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Beckwith-Wiedemann Syndrome

Synonym: Wiedemann-Beckwith Syndrome

, MS, CGC, , MD, , PhD, and , MD, PhD, FRCPC, FCCMG, FACMG.

Author Information
, MS, CGC
Director, Genetic Counseling
The Hospital for Sick Children
Program Director, MSc Program
Associate Professor, Molecular Genetics
University of Toronto
Toronto, Ontario
, MD
Department of Pathology and Human Anatomy
Loma Linda University
Loma Linda, California
, PhD
Clinical Cytogenetics Fellow
Department of Paediatric and Laboratory Medicine
The Hospital for Sick Children
Toronto, Ontario
, MD, PhD, FRCPC, FCCMG, FACMG
Geneticist, Clinical and Metabolic Genetics
Senior Associate Scientist, Research Institute
The Hospital for Sick Children
Professor, Department of Pediatrics
University of Toronto
Toronto, Ontario

Initial Posting: ; Last Update: December 14, 2010.

Summary

Disease characteristics. Beckwith-Wiedemann syndrome (BWS) is a growth disorder characterized by macrosomia, macroglossia, visceromegaly, embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma), omphalocele, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, and renal abnormalities (e.g., medullary dysplasia, nephrocalcinosis, medullary sponge kidney, and nephromegaly). 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: (1) loss of methylation on the maternal chromosome at imprinting center 2 (IC2) in 50% of affected individuals; (2) paternal uniparental disomy for chromosome 11p15 in 20%; and (3) gain of methylation on the maternal chromosome at imprinting center 1 (IC1) in 5%. Methylation alterations that are associated with microdeletions or microduplications in this region are associated with high heritability. Sequence analysis of CDKN1C identifies mutations 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 lengths 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.

Prevention of secondary complications: Annual renal ultrasound examination for affected individuals between age eight years and mid-adolescence to identify those with nephrocalcinosis or medullary sponge kidney disease.

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.

Genetic counseling. Beckwith-Wiedemann syndrome is associated with abnormal regulation of gene transcription in the imprinted domain 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 while approximately 15% have a family history consistent with autosomal dominant transmission of BWS. Children of subfertile parents conceived by assisted reproductive technology (ART) may have an 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 not previously known to be at increased risk for BWS by ultrasound examination and maternal serum alpha-fetoprotein assay may lead to the consideration of chromosome analysis 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.

Diagnosis

Clinical Diagnosis

No 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 BWS

  • Positive 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 kidney
  • Cleft palate (rare in BWS)
  • Placental mesenchymal dysplasia [Wilson et al 2008]
  • Cardiomegaly
  • Cardiomyopathy (rare in BWS)

Minor findings associated with BWS

  • Pregnancy-related findings including polyhydramnios and prematurity
  • Neonatal hypoglycemia
  • Facial nevus flammeus, other vascular malformations
  • Characteristic facies, including midface hypoplasia and infraorbital creases
  • Structural cardiac anomalies
  • Diastasis recti
  • Advanced bone age (common in overgrowth/endocrine disorders)

Molecular Genetic Testing

Genes. 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.

Figure 1

Figure

Figure 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]:

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.

Figure 2

Figure

Figure 2. Causes of Beckwith-Wiedemann syndrome by molecular mechanism

Table 1. Summary of Molecular Genetic Testing Used in Beckwith-Wiedemann Syndrome

Cause of BWS by Molecular MechanismTest MethodMutations/Alterations DetectedProportion of BWS Alterations Detected 1
Loss of methylation at IC2 on the maternal chromosomeMethylation analysis 2Methylation abnormalities at IC2 on the maternal chromosome50% 3
Gain of methylation at IC1 on the maternal chromosomeMethylation abnormalities at IC1 on the maternal chromosome5% 3
Mutation 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 5
Paternal uniparental disomy of 11p15.5UPD analysis 611p15.5 paternal uniparental disomy 720% 3
Duplication, 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 11
Submicroscopic genomic alteration within chromosome 11p15.5Microdeletion / microduplication analysis 2Genomic alterations involving IC1 and/or IC2 Not yet accurately determined

1. 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 testing

  • Methylation analysis

    Methylation 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 Strategy

To establish/confirm the diagnosis in a proband

  • Karyotype (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.

Clinical Description

Natural History

Incidence 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 Correlations

Phenotype-genotype correlations have been reported as follows:

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 mutation but have no features of BWS because the CDKN1C mutation was in the paternal allele, which is normally not expressed; i.e., the mutation 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 incidence of approximately 1:13,700 is probably 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.

Differential Diagnosis

Overgrowth. 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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To 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 hepatoblastoma

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 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 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
  • 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 elevated
  • Standard interventions such as infant stimulation programs, occupational and physical therapy, and individualized education programs for children with developmental delay
  • Referral of children with structural renal or GI tract abnormalities to the relevant specialists
  • Management of cleft palate following standard protocols
  • Management of cardiac problems following standard protocols

Prevention of Secondary Complications

Suspicion of potential urinary tract infection should be assessed and treated promptly to prevent secondary renal damage.

Surveillance

The following are appropriate:

  • Monitoring for hypoglycemia, especially in the neonatal period
  • Developmental 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 Risk

Even 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 Investigation

Search 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The etiology of Beckwith-Wiedemann syndrome (BWS) is complex [Li et al 1997, Li et al 1998].

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 2).

Approximately 85% of individuals with BWS have a negative family history and a normal karyotype. For such individuals, the recurrence risks associated with the five clinically relevant categories presented in Figure 1 are:

  • Loss of methylation at IC2 (Figure 1-B1). Very low in the absence of a genomic abnormality (e.g., microdeletion/microduplication (confirmed by MS-MLPA) or mutations at another locus, such as NLRP2)
  • Gain of methylation at IC1 (Figure 1-B2). Very low in the absence of a genomic abnormality (confirmed by MS-MLPA)
  • CDKN1C mutation. When the family history is negative and a CDKN1C mutation has been identified in the proband, both parents should be tested for that CDKN1C mutation. Several instances of maternal transmission of a CDKN1C mutation from a clinically unaffected mother to her affected offspring have been reported [Hatada et al 1997, O'Keefe et al 1997, Lew et al 2004]. Unexpectedly, one instance of paternal transmission of a CDKN1C mutation from a clinically unaffected father has also been reported [Lee et al 1997]. The recurrence risk for such families may be as high as 50%. In addition, other at-risk family members should be offered testing for the familial CDKN1C mutation to clarify their genetic status/risks.
  • Paternal uniparental disomy for chromosome 11p15. Very low because the UPD in this region appears to arise from a post-zygotic somatic recombination
  • Microdeletion/microduplication of chromosome 11p15.5. May be as high as 50%. When a genomic abnormality (e.g., microdeletion or microduplication) leads to a methylation alteration, molecular testing to detect microdeletion/microduplication should be considered for both parents even in the absence of a positive family history. If one parent has the same genomic abnormality, parent-of-origin effects must be considered as the recurrence risk may be as high as 50%.
  • If no primary etiology has been identified:
    • The risk to members in these families is unknown but empirically low.
    • A proportion of these individuals, especially those involving hemihyperplasia, may have mosaicism for UPD 11p15 which may not have been detected because of low levels of the alteration in the tissue sampled. Consideration should be given to testing additional tissues (e.g., skin from the larger side).
    • In a consanguineous relationship in which the female was homozygous for an inactivating mutation in NLRP2 and the male was heterozygous for an inactivating mutation in NLRP2, the couple had a molar pregnancy and two children with BWS (one was heterozygous and the other homozygous for the NLRP2 mutation). This case suggests that a female homozygous for an NLRP2 inactivating mutation is at increased risk for having a child with BWS and/or molar pregnancies. The risk for other imprinting disorders is unknown [Meyer et al 2009].

Approximately 10%-15% of individuals with BWS have a positive family history and a normal karyotype. In such families two categories are identified:

  • Proband has an identified CDKN1C mutation (40%):
    • If the mother has a CDKN1C mutation, the risk to sibs of the proband is 50%.
    • If the father has a CDKN1C mutation, the risk to sibs is increased but the exact figure must await further empiric studies.
    • If neither parent has the CDKN1C mutation identified in the proband, the risk to sibs is low; however, germline mosaicism is possible.
  • Proband does not have an identified CDKN1C mutation (~60%). In this instance, the risk to sibs is up to 50%.

Offspring of a proband with:

  • Loss of methylation at IC2. The recurrence risk for offspring of individuals with BWS caused by IC2 loss of methylation is low in the absence of a genomic abnormality as the imprint normally is reset in the germline; empiric data are not yet available [Niemitz et al 2004].
  • Gain of methylation at IC1. The recurrence risk for offspring of individuals with BWS caused by ICI gain of methylation is theoretically low in the absence of a genomic abnormality as the imprint normally is reset in the germline; empiric data are not yet available.
  • CDKN1C mutation. The risk to offspring of a female with a CDKN1C mutation is 50%. The risk to offspring of a male with a CDKN1C mutation is lower than 50%, but too few cases have been reported to generate a risk figure.
  • Paternal uniparental disomy for chromosome 11p15.5. The risk to offspring of an individual with UPD for 11p15 is likely very low; however, empiric data are not yet available.
  • Microdeletion/microduplication of chromosome 11p15.5. The recurrence risk for offspring would be 50% and the phenotype could be BWS or Russell-Silver syndrome depending on the sex of the transmitting parent [Sparago et al 2004].

Table 2. Risk to Sibs and Offspring of a Proband with BWS Based on Family History and Molecular Genetic Test Results

Percent of Individuals with BWS / Family HistoryMolecular Genetic Test ResultsRisk to Sibs of a Proband Risk to Offspring of a Proband
~85% / Negative family history, normal karyotype 1, 2IC2 loss of methylation detected; no genomic abnormalityProbably lowProbably low
IC1 gain of methylation detected; no genomic abnormalityProbably lowProbably low
Paternal UPD of 11p15 presentVery low Very low
CDKN1C mutation present in a parent≤50%If transmitting parent is female: ~50%
If transmitting parent is male : <50% (exact figure not known)
~10%-15% / Positive family history, normal karyotype 2≤50%If transmitting parent is female : ~50%
If transmitting parent is male: <50% (exact figure not known)
<1% / Monozygous twinsLowTheoretically low but available empiric data are insufficient

1. 20% of individuals with BWS and no known family history of BWS have paternal uniparental disomy of 11p15.

2. ~5% of all individuals with BWS with a normal karyotype have identifiable mutations in CDKN1C.

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

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.

Table 3. Risk to Sibs and Offspring of a Proband with BWS and a Cytogenetic Abnormality

Cytogenetic Abnormality Risk to Sibs of a ProbandRisk to Offspring
Cytogenetically detected maternal 11p15 translocation or inversionMay be as high as 50% if the transmitting parent is a female May be as high as 50% if the transmitting parent is a female
Cytogenetically detected paternal 11p15 duplicationNot definedNot defined

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

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. Although no recurrences are reported in the sibs of these twins, the recurrence risk is not known.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

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 microduplications and microdeletions can be detected via analysis of fetal DNA from samples obtained by CVS or amniocentesis. Amniocytes can be reliably used for methylation analysis [B Baskin, personal communication]; however analysis of methylation alterations in tissue obtained by CVS requires further study.

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:

  • Molecular genetic testing for methylation alterations in amniocytes; if no methylation alteration is identified, testing for a CDKN1C mutation
  • Serial ultrasound examinations to assess fetal growth and to detect other abnormalities characteristic of BWS
  • Cytogenetic testing to look for a duplication, inversion, or translocation involving 11p15

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.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information 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 Databases

Data 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)

103280H19, IMPRINTED MATERNALLY EXPRESSED NONCODING TRANSCRIPT; 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; KCNQ1

Molecular 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 p57KIP2, 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 (p57Kip2) result in phenotypes analogous to BWS in mouse models [Caspary et al 1999].

References

Published Guidelines/Consensus Statements

  1. 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 6-26-12. [PMC free article: PMC3111049] [PubMed: 11388763]

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Suggested Reading

  1. Bliek J, Gicquel C, Maas S, Gaston V, Le Bouc Y, Mannens M. Epigenotyping as a toll for the predicition of tumor risk and tumor type in patients with Beckwith–Wiedemann syndrome (BWS). J Pediatr. 2004;145:796–9. [PubMed: 15580204]
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  3. Nicholls RD. The impact of genomic imprinting for neurobehavioral and developmental disorders. J Clin Invest. 2000;105:413–8. [PMC free article: PMC289176] [PubMed: 10683369]
  4. Schwienbacher C, Sabbioni S, Campi M, Veronese A, Bernardi G, Menegatti A, Hatada I, Mukai T, Ohashi H, Barbanti-Brodano G, Croce CM, Negrini M. Transcriptional map of 170-kb region at chromosome 11p15.5: identification and mutational analysis of the BWR1A gene reveals the presence of mutations in tumor samples. Proc Natl Acad Sci U S A. 1998;95:3873–8. [PMC free article: PMC19930] [PubMed: 9520460]

Chapter Notes

Acknowledgments

Madeline Li

Revision History

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