DiagnosisClinical DiagnosisNo consensus diagnostic criteria for Beckwith-Wiedemann syndrome (BWS) exist, although the presence of several findings (e.g., three major or two major and one minor) is often used to confer a clinical or provisional diagnosis. In general, major findings are those associated with BWS and uncommon in the general population whereas minor findings are those associated with BWS but common in the general population. Note: Children who have milder phenotypes (e.g., macroglossia and umbilical hernia) may develop tumors associated with BWS (see Clinical Description). This is in part because BWS-associated molecular changes may be mosaic, i.e., many cells with BWS-associated changes may reside in organs “at risk” for tumor development such as liver or kidneys but not in tissues that influence clinical presentation. Therefore, the index of suspicion should be high when evaluating children with minimal clinical features in the BWS phenotypic spectrum with strong consideration of the use of molecular genetic testing to confirm the diagnosis.Major findings associated with BWSPositive family history (one or more family members with a clinical diagnosis of BWS or a history or features suggestive of BWS) Macrosomia (traditionally defined as height and weight >97th centile) Anterior linear ear lobe creases/posterior helical ear pits Macroglossia Omphalocele (also called exomphalos)/umbilical hernia Visceromegaly involving one or more intra-abdominal organs including liver, spleen, kidneys, adrenal glands, and pancreas Embryonal tumor (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma) in childhood Hemihyperplasia (asymmetric overgrowth of one or more regions of the body) Cytomegaly of the fetal adrenal cortex (pathognomonic) Renal abnormalities including structural abnormalities, nephromegaly, nephrocalcinosis, later development of medullary sponge kidneyCleft palate (rare in BWS) Placental mesenchymal dysplasia [Wilson et al 2008] Cardiomegaly Cardiomyopathy (rare in BWS)Minor findings associated with BWSPregnancy-related findings including polyhydramnios and prematurity Neonatal hypoglycemia Facial nevus flammeus, other vascular malformationsCharacteristic facies, including midface hypoplasia and infraorbital creases Structural cardiac anomalies Diastasis recti Advanced bone age (common in overgrowth/endocrine disorders)Molecular Genetic TestingGenes. Beckwith-Wiedemann syndrome is associated with abnormal regulation of gene transcription in an imprinted domain on chromosome 11p15.5 (also known as the BWS critical region). Regulation may be disrupted by any one of numerous mechanisms; a simplified description of pathogenetic mechanisms is given here to clarify the testing process and Testing Strategy. See Molecular Genetic Pathogenesis for a detailed description of the regulation of gene expression in this region. The BWS critical region includes two domains: imprinting center 1 (IC1) regulates the expression of IGF2 and H19 in domain 1; imprinting center 2 (IC2) regulates the expression of CDKN1C, KCNQ10T1, and KCNQ1 in domain 2 (Figure 1). Genomic imprinting is a phenomenon whereby the DNA of the two alleles of a gene is differentially modified so that only one parental allele, parent-specific for each gene, is normally expressed [Barlow 1994]. As shown in Figure 1-A, differential methylation of IC1 and IC2 is associated with expression of specific genes on the paternal and maternal alleles in unaffected individuals. FigureFigure 1. Beckwith-Wiedemann syndrome: schematic representation of the imprinting cluster
A. The chromosome 11p15.5 imprinting cluster is functionally divided into two domains. Domain 1 has two imprinted genes: 1GF2 encoding insulin-like (more...)Note: IC1 and IC2 are sometimes referred to as differentially methylated regions DMR1 and DMR2, respectively.In more than 80% of individuals with BWS, molecular genetic testing can detect one of five alterations [Weksberg et al 2003, Weksberg et al 2005]: A schematic of the following two resulting changes is shown in Figure 1:Loss of methylation of IC2 on the maternal chromosome (Figure 1-B1) Gain of methylation of IC1 on the maternal chromosome (Figure 1-B2)The following three resulting changes are not represented in Figure 1: Mutation of the maternal CDKN1C allele Paternal uniparental disomy of 11p15.5 Duplication, inversion, or translocation involving the p15.5 band of chromosome 11 Note: Rarely, methylation changes are associated with primary changes in DNA sequence, i.e., microdeletions or microduplications [Sparago et al 2004, Niemitz et al 2004, Prawitt et al 2005]. The causes of BWS by molecular mechanism are shown in Figure 2.FigureFigure 2. Causes of Beckwith-Wiedemann syndrome by molecular mechanism Table 1. Summary of Molecular Genetic Testing Used in Beckwith-Wiedemann SyndromeView in own windowCause of BWS by Molecular MechanismTest MethodMutations/Alterations DetectedProportion of BWS Alterations Detected ^{1Test Availability Loss of methylation at IC2 on the maternal chromosomeMethylation analysis 2Methylation abnormalities at IC2 on the maternal chromosome50% 3ClinicalGain of methylation at IC1 on the maternal chromosomeMethylation abnormalities at IC1 on the maternal chromosome5% 3Mutation of the maternal CDKN1C alleleSequence analysisCDKN1C mutations 45% in persons with no family history of BWS 5~40% in persons with a positive family history of BWS 5Paternal uniparental disomy of 11p15.5UPD analysis 611p15.5 paternal uniparental disomy 720% 3Duplication, inversion, or translocation of 11p15.5Cytogenetic analysis (karyotype)Cytogenetic duplication, inversion, or translocation 1%FISHPrimarily used to clarify the relative positions of a chromosome 11 inversion or translocation and to confirm duplication of chromosome 11Submicroscopic genomic alteration within chromosome 11p15.5Microdeletion / microduplication analysis 2Genomic alterations involving IC1 and/or IC2 Not yet accurately determined1. Proportion of affected individuals with a mutation(s) as classified by gene/locus, phenotype, population group, and/or test method, in individuals fulfilling clinical diagnostic criteria for BWS. Note: Frequencies may vary in different populations [Sasaki et al 2007].2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. In the case of BWS, deletion/duplication analysis may also be combined with methylation analysis, e.g., MS-MLPA (methylation-specific multiplex ligation-dependent probe amplification).3. Bliek et al [2001], Weksberg et al [2001]4. Examples of sequence variants include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.5. Lam et al [1999], Li et al [2001]6. Various methods (e.g., SNP or marker analysis, PCR/restriction endonuclease analysis, Southern blot, and MS-MLPA) can detect UPD. Testing may require parental blood specimens.7. False negatives may occur as a result of somatic mosaicism for UPD, which has been reported in all affected individuals to date. Testing of tissue from a second source (e.g., fibroblast cells from a skin biopsy) may be helpful.Clinical testingMethylation analysisMethylation at imprinting center 2 (IC2). IC2 is normally methylated on the maternal chromosome only (Figure 1-A). Approximately 50% of individuals fulfilling diagnostic criteria for BWS have detectable IC2 methylation abnormalities (Figure 1-B1). IC2 was formerly called the differentially methylated region 2 (DMR2) or LIT1.
Methylation at imprinting center 1 (IC1). IC1 is normally methylated on the paternal chromosome only (Figure 1-A). Approximately 5% of individuals fulfilling diagnostic criteria for BWS have detectable IC1 methylation abnormalities (Figure 1-B2). IC1 was formerly called the differentially methylated region 1 (DMR1).
Note: (1) Individuals with abnormal methylation at either IC1 or IC2 can be distinguished from those with uniparental disomy (UPD) (see Uniparental disomy analysis) because the latter have abnormal methylation at both IC1 and IC2. (2) Interpretation of methylation data should take into account results of karyotype analysis because karyotypic abnormalities that alter the relative dosage of parental contributions (e.g., paternal duplication) are associated with abnormal methylation status.
Of note, some methylation defects are associated with microdeletions or microduplications not visible on a high-resolution karyotype. Therefore, analysis of genomic DNA should be offered in cases of abnormal methylation to identify the small percentage of families with significantly increased recurrence risk. At present, methylation-sensitive multiplex ligation probe analysis (MS-MLPA) provides the most robust detection of epigenetic and genomic alterations of 11p15.5 as it detects microdeletions, microduplications, gene dosage alterations, and DNA methylation alterations, including those resulting from UPD. Sequence analysis – CDKN1C. The mutation detection frequency for mutations in CDKN1C varies by family history. The majority of CDKN1C mutations found in BWS are located in exons 1 and 2 [Hatada et al 1997, Lee et al 1997, O'Keefe et al 1997, Lam et al 1999, Algar et al 2000, Li et al 2001]. Uniparental disomy (UPD) analysis. Approximately 20% of individuals fulfilling diagnostic criteria for BWS have paternal UPD for the BWS critical region. Most demonstrate segmental paternal mosaicism for UPD for 11p15, suggesting that the underlying mechanism is a post-zygotic somatic recombination event resulting in mosaicism for UPD of chromosome 11p15. Therefore, UPD may not be detected if a low level of mosaicism occurs in the tissue sampled. Testing of other tissues (e.g., skin fibroblasts, tumor biopsy) should be considered. Various methods may be employed (see Table 1, footnote 6).
Note: If UPD is suspected based on analysis of the proband's sample, parental samples may be required for confirmation.Cytogenetic analysis (karyotype). Chromosome analysis at a band level of at least 550 in 20 metaphases reveals a cytogenetically detectable translocation or inversion of chromosome 11 or a cytogenetically detectable duplication of chromosome 11 involving band 11p15.5 in fewer than 1% of individuals with BWS [Slavotinek et al 1997, Li et al 1998].
For de novo cytogenetic abnormalities, molecular testing can in most cases identify the parent of origin. Translocations/inversions are typically of maternal origin, whereas duplications are typically of paternal origin.FISH. Only 1%-2% of individuals with BWS have chromosomal abnormalities. FISH studies can be used to clarify the relative positions of a chromosome 11 translocations or inversions and to confirm duplications of chromosome 11. Deletion/duplication analysis. Families have been reported with microdeletions or microduplications of IC1 Research testing Mutations in NLRP2 at 19q13.42 have been reported in two children of one family; both children had BWS and IC2 alterations and their mother had a homozygous mutation in NLRP2 [Meyer et al 2009]. This suggests that NLRP2 expression is required for normal imprinting of IC2.Methylation alterations at multiple imprinted loci. Individuals with BWS, especially those with loss of methylation at IC2, may show methylation alterations at multiple imprinted loci, e.g., PLAGL1 on chromosome 6q and/or GNAS on chromosome 20. The clinical significance of these changes is still under investigation [Azzi et al 2009, Bliek et al 2009]. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo establish/confirm the diagnosis in a probandKaryotype (can be initiated at the same time as the molecular testing)Methylation studies of IC1 and IC2 can be performed simultaneously; however, if the proband has intellectual disability, a karyotype should be performed first. Further testing can be undertaken to evaluate for genomic alterations leading to methylation changes; methylation alterations at both IC1 and IC2 suggest uniparental disomy. Currently, MS-MLPA is the most robust testing methodology for the detection of these alterations.Sequence analysis of CDKN1C should be undertaken in familial cases, in individuals with BWS and cleft palate, or in individuals who meet diagnostic criteria for BWS but have no detectable cytogenetic abnormalities, methylation abnormalities, or UPD. Testing for heritable microdeletions/microduplications should be undertaken in familial cases in which a CDKN1C mutation has not been detected and the karyotype is normal [Niemitz et al 2004, Sparago et al 2004, Prawitt et al 2005]. Prenatal diagnosis for at-risk pregnancies in families with heritable forms of BWS requires prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersMolecular alterations at 11p15 including loss of methylation at IC2, gain of methylation at IC1 [Martin et al 2005], and 11p15 paternal uniparental disomy [Shuman et al 2002] have been reported in individuals with isolated hemihyperplasia. Somatic mosaicism for loss of methylation at the paternal IC1 is associated with Russell-Silver syndrome (RSS) and/or isolated hemihypoplasia [Zeschnigk et al 2008, Eggermann 2009]. Isolated Wilms tumor can be associated with constitutional alterations of chromosome 11p15 including hypermethylation at IC1, paternal uniparental disomy of 11p15, and genomic abnormalities including microdeletion and microinsertion [Scott et al 2008a].}

Natural HistoryIncidence figures for the specific individual clinical findings in Beckwith-Wiedemann syndrome (BWS) vary widely in published reports. The following features, however, are clearly part of the phenotype.Prenatal and perinatal. The incidence of polyhydramnios, premature birth, and fetal macrosomia may be as high as 50%. Other common features include a long umbilical cord and an enlarged placenta that averages almost twice the normal weight for gestational age. Placental mesenchymal dysplasia has been reported in babies subsequently found to have features of BWS [Wilson et al 2008].Infants with BWS are at increased risk for mortality mainly as a result of complications of prematurity, macroglossia, hypoglycemia, and, rarely, cardiomyopathy. However, the previously reported mortality rate of 20% may be an overestimate given the recent improvements in syndrome recognition and treatment.Growth. Macroglossia and macrosomia are generally present at birth, though postnatal onset of both features has also been observed [Chitayat et al 1990; Weksberg, personal observation]. Although most individuals with BWS show rapid growth in early childhood, height typically remains at the upper range of normal. Growth rate usually appears to slow around age seven to eight years. Hemihyperplasia, if present, can generally be appreciated at birth, but may become more or less evident as the child grows. Hemihyperplasia may affect segmental regions of the body or selected 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) [Hoyme et al 1998]. Note: Hemihyperplasia refers to an abnormality of cell proliferation leading to asymmetric overgrowth; in BWS, hemihyperplasia, referring to increased cell number, has replaced the term hemihypertrophy, which refers to increased cell size.Metabolic abnormalities. Neonatal hypoglycemia is well documented; if undetected or untreated, it poses a significant risk for developmental sequelae. Most cases of hypoglycemia are mild and transient; however, in more severe cases hypoglycemia can persist. Delayed onset of hypoglycemia (i.e., in the first month of life) is occasionally observed. Other less common endocrine/metabolic/hematologic findings include hypothyroidism, hyperlipidemia/hypercholesterolemia, and polycythemia.Hypercalciuria can be found in children with BWS even in the absence of renal abnormalities. On ultrasound examination 22% of individuals with BWS demonstrate nephrocalcinosis as compared to 7%-10% in the general population [Goldman et al 2003].Structural anomalies. Anterior abdominal wall defects, including omphalocele, umbilical hernia, and diastasis recti, are common. Cleft palate, seen in very few individuals with BWS, is associated with mutations in CDKN1C [Hatada et al 1997, Li et al 2001].Much of the information regarding cardiovascular problems in BWS is anecdotal. Cardiomegaly is commonly detected in infancy if a chest x-ray is done, but typically resolves without treatment. Cardiomyopathy has been reported but is rare. Renal anomalies can include medullary dysplasia, duplicated collecting system, nephrocalcinosis, medullary sponge kidney, cystic changes, diverticula, and nephromegaly [Choyke et al 1998, Borer et al 1999].Neoplasia. Children with BWS have an increased risk of mortality associated with neoplasia, particularly Wilms tumor and hepatoblastoma, but also neuroblastoma, adrenocortical carcinoma, and rhabdomyosarcoma. Also seen are a wide variety of other tumors, both malignant and benign [Cohen 2005]. The estimated risk for tumor development in children with BWS is 7.5% with a range of risks estimated between 4% and 21% [Sotelo-Avila et al 1980, Wiedemann 1983, Pettenati et al 1986, Elliott et al 1994, Weng et al 1995, Schneid et al 1997, DeBaun & Tucker 1998, Cohen 2005, Tan & Amor 2006]. This increased risk for neoplasia seems to be concentrated in the first eight years of life. Tumor development in affected individuals older than age eight years, although uncommon, has been reported.Development is usually normal in children with BWS unless there is a chromosome abnormality [Slavotinek et al 1997] 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 ascertained by parental report. However, additional studies including formal neurodevelopmental assessments are needed to assess the frequencies of such problems in BWS.Adulthood. After childhood, prognosis is generally favorable. However, complications can occur (e.g., renal medullary dysplasia, subfertility in males). Such issues may be associated with specific molecular subtypes [Greer et al 2008].

Genotype-Phenotype CorrelationsPhenotype-genotype correlations have been reported as follows:Hemihyperplasia is associated with mosaicism for paternal UPD of 11p15 or molecular alterations at IC2 or IC1 [DeBaun et al 2002, Shuman et al 2002, Enklaar et al 2006].Positive family history is associated with mutations in CDKN1C or microdeletions at IC1 and rarely microduplication at IC2 [Hatada et al 1997, Lee et al 1997, Sparago et al 2004, Weksberg & Shuman 2004, Cooper et al 2005, Prawitt et al 2005, Enklaar et al 2006, Percesepe et al 2008, Scott et al 2008b, Bliek et al 2009].Cleft palate is associated with mutations in CDKN1C [Hatada et al 1997, Li et al 2001].Omphalocele is associated with mutations in CDKN1C or alterations at IC2 [Enklaar et al 2006].Neoplasia: UPD of 11p15 or gain of methylation at IC1 is associated with the highest risk for Wilms tumor and hepatoblastoma. Loss of methylation at IC2 is associated with a lower risk for tumor development and the tumors reported to date do not include Wilms tumor. Mutation of CDKN1C has only been associated with a small number of cases of neuroblastoma [Bliek et al 2001, Weksberg et al 2001, DeBaun et all 2002, Cooper et al 2005, Rump et al 2005, Alsultan et al 2008, Kuroiwa et al 2009].Developmental delay is associated with paternally derived duplications of 11p15 detectable by cytogenetic analysis [Slavotinek et al 1997].Severe BWS phenotype is associated with high levels of somatic mosaicism for UPD of 11p15 [Smith et al 2006]. Female monozygotic twinning with discordance for BWS appears to be associated with loss of methylation at IC2; male monozygotic twinning occurs far less frequently and is associated with a range of molecular alterations [Weksberg et al 2002, Smith et al 2006].Subfertility with or without the use of assisted reproductive technologies (ART) appears to be associated with an increased incidence of babies with BWS caused by loss of methylation at IC2 [DeBaun et al 2003, Gicquel et al 2003, Maher et al 2003a, Maher et al 2003b, Halliday et al 2004].

Differential DiagnosisOvergrowth. Beckwith-Wiedemann syndrome (BWS) is often considered in the differential diagnosis of children presenting with overgrowth. It is important to note the existence of as-yet unclassified overgrowth syndromes that need to be differentiated from BWS. In children considered to have BWS and developmental delay who have a normal chromosome study and no history of hypoxia or hypoglycemia, other causes for developmental delay need to be considered. If structural or cardiac conduction defects are present, the differential diagnosis should include Simpson-Golabi-Behmel syndrome and Costello syndrome. The following disorders should be included in the differential diagnosis:Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked recessive condition that shares many features with BWS (e.g., macrosomia, visceromegaly, macroglossia, and renal anomalies). It is distinguished by the presence of distinctive facial features, cleft lip, structural and conduction cardiac abnormalities, and skeletal abnormalities including polydactyly. Developmental delay may be present. Although affected individuals with tumors have been reported, the tumor risk and range of tumors remain to be defined. Sequence analysis and deletion analysis of GPC3 have a mutation detection rate of 37%-70%. GPC3 encodes glypican-3, an extracellular proteoglycan believed to function in the regulation of cell growth [Neri et al 1998, Shi & Filmus 2009].Perlman syndrome (PS) is a rare autosomal recessive condition with macrosomia and a high incidence of Wilms tumor. Facial features are distinctive; neonatal mortality is high and significant intellectual handicap is common. PS is thought to be genetically distinct from BWS; the gene causing PS has not yet been identified. Costello syndrome (CS) can be similar to BWS in the neonatal period, when affected infants present with macrosomia. Cardiac abnormalities may include structural defects, hypertrophic cardiomyopathy, or arrhythmias. Over time, individuals with CS exhibit failure to thrive, developmental delay, and other distinctive features including coarsening of the facial features [van Eeghen et al 1999].Sotos syndrome is an autosomal dominant disorder characterized by a typical facial appearance, intellectual impairment, and overgrowth involving both height and head circumference. About 85% of individuals with Sotos syndrome have a mutation or deletion of NSD1. If the clinical phenotype of macrosomia is not accompanied by features characteristic of BWS, consideration should be given to testing NSD1 mutations [Baujat et al 2004]. Mucopolysaccaridosis type VI (Maroteaux-Lamy syndrome) is an autosomal recessive disorder caused by a deficiency of the enzyme arylsulfatase B. In the first year of life children with this disorder may present with accelerated growth and advanced bone age suggestive of an overgrowth condition. However, at age two to three years, the presentation includes corneal clouding, hepatosplenomegaly, short stature, dysostosis multiplex, cardiac abnormalities, and coarsened facial features.Hemihyperplasia can occur as an isolated finding or may be associated with other syndromes such as Proteus syndrome (see PTEN Hamartoma Tumor Syndrome), Klippel-Trenauny-Weber syndrome, and neurofibromatosis type 1 [Hoyme et al 1998]. Of note, a subgroup of individuals with apparently isolated hemihyperplasia may actually have BWS with minimal clinical findings. Asymmetries, such as of the face or chest, should be evaluated to exclude plagiocephaly and chest wall deformities. Children with isolated hemihyperplasia have an increased tumor risk of 5.9% [Hoyme et al 1998] and should be offered tumor surveillance. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Beckwith-Wiedemann syndrome (BWS), the following evaluations are recommended: 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 persists beyond the first few days of life.Abdominal ultrasound examination to assess for organomegaly, structural abnormality, and tumors; a baseline MRI or CT examination of the abdomen to screen for tumors [Beckwith 1998] Comprehensive cardiac evaluation including ECG and echocardiogram prior to any surgical procedures or when a cardiac abnormality is suspected on clinical evaluation Alpha-fetoprotein assay at the time of initial diagnosis to evaluate for hepatoblastomaTreatment of ManifestationsThe following are appropriate:Prompt treatment of hypoglycemia to reduce the risk of central nervous system complications. Because onset of hypoglycemia is occasionally delayed for several days, or even months, parents should be informed of the symptoms of hypoglycemia so that they can seek appropriate medical attention. Abdominal wall repair soon after birth for omphalocele. Generally, this surgery is well tolerated. Management of difficulties arising from macroglossia:Anticipation of difficulties with endotracheal intubation [Kimura et al 2008]Assessment of respiratory function, possibly including sleep study to address concern regarding potential sleep apneaManagement 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. Tongue growth does slow over time and jaw growth can accelerate to accommodate the enlarged tongue. Some children benefit from tongue reduction surgery; however, surgical reduction typically affects tongue length but not thickness; residual cosmetic and speech issues may require further assessment/treatment [Tomlinson et al 2007]. Orthodontic intervention as needed in later childhood/adolescence Assessment of speech difficulties 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. Referral to a craniofacial surgeon if facial hemihyperplasia is significant Treatment of neoplasias following standard pediatric oncology protocols In some individuals with BWS, developmental anomalies of the renal tract are associated with increased calcium excretion and deposition (i.e., nephrocalcinosis). In individuals with evidence of calcium deposits on renal ultrasound examination, assessment for hypercalciuria and a CT scan of the kidneys may be helpful. Referral to a pediatric nephrologist if the urinary calcium is elevatedStandard interventions such as infant stimulation programs, occupational and physical therapy, and individualized education programs for children with developmental delay Referral of children with structural renal or GI tract abnormalities to the relevant specialistsManagement of cleft palate following standard protocolsManagement of cardiac problems following standard protocols Prevention of Secondary ComplicationsSuspicion of potential urinary tract infection should be assessed and treated promptly to prevent secondary renal damage.SurveillanceThe following are appropriate:Monitoring for hypoglycemia, especially in the neonatal periodDevelopmental screening as part of routine childcare Annual renal ultrasound examination between ages eight years and mid-adolescence to identify those requiring further evaluation. Those with positive findings should be referred to a nephrologist for further assessment and follow up. Since the natural history of renal disease in adults has not as yet been evaluated, adult-onset renal disease without early findings remains a possibility. Consideration of measurement of urinary calcium/creatinine ratio annually or biannually from the time of BWS diagnosis as it may be abnormal in individuals with BWS who have normal findings on ultrasound examination [Goldman et al 2003]Screening for embryonal tumors by: Abdominal ultrasound examination every three months until age eight years [Beckwith 1998, Tan & Amor 2006, Clericuzio & Martin 2009, Zarate et al 2009] Measurement of serum alpha-fetoprotein (AFP) concentration every two to three months in the first four years of life for early detection of hepatoblastoma [Clericuzio & Martin 2009]. (AFP serum concentration may be elevated in children with BWS in the first year of life [Everman et al 2000].) If the AFP is elevated and imaging reveals no suspicious lesion, follow-up measurement of serum AFP concentration plus baseline liver function tests one month later can be used to determine the trend in serum AFP concentrations over time. If the concentration is not decreasing, it is appropriate to undertake an exhaustive search for an underlying tumor [Clericuzio et al 2003].
Note: Although periodic chest x-ray and urinary VMA and VHA assays to screen for neuroblastoma have been suggested, they have not been incorporated into most screening protocols because of their low yield.Evaluation of Relatives at RiskEven in the absence of obvious clinical findings on prenatal investigation, the newborn sib of an individual with BWS should be monitored for hypoglycemia.Tumor surveillance should be strongly considered for the apparently unaffected twin of monozygotic twins who are discordant for BWS, given the possibility of shared fetal circulation and resulting somatic mosaicism. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Beckwith-Wiedemann Syndrome: Genes and DatabasesView in own windowCritical RegionGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCDKN1C11p15​.4Cyclin-dependent kinase inhibitor 1CCDKN1C homepage - Mendelian genesCDKN1CKCNQ111p15​.5-p15.4Potassium voltage-gated channel subfamily KQT member 1Deafness Gene Mutation Database
Gene Connection for the Heart - KCNQ1 (KVLQT1)
KCNQ1 @ LOVD
KCNQ1 @ ZAC-GGMKCNQ1IGF211p15​.5Insulin-like growth factor IILOVD - Growth ConsortiumIGF2H1911p15​.5UnknownH19 @ LOVDH19BWSUnknown11p15​.4Unknown KCNQ1OT111p15​.5UnknownKCNQ1OT1 @ LOVDKCNQ1OT1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Beckwith-Wiedemann Syndrome (View All in OMIM) View in own window 103280H19 GENE; H19 130650BECKWITH-WIEDEMANN SYNDROME; BWS 147470INSULIN-LIKE GROWTH FACTOR II; IGF2 600856CYCLIN-DEPENDENT KINASE INHIBITOR 1C; CDKN1C 604115KCNQ1-OVERLAPPING TRANSCRIPT 1; KCNQ1OT1 607542POTASSIUM CHANNEL, VOLTAGE-GATED, KQT-LIKE SUBFAMILY, MEMBER 1; KCNQ1Molecular Genetic Pathogenesis Imprinting is an epigenetic process whereby the DNA of the two alleles of a gene is differentially modified so that only one parental allele, parent-specific for each gene, is normally expressed [Barlow 1994]. Imprinted genes cluster to distinct domains in the genome and an imprinting center controls resetting of a group of closely linked imprinted genes during transmission through the germline [Nicholls 1994].Gene/locus name. A number of candidate imprinted genes including growth factors and tumor suppressor genes mapping to the 11p15 region have been implicated. Imprinting centers (IC1 and IC2) control gene expression across large chromosomal domains. Many different molecular alterations in this region occur in association with Beckwith-Wiedemann syndrome (BWS).Alterations of imprinted gene expression associated with BWS. There are two imprinted domains in the BWS critical region (see Figure 1-A).Domain 1 is telomeric and contains the imprinted genes H19 and IGF2. H19 is a non-coding, non-translated RNA that may function as a tumor suppressor. IGF2 is a potent fetal growth factor. H19 and IGF2 are reciprocally expressed imprinted genes with H19 maternally expressed and IGF2 paternally expressed. The expression of this domain is regulated by an imprinting center upstream of H19 called imprinting center 1 (IC1) (also known as differentiallly methylated region 1 [DMR1]). 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 CTCF to its consensus sequence within IC1. CTCF only binds to unmethylated sequence (maternal allele) and interferes with downstream enhancers interacting with the IGF2 promoters [Hark et al 2000].Domain 2 is located centromerically and contains the imprinted genes CDKN1C, KCNQ1, and KCNQ1OT1. Regulation of this domain is controlled by imprinting center 2 (IC2) (previously known as differentially methylated region2 [DMR2]). IC2 is located in intron 10 of KCNQ1. IC2 [Smilinich et al 1999] contains the promoter for KCNQ1OT1 — a non-coding RNA with potential regulatory function [Pandey et al 2008]. Although the exact regulation of this region is not clear it is known that loss of methylation at IC2 on the maternal chromosome results in biallelic expression of the normally paternally expressed KCNQ1OT1. Additionally, it has been shown that individuals with BWS and loss of methylation at IC2 on the maternal chromosome have reduced CDKN1C expression [Diaz-Meyer et al 2003]. An imprinting center (IC) is a region of DNA that can regulate in cis the expression of neighboring imprinted genes over large distances. ICs are usually characterized by differential DNA methylation and differential histone modifications and may also be referred to as imprinting control regions (ICRs) or differentially methylated regions (DMRs).IC1 is the telomeric imprinting centre on chromosome 11p15.5 that maps upstream of the H19 promoter and regulates H19 and IGF2. It may also be referred to as ICR1, DMR1, or H19DMR. It is normally methylated on the paternal allele and unmethylated on the maternal allele, i.e., differentially methylated.IC2 is the centromeric imprinting centre that regulates several genes including KCNQ1OT1, KCNQ1, and CDKN1C. It may also be referred to as ICR2, DMR2 and KvDMR1. It is normally methylated on the maternal allele and unmethylated on the paternal allele, i.e., differentially methylated.Gain of methylation or hypermethylation – increased level of DNA methylation compared to control samples. For imprinted regions this may be associated with methylation of a normally unmethylated allele.Loss of methylation or hypomethylation– decreased level of DNA methylation compared to control samples. For imprinted regions, this may be associated with loss of methylation of a normally methylated allele. Uniparental disomy (UPD). In BWS, somatic mosaicism for 11p15 UPD is found in 20% of affected individuals. The UPD appears to consistently arise from a somatic recombination event resulting in paternal isodisomy.IGF2 is an imprinted gene encoding a paternally expressed embryonic growth factor. Disruption of IGF2 imprinting resulting in biallelic expression has been observed in some individuals with BWS as well as in multiple tumors, including Wilms tumor. Mice with a mutation in the paternally derived igf2 allele are small at birth whereas the same mutation in the maternally inherited allele does not affect fetal growth. Also, overgrowth of mice is seen with overexpression of igf2 or disruption of the Iigf2 receptor.H19. This maternally expressed gene encodes a biologically active non-coding mRNA that may function as a tumor suppressor. Approximately 50% of individuals with BWS exhibit biallelic IGF2 expression in their tissues demonstrating uncoupled expression of IGF2 and H19; that is, most retain normal maternal monoallelic expression of H19. Less commonly, changes in H19 expression or methylation are reported in patients with BWS [Joyce et al 1997, Sparago et al 2004].CDKN1C encodes the protein p57^KIP2, a member of the cyclin-dependent kinase inhibitor family which acts to negatively regulate cell proliferation. This gene is both a putative tumor suppressor gene and a potential negative regulator of fetal growth. Both these functions and the preferential maternal expression (incomplete repression of transcription of the paternal allele) of this gene suggested it as a candidate gene for BWS. Mutations in this gene have been reported in approximately 5% of affected individuals. CDKN1C mutations are found more frequently in individuals with omphalocele, cleft palate, and a positive family history. However, not all instances of vertical transmission of BWS can currently be ascribed to mutations in CDKN1C [Hatada et al 1997, Lee et al 1997].KCNQ1. The protein encoded by KCNQ1 forms part of a potassium channel and has also been implicated in at least two cardiac arrhythmia syndromes, Romano-Ward syndrome and Jervell and Lange-Nielsen syndrome. This gene is maternally expressed in most tissues (excluding the heart) and has four alternatively spliced transcripts, two of which are untranslated.KCNQ1OT1 is an anti-sense transcript which originates in intron 10 of KCNQ1. Loss of imprinting occurs in the 5' differentially methylated promoter region (IC2) of KCNQ1OT1 in 50% of individuals with BWS [Bliek et al 2001, Weksberg et al 2001].Other imprinted genes. PHLDA2 (also known as IPL, HLDA2, or BWR1C) and SLC22A18 (also known as TSSC5, BWR1A, or ITM) are imprinted genes in the 11p15 region [Qian et al 1997, Dao et al 1998]. Both genes show preferential maternal expression in fetal life and are located centromeric to CDKN1C. While neither gene has been directly implicated in BWS, both are hypothesized to have negative growth regulatory functions. Recently, PHLDA2 has been shown to be important for normal placental/fetal development [Dória et al 2010, Tunster et al 2010].Dosage of gene expression in this region is important for the regulation of fetal growth in mice. Upregulation of Igf2 expression and downregulation of Cdkn1c (p57^Kip2) result in phenotypes analogous to BWS in mouse models [Caspary et al 1999].