Beckwith-Wiedemann Syndrome

Clinical characteristics.

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

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

Diagnosis/testing.

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

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

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

Management.

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

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

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

Genetic counseling.

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

Suggestive Findings

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

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

Major findings associated with BWS

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

Minor findings associated with BWS

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

Establishing the Diagnosis

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

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

BWS is associated with abnormal regulation of gene transcription in two imprinted domains on chromosome 11p15.5 (also known as the BWS critical region). Regulation may be disrupted by any one of numerous mechanisms; a simplified description of known etiologic mechanisms is given here to clarify the testing pipelines described in Genetic Testing. See Molecular Pathogenesis for a detailed description of the regulation of gene expression in this region.

The BWS critical region includes two domains: imprinting center 1 (IC1) regulates the expression of IGF2 and H19 in domain 1; imprinting center 2 (IC2) regulates the expression of CDKN1C, KCNQ10T1, and KCNQ1 in domain 2 (Figure 1). Genomic imprinting is a phenomenon whereby the DNA of the two alleles of a gene is differentially modified so that only one parental allele – parent-specific for each gene – is normally expressed [Barlow 1994]. As shown in Figure 1a, differential methylation of IC1 and IC2 is associated with expression of specific genes on the paternal and maternal alleles in unaffected individuals.

Figure 1.

Map of the BWS locus on 11p15.5 a) shows a schematic representation of the normal parent of origin-specific imprinted allelic expression. Note: b) and c) show the altered region only. IC = imprinting center, Cen = centromere, Tel = telomere, P = paternal, (more...)

Note: IC1 and IC2 are sometimes referred to as differentially methylated regions DMR1 and DMR2, respectively.

In more than 80% of individuals with BWS, genetic testing can detect one of five alterations [Weksberg et al 2003, Weksberg et al 2005]:

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

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

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

Figure 2.

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

Clinical Description

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

Incidence figures for the specific individual clinical findings in Beckwith-Wiedemann syndrome (BWS) vary widely in published reports, in part due to ascertainment bias. The following features, however, are clearly part of the phenotype.

Prenatal and perinatal. The incidence of polyhydramnios, premature birth, and fetal macrosomia may be as high as 50%. Other common features include a long umbilical cord and an enlarged placenta that averages almost twice the normal weight for gestational age. Placental mesenchymal dysplasia has been reported in babies subsequently found to have features of BWS [Wilson et al 2008].

Infants with BWS are at increased risk for mortality mainly as a result of complications of prematurity, macroglossia, hypoglycemia, and, rarely, cardiomyopathy. However, the previously reported mortality rate of 20% may be an overestimate given the recent improvements in syndrome recognition and treatment.

Metabolic abnormalities. Neonatal hypoglycemia is well documented and occurs in approximately 50% of infants with BWS [Mussa et al 2016a]. If undetected or untreated, it poses a significant risk for developmental sequelae. Most cases of hypoglycemia are mild and transient; however, in more severe cases hypoglycemia can persist. Delayed onset of hypoglycemia (i.e., in the first month of life) is occasionally observed.

Other less common endocrine/metabolic/hematologic findings include hypothyroidism, hyperlipidemia/hypercholesterolemia, and polycythemia.

Hypercalciuria can be found in children with BWS even in the absence of renal abnormalities. On ultrasound examination 22% of individuals with BWS demonstrate nephrocalcinosis as compared to 7%-10% in the general population [Goldman et al 2003].

Growth. Macroglossia (present in ~90%) and macrosomia (present in ~50%) are generally present at birth, though postnatal onset of both features has also been observed [Chitayat et al 1990, Brioude et al 2013, Ibrahim et al 2014, Mussa et al 2016b]. Although most individuals with BWS show rapid growth in early childhood, height typically remains at the upper range of normal. Growth rate usually appears to slow around age seven to eight years.

Hemihyperplasia* can generally be appreciated at birth, but may become more or less evident as the child grows. Hemihyperplasia may affect segmental regions of the body or selected organs and tissues. When several segments are involved, hemihyperplasia may be limited to one side of the body (ipsilateral) or involve opposite sides of the body (contralateral) [Hoyme et al 1998].

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

Neoplasia. Children with BWS are at increased risk for mortality associated with neoplasia, particularly Wilms tumor and hepatoblastoma, but also neuroblastoma, adrenocortical carcinoma, and rhabdomyosarcoma. Also seen are a wide variety of other tumors, both malignant and benign [Cohen 2005]. The estimated risk for tumor development in children with BWS is 7.5% with a range of risks estimated between 4% and 21% [Cohen 2005, Tan & Amor 2006, Mussa et al 2016a]. The increased risk for neoplasia appears to be concentrated in the first eight years of life. Tumor development in affected individuals older than age eight years, although uncommon, has been reported.

Children who have milder phenotypes (e.g., macroglossia and umbilical hernia) may have a somatic form of BWS and may still be at increased risk (compared to the general population) of developing tumors associated with BWS. This is in part because BWS-associated molecular changes may be mosaic; that is, many cells with BWS-associated changes may reside in organs "at risk" for tumor development (e.g., liver or kidneys) but not in tissues that influence clinical presentation. Therefore, the index of suspicion should be high when evaluating children with minimal clinical features in the BWS phenotypic spectrum, with strong consideration of the use of genetic testing to confirm the diagnosis.

Other involved organ systems

• Anterior abdominal wall defects including omphalocele, umbilical hernia, and diastasis recti are common.
• Cleft palate, seen in very few individuals with BWS, is typically associated with heterozygous, maternally inherited pathogenic variants in CDKN1C [Hatada et al 1997, Li et al 2001, Mussa et al 2016c].
• Much of the information regarding cardiovascular problems in BWS is anecdotal. Cardiomegaly is present in approximately 20% of affected individuals [Pettenati et al 1986] and may be detected in infancy if a chest x-ray is performed, but typically resolves without treatment.
  • Cardiomyopathy has been reported but is rare.
  • Long QT syndrome has been reported in a child with BWS who had a balanced translocation between chromosomes 11 and 17 which interrupted KCNQ1 [Kaltenbach et al 2013].
• Renal anomalies can include medullary dysplasia, duplicated collecting system, nephrocalcinosis, medullary sponge kidney, cystic changes, diverticula, and nephromegaly [Choyke et al 1998, Borer et al 1999, Mussa et al 2012].
• Hearing loss is rarely reported in individuals with BWS and is either sensorineural [Kantaputra et al 2013] or conductive due to stapedial fixation [Hopsu et al 2003].
  Note: Although parents of children with BWS occasionally raise concerns regarding hearing loss and hypotonia, it is difficult to ascertain whether these and other issues occur with a greater frequency in individuals with BWS compared to the general population rate.
• Brain abnormalities involving the posterior fossa have been rarely reported [Gardiner et al 2012, Brioude et al 2015].

Development is usually normal in children with BWS unless there is a chromosome abnormality, brain malformation, or history of hypoxia or significant untreated hypoglycemia. Neurobehavioral issues such as autism spectrum disorder have been reported with increased frequency in children with BWS ascertained by parental report. However, additional studies including formal neurodevelopmental assessments are needed to assess the frequencies of such problems in BWS.

Adulthood. After childhood, prognosis is generally favorable. However, complications – including renal medullary dysplasia and subfertility in males – can occur. Such issues may be associated with specific molecular subtypes [Greer et al 2008].

Phenotype Correlations by Molecular Mechanism

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

Neoplasia

• UPD of 11p15 or gain of methylation at IC1 is associated with the highest risk for Wilms tumor and hepatoblastoma.
• Loss of methylation at IC2 is associated with a lower risk for tumor development and the tumors reported to date do not include Wilms tumor.
• Intragenic variants on the maternally derived CDKN1C allele are associated with:
  • A small number of cases of neuroblastoma [Bliek et al 2001, Weksberg et al 2001, DeBaun et all 2002, Rump et al 2005, Alsultan et al 2008, Kuroiwa et al 2009];
  • Single cases of ganglioneuroblastoma, acute lymphocytic leukemia, and neuroblastoma in children and melanoma in an adult [Brioude et al 2015].
    Note: Given that leukemia and melanoma occur with some frequency in individuals who do not have BWS, it is difficult to determine whether these single cases represent a coincidental occurrence of two unrelated conditions or if the malignancy was indeed related to BWS.

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

Positive family history is associated with heterozygous pathogenic variants in CDKN1C, deletions at IC1, or (rarely) duplication at IC2 [Weksberg & Shuman 2004, Cooper et al 2005, Prawitt et al 2005, Enklaar et al 2006, Percesepe et al 2008, Scott et al 2008b, Bliek et al 2009].

Cleft palate is associated with heterozygous pathogenic variants of the maternally derived CDKN1C allele [Hatada et al 1997, Li et al 2001].

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

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

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

Developmental delay is associated with paternally derived duplications of 11p15 detectable by cytogenetic analysis [Slavotinek et al 1997].

Severe BWS phenotype is associated with high levels of somatic mosaicism for UPD of 11p15 [Smith et al 2006].

Female monozygotic twinning with discordance for BWS appears to be associated with loss of methylation at IC2; male monozygotic twinning occurs far less frequently and is associated with a range of molecular alterations [Weksberg et al 2002, Smith et al 2006].

Subfertility with or without the use of assisted reproductive technologies (ART) appears to be associated with an increased incidence of babies with BWS caused by loss of methylation at IC2 [DeBaun et al 2003, Gicquel et al 2003, Maher et al 2003a, Maher et al 2003b, Halliday et al 2004].

Penetrance

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

Nomenclature

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

Prevalence

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

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

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Beckwith-Wiedemann syndrome (BWS), the following evaluations are recommended:

• Assessment for airway sufficiency in the presence of macroglossia
• Evaluation by a feeding specialist if macroglossia causes significant feeding difficulties
• Assessment of neonates for hypoglycemia; evaluation by a pediatric endocrinologist if hypoglycemia persists beyond the first few days of life.
• Abdominal ultrasound examination to assess for organomegaly, structural abnormality, and tumors
• Comprehensive cardiac evaluation including ECG and echocardiogram prior to surgical procedures or when a cardiac abnormality is suspected on clinical evaluation
• Alpha-fetoprotein assay at the time of initial diagnosis to evaluate for hepatoblastoma. It is important to utilize normal ranges for specific age categories to guide result interpretation, especially in very young infants.
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

The following are appropriate:

• Prompt treatment of hypoglycemia to reduce the risk of central nervous system complications. Because onset of hypoglycemia is occasionally delayed for several days, or even months, parents should be informed of the symptoms of hypoglycemia so that they can seek appropriate medical attention.
• Abdominal wall repair for omphalocele soon after birth. Generally, this surgery is well tolerated.
• Management of difficulties arising from macroglossia:
  • Anticipation of difficulties with endotracheal intubation [Kimura et al 2008]
  • Assessment of respiratory function, possibly including sleep study to address concern regarding potential sleep apnea
  • Management of feeding difficulties using specialized nipples such as the longer nipple recommended for babies with cleft palate or, rarely, short-term use of nasogastric tube feedings
  • Follow up by a craniofacial team including plastic surgeons, orthodontists, and speech pathologists familiar with the natural history of BWS. Tongue growth does slow over time and jaw growth can accelerate to accommodate the enlarged tongue. Some children benefit from tongue reduction surgery; however, surgical reduction typically affects tongue length but not thickness; residual cosmetic and speech issues may require further assessment/treatment [Tomlinson et al 2007].
  • Orthodontic intervention as needed in later childhood/adolescence
  • Assessment of speech difficulties
• Management of cleft palate following standard protocols
• Referral to a craniofacial surgeon if facial hemihyperplasia is significant
• Consultation with an orthopedic surgeon if hemihyperplasia results in a significant difference in leg length. Surgery may be necessary during early puberty to close the growth plate of the longer leg in order to equalize the final leg lengths.
• Treatment of neoplasias following standard pediatric oncology protocols
• In some individuals with BWS, developmental anomalies of the renal tract are associated with increased calcium excretion and deposition (i.e., nephrocalcinosis). In individuals with evidence of calcium deposits on renal ultrasound examination, assessment for hypercalciuria and a CT scan of the kidneys may be helpful.
  • Referral to a pediatric nephrologist if urinary calcium is elevated and/or a structural renal anomaly is identified
• Referral of children with structural GI tract abnormalities to the relevant specialist
• Management of cardiac problems following standard protocols
• Standard interventions such as infant stimulation programs, occupational and physical therapy, and individualized education programs for children with developmental delay

Prevention of Secondary Complications

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

Surveillance

The following are appropriate:

• Monitoring for hypoglycemia, especially in the neonatal period
• Screening for embryonal tumors, which has traditionally involved the following (see also Note):
  • Abdominal ultrasound examination every three months until age eight years [Beckwith 1998, Tan & Amor 2006, Clericuzio & Martin 2009, Zarate et al 2009]
  • Measurement of serum alpha-fetoprotein (AFP) concentration every two to three months in the first four years of life for early detection of hepatoblastoma [Clericuzio & Martin 2009]. AFP serum concentration may be elevated in children with BWS in the first year of life [Everman et al 2000]. If the AFP is elevated and imaging reveals no suspicious lesion, follow-up measurement of serum AFP concentration plus baseline liver function tests one month later can be used to determine the trend in serum AFP concentrations over time. If the concentration is not decreasing, it is appropriate to undertake an exhaustive search for an underlying tumor [Clericuzio et al 2003].
    Note: (1) Some have proposed revising the tumor surveillance guidelines based on the molecular alteration detected. Scott et al [2006] suggested that children with BWS and IC2 alterations did not require Wilms tumor screening. Brioude et al [2013] proposed that children with BWS and loss of methylation at IC2 should have an ultrasound evaluation at the time of clinical diagnosis and only continue with ultrasound surveillance if visceromegaly or "severe" hemihyperplasia are present; otherwise, clinical examination alone was recommended. Mussa et al [2016b] questioned the rationale for ultrasound surveillance and "tumor markers" for individuals with loss of methylation at IC2 but subsequently, in their guidelines from the Italian Scientific Committee on BWS, suggested that in the near future, tumor screening in clinical practice will cease. Based on personal experience, the present authors continue to recommend tumor surveillance for all children with BWS regardless of the molecular etiology. (2) Although periodic chest x-ray and urinary VMA and VHA assays to screen for neuroblastoma have been suggested, they have not been incorporated into most screening protocols because of their low yield.
• Annual renal ultrasound examination between age eight years and mid-adolescence to identify those requiring further evaluation for findings such as nephrocalcinosis and medullary sponge kidney disease. Those with positive findings should be referred to a nephrologist for further assessment and follow up. Since the natural history of renal disease in adults has not as yet been evaluated, adult-onset renal disease without early findings remains a possibility. Therefore, consideration should be given to periodic renal evaluation in adulthood.
• Consideration of annual or biannual measurement of urinary calcium/creatinine ratio from the time of BWS diagnosis as it may be abnormal in individuals with BWS who have normal findings on ultrasound examination [Goldman et al 2003]
• Developmental screening as part of routine childcare

Evaluation of Relatives at Risk

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

Evaluations can include:

• Genetic testing if a maternal CDKN1C pathogenic variant or familial duplication, deletion, or cytogenetically visible alteration of 11p15 is known;
• Monitoring of an at-risk newborn sib for hypoglycemia, even in the absence of obvious clinical findings on prenatal investigation;
• Strong consideration of tumor surveillance for the apparently unaffected twin of monozygotic twins who are discordant for BWS, given the possibility of shared fetal circulation and resulting somatic mosaicism.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.