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Beckwith-Wiedemann Syndrome

[Wiedemann-Beckwith Syndrome]

Summary

Disease characteristics.  Beckwith-Wiedemann syndrome (BWS) is a disorder of growth characterized by macrosomia (large body size), macroglossia, visceromegaly, embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma), omphalocele, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, and renal abnormalities (e.g., medullary dysplasia, nephrocalcinosis, medullary sponge kidney, and nephromegaly). Infants with BWS have an approximately 20% mortality rate, mainly caused by complications of prematurity. Macroglossia and macrosomia are generally present at birth but may have postnatal onset. Growth rate slows around seven to eight years of age. Hemihyperplasia may affect segmental regions of the body or selected organs and tissues.

Diagnosis/testing.  The diagnosis of Beckwith-Wiedemann syndrome relies primarily on clinical findings. Cytogenetically detectable abnormalities involving 11p15 are found in 1% or less of cases. Clinically available molecular genetic testing can identify several different types of 11p15 abnormalities in individuals with BWS: (1) loss of methylation at DMR2 is observed in 50% of individuals; (2) gain of methylation at DMR1 is observed in 2% to 7%; (3) paternal uniparental disomy for chromosome 11p15 is observed in 10-20%. Testing reveals mutations in the CDKN1C gene (previously called p57 ^KIP2 ) in 40% of familial cases and 5-10% of simplex cases (individuals with no known family history of BWS).

Management.  Management for BWS includes treatment of hypoglycemia to reduce the risk of central nervous system complications, abdominal wall and omphalocele repair in neonates, endotracheal intubation for insufficient airway, and use of specialized nipples or nasogastric tube feedings to manage feeding difficulties resulting from macroglossia. Children with enlarged tongues may benefit from surgery performed between two and four years of age and from speech therapy. Surgery may be performed during puberty to equalize different leg lengths; craniofacial surgery may benefit individuals with facial hemihyperplasia. Screening for embryonal tumors is performed by abdominal ultrasound examination every three months until eight years of age. Serum alpha fetoprotein (AFP) concentration is monitored in the first few years of life for early detection of hepatoblastoma. Neoplasias are treated using standard pediatric oncology protocols. Nephrocalcinosis is treated by a pediatric nephrologist.

Genetic counseling. Most individuals with BWS have normal chromosomes. In addition, approximately 85% of individuals with BWS have no family history of BWS; approximately 15% of individuals have a family history consistent with autosomal dominant transmission of BWS. Identification of the underlying genetic mechanism helps determine recurrence risk. Prenatal testing is available by ultrasound examination and maternal serum alpha fetoprotein assay. Prenatal testing is also available by chromosome analysis for families with an inherited chromosome abnormality or by molecular genetic testing for families with a defined molecular mechanism. Several studies have suggested an increased risk for imprinting disorders, including BWS, in children conceived using assisted reproductive technology (ART).

Diagnosis

Clinical Diagnosis

No consensus diagnostic criteria for BWS exist, although it is generally accepted that a diagnosis requires the presence of at least three findings (two major and one minor):

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)
• Adrenocortical cytomegaly
• Renal abnormalities including structural abnormalities, nephromegaly, and nephrocalcinosis
• Cleft palate (rare)

Minor findings associated with BWS:

• Polyhydramnios
• Prematurity
• Neonatal hypoglycemia
• Facial nevus flammeus
• Hemangioma
• Characteristic facies, including midfacial hypoplasia and infraorbital creases [Pettenati et al 1986].
• Cardiomegaly / structural cardiac anomalies / cardiomyopathy (rare)
• Diastasis recti
• Advanced bone age
• Monozygotic twinning. Monozygous twins with BWS are usually female and discordant; however, both male and female monozygous twins concordant for BWS have been reported, as well as monozygous male twins discordant for BWS [Orstavik et al 1995 , Leonard et al 1996].

Note: Children with milder phenotypes (e.g., macroglossia and umbilical hernia, or hemihyperplasia only) have developed tumors (see Management).

Testing

Cytogenetic testing.   Chromosome analysis at a band level of at least 550 in 20 metaphases reveals a cytogenetically detectable translocation or inversion of a maternal chromosome 11 or a cytogenetically detectable duplication of a paternal chromosome 11 involving band 11p15 in 1% or fewer of individuals with BWS [Slavotinek et al 1997 , Li et al 1998].

Note: (1) Cytogenetic testing is necessary for correct interpretation of molecular genetic test results. (2) FISH testing may be used to clarify interpretation of cytogenetic test results when necessary.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.

Genes.  Beckwith-Weidemann syndrome is associated with abnormal transcription and regulation of genes in the imprinted domain on chromosome 11p15.5.

For key concepts of genomic imprinting, click here .

Molecular genetic testing: Clinical uses

• Confirmatory diagnostic testing
• Definition of recurrence risk
• Prenatal diagnosis

Molecular genetic testing: Clinical methods

• FISH.  FISH studies can be used to clarify the position of a chromosome 11 translocation or inversion and to confirm duplications of chromosome 11. Only 1-2% of individuals with BWS have chromosomal abnormalities detectable by FISH.

• Uniparental disomy (UPD) studies.  Approximately 10-20% of individuals fulfilling diagnostic criteria for BWS have paternal UPD for the BWS critical region. Most demonstrate segmental paternal UPD for 11p15, suggesting that the underlying mechanism is a post-zygotic somatic recombination event resulting in mosaicism. Therefore, UPD may not be detected because of a low level of mosaicism in the tissue sampled. Testing of other tissues (e.g., skin fibroblasts, tumor biopsy) should be considered.

  Note: If UPD is suspected based on analysis of the proband's sample, parental samples are required for confirmation.

• Methylation studies

  • KCNQ1OT1 methylation (DMR2).  Up to 60% of individuals fulfilling diagnostic criteria for BWS have detectable KCNQ1OT1 methylation abnormalities.

  • H19 methylation (DMR1).  Between 2% and 7% of individuals fulfilling diagnostic criteria for BWS have gain of methylation at H19.

    Note: (1) Individuals with UPD can be distinguished from individuals with abnormal methylation of either KCNQ10T1 or H19 because those with UPD have methylation abnormalities at both KCNQ1OT1 and H19. (2) Interpretation of methylation data should take into account results of karyotype analysis because karyotypic abnormalities are associated with abnormal methylation status.

  • Heritable microdeletions.  Although most methylation defects at DMR1 and DMR2 are sporadic, a few families have been reported with microdeletions of DMR1 (Sparago et al 2004 , Prawitt et al 2005 ; three pedigrees) and of DMR2 (Niemetz et al 2004 ; one pedigree).

    Note: (1) Currently no clinical testing for microdeletions of the BWS critical region is available. (2) Such rare pedigrees may be identified in the context of a positive family history with a methylation change at DMR1 or DMR2.

• Mutation scanning.  The majority of CDKN1C mutations found in BWS are located in exons 1 and 2 [Hatada et al 1996 , 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]. Clinical testing for exon 1 and 2 mutations is available; testing for mutations in other exons and rare intronic splicing mutations [Lew et al 2004] may be done on a research basis.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Beckwith-Wiedemann Syndrome Test Method Alterations Detected Detection Rates  1 Test Availability Karyotype, FISH Cytogenetic duplication, translocation, or inversion 1-2% Clinical Microsatellite analysis OR dual methylation analysis at DMR1 and DMR2 11p15.5 paternal uniparental disomy  2 10-20%  3 Methylation studies Methylation abnormalities in KCNQ1OT1 (DMR2) 50-60%  3 Methylation abnormalities in H19 2-7%  3 Sequence analysis/mutation scanning CDKN1C mutations 5-10% in simplex cases  4 ~40% in autosomal dominant families  4

1. In individuals fulfilling clinical diagnostic criteria for BWS 2. False negatives may occur as a result of somatic mosaicism for UPD, which has been reported in all cases to date. Testing of tissue from a second source (e.g., fibroblast cells from a skin biopsy) may be helpful. 3. Bliek et al 2001 , Weksberg et al 2001 4. Lam et al 1999 , Li et al 2001

Interpretation of test results.  For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

1. Karyotype
2. Methylation studies

Note: 1 and 2 can be performed simultaneously; however, if the proband has mental retardation, a karyotype should be performed first.

1. Uniparental disomy studies if a simplex case OR mutation scanning of CDKN1C if a familial case.
2. In familial cases in which a CDKN1C mutation has not been detected and the karyotype is normal, screening for methylation changes at both DMR1 and DMR2 is advised as rare heritable microdeletions have been reported [Niemetz et al 2004 , Sparago et al 2004 , Prawitt et al 2005].

Genetically Related (Allelic) Disorders

Molecular alterations at 11p15 including hypomethylation at DMR2, hypermethylation at DMR1 [Martin et al 2005], and 11p15 paternal uniparental disomy [Grundy et al 1991 , Shuman et al 2002] have been reported in individuals with hemihyperplasia.

Clinical Description

Natural History

Specific incidence figures for the individual clinical findings in BWS vary widely in published reports. The following features, however, are clearly part of the BWS phenotype.

Prenatal and perinatal.   BWS is associated with perhaps as high as 50% incidence of polyhydramnios, premature birth, and fetal macrosomia [Elliot et al 1994]. Other common features include a long umbilical cord and an enlarged placenta, averaging almost twice the normal weight for gestational age [Weng, Moeschler et al 1995].

Infants with BWS have an approximately 20% mortality rate, mainly as a result of complications of prematurity associated with omphalocele, macroglossia, neonatal hypoglycemia, and, rarely, cardiomyopathy [Pettenati et al 1986].

Growth.   Macroglossia and macrosomia are generally present at birth, though postnatal onset of both features has also been observed [Chitayat, Rothchild 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 seven to eight years of age.

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) [Viljoen et al 1984 , Hoyme et al 1998].

Note: Hemihyperplasia refers to an abnormality of cell proliferation leading to asymmetric overgrowth; in BWS, hemihyperplasia has replaced the term hemihypertrophy, which refers to increased cell size.

Metabolic abnormalities.   Neonatal hypoglycemia is well documented [Engstrom et al 1988]; if undetected or untreated, it poses a significant risk for developmental sequelae. Most cases of hypoglycemia are mild and transient [Elliott & Maher 1994]; 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 as detected on ultrasound examination (22% in BWS as compared to 7-10% in the general population). [Goldman et al 2003] This may reflect an underlying primary structural abnormality in the kidneys.

Structural anomalies.   Anterior abdominal wall defects, including omphalocele [Weng, Moeschler et al 1995 ; Pettenati et al 1986], umbilical hernia, and diastasis recti, are common. Much of the information regarding cardiovascular problems in BWS is anecdotal. Cardiomegaly is sometimes detected in infancy but typically resolves without treatment [Elliot & Maher 1994 , Pettenati et al 1986]. 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 [Sotelo-Avila et al 1980 , Wiedemann 1983]. The estimated risk for tumor development in children with BWS is 7.5%. This increased risk for neoplasia seems to be concentrated in the first eight years of life. Tumor development is uncommon in affected individuals older than age eight years.

Development.   Development is usually normal in children with BWS unless there is a chromosome abnormality [Waziri et al 1983 , Slavotinek et al 1997] or a history of hypoxia or significant, untreated hypoglycemia.

Adulthood.   After childhood, complications for individuals with BWS are infrequent and prognosis is favorable.

Genotype-Phenotype Correlations

Genotype-phenotype correlations have been reported as follows:

• CDKN1C mutations are associated with positive family history, omphalocele, and/or cleft palate [Hatada et al 1997 , Li et al 2001].
• Paternal UPD for 11p15 is associated with isolated hemihyperplasia and Wilms tumor [Grundy et al 1991 , Shuman et al 2002].
• Loss of methylation at KCNQ1OT1 has been associated with monozygotic twinning [Weksberg et al 2002] and embryonal tumors other than Wilms tumor [Weksberg et al 2001].
• H19 hypermethylation is associated with Wilms tumor [Bliek et al 2001 , Weksberg et al 2001].

Nomenclature

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

Prevalence

The reported incidence of approximately one in 13,700 [Thorburn et al 1970] is probably an underestimate given the existence of milder, undiagnosed cases. BWS has been reported in a wide variety of ethnic populations with an equal incidence in males and females [Pettenati et al 1986].

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

Overgrowth.   BWS is often considered in the differential diagnosis of children presenting with overgrowth. It is important to note that there are 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 a cardiac conduction defect is present, the differential diagnosis should include both 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, and skeletal abnormalities, including polydactyly. Developmental delay may be present. Although cases with tumors have been reported, the tumor risk and range of tumors remain to be defined. In 30% of individuals with SGBS, deletions of the glypican-3 (GPC3) gene are detected. This gene encodes an extracellular proteoglycan believed to function in the regulation of growth during development [Weksberg et al 1996 , Neri et al 1998].
• 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, though the gene causing PS has not yet been identified [Greenberg et al 1986 , Grundy et al 1992].
• Costello syndrome (CS) can be similar to BWS in the neonatal period, when affected individuals present with macrosomia, coarse facial features, and cardiac defects. Over time, however, 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 80-90% of individuals with Sotos syndrome have a demonstrable mutation or deletion of NSD1. Because of some clinical overlap between Sotos syndrome and BWS, consideration should be given to testing NSD1 in individuals with BWS who do not have a 11p15 alteration and testing for chromosome 11p15 alterations in individuals with Sotos syndrome with no identified NSD1 mutation [Baujat et al 2004].

Hemihyperplasia.  Hemihyperplasia can occur as an isolated finding or may be associated with other syndromes such as Proteus syndrome, Klippel-Trenauny-Weber syndrome (KTW), and neurofibromatosis type 1 [Hoyme et al 1998]. Of note, a subgroup of individuals with apparently isolated hemihyperplasia may have BWS with minimal clinical findings. Asymmetries, such as of the face or chest, should be evaluated carefully to exclude plagiocephaly and chest wall deformities. Children with isolated hemihyperplasia carry an increased tumor risk of 5.9% [Hoyme et al 1998] and should be offered tumor surveillance.

Management

Evaluations at Initial Diagnosis to Establish the Extent of Disease

• 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
• Abdominal ultrasound examination to assess for organomegaly, structural abnormality, and tumors; a baseline MRI or CT examination of the abdomen to screen for tumors [Clericuzio et al 1993 , Beckwith 1998]
• A comprehensive cardiac evaluation including ECG and echocardiogram prior to any surgical procedures or when a cardiac abnormality is suspected on clinical evaluation

Treatment of Manifestations

• Prompt treatment of hypoglycemia by standard methods to reduce the risk of central nervous system complications. Because onset of hypoglycemia is occasionally delayed for several months, parents should be informed of the symptoms of hypoglycemia so that they can seek appropriate medical attention.
• Abdominal wall repair soon after birth in neonates with BWS and omphalocele as necessary. Generally, this surgery is well tolerated [Elliott & Maher 1994].
• Anticipation of difficulties with endotracheal intubation that may result from macroglossia [Weng, Mortier et al 1995]
• Management of feeding difficulties secondary to macroglossia by use of specialized nipples such as the longer nipple used for babies with cleft palate or, rarely, short term use of nasogastric tube feedings
• Follow-up of children with enlarged tongues by a craniofacial team including plastic surgeons, orthodontists, and speech pathologists familiar with the natural history of BWS. Although tongue growth slows over time and jaw growth accelerates to accommodate the enlarged tongue, some children may benefit from tongue reduction surgery, typically performed between two and four years of age.
• Assessment of macroglossia-related speech difficulties by a speech pathologist, preferably one familiar with Beckwith-Wiedemann syndrome and its natural history
• Consultation with an orthopedic surgeon if hemihyperplasia includes a significant difference in leg length. Surgery may be necessary during 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
• 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 abnormalities or GI tract abnormalities to the relevant specialists

Prevention of Secondary Complications

• In some individuals with BWS, developmental anomalies of the renal tract are associated with increased calcium excretion and deposition (i.e., nephrocalcinosis). Individuals over the age of eight years may be assessed with annual renal ultrasound examination through adolescence to identify those requiring further evaluation. In individuals with evidence of calcium deposits on renal ultrasound examination, a CT scan of the kidneys may be helpful.
• Referral to a pediatric nephrologist is recommended if the urinary calcium is elevated.

Surveillance

• Monitoring for hypoglycemia, especially in the first seven days of life
• Developmental screening as part of routine childcare
• When hemihyperplasia includes a significant difference in leg length, orthopedic consultation is recommended. Surgery may be necessary during puberty to close the growth plate of the longer leg in order to equalize the final leg lengths.
• Measurement of urinary calcium/creatinine ratio annually or biannually as it may be abnormal in individuals with BWS who have normal findings on ultrasound examination
• Screening for embryonal tumors by:
  • Abdominal ultrasound examination every three months until eight years of age [Beckwith 1998]
  • Measurement of serum alpha fetoprotein (AFP) concentration in the first few years of life for early detection of hepatoblastoma. (AFP serum concentration may be elevated in children with BWS in the first year of life [Everman et al 2000].) If 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 the serum AFP concentration. If the concentration is not decreasing, it is appropriate to undertake an exhaustive search for an underlying tumor [Clericuzio et al 2003].
  • Although periodic chest x-ray and urinary VMA and VHA assays to screen for neuroblastoma [Chitayat, Friedman et al 1990] have been suggested, they have not been incorporated into most screening protocols because of their low yield.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.

Mode of Inheritance

The etiology of BWS is complex and not well understood [Li et al 1997 , Li et al 1998].

• About 85% of affected individuals represent single occurrences in a family and are chromosomally normal.
• About 10-15% of cases are associated with an autosomal dominant mode of inheritance with incomplete penetrance and preferential maternal transmission.
• Fewer than 1% have a demonstrable chromosome abnormality.

Risk to Family Members of Probands 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 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.

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. Of such individuals, four clinically relevant categories are identified:

• Proband has KCNQ1OT1 hypomethylation (~50-60%).  No recurrences of loss of methylation at KCNQ1OT1 have been reported in first-degree relatives of individuals with BWS who have this molecular lesion. Thus, the recurrence risk appears to be very low.

• Proband has uniparental disomy (~10-20%). In families in which the proband has paternal uniparental disomy for chromosome 11p15, the recurrence risk is empirically very low because the UPD in this region appears to arise from a post-zygotic somatic recombination.

• Proband has a CDKN1C mutation (~5-10%).   When the family history is negative and a CDKN1C mutation has been identified in the proband, both parents should be tested for mutations. Several instances [Hatada et al 1996 , Hatada et al 1997 , O'Keefe et al 1997 , Lew et al 2004] of maternal transmission of CDKN1C mutations from clinically unaffected mothers to affected offspring have been reported, as well as two instances of paternal transmission from clinically unaffected fathers [Lee et al 1997 , Li et al 2001]. The recurrence risk for such parents may be as high as 50%. In addition, other at-risk family members should be offered testing for mutation in this gene to clarify their genetic status.

• No identifiable primary etiology exists (13-15%).   The risk to members in these families is unknown but empirically low. In cases in which loss of imprint for IGF2 in the absence of the above 11p15 molecular alterations has been identified as part of a research study, the basic underlying molecular defect is unknown [Weksberg et al 1993] and the risk of recurrence in the families is also unknown.

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 the 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.

• Proband does not have an identified CDKN1C mutation (~60%). In this instance, the risk to sibs is up to 50%.

Offspring of a proband

• KCNQ1OT1 hypomethylation.  The recurrence risk for offspring of individuals with BWS caused by KCNQ1OT1 hypomethylation is low; empiric data are not yet available [Niemetz et al 2004].

• Uniparental disomy.  The risk to offspring of an individual with UPD for 11p15 is likely very low; however, empiric data are not yet available.

• Identified CDKN1C mutation in proband.  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.

Table 2. Risk to Sibs and Offspring of a Proband with BWS Based on Family History and Molecular Genetic Testing % of Individuals with BWS Characteristics Risk to Sibs of a Proband Risk to Offspring of a Proband ~85% Negative family history, normal karyotype  1,  2 Probably low if KCNQ1OT1 hypomethylation is detected Probably low Very low if paternal UPD of 11p15 is present Very low 50% if CDKN1C mutation is present in a parent ~50% if transmitting parent is female; <50% (exact figure not known) if transmitting parent is male ~10-15% Positive family history, normal karyotype  2 50% ~50% if transmitting parent is female; <50% (exact figure not known) if transmitting parent is male <1% Monozygous twins Low Theoretically low but available empiric data are insufficient

1. 10-20% of individuals with BWS and no known family history of BWS have paternal uniparental disomy of 11p15. 2.  5-10% 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 upon 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 balanced chromosome rearrangement and should be offered chromosome analysis.

Sibs of a proband with a chromosome abnormality.

• The risk to sibs depends upon 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 not clearly defined.

Offspring of a proband with a chromosome abnormality.   The risk may be as high as 50% if the proband is a female.

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. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.

Possible imprinting risks associated with assisted reproductive technology (ART).   Data have suggested the possibility of a link between assisted reproductive technology (ART) and imprinting disorders [DeBaun et al 2001 , Maher et al 2003]. More recently DeBaun et al (2003), Gicquel et al (2003), and Maher et al (2003) reported data suggesting that ART may favor imprinting alterations at the centromeric imprinted 11p15 locus DMR2 and thus may increase the incidence of Beckwith-Wiedemann syndrome in women undergoing this procedure.

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 stimulation protocol, the biological technique, the stage of maturation of the gametes, the culture media, and the timing of embryo transfer.

It is unknown what role the underlying issues of infertility (as opposed to the ART procedures) play in these imprinting defects.

Reports of Angelman syndrome and 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 infertility of the parents [DeBaun et al 2003 , Gicquel et al 2003 , Gosden et al 2003 , Maher et al 2003 , Schieve et al 2004 , Weksberg et al 2003 , 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 KCNQ1OT1 [Weksberg et al 2002]. Although no recurrences are reported in the siblings of these twins, the recurrence risk is not known.

DNA banking.  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, particularly in situations in which molecular genetic testing is available on a research basis only or when the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

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 fetus is possible. In all cases, whether or not the genetic mechanism is known, measurement of maternal serum alpha fetoprotein (AFP) concentration can be offered. Maternal serum AFP concentration may be elevated at 16 weeks' gestation in the presence of omphalocele.

In all cases, whether or not the genetic mechanism is known, ultrasound examination can be offered. 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 10 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 the family history is negative for BWS but an abnormality such as omphalocele is detected, well-accepted protocols for prenatal investigation of this isolated finding exist.

• For the purpose of detecting BWS, ultrasound examination can be used to assess fetal growth and to detect abnormalities characteristic of BWS.
• Cytogenetic testing is appropriate to look for translocations, inversions, and duplications involving 11p15.
• Molecular genetic testing can be offered if there is a high index of suspicion for 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 genetic testing can be offered if there is a high index of suspicion for BWS.

Molecular Genetics

Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.

Gene/locus name: A number of candidate imprinted genes including growth factors and tumor suppressor genes mapping to the 11p15 region have been implicated. In addition, many different molecular alterations in this region occur in association with BWS. Furthermore, putative imprinting centers may control gene expression across large chromosomal domains.

Alterations of imprinted gene expression associated with BWS:

• Imprinting is an epigenetic 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]. Imprinted genes cluster to distinct domains in the genome and an imprinting center is believed to control resetting of a group of closely linked imprinted genes during transmission through the germline [Nicholls 1994].

• Uniparental disomy (UPD).   In BWS, somatic mosaicism for 11p15 UPD is found in 10-20% of cases. 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 [Weksberg et al 1993] as well as in multiple tumors, including Wilms tumor [Steenman et al 1994]. 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 the IGF2 gene or disruption of the IGF2 receptor [Lau et al 1994].

• H19.  This maternally expressed gene encodes a biologically active non-translated mRNA that may function as a tumor suppressor [Hao et al 1993]. Approximately 50% of cases of BWS are biallelic for IGF2 expression with uncoupled expression of IGF2 and H19; that is, most retain normal maternal monoallelic expression of H19 [Weksberg & Squire 1995]. Only rarely are changes in H19 expression or methylation reported in cases of BWS [Joyce et al 1997].

• CDKN1C.   This is a member of the cyclin-dependent kinase inhibitor family, which acts to negatively regulate cell proliferation. This gene is both a tumor suppressor gene and a potential negative regulator of fetal growth. Both these functions and the preferential maternal expression (incomplete paternal imprinting) of this gene suggested it as a candidate gene for BWS. Mutations in this gene have been reported in approximately 5-10% of BWS cases. Preliminary data suggest that CDKN1C mutations are found more frequently in cases with omphalocele, cleft palate, and positive family history. However, not all cases of vertical transmission of BWS can currently be ascribed to mutations in CDKN1C [Hatada et al 1996 , Hatada et al 1997 , Lee et al 1997].

• KCNQ1.   The KCNQ1 gene product 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 KvLQT1. Loss of imprinting occurs in the 5' differentially methylated region (KvDMR) of KCNQ1OT1 in 50-60% 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 two identified imprinted genes in the 11p15 region [Qian et al 1997 , Dao et al 1998]. Both genes show preferential maternal expression in the fetus and are located centromeric to CDKN1C. While neither gene has been directly implicated in BWS, both are hypothesized to have negative growth regulatory functions. PHLDA2 has sequence similarity to PHLDA1 (TDAG51), a gene involved in mediating apoptosis [Qian et al 1997], and SLC22A18 mutations have been identified in breast cancer and rhabdomyosarcoma cell lines [Schwienbacher et al 1998].

Resources

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References

Published Statements and Policies Regarding Genetic Testing

• American College of Medical Genetics (2001) Statement on diagnostic testing for uniparental disomy (pdf)

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