Beckwith-Wiedemann syndrome

INTRODUCTION — Beckwith-Wiedemann syndrome (BWS; MIM #130650) is a pediatric overgrowth disorder involving a predisposition to tumor development [1]. The clinical presentation is highly variable, and some cases lack the characteristic features originally described by Beckwith and Wiedemann [2,3]. BWS exhibits etiologic molecular heterogeneity, and some molecular alterations correlate with specific phenotypic features of BWS.

The epidemiology, genetics, pathogenesis, clinical manifestations, diagnosis, management, and prognosis of BWS are reviewed in this topic.

EPIDEMIOLOGY — BWS is a panethnic disorder with an estimated population prevalence of 1 in 10,300 to 13,700 [4,5]. This figure most likely represents an underestimate because milder phenotypes may not be ascertained. The prevalence is approximately equal in males and females, with the notable exception of an increased frequency of female versus male monozygotic twins [6]. BWS usually occurs sporadically (85 percent), but familial transmission occurs in approximately 15 percent of cases. Subfertility and/or use of assisted reproductive technology (ART) is associated with an increased risk of imprinting disorders [7], with a 10-fold increased risk of BWS seen in live births from ART compared with natural conception in one Italian study [8].

GENETICS AND PATHOGENESIS — Generally, both the maternally and paternally inherited alleles of each autosomal gene pair are expressed. Approximately 100 genes across the genome are known to be imprinted, with many more predicted [9]. Imprinted genes are expressed monoallelically in a parent of origin-specific manner (figure 1). That is, for a given imprinted gene pair, one parental allele is exclusively or preferentially expressed, whereas the other allele is silenced or weakly expressed. Genomic imprinting is regulated by epigenetic mechanisms. These include noncoding RNAs and chemical modifications extrinsic to the primary nucleotide sequence, such as DNA methylation and histone protein tail modifications. Different DNA methylation and histone modification states underpin the expression or silencing of imprinted alleles. Thus, imprinted alleles demonstrate differential DNA methylation. Imprinted genes occur in clusters referred to as imprinted domains and are regulated in cis (on the same chromosome) by imprinting centers (ICs). ICs are comprised of differentially methylated regions (DMRs) of DNA. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Parent-of-origin effects (imprinting)'.)

Dysregulation of imprinted gene expression in the chromosome 11p15.5 region can result in the BWS phenotype [10-12]. The critical BWS genes in that region include insulin-like growth factor 2 (IGF2) and H19 in domain 1 and cyclin-dependent kinase inhibitor 1C (CDKN1C), potassium channel voltage-gated KQT-like subfamily member 1 (KCNQ1), and KCNQ1-overlapping transcript 1 (KCNQ1OT1, or long QT intronic transcript 1) in domain 2. A chromosome 11p15 molecular alteration is identified in only approximately 80 percent of persons with BWS. This is due in part to somatic mosaicism for some of the molecular alterations.

Several different mechanisms can lead to BWS via epigenetic and/or genetic alterations in the chromosome 11p15.5 imprinted domains. These modifications change the relative contributions of parental alleles [10-12] and include parent of origin-specific duplications, translocations/inversions, microdeletions, microduplications, DNA methylation changes at IC1 or IC2, and uniparental disomy (UPD). IC1 and IC2 regulated expression of genes in domains 1 and 2, respectively. UPD refers to the presence of two homologous chromosomal regions from one parent and none from the other.

The following molecular alterations on chromosome 11p15.5 can be detected in persons with BWS [12,13] (the approximate percentages for each type of alteration are noted [14-18]):

●Loss of methylation at IC2 (50 percent)

●Paternal UPD 11 (20 percent)

●Gain of methylation at IC1 (5 percent)

●Pathogenic variants of CDKN1C (5 percent in sporadic cases)

●Paternal duplication, maternal inversion, or translocation involving the p15.5 band of chromosome 11 (less than 1 percent)

●Unknown/undetected alteration (20 percent)

In a proportion of persons with BWS, DNA methylation changes are associated with genomic alterations (microdeletions or microduplications); these usually involve IC1 and only rarely IC2 [15-17,19-21]. A de novo deletion of the maternal IGF2 allele (domain 1) along with KCNQ1OT1 and a significant portion of KCNQ1 (domain 2) alleles was reported in association with loss of methylation at IC2 and a BWS phenotype [22]. Genomic alterations with or without changes in methylation are important because of their heritability.

Domain 1 of the chromosome 11p15.5 region is the telomeric imprinted domain that contains the imprinted genes H19 and IGF2. H19 is a nontranslated RNA that may function as a tumor suppressor gene. IGF2 is a potent fetal growth factor. IGF2 overexpression is considered to be a key determinant in the development of BWS. H19 and IGF2 are reciprocally expressed imprinted genes, with H19 maternally expressed and IGF2 paternally expressed. The expression of genes within this domain is regulated by an IC upstream of H19 called IC1 (H19/IGF2:IG DMR). IC1 is normally methylated on the paternal allele and unmethylated on the maternal allele. Regulation of transcription is accomplished by binding of the zinc-finger insulator protein CCCTC-binding factor (CTCF) to its consensus sequence within IC1. CTCF only binds to the unmethylated sequence (maternal allele) and modulates the interaction of downstream enhancers interacting with the H19 and IGF2 promoters [23]. Approximately 20 percent of patients with BWS and isolated IC1 gain of methylation carry single nucleotide variants or microdeletions that affect the octamer-binding transcription factor 4 (OCT4) or sex-determining region Y (SRY) box 2 (SOX2) transcription factor binding sites [24]. The phenotype depends upon both the parental origin of the genomic alteration and the involvement of transcription factor binding sites [25]. Such novel genomic aberrations continue to be described in both imprinted domains on 11p15.5.

Domain 2 is the centromeric imprinted domain that contains the imprinted genes CDKN1C, KCNQ1, and KCNQ1OT1. Regulation of this domain is controlled by an imprinting center, IC2 (KCNQ1OT1:TSS DMR), located in intron 10 of the KCNQ1 gene. IC2 is a differentially methylated region [26] that contains the promoter for KCNQ1OT1, a noncoding RNA with regulatory function. In BWS, loss of methylation at IC2 results in biallelic expression of the normally paternally expressed KCNQ1OT1. Individuals with BWS and loss of methylation at IC2 have reduced CDKN1C expression [27].

Epigenetic alterations that involve both IC1 and IC2 generally indicate paternal UPD for a chromosomal segment including the 11p15.5 region [10,14]. Segmental UPD of chromosome 11 is thought to arise from a postzygotic somatic recombination event, and, therefore, a mosaic distribution of this molecular change is found in most cases.

Genomic alterations may also span domains 1 and 2.

In approximately 20 percent of persons with BWS, clinical testing indicates normal methylation at IC1 and IC2 and no genomic abnormality involving chromosome 11p15.5. The absence of a detectable finding may be due to somatic mosaicism (see 'Genetic testing' below), alterations that do not involve the 11p15.5 region, or molecular etiologies not yet determined.

Genomic loci outside of the chromosome 11p15.5 region have also been implicated in the etiology of BWS [28]. As an example, an infant with features of BWS was found to have a large chromosome 7 deletion [29]. This deletion included the growth factor receptor-bound protein 10 gene (GRB10), an imprinted gene that inhibits the growth-promoting activities of insulin and insulin-like growth factors 1 and 2 by binding to the receptors for these molecules (insulin receptor and insulin-like growth factor 1 receptor). Chromosome 18q deletions have also been reported in persons with some features of BWS and developmental delay [30].

Approximately 25 percent of persons with BWS and with loss of methylation at IC2 exhibit errors at additional imprinted loci beyond chromosome 11p15.5 [18]. This condition, known as multi-locus imprinting disturbance (MLID) [31], occurs in females more frequently than males at a ratio of 4:1 [32]. MLID was previously reported exclusively in association with epigenetic errors rather than with UPD and copy number variations (CNVs) [33]. However, a patient with BWS who had IC2 loss of methylation and MLID was identified with paternal UPD for chromosome 20 [34]. Although the etiology of MLID is unknown in most cases, a number of mothers in these families have been shown to harbor compound heterozygous pathogenic variants in maternal effect genes that impact proteins of the subcortical maternal complex (SCMC) in the oocyte. These genes are important for early embryonic development including epigenetic reprogramming of the zygote [35]. The phenotypic expression of pathogenic variants in the SCMC genes, NLR family pyrin domain containing 2 (NLRP2), NLRP5, NLRP7, and peptidyl arginine deiminase 6 (PADI6), include reproductive failure and molar pregnancies. The phenotypic consequences of such pathogenic variants have been extended to include children with BWS and/or Russell-Silver syndrome (RSS) with MLID [36-40]. In some cases of BWS with MLID, there are relevant clinical findings due to imprinting errors outside of chromosome 11p15 (eg, hyperglycemia or hypocalcemia in BWS cases with concomitant imprinting errors on chromosome 6 [transient neonatal diabetes mellitus (TNDM)] or chromosome 20 [pseudohypoparathyroidism (PHP-1b)], respectively) [34].

CLINICAL MANIFESTATIONS — The classic hallmark features of BWS include omphalocele (exomphalos), macroglossia, and macrosomia (gigantism) [2,3].

Findings variably associated with BWS include [41]:

●Macrosomia (traditionally defined as height and weight >97^th percentile)

●Hemihyperplasia (asymmetric overgrowth of one or more regions of the body due to an abnormality of cell proliferation, [ie, increased cell number]); also referred to as lateralized overgrowth (picture 1)

●Macroglossia (picture 2)

●Omphalocele/umbilical hernia/diastasis recti (figure 2 and picture 3)

●Anterior linear ear lobe creases/posterior helical ear pits (picture 4)

●Visceromegaly involving one or more intraabdominal organs including liver, spleen, kidneys, adrenal glands, and pancreas

●Embryonal tumors (eg, Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma) in childhood (see "Presentation, diagnosis, and staging of Wilms tumor" and "Rhabdomyosarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis" and "Clinical presentation, diagnosis, and staging evaluation of neuroblastoma" and "Pathology of malignant liver tumors", section on 'Hepatoblastoma')

●Cytomegaly of the fetal adrenal cortex

●Kidney abnormalities including structural anomalies, nephromegaly, nephrocalcinosis, later development of medullary sponge kidney

●Cleft palate (rare)

●Neonatal hypoglycemia (see "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia")

●Facial nevus simplex and other vascular malformations (see "Vascular lesions in the newborn")

●Characteristic facies, including midface hypoplasia and infraorbital creases (picture 2)

●Cardiomegaly/structural cardiac anomalies; cardiomyopathy (rare)

●Advanced bone age

●Family history of BWS and/or maternal history of recurrent pregnancy loss or molar pregnancy

Incidence figures for the specific individual clinical findings in BWS vary widely in published reports, probably representing different ascertainment biases. These and other clinical features are discussed in greater detail in the sections that follow.

Prenatal and perinatal — The most common features of BWS observed prenatally are macrosomia (90 percent) and polyhydramnios (50 percent) [42,43]. When omphalocele is detected prenatally, BWS is diagnosed in over 35 percent of fetuses with isolated omphalocele and 5 percent with nonisolated omphalocele [44]. Additionally, features of BWS such as macroglossia, kidney abnormalities, visceromegaly, and large for gestational age may be detected on fetal ultrasound in the second or third trimester [45]. Fifty percent of infants with BWS are born preterm. The umbilical cord can be long, and the placenta can average almost twice the normal weight for gestational age. Manifestations of BWS have been observed in approximately 17 to 25 percent of fetuses/liveborn infants from pregnancies complicated by placental mesenchymal dysplasia, which is distinctive cystic placental phenotype [46-48]. Additional prenatal maternal complications may include diabetes mellitus, gestational hypertension, and/or proteinuria [49], which may be associated with preeclampsia.

Growth — Macroglossia and macrosomia are generally present at birth, although postnatal onset of each of these features is sometimes observed [50,51]. Adult height typically remains at the upper range of normal despite rapid growth in early childhood. The growth rate usually slows around age seven to eight years of age.

When present, hemihyperplasia (also referred to as lateralized overgrowth or hemihypertrophy) is generally appreciated at birth but may become more or less evident as the child grows. Isolated lateralized overgrowth has been suggested as an alternate descriptor of this feature [52]. Hemihyperplasia may affect segmental regions of the body and/or specific organs and tissues. When several segments are involved, hemihyperplasia may be limited to one side of the body (ipsilateral) or involve opposite sides of the body (contralateral) [53].

Metabolic abnormalities — Neonatal hypoglycemia is well documented [4,54]. It poses a significant risk for developmental sequelae if severe and undetected or untreated. In those pregnancies deemed at increased risk for BWS either because of a positive family history or detection of fetal omphalocele on ultrasound, the newborn should be evaluated for hypoglycemia. Most cases of hypoglycemia are mild and transient; however, hypoglycemia can persist due to hyperinsulinism and be refractory to treatment. Delayed onset of hypoglycemia (ie, beyond the first two weeks of life) is also rarely observed.

Other, less common endocrine/metabolic/hematologic findings include hypothyroidism, hypocalcemia, hyperlipidemia/hypercholesterolemia, and polycythemia [54,55].

Structural anomalies — Anterior abdominal wall defects, including omphalocele, umbilical hernia, and diastasis recti, are common [1,12].

Much of the information regarding cardiovascular problems in BWS is anecdotal. Cardiomegaly is commonly detected in infancy if a chest radiograph is done, but this typically resolves without treatment. There are rare reports of cardiomyopathy.

Kidney anomalies include medullary dysplasia, duplicated collecting system, nephrocalcinosis, nephrolithiasis, medullary sponge kidney, cystic changes, and nephromegaly [56-60]. Hypercalciuria can be found in children with BWS even in the absence of kidney abnormalities visualized by ultrasound [56].

Rare cases of posterior fossa brain abnormalities have been reported in patients with BWS who have involvement of the centromeric imprinted domain (domain 2) [61]. (See 'Genetics and pathogenesis' above and 'Development' below.)

Neoplasia — Children with BWS have an increased risk of mortality associated with neoplasia. Most commonly observed are Wilms tumor and hepatoblastoma, but also neuroblastoma, adrenocortical carcinoma, and rhabdomyosarcoma, as well as a wide variety of other tumors, both malignant and benign [62]. The estimated risk for tumor development in children with BWS is 7.5 percent, with a range of risks between 4 and 21 percent [4,62-70]. This increased risk for neoplasia is concentrated in the first eight years of life. Tumor development is uncommon in affected persons older than eight years of age; however, malignancies including Wilms tumor and hepatoblastoma have been reported in later childhood and adulthood [71].

Development — Development is usually normal in children with BWS unless there is a chromosome abnormality [72,73], a posterior fossa abnormality [61], or a history of hypoxia or significant, untreated hypoglycemia. Neurobehavioral issues, such as autism spectrum disorder, have been reported with increased frequency in children with BWS [74]; however, these cases were ascertained by parental report only. Additional studies, including formal neurodevelopmental assessments, are needed to assess the frequencies of these issues in BWS.

PHENOTYPE-(EPI)GENOTYPE CORRELATIONS — A number of genetic and/or epigenetic alterations in growth regulatory genes on chromosome 11p15.5 are associated with specific phenotype-(epi)genotype correlations and different inheritance risks.

Tumor development — Individuals with uniparental disomy (UPD) of 11p15.5 or gain of methylation at the H19 imprinting center (IC1) carry the highest risk of tumor development, primarily Wilms tumor or hepatoblastoma (approximately 16 and 30 percent, respectively) but also others including some benign tumors [10,66,75-81]. Those with loss of maternal methylation at IC2 also carry an increased risk of approximately 2.6 percent for tumors. Though comparatively less frequent than in other molecular subtypes, Wilms tumor has now been reported in over 10 children with BWS and loss of maternal methylation at IC2 [67]. In addition, hepatoblastoma has been reported in children with loss of maternal methylation at IC2 [66]. Interpretation of the relatively low risk for Wilms tumor development associated with loss of methylation at IC2 varies across international jurisdictions, leading to divergent clinical practice in different countries. Specifically, surveillance beyond an initial baseline ultrasound is not recommended for children with loss of methylation at IC2 who reside in the United Kingdom and Europe, whereas these children are offered ongoing surveillance in North America (see 'Surveillance' below). Persons with pathogenic variants in CDKN1C have a low but increased risk of tumor formation, with primarily neuroblastoma reported. In addition, those with cytogenetically visible alterations have a very low risk for tumor development.

Of note, children clinically suspected to have, or diagnosed with, BWS who have no detectable molecular alteration have a significant risk for tumor development. This is probably due to a lack of detection of somatic mosaicism for chromosome 11p15.5 UPD or other molecular anomalies in testing of peripheral blood samples.

Tumor surveillance will undoubtedly become universally stratified by molecular etiology once reliably sensitive molecular methods are available along with optimized data for incidence by age from larger cohorts of children with BWS. (See 'Surveillance' below.)

Hemihyperplasia — Somatic mosaicism for UPD of chromosome 11p15.5 resulting in methylation alterations at IC2 and IC1 is associated with hemihyperplasia [11,82]. Less frequently, alterations in IC1 and IC2 are also seen in hemihyperplasia.

Omphalocele — IC2 alterations and CDKN1C pathogenic variants are associated with omphalocele [83].

Cleft palate — Only CDKN1C pathogenic variants have been reported in patients with BWS who have cleft palate [84,85].

Developmental delay — Developmental delay is associated with cytogenetically detectable duplications involving the paternal copy of chromosome 11p15.5 [11,73,74], although it may also be due to significant neonatal hypoglycemia or other perinatal complications, such as prematurity. In addition, developmental delay with posterior fossa brain abnormalities occurs rarely in association with IC2 alterations or CDKN1C pathogenic variants [61].

Undescended testes — Undescended testes are more common in males with IC2 or IC1 methylation alterations than in males with UPD of chromosome 11p15.5 or CDKN1C pathogenic variants. Undescended testes may reflect the increased rate of premature delivery for infants with BWS and methylation alterations [71,81].

Severe BWS phenotype — Cases of severe BWS have been reported in association with very high levels of somatic mosaicism for paternal UPD for chromosome 11p15.5 [86,87].

Positive family history — Most familial cases of BWS are due to pathogenic variants in CDKN1C or microdeletions of IC1 or, very rarely, IC2 microduplications [11,14,16,17,84,88-90]. Vertical transmission of BWS can also occur with chromosome 11p15.5 translocations or inversions.

Female monozygotic twins — There is a larger than expected number of female monozygotic twins discordant for BWS [6]. The affected females usually demonstrate loss of methylation at IC2. In contrast, the less frequently observed male monozygotic twins show a broad spectrum of BWS-associated molecular alterations [86].

Subfertility/assisted reproductive technology — Subfertility with or without use of assisted reproductive technology (ART) is associated with an increased risk of BWS cases due to loss of methylation at IC2 [82,91-93]. It is not clear what specific aspects of subfertility or its treatment drive this association.

Pregnancy history — A maternal history of recurrent spontaneous abortion and/or molar pregnancy may indicate heritable pathogenic variant(s) in a maternal effect gene leading to abnormal imprinting in BWS with multi-locus imprinting disturbance (MLID).

DIAGNOSIS — The phenotype of BWS is highly variable. Given this variability and the ensuing challenges in determining medical management, a number of approaches have been developed to support the diagnostic process [18]. One such approach includes the presence of three major clinical findings or two major and one minor finding for a clinical diagnosis of BWS, with the proviso that the diagnosis should be considered and tumor surveillance offered for children presenting with fewer findings [1,41,94]. In 2018, a consensus group developed a numeric scoring algorithm for findings considered "cardinal" and those considered "suggestive," with the overall score guiding diagnostic categorization, molecular testing, and, potentially, management strategies [18]. However, regardless of which set of diagnostic criteria are applied, children with "mild" or "low scoring" phenotypes may still have BWS and be at increased risk for tumor development [49,81]. Thus, there should be a high index of suspicion when evaluating children with minimal clinical features in the BWS phenotypic spectrum, particularly if there is a positive family history (one or more family members with a clinical diagnosis of BWS or a history or features suggestive of BWS). In such cases, anticipatory medical management (eg, tumor surveillance) and molecular testing should be considered (see 'Management' below). As noted above, tumor surveillance should not be discontinued in the absence of a detectable molecular alteration.

Approximately 15 percent of cases of BWS are familial. Thus, targeted information should be elicited regarding family history, including parental features during childhood, since these may normalize over time. In addition, type of conception (ie, natural versus assisted conception) and pregnancy-related findings, such as polyhydramnios, placental mesenchymal dysplasia [48], and prematurity, should be ascertained. (See 'Clinical manifestations' above and 'Epidemiology' above.)

Genetic testing — Methylation-sensitive multiplex ligation probe analysis (MS-MLPA) is the most robust method clinically available for detecting the majority of epigenetic and genetic etiologies associated with BWS. MS-MLPA detects microdeletions/microduplications and alterations in gene dosage and DNA methylation including uniparental disomy (UPD) [88]. Somatic mosaicism associated with UPD may lead to weak signals on MS-MLPA. UPD can be confirmed by analysis of short tandem repeats when it is suggested by methylation alterations at both imprinting centers 1 and 2 (IC1 and IC2). In addition, failure to detect a methylation alteration or UPD in one tissue (usually leukocytes) is not conclusive, especially in cases involving hemihyperplasia. One study noted that testing of multiple tissues increases the diagnostic yield from 70 to 82 percent, particularly in children with hemihyperplasia or with atypical presentations [81]. Thus, testing of at least two tissues/cell populations, for example leukocytes and skin, is advised in patients with these features.

MS-MLPA may not detect somatic mosaicism for 11p15 UPD; therefore, testing using single nucleotide polymorphism (SNP) arrays should be undertaken in parallel to support the interpretation of the IC1 and IC2 methylation data [67,95,96]. Additionally, SNP array may identify genomewide UPD. (See 'Differential diagnosis' below.)

Rarely, microarray testing undertaken for a clinical reason unrelated to BWS reveals a copy number variation (CNV; a microdeletion or microduplication) involving 11p15.5. In such situations, a clinical diagnosis of BWS would not be assigned when careful evaluation does not reveal any BWS-associated clinical findings. However, tumor surveillance (see 'Surveillance' below) is suggested given that Wilms tumor has been reported in children with constitutional 11p15.5 molecular alterations in the absence of other BWS clinical features [75].

Karyotype analysis is required to detect the rare de novo and maternally transmitted translocations/inversions and will also detect paternally derived duplications of chromosome 11p15.5 associated with BWS. Translocations/inversions almost always disrupt the gene potassium channel voltage-gated KCNQ1 [26] and are not usually detectable by MS-MLPA, because most do not demonstrate DNA copy number changes or DNA methylation changes.

DNA sequencing is required to detect genomic alterations in the CDKN1C gene associated with BWS. CDKN1C pathogenic variants are seen both sporadically (5 percent of cases) and in autosomal-dominant pedigrees modified by preferential parent of origin-specific transmission (40 percent of cases) [85].

Targeted clinical testing for maternal effect genes is not available. However, whole-exome sequencing or whole-genome sequencing should be considered based on clinical findings (eg, hyperglycemia, hypocalcemia), family history, and/or maternal reproductive history (eg, recurrent pregnancy loss, molar pregnancy). Such testing may identify compound heterozygous pathogenic variants in maternal effect genes leading to aberrant imprinting. The cost-benefit of using methylation arrays as a clinical test to investigate possible MLID remains to be determined as the prevalence of MLID associated findings appears to be rare, and MLID may vary across tissues. Further research in this area will help defining clinical recommendations for diagnostic testing.

Prenatal diagnosis — Indications for prenatal testing may include a previous child with BWS or a positive family history of BWS. Prenatal testing may be undertaken by chorionic villus sampling (CVS) or amniocentesis, if the cytogenetic or genomic abnormality (eg, microdeletion, CDKN1C pathogenic variant) in the affected family member is known. Epigenetic analysis of chromosome 11p15.5 in amniocytes is sufficiently reliable for prenatal diagnosis [97], with the caution that mosaicism can confound the reliability of the test result [98]. Analysis of methylation alterations in CVS requires further validation before this can be offered as a clinical test since methylation status of chromosome 11p15.5 ICs is known to vary significantly in extra-embryonic tissues in early pregnancy.

Prenatal testing via amniocentesis may also be indicated for BWS-associated findings detected on fetal ultrasound, such as omphalocele, kidney enlargement, or macroglossia [99]. A follow-up study of apparently isolated fetal omphalocele (ie, no known family history of BWS and no additional findings detected on fetal ultrasound) reported BWS in 20 percent of cases based upon subsequent clinical evaluation and/or molecular testing [100]. Thus, molecular testing is suggested in such cases.

Prenatal screening is an option if the molecular defect is not known or if invasive prenatal testing is not undertaken. This screening includes ultrasound evaluation for assessment of growth parameters that may become advanced for gestational age (usually after 24 weeks), abdominal wall defects, organomegaly, kidney abnormalities, cleft palate, cardiac anomalies, and macroglossia [45]. Nuchal translucency measurements between 10 to 14 weeks can be informative [101], and detailed ultrasound is typically performed at 18 to 20 weeks and again at 25 to 32 weeks gestation. Measurement of maternal serum alpha fetoprotein (AFP), elevated in association with abdominal wall defects, may provide additional information, although imaging detects virtually all cases of omphalocele [45].

DIFFERENTIAL DIAGNOSIS — The presentation of a newborn with large growth parameters (table 1 and table 2), macroglossia, and/or hypoglycemia should prompt a comprehensive clinical examination followed by relevant investigations. A number of endocrine disorders and overgrowth syndromes should be considered in the differential diagnosis, including maternal diabetes mellitus and congenital hypothyroidism. (See "Infants of mothers with diabetes (IMD)".)

Several genetic syndromes have features in common with BWS but can be distinguished by genetic testing, ancillary tests (eg, brain imaging, molecular, and/or biochemical testing), and follow-up for the appearance of defining features. Neurofibromatosis type 1, Proteus syndrome, PIK3CA-related overgrowth spectrum (PROS), and PTEN hamartoma tumor syndrome (PHTS) are all syndromes that can have associated hemihyperplasia. Perlman syndrome, Sotos syndrome, Simpson-Golabi-Behmel syndrome, mosaic genome-wide paternal uniparental disomy (UPD), and isolated hemihyperplasia all are associated with an increased risk of Wilms tumor. (See "Presentation, diagnosis, and staging of Wilms tumor", section on 'Other congenital anomalies'.)

The differential diagnosis includes:

●Isolated hemihyperplasia (MIM #235000; also termed isolated lateralized overgrowth) – Evaluation should be undertaken for the presence of clinical findings that may indicate a syndromic diagnosis, especially as this may influence management [102]. For patients with asymmetry as an isolated finding, it is important to determine if the asymmetry represents overgrowth (hemihyperplasia) [53,103-105] or decreased growth (hemihypoplasia) since the latter is not associated with an increased risk for tumor development. Molecular testing may provide clarification in that hemihypoplasia is sometimes associated with hypomethylation of imprinting center (IC) 1, whereas hemihyperplasia is associated with hypermethylation of IC1 or chromosome 11p15.5 UPD [106]. (See 'Growth' above and 'Genetic testing' above.)

●Mosaic genome-wide paternal UPD – Testing for genome-wide UPD is advised if features of BWS are associated with additional findings (eg, higher incidence of tumors that occur into later childhood and adulthood and that are of different types than that typically seen in BWS, hyperinsulinism) suggestive of a complex genomic etiology [107-110].

●Simpson-Golabi-Behmel syndrome (type 1 MIM #312870; type 2 MIM #300209) – Defining features of this syndrome include craniofacial anomalies (macrocephaly; coarse facies; ocular hypertelorism; broad, flat nose; macrostomia; macroglossia; cleft lip), kidney anomalies, moderate intellectual disability, and other congenital malformations. (See "Renal hypodysplasia", section on 'Genetic disorders'.)

●Costello syndrome (MIM #218040) – Features suggestive of Costello syndrome include coarse facies; loose skin; diffuse hypotonia; joint laxity; sparse, fine hair; failure to thrive; and nonprogressive cardiomyopathy.

●Perlman syndrome (MIM #267000) – Common characteristics seen in patients with Perlman syndrome include unusual facies (depressed nasal bridge, anteverted upper lip, mild micrognathia) and intellectual disability.

●Weaver syndrome (MIM #277590) – Patients with Weaver syndrome have overgrowth involving both height and head circumference, as well as camptodactyly (fixed flexion deformity of the proximal interphalangeal joints) and increased risk of leukemia.

MANAGEMENT

Evaluation following initial diagnosis — The following evaluations are advised to establish the extent of disease in an individual diagnosed with BWS:

●Assessment for airway sufficiency in the presence of macroglossia.

●Evaluation by a feeding specialist if macroglossia causes significant feeding difficulties.

●Assessment of neonates for hypoglycemia; evaluation by a pediatric endocrinologist if hypoglycemia is severe or persists beyond the first few days of life.

●Abdominal ultrasound examination to assess for organomegaly, structural abnormality, and tumors. A baseline magnetic resonance imaging (MRI) or computed tomography (CT) examination of the abdomen to screen for tumors may be considered at the time of diagnosis or later [111].

●If diagnosis is made in late adolescence or adulthood, kidney ultrasound should be undertaken to screen for abnormalities such as nephrolithiasis and medullary sponge kidney.

●Comprehensive cardiac evaluation including electrocardiogram (ECG) and echocardiogram prior to any surgical procedures or when a cardiac abnormality is suspected on baseline or follow-up clinical evaluation. While congenital arrhythmia disorders such as long QT syndrome (LQTS) are rarely reported in BWS [112], there are several reports of LQTS in persons with BWS and genomic alterations disrupting KCNQ1 transcription.

●Alpha fetoprotein (AFP) assay at the time of initial diagnosis to assess for hepatoblastoma.

●Hemihyperplasia involving leg-length discrepancy should be monitored periodically, particularly during periods of active overall growth and when associated with paternal UPD of 11p15.5 [113].

●Clinicians should be aware of the rare occurrence of metabolic abnormalities (eg. hyperglycemia [transient neonatal diabetes mellitus (TNDM)] or hypocalcemia [pseudohypoparathyroidism]) in persons with BWS who may have multi-locus imprinting disturbance (MLID) in order to appropriately investigate.

Treatment of manifestations — The following measures are advised for disease manifestations that may appear throughout the course of the disease:

●Prompt treatment of hypoglycemia to reduce the risk of central nervous system complications. The onset of hypoglycemia is variable, and therefore parents should be informed of the symptoms of hypoglycemia so that they know when to seek appropriate medical attention for their child.

●Abdominal wall repair soon after birth for omphalocele. This surgery is generally well tolerated.

●Management of difficulties arising from macroglossia:

•Anticipation of difficulties with endotracheal intubation [114].

•Pulmonary assessment, possibly including sleep study, to address concerns regarding potential sleep apnea.

•Management of feeding difficulties using specialized nipples, such as the longer nipple recommended for babies with cleft palate or, rarely, short-term use of nasogastric tube feedings.

•Follow-up by a craniofacial team including plastic surgeons, orthodontists, and speech pathologists familiar with the natural history of BWS. Some children benefit from tongue reduction surgery; however, surgical reduction typically impacts tongue length, not thickness. Residual cosmetic, orthodontic, and speech issues may require further assessment/treatment [115].

●Consultation with an orthopedic surgeon if hemihyperplasia results in a significant difference in leg length. Surgery may be necessary during early puberty to close the growth plate of the longer leg in order to equalize the final leg lengths. An alternative option is leg lengthening of the shorter leg.

●Referral to a craniofacial surgeon if facial hemihyperplasia is significant.

●Treatment of neoplasia following standard pediatric oncology protocols.

●Standard interventions, such as infant stimulation programs, occupational and physical therapy, and individualized education programs for children with developmental delay.

●Referral of children with structural kidney or gastrointestinal tract abnormalities to the relevant specialists.

Surveillance — The following surveillance is advised in patients with BWS:

●Monitor for hypoglycemia in the first few days of life by random blood glucose measurements to detect asymptomatic hypoglycemia and have a higher index of suspicion for/awareness of clinical signs of hypoglycemia.

●Screen for developmental issues as part of routine childcare, especially when there is a history of hypoglycemia, prematurity, or evidence of chromosome 11p15.5 duplication.

●Screen for embryonal tumors [116]. Screening protocols vary in different geographic locations (see 'Tumor development' above). In some centers, screening is modified based upon molecular test results. Specifically, in many countries in Europe, a tumor risk of at least 5 percent is required for surveillance to be undertaken. Therefore, in these geographic regions, tumor surveillance is typically not recommended for children with loss of methylation at imprinting center 2 (IC2) beyond baseline abdominal ultrasound [18,117]. As well, serial alpha fetoprotein assay is variably included at different centers in the surveillance protocols for children with BWS. In North America, tumor surveillance is generally undertaken every three months to the seventh birthday or through the seventh year for all children with BWS regardless of the molecular alteration detected (including no detectable alteration) given that the risk for tumor development is greater than 1 percent [67,116]. As well, the risk of approximately 3 percent for Wilms tumor and hepatoblastoma in children with loss of methylation at IC2 represents an 11-fold increase to that seen in the general pediatric population [118,119]. This recommended surveillance approach is detailed below and includes both serial imaging and alpha fetoprotein assay given that early detection of hepatoblastoma and Wilms tumor have been shown to positively impact treatment outcomes [120]. Evidence-based decisions regarding tumor surveillance must await the results of a properly designed, prospective, large-scale study and improved molecular diagnostic test modalities.

•Abdominal ultrasound examination every three months until age four years [64,111,121,122] and then kidney ultrasound including the adrenal glands every three months to the seventh birthday or through the seventh year [67,116,123].

•Measure serum AFP concentration every two to three months in the first four years of life for early detection of hepatoblastoma [121]. This recommendation may be revised if there is replication of one study suggesting that hepatoblastoma screening until 30 months of age captures all cases of hepatoblastoma [124]. AFP serum concentration may be mildly elevated in children with BWS in the first year of life in the absence of a hepatoblastoma [125]. If the AFP is elevated in the absence of a suspicious lesion on imaging, follow-up measurement of serum AFP concentration plus baseline liver function tests four to six weeks later can be used to determine the trend in serum AFP concentrations over time. If a decline in AFP concentration is not seen, it is appropriate to refer to an oncologist and/or undertake an exhaustive search for an underlying tumor [126].

•Periodic chest radiograph and urinary homovanillic acid (HVA) and vanilmandelic acid (VMA) assays to screen for neuroblastoma have been suggested but have not been incorporated into most screening protocols, because of their low yield and the challenges of high rates of false-positive testing.

•While serial tumor surveillance is typically discontinued after the seventh or eighth birthday, a heightened degree of clinical suspicion should be maintained for any concerns potentially indicating a malignancy, and these should be investigated promptly.

●Assess for kidney anomalies as part of the abdominal ultrasound examination for embryonal tumor screening in patients eight years of age and under. Assess individuals over eight years of age through adolescence with annual or biennial (ie, every two years) kidney ultrasound examination to identify those requiring further evaluation/management since nephrocalcinosis, nephrolithiasis, and medullary sponge kidney develop at a later age.

●Consider measurement of urinary calcium/creatinine ratio annually or biannually since it may be abnormal in individuals with kidney disease who have normal kidney ultrasound examinations [56].

●Annual ECG and cardiac evaluation are suggested for persons with BWS associated with genomic alterations involving the IC2 region [18].

●Periodic assessment of leg lengths on physical examination or by caregiver report.

●Consideration should be given to offering tumor surveillance for those cases presenting with a "mild" phenotype (see 'Diagnosis' above). Additionally, tumor surveillance is suggested for the clinically unaffected monozygotic twin of a child with BWS because of the possibility of low-level mosaicism and shared-fetal circulation [41].

Genetic counseling — Genetic counseling regarding BWS etiology and recurrence risk (ie, risk of a subsequent affected child) is most accurate if data from a complete diagnostic evaluation are available, including molecular testing. These data include family history, clinical findings, karyotype, methylation-sensitive multiplex ligation probe analysis (MS-MLPA), single nucleotide polymorphism (SNP) array, and CDKN1C variant analysis if indicated.

The recurrence risk is low if molecular testing reveals uniparental disomy (UPD) or a methylation alteration in the absence of a transmissible genomic alteration. Information regarding recurrence risk for some of the molecular subtypes remains theoretical since there is a paucity of confirmatory empiric data. This is especially relevant when providing genetic counseling for affected individuals with theoretically low recurrence risk (eg, UPD for chromosome 11p15, methylation alterations at IC2). Molecular testing is typically not indicated for parents or other family members when UPD is found, since these cases arise via postzygotic somatic recombination. Parental studies are recommended if genomic alterations are found (eg, karyotype abnormalities, CDKN1C variants, or microduplications or microdeletions of the chromosome 11p15.5 region).

Molecular alterations that are associated with significant recurrence risk include:

●Maternal transmission of chromosome 11p15.5 translocation/inversion [4]

●Maternal transmission of CDKN1C variant [89]

●Chromosome 11p15.5 duplication of paternal origin [73]

●11p15.5 microdeletion/microduplication [16]

Molecular testing or chromosome analysis is indicated for both parents and potentially other family members if either a translocation or inversion involving chromosome 11p15.5 or a CDKN1C variant is found in the proband. The recurrence risk is 50 percent for CDKN1C variants and for translocations or inversions involving chromosome 11p15.5 if the transmitting parent is the mother [89]. The risk is low if the CDKN1C variant is found in the father; however, at least one case of BWS and paternal transmission of a CDKN1C variant has been reported in the literature [90]. The recurrence risk for paternally derived duplications is not specifically defined but is probably significant if the father carries a translocation. Familial transmissions involving microdeletions of IC1, and rarely of IC2, have been reported. Thus, parental testing is indicated when these alterations are identified [16,17,88].

The recurrence risk can be estimated empirically in the case of a positive family history in the absence of an abnormal genetic test result. Information incorporated into such estimates includes the sex and potential carrier status of the transmitting parent. All potential etiologies consistent with the positive family history should be considered. The recurrence risk for BWS in cases where there is no identified cause may be as high as 50 percent. Gonadal mosaicism remains a possibility, although it has not been reported to date. It should be considered when there is more than one affected offspring and/or the parents are not found to carry a transmissible microdeletion or variant associated with BWS.

When a pathogenic variant is detected in a maternal effect gene, genetic counseling should include information regarding the increased risk for adverse reproductive outcomes such as pregnancy loss or molar pregnancy as well as the risk for children with imprinting disorders [33]. Molecular testing (DNA methylation) for imprinting status, including prenatal testing, can be confounded by somatic mosaicism and the heterogeneous molecular etiologies [33]. Our understanding of the impact of maternal effect gene variants and the molecular testing for such variants will evolve based upon research efforts.

PROGNOSIS — Infants with BWS are at increased risk for mortality mainly due to complications of prematurity, macroglossia, hypoglycemia, tumors, and, rarely, cardiomyopathy. A previously reported mortality rate of 20 percent may be an overestimate given the improvements in syndrome recognition and treatment [4,43,87]. Prognosis is generally favorable after childhood. However, complications in adolescence/adulthood can occur (eg, kidney medullary dysplasia, subfertility in males). Such issues may be associated with specific molecular subtypes [127]. (See 'Phenotype-(epi)genotype correlations' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Beckwith-Wiedemann syndrome".)

SUMMARY AND RECOMMENDATIONS

●Definition – Beckwith-Wiedemann syndrome (BWS) is a pediatric overgrowth disorder involving a predisposition to tumor development. (See 'Introduction' above.)

●Epidemiology – BWS usually occurs sporadically, but familial transmission occurs in approximately 15 percent of cases. (See 'Epidemiology' above.)

●Genetics – Dysregulation of imprinted genes within the chromosome 11p15.5 region results in the BWS phenotype. However, a chromosome 11p15 molecular alteration is identified in only approximately 80 percent of persons with BWS. This may be due to low-level somatic mosaicism in the tissue sampled for testing or to other genomic loci that are probably involved in the etiology of BWS. (See 'Genetics and pathogenesis' above.)

●Clinical manifestations – The hallmark features of BWS are omphalocele (exomphalos), macroglossia, and macrosomia (gigantism). However, the clinical presentation is highly variable, and some cases lack these characteristic features. Children with otherwise mild phenotypes can present with tumors. (See 'Clinical manifestations' above.)

●Phenotype-(epi)genotype correlations – A number of genetic and/or epigenetic alterations in growth regulatory genes on chromosome 11p15.5 are associated with specific phenotype-(epi)genotype correlations and different recurrence risks. Information is emerging regarding genetic etiologies involving loci outside of the 11p15.5 region. (See 'Phenotype-(epi)genotype correlations' above.)

●Diagnosis – Several diagnostic approaches have been developed to address the challenges associated with the heterogeneous clinical presentation of BWS. However, children with minimal features not meeting diagnostic criteria may still develop a tumor, and therefore a cautious approach is advised. Molecular testing can be performed to determine the precise genetic defect and confirm the diagnosis. Methylation-sensitive multiplex ligation probe analysis (MS-MLPA) is the most robust method available for detecting most epigenetic and genetic etiologies associated with BWS. Prenatal testing is available, although consideration should be given to test modality for genomic versus methylation alteration. In addition, somatic mosaicism can confound test reliability. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis includes both genetic and nongenetic causes of macrosomia (table 1 and table 2). (See 'Differential diagnosis' above.)

●Management – Initial evaluation includes assessment for hypoglycemia, airway sufficiency, feeding difficulties, and screening for tumors. Surveillance includes monitoring for hypoglycemia, tumors, developmental issues, and kidney disease. Disease manifestations that appear throughout the course of the disease, including hypoglycemia, macroglossia, hemihyperplasia, and neoplasia, are treated with the normal standard of care. (See 'Management' above.)

●Genetic counseling – Cases involving uniparental disomy (UPD) arise from postzygotic somatic recombination and are therefore not known to be associated with a significantly increased risk for recurrence. Parental studies are recommended if genomic alterations are found (eg, karyotype abnormalities, cyclin-dependent kinase inhibitor 1C [CDKN1C] variants, or microduplications or microdeletions of the chromosome 11p15.5 region), and these test results are then incorporated into estimates of recurrence risks. (See 'Genetic counseling' above.)

●Prognosis – Infants with BWS are at increased risk for mortality, mainly due to complications of prematurity, macroglossia, hypoglycemia, tumors, and, rarely, cardiomyopathy. The increased risk for neoplasia is concentrated in the first eight years of life. Thus, prognosis is generally favorable after early childhood. (See 'Prognosis' above.)