Clinical characteristics.

Beckwith-Wiedemann syndrome (BWS) is a growth disorder variably characterized by neonatal hypoglycemia, macrosomia, macroglossia, hemihyperplasia, omphalocele, embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma), visceromegaly, adrenocortical cytomegaly, renal abnormalities (e.g., medullary dysplasia, nephrocalcinosis, medullary sponge kidney, and nephromegaly), and ear creases/pits.

BWS is considered a clinical spectrum, in which affected individuals may have many of these features or may have only one or two clinical features. Early death may occur from complications of prematurity, hypoglycemia, cardiomyopathy, macroglossia, or tumors. However, the previously reported mortality of 20% is likely an overestimate given better recognition of the disorder along with enhanced treatment options. Macroglossia and macrosomia are generally present at birth but may have postnatal onset. Growth rate slows around age seven to eight years. Hemihyperplasia may affect segmental regions of the body or selected organs and tissues.

Diagnosis/testing.

A provisional diagnosis of BWS based on clinical assessment may be confirmed by molecular/cytogenetic testing. Cytogenetically detectable abnormalities involving chromosome 11p15 are found in 1% or fewer of affected individuals. Molecular genetic testing can identify epigenetic and genomic alterations of chromosome 11p15 in individuals with BWS:

• Loss of methylation on the maternal chromosome at imprinting center 2 (IC2) in 50% of affected individuals;
• Paternal uniparental disomy for chromosome 11p15 in 20%; and
• Gain of methylation on the maternal chromosome at imprinting center 1 (IC1) in 5%. Methylation alterations associated with deletions or duplications in this region have high heritability.

Sequence analysis of CDKN1C identifies a heterozygous maternally inherited pathogenic variant in approximately 40% of familial cases and 5%-10% of cases with no family history of BWS.

Management.

Treatment of manifestations: Treatment of hypoglycemia to reduce the risk of central nervous system complications; abdominal wall repair for omphalocele; endotracheal intubation for a compromised airway and use of specialized nipples or nasogastric tube feedings to manage feeding difficulties resulting from macroglossia. Children with macroglossia may benefit from tongue reduction surgery in infancy or early childhood and from speech therapy. Surgery may be performed during early puberty to equalize significant differences in leg length secondary to hemihyperplasia; craniofacial surgery may benefit individuals with facial hemihyperplasia. Neoplasias are treated using standard pediatric oncology protocols. Nephrocalcinosis and other renal findings should be assessed and treated by a pediatric nephrologist. Referral of children with structural GI tract anomalies to the relevant specialist; standard management for cardiac problems; standard interventions for children with developmental delay.

Prevention of secondary complications: Prompt evaluation and standard treatment for suspected urinary tract infections to prevent secondary renal damage.

Surveillance: Monitor for hypoglycemia, especially in the neonatal period; screen for embryonal tumors by abdominal ultrasound examination every three months until age eight years; monitor serum alpha-fetoprotein (AFP) concentration every two to three months in the first four years of life for early detection of hepatoblastoma. Annual renal ultrasound examination for affected individuals between age eight years and mid-adolescence to identify those with nephrocalcinosis or medullary sponge kidney disease; consideration of annual or biannual measurement of urinary calcium/creatinine ratio.

Genetic counseling.

Beckwith-Wiedemann syndrome is associated with abnormal regulation of gene transcription in two imprinted domains on chromosome 11p15.5. Most individuals with BWS are reported to have normal chromosome studies or karyotypes. Approximately 85% of individuals with BWS have no family history of BWS; approximately 15% have a family history consistent with parent-of-origin autosomal dominant transmission. Children of subfertile parents conceived by assisted reproductive technology (ART) may be at increased risk for imprinting disorders, including BWS. Identification of the underlying genetic mechanism causing BWS permits better estimation of recurrence risk. Prenatal screening for pregnancies in the general population that identifies findings suggestive of a diagnosis of BWS may lead to the consideration of chromosome analysis, chromosomal microarray, and/or molecular genetic testing. Specific prenatal testing is possible by chromosome analysis for families with an inherited chromosome abnormality or by molecular genetic testing for families in which the molecular mechanism of BWS has been defined.

Suggestive Findings

No consensus clinical diagnostic criteria for Beckwith-Wiedemann syndrome (BWS) exist.

Beckwith-Wiedemann syndrome (BWS) should be suspected in individuals who have one or more of the following major and/or minor findings.

Major findings associated with BWS

• Macrosomia (traditionally defined as weight and length/height >97th centile)
• Macroglossia
• Hemihyperplasia (asymmetric overgrowth of one or more regions of the body)
• Omphalocele (also called exomphalos) or umbilical hernia
• Embryonal tumor (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma) in childhood
• Visceromegaly involving one or more intra-abdominal organs including liver, spleen, kidneys, adrenal glands, and/or pancreas
• Cytomegaly of the fetal adrenal cortex (pathognomonic)
• Renal abnormalities including structural abnormalities, nephromegaly, nephrocalcinosis, and/or later development of medullary sponge kidney
• Anterior linear ear lobe creases and/or posterior helical ear pits
• Placental mesenchymal dysplasia [Wilson et al 2008]
• Cleft palate (rare in BWS)
• Cardiomyopathy (rare in BWS)
• Positive family history (≥1 family members with a clinical diagnosis of BWS or a history or features suggestive of BWS)

Minor findings associated with BWS

• Pregnancy-related findings including polyhydramnios and prematurity
• Neonatal hypoglycemia
• Vascular lesions including nevus simplex (typically appearing on the forehead, glabella, and/or back of the neck) or hemangiomas (cutaneous or extracutaneous)
• Characteristic facies including midface retrusion and infraorbital creases
• Structural cardiac anomalies or cardiomegaly
• Diastasis recti
• Advanced bone age (common in overgrowth/endocrine disorders)

Establishing the Diagnosis

The diagnosis of BWS is established in a proband with either of the following:

• Three major or two major plus at least one minor criteria (See Suggestive Findings.)
  Note: BWS should be considered a clinical spectrum, with some affected individuals having only one or two suggestive clinical findings. Therefore, the generally accepted clinical criteria proposed here should not be viewed as absolute but rather as guidelines. In other words, they cannot be used to rule out a diagnosis of BWS and cannot substitute for clinical judgment.
• An epigenetic or genomic alteration leading to abnormal methylation at 11p15.5 or a heterozygous BWS-causing pathogenic variant in CDKN1C in the presence of one or more clinical findings (See following and Table 1.)

BWS is associated with abnormal regulation of gene transcription in two imprinted domains 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 known etiologic mechanisms is given here to clarify the testing pipelines described in Genetic Testing. See Molecular 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 1a, differential methylation of IC1 and IC2 is associated with expression of specific genes on the paternal and maternal alleles in unaffected individuals.

Figure 1.

Map of the BWS locus on 11p15.5 a) shows a schematic representation of the normal parent of origin-specific imprinted allelic expression. Note: b) and c) show the altered region only. IC = imprinting center, Cen = centromere, Tel = telomere, P = paternal, (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, genetic testing can detect one of five alterations [Weksberg et al 2003, Weksberg et al 2005]:

• A schematic of the following four molecular alterations is shown in Figure 1:
  • Loss of methylation of IC2 on the maternal chromosome (Figure 1b)
  • Gain of methylation of IC1 on the maternal chromosome (Figure 1c)
  • Paternal uniparental disomy of 11p15.5 (Figure 1d)
  • A heterozygous pathogenic variant on the maternal CDKN1C allele (Figure 1e)
• The following genetic alteration is not represented in Figure 1:
  Genomic variants involving chromosome 11p15.5 including cytogenetically visible duplications, inversions or translocations, or copy number variants including microduplications or microdeletions of 11p15.5

Note: Methylation changes may be associated with any of the primary genomic variants above except for pathogenic variants on the maternal CDKN1C allele [Niemitz et al 2004, Sparago et al 2004, Prawitt et al 2005, Baskin et al 2014].

Figure 2 summarizes the percentage of individuals with BWS by genetic mechanism.

Figure 2.

Causes of Beckwith-Wiedemann syndrome by genetic mechanism *These molecular subgroups, defined by DNA methylation abnormalities, may also be the result of an underlying genomic alteration. Such genomic aberrations are most common for hypermethylation (more...)

Clinical Description

Beckwith-Wiedemann syndrome (BWS) is a growth disorder variably characterized by neonatal hypoglycemia, macrosomia, macroglossia, hemihyperplasia, omphalocele, embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma), visceromegaly, adrenocortical cytomegaly, renal abnormalities (e.g., medullary dysplasia, nephrocalcinosis, medullary sponge kidney, and nephromegaly), and ear creases/pits. BWS is considered a clinical spectrum, in which affected individuals may have many or only one or two of the characteristic clinical features.

Incidence figures for the specific individual clinical findings in Beckwith-Wiedemann syndrome (BWS) vary widely in published reports, in part due to ascertainment bias. 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.

Metabolic abnormalities. Neonatal hypoglycemia is well documented and occurs in approximately 50% of infants with BWS [Mussa et al 2016a]. 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].

Growth. Macroglossia (present in ~90%) and macrosomia (present in ~50%) are generally present at birth, though postnatal onset of both features has also been observed [Chitayat et al 1990, Brioude et al 2013, Ibrahim et al 2014, Mussa et al 2016b]. 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* 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.

Neoplasia. Children with BWS are at increased risk for 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% [Cohen 2005, Tan & Amor 2006, Mussa et al 2016a]. The increased risk for neoplasia appears 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.

Children who have milder phenotypes (e.g., macroglossia and umbilical hernia) may have a somatic form of BWS and may still be at increased risk (compared to the general population) of developing tumors associated with BWS. This is in part because BWS-associated molecular changes may be mosaic; that is, many cells with BWS-associated changes may reside in organs "at risk" for tumor development (e.g., 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 genetic testing to confirm the diagnosis.

Other involved organ systems

• Anterior abdominal wall defects including omphalocele, umbilical hernia, and diastasis recti are common.
• Cleft palate, seen in very few individuals with BWS, is typically associated with heterozygous, maternally inherited pathogenic variants in CDKN1C [Hatada et al 1997, Li et al 2001, Mussa et al 2016c].
• Much of the information regarding cardiovascular problems in BWS is anecdotal. Cardiomegaly is present in approximately 20% of affected individuals [Pettenati et al 1986] and may be detected in infancy if a chest x-ray is performed, but typically resolves without treatment.
  • Cardiomyopathy has been reported but is rare.
  • Long QT syndrome has been reported in a child with BWS who had a balanced translocation between chromosomes 11 and 17 which interrupted KCNQ1 [Kaltenbach et al 2013].
• 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, Mussa et al 2012].
• Hearing loss is rarely reported in individuals with BWS and is either sensorineural [Kantaputra et al 2013] or conductive due to stapedial fixation [Hopsu et al 2003].
  Note: Although parents of children with BWS occasionally raise concerns regarding hearing loss and hypotonia, it is difficult to ascertain whether these and other issues occur with a greater frequency in individuals with BWS compared to the general population rate.
• Brain abnormalities involving the posterior fossa have been rarely reported [Gardiner et al 2012, Brioude et al 2015].

Development is usually normal in children with BWS unless there is a chromosome abnormality, brain malformation, or 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 – including renal medullary dysplasia and subfertility in males – can occur. Such issues may be associated with specific molecular subtypes [Greer et al 2008].

Phenotype Correlations by Molecular Mechanism

While general phenotypic correlations by molecular mechanism are provided below, specific clinical outcomes in any individual with BWS cannot be precisely predicted based on the molecular alteration. The remaining variability in individuals with BWS may be due to somatic mosaicism, genetic background, and/or other unidentified factors.

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.
• Intragenic variants on the maternally derived CDKN1C allele are associated with:
  • A small number of cases of neuroblastoma [Bliek et al 2001, Weksberg et al 2001, DeBaun et all 2002, Rump et al 2005, Alsultan et al 2008, Kuroiwa et al 2009];
  • Single cases of ganglioneuroblastoma, acute lymphocytic leukemia, and neuroblastoma in children and melanoma in an adult [Brioude et al 2015].
    Note: Given that leukemia and melanoma occur with some frequency in individuals who do not have BWS, it is difficult to determine whether these single cases represent a coincidental occurrence of two unrelated conditions or if the malignancy was indeed related to BWS.

Hemihyperplasia is most commonly associated with mosaicism for paternal UPD of 11p15 but is also seen in individuals with molecular alterations at IC2 or IC1 [DeBaun et al 2002, Shuman et al 2002, Enklaar et al 2006, Ibrahim et al 2014, Mussa et al 2016b].

Positive family history is associated with heterozygous pathogenic variants in CDKN1C, deletions at IC1, or (rarely) duplication at IC2 [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 heterozygous pathogenic variants of the maternally derived CDKN1C allele [Hatada et al 1997, Li et al 2001].

Omphalocele is primarily associated with alterations at IC2 or a heterozygous pathogenic variant on the maternally derived CDKN1C allele [Ibrahim et al 2014, Brioude et al 2015, Mussa et al 2016a, Mussa et al 2016c].

Macroglossia and macrosomia are prominent features across all molecular subtypes [Ibrahim et al 2014, Mussa et al 2016b].

Brain abnormalities involving the posterior fossa are associated with molecular alterations of IC2 or a heterozygous pathogenic variant on the maternally inherited CDKN1C allele [Gardiner et al 2012, Brioude et al 2015].

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].

Penetrance

Penetrance in familial cases is high if the parent-of-origin effect of imprinted domains is considered. For example, a person may inherit a CDKN1C pathogenic variant but have no features of BWS because the CDKN1C pathogenic variant was on the paternally derived allele, which is normally not expressed (i.e., the pathogenic variant is silenced by the normal imprinting process).

Nomenclature

BWS was originally called EMG, based on the three clinical findings of exomphalos, macroglossia, and gigantism.

Prevalence

The reported prevalence of 1:10,000 [Mussa et al 2013] to 1:13,700 [Thorburn et al 1970] likely represents an underestimate given the existence of undiagnosed individuals with milder phenotypes.

BWS has been reported in a wide variety of ethnic populations with an equal incidence in males and females.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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
• Comprehensive cardiac evaluation including EKG and echocardiogram prior to surgical procedures or when a cardiac abnormality is suspected on clinical evaluation
• Alpha-fetoprotein assay at the time of initial diagnosis to evaluate for hepatoblastoma. It is important to utilize normal ranges for specific age categories to guide result interpretation, especially in very young infants.
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

The 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 for omphalocele soon after birth. 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 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. 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
• Management of cleft palate following standard protocols
• Referral to a craniofacial surgeon if facial hemihyperplasia is significant
• 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.
• 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 is indicated if urinary calcium is elevated and/or a structural renal anomaly is identified
• Referral of children with structural GI tract abnormalities to the relevant specialist
• Management of cardiac problems following standard protocols
• Standard interventions such as infant stimulation programs, occupational and physical therapy, and individualized education programs for children with developmental delay

Prevention of Secondary Complications

Prompt evaluation and standard treatment for suspected urinary tract infections is appropriate to prevent secondary renal damage.

Surveillance

The following are appropriate:

• Monitoring for hypoglycemia, especially in the neonatal period
• Screening for embryonal tumors, which has traditionally involved the following (see also Note):
  • 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: (1) Some have proposed revising the tumor surveillance guidelines based on the molecular alteration detected. Scott et al [2006] suggested that children with BWS and IC2 alterations did not require Wilms tumor screening. Brioude et al [2013] proposed that children with BWS and loss of methylation at IC2 should have an ultrasound evaluation at the time of clinical diagnosis and only continue with ultrasound surveillance if visceromegaly or "severe" hemihyperplasia are present; otherwise, clinical examination alone was recommended. Mussa et al [2016b] questioned the rationale for ultrasound surveillance and "tumor markers" for individuals with loss of methylation at IC2 but subsequently, in their guidelines from the Italian Scientific Committee on BWS, suggested that in the near future, tumor screening in clinical practice will cease. Based on personal experience, the present authors continue to recommend tumor surveillance for all children with BWS regardless of the molecular etiology. (2) 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.
• Annual renal ultrasound examination between age eight years and mid-adolescence to identify those requiring further evaluation for findings such as nephrocalcinosis and medullary sponge kidney disease. 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. Therefore, consideration should be given to periodic renal evaluation in adulthood.
• Consideration of annual or biannual measurement of urinary calcium/creatinine ratio 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]
• Developmental screening as part of routine childcare

Evaluation of Relatives at Risk

It is appropriate to evaluate the newborn sib of an individual with BWS in order to identify as early as possible those who would benefit from initiation of preventive measures.

Evaluations can include:

• Genetic testing if a maternal CDKN1C pathogenic variant or familial duplication, deletion, or cytogenetically visible alteration of 11p15 is known;
• Monitoring of an at-risk newborn sib for hypoglycemia, even in the absence of obvious clinical findings on prenatal investigation;
• Strong consideration of tumor surveillance 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 Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Mode of Inheritance

Beckwith-Wiedemann syndrome (BWS) is associated with abnormal expression of imprinted genes in the BWS critical region caused by one of several genetic mechanisms.

Risk to Family Members of a Proband with Normal Chromosomes

Parents of a proband

• Most individuals with BWS do not have an affected parent.
• Recommendations for the evaluation of parents of a child with BWS and no known family history of BWS include a medical and family history focused on BWS-associated medical problems in early childhood. Infant and childhood photographs may be useful. Physical examination may be of limited value in adulthood, but ear pits/creases may still be present. Such creases are also not uncommon in the general population.
• Methylation alterations that are not associated with underlying microdeletions or microduplications are not typically heritable and therefore testing of parents is likely to yield normal methylation findings.

Sibs of a proband

• The risk to the sibs of a child with BWS depends on the genetic basis for BWS in the proband (Table 3). The majority of families have a recurrence risk of less than 1%; however, certain etiologies involve a recurrence risk as high as 50%.
• For recurrence risk assessment. The underlying genetic mechanism should be determined for genetic counseling purposes (see Diagnosis).

Offspring of a proband

Other family members of a proband. The risk to other family members depends on the molecular etiology.

Risk to Family Members of a Proband with a Chromosome Abnormality

Parents of a proband. Parents of a proband with a structural balanced or unbalanced chromosome constitution are at risk of having a balanced chromosome rearrangement and should be offered chromosome analysis.

Sibs of a proband with a chromosome abnormality

• The risk to sibs depends on the cytogenetic findings in the parents.
• For mothers carrying a balanced 11p15 translocation, the recurrence risk may be as high as 50% and the BWS phenotype appears to segregate with maternal transmission of this translocation.
• For fathers carrying a balanced translocation involving chromosome 11p15 who have an offspring with an 11p duplication, recurrence risk is increased but an exact figure is not available.

Offspring of a proband with a chromosome abnormality. The risk may be as high as 50% if the proband is a female. For a male proband, the risk is expected to be low.

Other family members of a proband. Whenever a chromosome abnormality is identified, other at-risk family members should be offered chromosome testing to clarify their status.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and genetic counseling regarding prenatal testing is before pregnancy. Decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or who carry genomic alterations that increase their risk (e.g., a normal female who has inherited a balanced 11p15 translocation from her father).

Possible imprinting risks associated with assisted reproductive technology (ART). Data have suggested the possibility of a link between subfertility/ART and imprinting disorders [DeBaun et al 2002, Maher et al 2003a, Maher et al 2003b]. More recently DeBaun et al [2003], Gicquel et al [2003], Maher et al [2003a], and Halliday et al [2004] reported data suggesting that ART may favor imprinting alterations at the centromeric imprinted 11p15 locus IC2 and, thus, may increase the incidence of BWS in the offspring of couples who are subfertile and/or women undergoing ART procedures. It is unknown what role the underlying issues of subfertility as opposed to the ART procedures play in causing these imprinting defects.

The preimplantation phase of embryonic development is a critical time for imprint maintenance. Although no specific procedures of ART have been shown to increase the risk of Beckwith-Wiedemann syndrome, many procedures involved in ART may influence imprinting including the ovarian follicle stimulation protocol, the biologic technique, the stage of maturation of the gametes, the culture media, and the timing of embryo transfer.

Reports of Angelman syndrome associated with ART suggest that epigenetic errors in early development are not confined to Beckwith-Wiedemann syndrome.

These data, although retrospective, highlight the need for follow up of children born after ART and for larger prospective studies to clarify whether a significant increase in the risk of imprinting errors is associated with ART and if so, whether this finding is associated with ART procedures alone or with the underlying subfertility of the parents [DeBaun et al 2003, Gicquel et al 2003, Gosden et al 2003, Maher et al 2003a, Weksberg et al 2003, Schieve et al 2004, Weksberg et al 2005].

Monozygotic twinning. Monozygotic twins discordant for BWS (usually females) have been shown to also be discordant for loss of methylation at IC2 in skin fibroblasts but variably concordant in blood cells, probably as a result of shared fetal circulation [Weksberg et al 2002]. Male monozygotic twins are much less frequently observed and demonstrate additional molecular findings including UPD for 11p15 and gain of methylation at IC1. As no recurrences are reported in the sibs of these twins, the recurrence risk is not known.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing

Positive family history. A number of options exist for families who have had one child with BWS and are interested in prenatal diagnosis. Some families may wish to consider prenatal testing for management of the pregnancy and delivery; others may consider pregnancy termination.

If a cytogenetic or molecular genetic abnormality has been identified in the proband, appropriate testing of the pregnancy at risk is possible.

Genomic alterations including duplications/deletions involving 11p15 or pathogenic CDKN1C variants can be detected via analysis of fetal DNA from samples obtained by CVS or amniocentesis. However, DNA extracted from amniotic fluid is currently felt to provide the most reliable tissue source for evaluating fetal methylation status, although false negative findings have been reported [Eggermann et al 2015]. Cultured amniocytes may demonstrate clonal findings that are not representative of the fetal status, similar to postnatal testing issues related to somatic mosaicism. Similarly, tissue obtained via CVS for prenatal testing for methylation status may not yield reliable results; a false positive test has been reported [Eggermann et al 2015]. This latter issue reflects the timing of methylation establishment in early placental development. Genetic counseling regarding the potential limitations of prenatal testing for epigenetic alterations should be undertaken [Eggermann et al 2015].

For all pregnancies at increased risk for BWS, whether or not the genetic mechanism is known:

• Maternal serum alpha-fetoprotein (AFP) concentration may be elevated at 16 weeks' gestation in the presence of omphalocele.
• Ultrasound examination can be performed at 19-20 weeks' gestation and again at 25-32 weeks' gestation to assess growth parameters that may become advanced for gestational age late in the second trimester and to detect abdominal wall defects, organomegaly, renal anomalies, cleft palate, cardiac abnormalities, and macroglossia. In one report, ultrasound examination performed between ten and 14 weeks' gestation revealed increased nuchal thickness and omphalocele in a fetus later found to have BWS [Souka et al 1998].

Note: (1) If ultrasound examination does not show malformations or abnormalities of fetal growth, a residual risk for recurrence of BWS remains, given the variability in clinical presentation. (2) Even in the absence of obvious clinical findings on prenatal investigation, the newborn should be monitored for hypoglycemia.

Negative family history. In pregnancies in which there is no family history of BWS, but an abnormality such as apparently isolated omphalocele is detected on ultrasound examination, additional investigations that should be considered [Porter et al 2009, Wilkins-Haug et al 2009] include the following:

• Molecular genetic testing for methylation alterations in amniocytes; if no methylation alteration is identified, testing for a CDKN1C pathogenic variant
• Chromosomal microarray for copy number variants involving chromosome 11p15 and/or cytogenetic testing to evaluate for duplications, inversions, or translocations involving 11p15
• Serial ultrasound examinations to assess fetal growth and to detect other abnormalities characteristic of BWS

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. Molecular genetic testing can be offered if there is a high index of suspicion for BWS.

Molecular 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. 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 1a).

Domain 1 is telomeric and contains the imprinted genes H19 and IGF2. H19 is a noncoding, nontranslated 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 differentially 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 noncoding 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 center 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 center that regulates several genes including KCNQ1OT1, KCNQ1, and CDKN1C. It may also be referred to as ICR2, DMR2, or 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. Most UPD cases demonstrate segmental mosaicism for paternal UPD for 11p15, suggesting that the underlying mechanism is a postzygotic 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.
• 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 pathogenic variant in the paternally derived igf2 allele are small at birth whereas the same pathogenic variant 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 noncoding 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 individuals 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 of 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. Pathogenic variants in this gene have been reported in approximately 5% of affected individuals. CDKN1C pathogenic variants 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 pathogenic variants 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].

Acknowledgments

Sanaa Choufani, Adam Smith, Khadine Wiltshire

Author History

J Bruce Beckwith, MD (2000-present)
Cheryl Shuman, MS, CGC (2000-present)
Adam C Smith, PhD; The Hospital for Sick Children (2000-2016)
Rosanna Weksberg, MD, PhD, FRCPC, FCCMG, FACMG (2000-present)

Revision History

• 11 August 2016 (ma) Comprehensive update posted live
• 14 December 2010 (me) Comprehensive update posted live
• 8 September 2005 (me) Comprehensive update posted live
• 10 April 2003 (tk) Comprehensive update posted live
• 3 March 2000 (me) Review posted live
• 28 July 1999 (cs) Original submission

Published Guidelines / Consensus Statements

• Shaffer LG, Agan N, Goldberg JD, Ledbetter DH, Longshore JW, Cassidy SB. American College of Medical Genetics statement of diagnostic testing for uniparental disomy. Available online. 2001. Accessed 4-20-22.

Literature Cited

• Algar E, Brickell S, Deeble G, Amor D, Smith P. Analysis of CDKN1C in Beckwith Wiedemann syndrome. Hum Mutat. 2000;15:497–508. [PubMed: 10862080]
• Alsultan A, Lovell MA, Hayes KL, Allshouse MJ, Garrington TP. Simultaneous occurrence of right adrenocortical tumor and left adrenal neuroblastoma in an infant with Beckwith-Wiedemann syndrome. Pediatr Blood Cancer. 2008;51:695–8. [PubMed: 18668518]
• Arboleda VA, Lee H, Parnaik R, Fleming A, Banerjee A, Ferraz-de-Souza B, Délot EC, Rodriguez-Fernandez IA, Braslavsky D, Bergadá I, Dell'Angelica EC, Nelson SF, Martinez-Agosto JA, Achermann JC, Vilain E. Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nat Genet. 2012;44:788–92. [PMC free article: PMC3386373] [PubMed: 22634751]
• Barlow DP. Imprinting: a gamete's point of view. Trends Genet. 1994;10:194–9. [PubMed: 7864936]
• Baskin B, Choufani S, Chen YA, Shuman C, Parkinson N, Lemyre E, Micheil Innes A, Stavropoulos DJ, Ray PN, Weksberg R. High frequency of copy number variations (CNVs) in the chromosome 11p15 region in patients with Beckwith-Wiedemann syndrome. Hum Genet. 2014;133:321–30. [PubMed: 24154661]
• Baujat G, Rio M, Rossignol S, Sanlaville D, Lyonnet S, Le Merrer M, Munnich A, Gicquel C, Cormier-Daire V, Colleaux L. Paradoxical NSD1 mutations in Beckwith-Wiedemann syndrome and 11p15 anomalies in Sotos syndrome. Am J Hum Genet. 2004;74:715–20. [PMC free article: PMC1181947] [PubMed: 14997421]
• Beckwith JB. Nephrogenic rests and the pathogenesis of Wilms tumor: developmental and clinical considerations. Am J Med Genet. 1998;79:268–73. [PubMed: 9781906]
• Bliek J, Maas SM, Ruijter JM, Hennekam RC, Alders M, Westerveld A, Mannens MM. Increased tumour risk for BWS patients correlates with aberrant H19 and not KCNQ1OT1 methylation: occurrence of KCNQ1OT1 hypomethylation in familial cases of BWS. Hum Mol Genet. 2001;10:467–76. [PubMed: 11181570]
• Bliek J, Verde G, Callaway J, Maas SM, De Crescenzo A, Sparago A, Cerrato F, Russo S, Ferraiuolo S, Rinaldi MM, Fischetto R, Lalatta F, Giordano L, Ferrari P, Cubellis MV, Larizza L, Temple IK, Mannens MM, Mackay DJ, Riccio A. Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2009;17:611–9. [PMC free article: PMC2986258] [PubMed: 19092779]
• Borer JG, Kaefer M, Barnewolt CE, Elias ER, Hobbs N, Retik AB, Peters CA. Renal findings on radiological followup of patients with Beckwith-Wiedemann syndrome. J Urol. 1999;161:235–9. [PubMed: 10037413]
• Brioude F, Netchine I, Praz F, Le Jule M, Calmel C, Lacombe D, Edery P, Catala M, Odent S, Isidor B, Lyonnet S, Sigaudy S, Leheup B, Audebert-Bellanger S, Burglen L, Giuliano F, Alessandri JL, Cormier-Daire V, Laffargue F, Blesson S, Coupier I, Lespinasse J, Blanchet P, Boute O, Baumann C, Polak M, Doray B, Verloes A, Viot G, Le Bouc Y, Rossignol S. Mutations of the Imprinted CDKN1C Gene as a Cause of the Overgrowth Beckwith-Wiedemann Syndrome: Clinical Spectrum and Functional Characterization. Hum Mutat. 2015;36:894–902. [PubMed: 26077438]
• Brioude F, Oliver-Petit I, Blaise A, Praz F, Rossignol S, Le Jule M, Thibaud N, Faussat AM, Tauber M, Le Bouc Y, Netchine I. CDKN1C mutation affecting the PCNA-binding domain as a cause of familial Russell Silver syndrome. J Med Genet. 2013;50:823–30. [PubMed: 24065356]
• Caspary T, Cleary MA, Perlman EJ, Zhang P, Elledge SJ, Tilghman SM. Oppositely imprinted genes p57(Kip2) and igf2 interact in a mouse model for Beckwith-Wiedemann syndrome. Genes Dev. 1999;13:3115–24. [PMC free article: PMC317182] [PubMed: 10601037]
• Chitayat D, Rothchild A, Ling E, Friedman JM, Couch RM, Yong SL, Baldwin VJ, Hall JG. Apparent postnatal onset of some manifestations of the Wiedemann-Beckwith syndrome. Am J Med Genet. 1990;36:434–9. [PubMed: 2389800]
• Choufani S, Shuman C, Weksberg R. Beckwith-Wiedemann syndrome. Am J Med Genet C Semin Med Genet. 2010;154C:343–54. [PubMed: 20803657]
• Choyke PL, Siegel MJ, Oz O, Sotelo-Avila C, DeBaun MR. Nonmalignant renal disease in pediatric patients with Beckwith-Wiedemann syndrome. AJR Am J Roentgenol. 1998;171:733–7. [PubMed: 9725306]
• Clericuzio CL, Chen E, McNeil DE, O'Connor T, Zackai EH, Medne L, Tomlinson G, DeBaun M. Serum alpha-fetoprotein screening for hepatoblastoma in children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia. J Pediatr. 2003;143:270–2. [PubMed: 12970646]
• Clericuzio CL, Martin RA. Diagnostic criteria and tumor screening for individuals with isolated hemiphyperplasia. Genet Med. 2009;11:220–2. [PMC free article: PMC3111026] [PubMed: 19367194]
• Cohen MM Jr. Beckwith-Wiedemann syndrome: historical, clinicopathological, and etiopathogenetic perspectives. Pediatr Dev Pathol. 2005;8:287–304. [PubMed: 16010495]
• Cooper WN, Luharia A, Evans GA, Raza H, Haire AC, Grundy R, Bowdin SC, Riccio A, Sebastio G, Bliek J, Schofield PN, Reik W, Macdonald F, Maher ER. Molecular subtypes and phenotypic expression of Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2005;13:1025–32. [PubMed: 15999116]
• Dao D, Frank D, Qian N, O'Keefe D, Vosatka RJ, Walsh CP, Tycko B. IMPT1, an imprinted gene similar to polyspecific transporter and multi-drug resistance genes. Hum Mol Genet. 1998;7:597–608. [PubMed: 9499412]
• DeBaun MR, Niemitz EL, Feinberg AP. Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet. 2003;72:156–60. [PMC free article: PMC378620] [PubMed: 12439823]
• DeBaun MR, Niemitz EL, McNeil DE, Brandenburg SA, Lee MP, Feinberg AP. Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann syndrome with cancer and birth defects. Am J Hum Genet. 2002;70:604–11. [PMC free article: PMC384940] [PubMed: 11813134]
• Diaz-Meyer N, Day CD, Khatod K, Maher ER, Cooper W, Reik W, Junien C, Graham G, Algar E, Der Kaloustian VM, Higgins MJ. Silencing of CDKN1C (p57KIP2) is associated with hypomethylation at KvDMR1 in Beckwith-Wiedemann syndrome. J Med Genet. 2003;40:797–801. [PMC free article: PMC1735305] [PubMed: 14627666]
• Dória S, Sousa M, Fernandes S, Ramalho C, Brandão O, Matias A, Barros A, Carvalho F. Gene expression pattern of IGF2, PHLDA2, PEG10 and CDKN1C imprinted genes in spontaneous miscarriages or fetal deaths. Epigenetics. 2010;5:444–50. [PubMed: 20484977]
• Eggermann T. Silver-Russell and Beckwith-Wiedemann syndromes: opposite (epi)mutations in 11p15 result in opposite clinical pictures. Horm Res. 2009;71 Suppl 2:30–5. [PubMed: 19407494]
• Eggermann T, Soellner L, Buiting K, Kotzot D. Mosaicism and uniparental disomy in prenatal diagnosis. Trends Mol Med. 2015;21:77–87. [PubMed: 25547535]
• Enklaar T, Zabel BU, Prawitt D. Beckwith–Wiedemann syndrome: multiple molecular mechanisms. Expert Rev Mol Med. 2006;8:1–19. [PubMed: 16842655]
• Everman DB, Shuman C, Dzolganovski B, O'riordan MA, Weksberg R, Robin NH. Serum alpha-fetoprotein levels in Beckwith-Wiedemann syndrome. J Pediatr. 2000;137:123–7. [PubMed: 10891834]
• Gardiner K, Chitayat D, Choufani S, Shuman C, Blaser S, Terespolsky D, Farrell S, Reiss R, Wodak S, Pu S, Ray PN, Baskin B, Weksberg R. Brain abnormalities in patients with Beckwith-Wiedemann syndrome. Am J Med Genet A. 2012;158A:1388–94. [PubMed: 22585446]
• Gicquel C, Gaston V, Mandelbaum J, Siffroi JP, Flahault A, Le Bouc Y. In vitro fertilization may increase the risk of Beckwith-Wiedemann syndrome related to the abnormal imprinting of the KCN1OT gene. Am J Hum Genet. 2003;72:1338–41. [PMC free article: PMC1180288] [PubMed: 12772698]
• Goldman M, Shuman C, Weksberg R, Rosenblum ND. Hypercalciuria in Beckwith-Wiedemann syndrome. J Pediatr. 2003;142:206–8. [PubMed: 12584548]
• Gosden R, Trasler J, Lucifero D, Faddy M. Rare congenital disorders, imprinted genes, and assisted reproductive technology. Lancet. 2003;361:1975–7. [PubMed: 12801753]
• Greer KJ, Kirkpatrick SJ, Weksberg R, Pauli RM. Beckwith-Wiedemann syndrome in adults: observations from one family and recommendations for care. Am J Med Genet A. 2008;146A:1707–12. [PubMed: 18546283]
• Halliday J, Oke K, Breheny S, Algar E, J, Amor D. Beckwith–Wiedemann syndrome and IVF: a case – control study. Am J Hum Genet. 2004;75:526–8. [PMC free article: PMC1182036] [PubMed: 15284956]
• Hark AT, Schoenherr CJ, Katz DJ, Ingram RS, Levorse JM, Tilghman SM. CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature. 2000;405:486–9. [PubMed: 10839547]
• Hatada I, Nabetani A, Morisaki H, Xin Z, Ohishi S, Tonoki H, Niikawa N, Inoue M, Komoto Y, Okada A, Steichen E, Ohashi H, Fukushima Y, Nakayama M, Mukai T. New p57KIP2 mutations in Beckwith-Wiedemann syndrome. Hum Genet. 1997;100:681–3. [PubMed: 9341892]
• Hopsu E, Aarnisalo A, Pitkaranta A. Progressive stapedial fixation in Beckwith-Wiedemann syndrome. Arch Otolaryngol Head Neck Surg. 2003;129:1131–4. [PubMed: 14568801]
• Hoyme HE, Seaver LH, Jones KL, Procopio F, Crooks W, Feingold M. Isolated hemihyperplasia (hemihypertrophy): report of a prospective multicenter study of the incidence of neoplasia and review. Am J Med Genet. 1998;79:274–8. [PubMed: 9781907]
• Ibrahim A, Kirby G, Hardy C, Dias RP, Tee L, Lim D, Berg J, MacDonald F, Nightingale P, Maher ER. Methylation analysis and diagnostics of Beckwith-Wiedemann syndrome in 1,000 subjects. Clin Epigenetics. 2014;6:11. [PMC free article: PMC4064264] [PubMed: 24982696]
• Inbar-Feigenberg M, Choufani S, Cytrynbaum C, Chen YA, Steele L, Shuman C, Ray PN, Weksberg R. Mosaicism for genome-wide paternal uniparental disomy with features of multiple imprinting disorders: diagnostic and management issues. Am J Med Genet A. 2013;161A:13–20. [PubMed: 23239666]
• Joyce JA, Lam WK, Catchpoole DJ, Jenks P, Reik W, Maher ER, Schofield PN. Imprinting of IGF2 and H19: lack of reciprocity in sporadic Beckwith- Wiedemann syndrome. Hum Mol Genet. 1997;6:1543–8. [PubMed: 9285792]
• Kalish JM, Conlin LK, Bhatti TR, Dubbs HA, Harris MC, Izumi K, Mostoufi-Moab S, Mulchandani S, Saitta S, States LJ, Swarr DT, Wilkens AB, Zackai EH, Zelley K, Bartolomei MS, Nichols KE, Palladino AA, Spinner NB, Deardorff MA. Clinical features of three girls with mosaic genome-wide paternal uniparental isodisomy. Am J Med Genet A. 2013;161A:1929–39. [PMC free article: PMC4082120] [PubMed: 23804593]
• Kaltenbach S, Capri Y, Rossignol S, Denjoy I, Soudée S, Aboura A, Baumann C, Verloes A. Beckwith-Wiedemann syndrome and long QT syndrome due to familial-balanced translocation t(11;17)(p15.5;q21.3) involving the KCNQ1 gene. Clin Genet. 2013;84:78–81. [PubMed: 23061425]
• Kantaputra PN, Sittiwangkul R, Sonsuwan N, Romanelli V, Tenorio J, Lapunzina P. A novel mutation in CDKN1C in sibs with Beckwith-Wiedemann syndrome and cleft palate, sensorineural hearing loss, and supernumerary flexion creases. Am J Med Genet A. 2013;161A:192–7. [PubMed: 23197429]
• Keren B, Chantot-Bastaraud S, Brioude F, Mach C, Fonteneau E, Azzi S, Depienne C, Brice A, Netchine I, Le Bouc Y, Siffroi JP, Rossignol S. SNP arrays in Beckwith-Wiedemann syndrome: an improved diagnostic strategy. Eur J Med Genet. 2013;56:546–50. [PubMed: 23892181]
• Kimura Y, Yasuhiro K, Kimura S. Anesthetic management of two cases of Beckwith-Wiedemann syndrome. J Anesth. 2008;22:93–95. [PubMed: 18306025]
• Kuroiwa M, Sakamoto J, Shimada A, Suzuki N, Hirato J, Park MJ, Sotomatsu M, Hayashi Y. Manifestation of alveolar rhabdomyosarcoma as primary cutaneous lesions in a neonate with Beckwith-Wiedemann syndrome. J Pediatr Surg. 2009;44:e31–5. [PubMed: 19302842]
• Lam WW, Hatada I, Ohishi S, Mukai T, Joyce JA, Cole TR, Donnai D, Reik W, Schofield PN, Maher ER. Analysis of germline CDKN1C (p57KIP2) mutations in familial and sporadic Beckwith-Wiedemann syndrome (BWS) provides a novel genotype- phenotype correlation. J Med Genet. 1999;36:518–23. [PMC free article: PMC1734395] [PubMed: 10424811]
• Lee MP, DeBaun M, Randhawa G, Reichard BA, Elledge SJ, Feinberg AP. Low frequency of p57KIP2 mutation in Beckwith-Wiedemann syndrome. Am J Hum Genet. 1997;61:304–9. [PMC free article: PMC1715913] [PubMed: 9311734]
• Lew JM, Fei YL, Aleck K, Blencowe BJ, Weksberg R, Sadowski PD. CDKN1C mutation in Wiedemann-Beckwith syndrome patients reduces RNA splicing efficiency and identifies a splicing enhancer. Am J Med Genet A. 2004;127A:268–76. [PubMed: 15150778]
• Li M, Squire J, Shuman C, Fei YL, Atkin J, Pauli R, Smith A, Nishikawa J, Chitayat D, Weksberg R. Imprinting status of 11p15 genes in Beckwith-Wiedemann syndrome patients with CDKN1C mutations. Genomics. 2001;74:370–6. [PubMed: 11414765]
• Li M, Squire JA, Weksberg R. Molecular genetics of Wiedemann-Beckwith syndrome. Am J Med Genet. 1998;79:253–9. [PubMed: 9781904]
• Maher ER, Afnan M, Barratt CL. Epigenetic risks related to assisted reproductive technologies: epigenetics, imprinting, ART and icebergs? Hum Reprod. 2003a;18:2508–11. [PubMed: 14645164]
• Maher ER, Brueton LA, Bowdin SC, Luharia A, Cooper W, Cole TR, Macdonald F, Sampson JR, Barratt CL, Reik W, Hawkins MM. Beckwith-Wiedemann syndrome and assisted reproduction technology (ART). J Med Genet. 2003b;40:62–4. [PMC free article: PMC1735252] [PubMed: 12525545]
• Martin RA, Grange DK, Zehnbauer B, Debaun MR. LIT1 and H19 methylation defects in isolated hemihyperplasia. Am J Med Genet A. 2005;134A:129–31. [PubMed: 15651076]
• Milani D, Pezzani L, Tabano S, Miozzo M. Beckwith-Wiedemann and IMAGe syndromes: two very different diseases caused by mutations on the same gene. Appl Clin Genet. 2014;7:169–75. [PMC free article: PMC4173641] [PubMed: 25258553]
• Mussa A, Di Candia S, Russo S, Catania S, De Pellegrin M, Di Luzio L, Ferrari M, Tortora C, Meazzini MC, Brusati R, Milani D, Zampino G, Montirosso R, Riccio A, Selicorni A, Cocchi G, Ferrero GB. 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. 2016a;59:52–64. [PubMed: 26592461]
• Mussa A, Peruzzi L, Chiesa N, De Crescenzo A, Russo S, Melis D, Tarani L, Baldassarre G, Larizza L, Riccio A, Silengo M, Ferrero GB. Nephrological findings and genotype-phenotype correlation in Beckwith-Wiedemann syndrome. Pediatr Nephrol. 2012;27:397–406. [PubMed: 22015620]
• Mussa A, Russo S, De Crescenzo A, Chiesa N, Molinatto C, Selicorni A, Richiardi L, Larizza L, Silengo MC, Riccio A, Ferrero GB. Prevalence of Beckwith-Wiedemann syndrome in North West of Italy. Am J Med Genet A. 2013;161A:2481–6. [PubMed: 23918458]
• Mussa A, Russo S, De Crescenzo A, Freschi A, Calzari L, Maitz S, Macchiaiolo M, Molinatto C, Baldassarre G, Mariani M, Tarani L, Bedeschi MF, Milani D, Melis D, Bartuli A, Cubellis MV, Selicorni A, Cirillo Silengo M, Larizza L, Riccio A, Ferrero GB. (Epi)genotype-phenotype correlations in Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2016b;24:183–90. [PMC free article: PMC4717210] [PubMed: 25898929]
• Mussa A, Russo S, Larizza L, Riccio A, Ferrero GB. (Epi)genotype-phenotype correlations in Beckwith-Wiedemann syndrome: a paradigm for genomic medicine. Clin Genet. 2016c;89:403–15. [PubMed: 26138266]
• Nicholls RD. New insights reveal complex mechanisms involved in genomic imprinting. Am J Hum Genet. 1994;54:733–40. [editorial; comment] [PMC free article: PMC1918270] [PubMed: 8178814]
• Niemitz EL, DeBaun MR, Fallon J, Murakami K, Kugoh H, Oshimura M, Feinberg AP. Microdeletion of LIT1 in familial Beckwith-Wiedemann syndrome. Am J Hum Genet. 2004;75:844–9. [PMC free article: PMC1182113] [PubMed: 15372379]
• O'Keefe D, Dao D, Zhao L, Sanderson R, Warburton D, Weiss L, Anyane-Yeboa K, Tycko B. Coding mutations in p57KIP2 are present in some cases of Beckwith-Wiedemann syndrome but are rare or absent in Wilms tumors. Am J Hum Genet. 1997;61:295–303. [PMC free article: PMC1715902] [PubMed: 9311733]
• Pandey RR, Mondal T, Mohammad F, Enroth S, Redrup L, Komorowski J, Nagano T, Mancini-Dinardo D, Kanduri C. Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. Mol Cell. 2008;32:232–46. [PubMed: 18951091]
• Percesepe A, Bertucci E, Ferrari P, Lugli L, Ferrari F, Mazza V, Forabosco A. Familial Beckwith-Wiedemann syndrome due to CDKN1C mutation manifesting with recurring omphalocele. Prenat Diagn. 2008;28:447–9. [PubMed: 18395877]
• Pettenati MJ, Haines JL, Higgins RR, Wappner RS, Palmer CG, Weaver DD. Wiedemann-Beckwith syndrome: presentation of clinical and cytogenetic data on 22 new cases and review of the literature. Hum Genet. 1986;74:143–54. [PubMed: 3770742]
• Porter A, Benson CB, Hawley P, Wilkins-Haug L. Outcome of fetuses with a prenatal ultrasound diagnosis of isolated omphalocele. Prenat Diagn. 2009;29:668–73. [PubMed: 19367563]
• Prawitt D, Enklaar T, Gartner-Rupprecht B, Spangenberg C, Oswald M, Lausch E, Schmidtke P, Reutzel D, Fees S, Lucito R, Korzon M, Brozek I, Limon J, Housman DE, Pelletier J, Zabel B. Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms' tumor. Proc Natl Acad Sci U S A. 2005;102:4085–90. [PMC free article: PMC554791] [PubMed: 15743916]
• Qian N, Frank D, O'Keefe D, Dao D, Zhao L, Yuan L, Wang Q, Keating M, Walsh C, Tycko B. The IPL gene on chromosome 11p15.5 is imprinted in humans and mice and is similar to TDAG51, implicated in Fas expression and apoptosis. Hum Mol Genet. 1997;6:2021–9. [PubMed: 9328465]
• Rump P, Zeegers MP, van Essen AJ. Tumor risk in Beckwith–Wiedemann syndrome: a review and meta-analysis. Am J Med Genet. 2005;136:95–104. [PubMed: 15887271]
• Russo S, Calzari L, Mussa A, Mainini E, Cassina M, Di Candia S, Clementi M, Guzzetti S, Tabano S, Miozzo M, Sirchia S, Finelli P, Prontera P, Maitz S, Sorge G, Calcagno A, Maghnie M, Divizia MT, Melis D, Manfredini E, Ferrero GB, Pecile V, Larizza L. 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. [PMC free article: PMC4772365] [PubMed: 26933465]
• Sasaki K, Soejima H, Higashimoto K, Yatsuki H, Ohashi H, Yakabe S, Joh K, Niikawa N, Mukai T. Japanese and North American/European patients with Beckwith-Wiedemann syndrome have different frequencies of some epigenetic and genetic alterations. Eur J Hum Genet. 2007;15:1205–10. [PubMed: 17700627]
• Schieve LA, Rasmussen SA, Buck GM, Schendel DE, Reynolds MA, Wright VC. Are children born after assisted reproductive technology at increased risk for adverse health outcomes? Obstet Gynecol. 2004;103:1154–63. [PubMed: 15172847]
• Scott RH, Douglas J, Baskcomb L, Nygren AO, Birch JM, Cole TR, Cormier-Daire V, Eastwood DM, Garcia-Minaur S, Lupunzina P, Tatton-Brown K, Bliek J, Maher ER, Rahman N. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) robustly detects and distinguishes 11p15 abnormalities associated with overgrowth and growth retardation. J Med Genet. 2008b;45:106–13. [PubMed: 18245390]
• Scott RH, Walker L, Olsen ØE, Levitt G, Kenney I, Maher E, Owens CM, Pritchard-Jones K, Craft A, Rahman N. Surveillance for Wilms tumour in at-risk children: pragmatic recommendations for best practice. Arch Dis Child. 2006;91:995–9. [PMC free article: PMC2083016] [PubMed: 16857697]
• Scott RH, Douglas J, Baskcomb L, Huxter N, Barker K, Hanks S, Craft A, Gerrard M, Kohler JA, Levitt GA, Picton S, Pizer B, Ronghe MD, Williams D, Cook JA, Pujol P, Maher ER, Birch JM, Stiller CA, Pritchard-Jones K, Rahman N, et al. Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor. Nat Genet. 2008a;40:1329–34. [PubMed: 18836444]
• Shuman C, Steele L, Fei YL, Ray PN, Zackai E, Parisi M, Squire J, Weksberg R. Paternal uniparental disomy of 11p15 is associated with isolated hemihyperplasia and expands Beckwith-Wiedemann syndrome spectrum. Am J Hum Genet 2002;71:A1800, 477.
• Slavotinek A, Gaunt L, Donnai D. Paternally inherited duplications of 11p15.5 and Beckwith-Wiedemann syndrome. J Med Genet. 1997;34:819–26. [PMC free article: PMC1051088] [PubMed: 9350814]
• Smilinich NJ, Day CD, Fitzpatrick GV, Caldwell GM, Lossie AC, Cooper PR, Smallwood AC, Joyce JA, Schofield PN, Reik W, Nicholls RD, Weksberg R, Driscoll DJ, Maher ER, Shows TB, Higgins MJ. A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript and loss of imprinting in Beckwith-Wiedemann syndrome. Proc Natl Acad Sci U S A. 1999;96:8064–9. [PMC free article: PMC22188] [PubMed: 10393948]
• Smith AC, Rubin T, Shuman C, Estabrooks L, Aylsworth AS, McDonald MT, Steele L, Ray PN, Weksberg R. New chromosome 11p15 epigenotypes identified in male monozygotic twins with Beckwith–Wiedemann syndrome. Cytogenet Genome Res. 2006;113:313–7. [PubMed: 16575195]
• Souka AP, Snijders RJ, Novakov A, Soares W, Nicolaides KH. Defects and syndromes in chromosomally normal fetuses with increased nuchal translucency thickness at 10-14 weeks of gestation. Ultrasound Obstet Gynecol. 1998;11:391–400. [PubMed: 9674084]
• Sparago A, Cerrato F, Vernucci M, Ferrero GB, Silengo MC, Riccio A. Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome. Nat Genet. 2004;36:958–60. [PubMed: 15314640]
• Tan TY, Amor DJ. Tumour surveillance in Beckwith-Wiedemann syndrome and hemihyperplasia: a critical review of the evidence and suggested guidelines for local practice. J Paediatr Child Health. 2006;42:486–90. [PubMed: 16925531]
• Thorburn MJ, Wright ES, Miller CG, Smith-Read EH. Exomphalos-macroglossia-gigantism syndrome in Jamaican infants. Am J Dis Child. 1970;119:316–21. [PubMed: 5434588]
• Tomlinson JK, Morse SA, Bernard SP, Greensmith AL, Meara JG. Long-term outcomes of surgical tongue reduction in Beckwith–Wiedemann syndrome. Plast Reconstr Surg. 2007;119:992–1002. [PubMed: 17312506]
• Tunster SJ, Tycko B, John RM. The imprinted Phlda2 gene regulates extraembryonic energy stores. Mol Cell Biol. 2010;30:295–306. [PMC free article: PMC2798284] [PubMed: 19884348]
• van Eeghen AM, van Gelderen I, Hennekam RC. Costello syndrome: report and review. Am J Med Genet. 1999;82:187–93. [PubMed: 9934987]
• Weksberg R, Nishikawa J, Caluseriu O, Fei YL, Shuman C, Wei C, Steele L, Cameron J, Smith A, Ambus I, Li M, Ray PN, Sadowski P, Squire J. Tumor development in the Beckwith-Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of KCNQ1OT1. Hum Mol Genet. 2001;10:2989–3000. [PubMed: 11751681]
• Weksberg R, Shuman C, Caluseriu O, Smith AC, Fei YL, Nishikawa J, Stockley TL, Best L, Chitayat D, Olney A, Ives E, Schneider A, Bestor TH, Li M, Sadowski P, Squire J. Discordant KCNQ1OT1 imprinting in sets of monozygotic twins discordant for Beckwith-Wiedemann syndrome. Hum Mol Genet. 2002;11:1317–25. [PubMed: 12019213]
• Weksberg R, Shuman C, Smith AC. Beckwith-Wiedemann syndrome. Am J Med Genet C Semin Med Genet. 2005;137C:12–23. [PubMed: 16010676]
• Weksberg R, Shuman C. Beckwith-Wiedemann syndrome and hemihypertrophy In: Cassidy SB, Allanson JE, eds. Management of Genetic Syndromes. 2 ed. Hoboken, New Jersey: John Wiley & Sons; 2004:101-16.
• Weksberg R, Smith AC, Squire J, Sadowski P. Beckwith-Wiedemann syndrome demonstrates a role for epigenetic control of normal development. Hum Mol Genet. 2003;12(Spec No 1):R61–8. [PubMed: 12668598]
• Wilkins-Haug L, Porter A, Hawley P, Benson CB. Isolated fetal omphalocele, Beckwith-Wiedemann syndrome, and assisted reproductive technologies. Birth Defects Res A Clin Mol Teratol. 2009;85:58–62. [PubMed: 19107956]
• Wilson M, Peters G, Bennetts B, McGillivray G, Wu ZH, Poon C, Algar E. The clinical phenotype of mosaicism for genome-wide paternal uniparental disomy: Two new reports. Am J Med Genet. 2008;146A:137–148. [PubMed: 18033734]
• Zarate YA, Mena R, Martin LJ, Steele P, Tinkle BT, Hopkin RJ. Experience with hemihyperplasia and Beckwith-Wiedemann syndrome surveillance protocol. Am J Med Genet A. 2009;149A:1691–7. [PubMed: 19610116]
• Zeschnigk M, Albrecht B, Buiting K, Kanber D, Eggermann T, Binder G, Gromoll J, Prott EC, Seland S, Horsthemke B. IGF2/H19 hypomethylation in Silver-Russell syndrome and isolated hemihypoplasia. Eur J Hum Genet. 2008;16:328–34. [PubMed: 18159214]