65. Ochoa E, Lee S, Lan-Leung B, et al. ImprintSeq, a novel tool to interrogate DNA methylation at human imprinted regions and diagnose multilocus imprinting disturbance. Genet Med 2022;24:463-74. [Crossref] [PubMed]
66. Azzi S, Rossignol S, Steunou V, et al. Multilocus methylation analysis in a large cohort of 11p15-related foetal growth disorders (Russell Silver and Beckwith Wiedemann syndromes) reveals simultaneous loss of methylation at paternal and maternal imprinted loci. Hum Mol Genet 2009;18:4724-33. [Crossref] [PubMed]
67. Cerrato F, Sparago A, Ariani F, et al. DNA Methylation in the Diagnosis of Monogenic Diseases. Genes (Basel) 2020;11:355. [Crossref] [PubMed]
68. Court F, Martin-Trujillo A, Romanelli V, et al. Genome-wide allelic methylation analysis reveals disease-specific susceptibility to multiple methylation defects in imprinting syndromes. Hum Mutat 2013;34:595-602. [Crossref] [PubMed]
69. Docherty LE, Rezwan FI, Poole RL, et al. Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans. Nat Commun 2015;6:8086. [Crossref] [PubMed]
70. Fontana L, Bedeschi MF, Maitz S, et al. Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders. Epigenetics 2018;13:897-909. [Crossref] [PubMed]
71. Bilo L, Ochoa E, Lee S, et al. Molecular characterisation of 36 multilocus imprinting disturbance (MLID) patients: a comprehensive approach. Clin Epigenetics 2023;15:35. [Crossref] [PubMed]
72. Fontana L, Tabano S, Maitz S, et al. Clinical and Molecular Diagnosis of Beckwith-Wiedemann Syndrome with Single- or Multi-Locus Imprinting Disturbance. Int J Mol Sci 2021;22:3445. [Crossref] [PubMed]
73. Mackay DJ, Hahnemann JM, Boonen SE, et al. Epimutation of the TNDM locus and the Beckwith-Wiedemann syndrome centromeric locus in individuals with transient neonatal diabetes mellitus. Hum Genet 2006;119:179-84. [Crossref] [PubMed]
74. Mackay DJ, Callaway JL, Marks SM, et al. Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nat Genet 2008;40:949-51. [Crossref] [PubMed]
75. Boonen SE, Pörksen S, Mackay DJ, et al. Clinical characterisation of the multiple maternal hypomethylation syndrome in siblings. Eur J Hum Genet 2008;16:453-61. [Crossref] [PubMed]
76. Grosvenor SE, Davies JH, Lever M, et al. A patient with multilocus imprinting disturbance involving hypomethylation at 11p15 and 14q32, and phenotypic features of Beckwith-Wiedemann and Temple syndromes. Am J Med Genet A 2022;188:1896-903. [Crossref] [PubMed]
77. Bakker B, Sonneveld LJ, Woltering MC, et al. A Girl With Beckwith-Wiedemann Syndrome and Pseudohypoparathyroidism Type 1B Due to Multiple Imprinting Defects. J Clin Endocrinol Metab 2015;100:3963-6. [Crossref] [PubMed]
78. Pignata L, Cecere F, Acquaviva F, et al. Co-occurrence of Beckwith-Wiedemann syndrome and pseudohypoparathyroidism type 1B: coincidence or common molecular mechanism? Front Cell Dev Biol 2023;11:1237629. [Crossref] [PubMed]
79. Sano S, Matsubara K, Nagasaki K, et al. Beckwith-Wiedemann syndrome and pseudohypoparathyroidism type Ib in a patient with multilocus imprinting disturbance: a female-dominant phenomenon? J Hum Genet 2016;61:765-9. [Crossref] [PubMed]
80. Eggermann T, Yapici E, Bliek J, et al. Trans-acting genetic variants causing multilocus imprinting disturbance (MLID): common mechanisms and consequences. Clin Epigenetics 2022;14:41. [Crossref] [PubMed]
81. Jentoft IMA, Bäuerlein FJB, Welp LM, et al. Mammalian oocytes store proteins for the early embryo on cytoplasmic lattices. Cell 2023;186:5308-5327.e25. [Crossref] [PubMed]
82. Bebbere D, Albertini DF, Coticchio G, et al. The subcortical maternal complex: emerging roles and novel perspectives. Mol Hum Reprod 2021;27:gaab043. [Crossref] [PubMed]
83. Tannorella P, Calzari L, Daolio C, et al. Germline variants in genes of the subcortical maternal complex and Multilocus Imprinting Disturbance are associated with miscarriage/infertility or Beckwith-Wiedemann progeny. Clin Epigenetics 2022;14:43. [Crossref] [PubMed]
84. Begemann M, Rezwan FI, Beygo J, et al. Maternal variants in NLRP and other maternal effect proteins are associated with multilocus imprinting disturbance in offspring. J Med Genet 2018;55:497-504. [Crossref] [PubMed]
85. Sparago A, Verma A, Patricelli MG, et al. The phenotypic variations of multi-locus imprinting disturbances associated with maternal-effect variants of NLRP5 range from overt imprinting disorder to apparently healthy phenotype. Clin Epigenetics 2019;11:190. [Crossref] [PubMed]