Beckwith-Wiedemann syndrome (BWS) is the most common genetic imprinting, overgrowth, cancer predisposition, genetically and clinically heterogeneous disorder characterized by hemihypertrophy/lateralized overgrowth (LO), macroglossia, macrosomia, organomegaly, hyperinsulinism, omphalocele/umbilical hernia, and distinct facial features and varied clinical spectrum with a predisposition to developing tumors during early childhood. BWS is caused by changes on chromosome 11p15.5 and is characterized by a wide spectrum of symptoms and physical findings that vary in range and severity from person to person. Associated features include above-average birth weight (large for gestational age), increased growth after birth (macrosomia), a large tongue (macroglossia), enlargement of certain internal organs (organomegaly), and abdominal wall defects (omphalocele, umbilical hernia, or diastasis recti). BWS may also be associated with low blood sugar levels in the first few days of life (neonatal hypoglycemia) or beyond leading to persistent low blood sugars (hyperinsulinism), distinctive grooves in the ear lobes (ear creases and ear pits), facial abnormalities, abnormal enlargement of one side or structure of the body (lateralized overgrowth) resulting in unequal (asymmetric) growth, and an increased risk of developing certain childhood cancers, most commonly Wilms tumor (kidney tumor) and hepatoblastoma (liver tumor). Beckwith-Wiedemann syndrome has been recently reclassified as Beckwith-Wiedemann spectrum as the clinical presentation can vary from patient to patient. Approximately 80% of people with BWS have changes that appear to occur randomly (sporadically). Familial transmission (inherited forms) occurs in about 5-10% of patients with BWS. About 14% of patients with BWS have an unknown cause for diagnosis. BWS affects at least one in 10,340 live births. Researchers have determined that BWS results from various abnormalities affecting the normal, proper expression of certain genes that control growth within a specific region of chromosome 11 (BWS critical region).
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.
Types
BWS spectrum can be further divided into three subcategories;
- classic or typical BWS,
- atypical BWS, and
- isolated lateralized overgrowth.
A patient who presents with physically apparent features and who appears more affected is thought to present with classic or typical BWS. A patient with fewer isolated features, such as neonatal hyperinsulinism or an embryonal tumor, is thought to present with “atypical” BWS.
Mirror phenotypes in BWS and IMAGe syndrome
| BWS | IMAGe syndrome |
|---|---|
| Macrosomia/hemihyperplasia | Short stature |
| Abdominal wall defects | – |
| Visceromegaly, macroglossia, increased risk of cancer | – |
| Adrenal hyperplasia | Adrenal hypoplasia |
| Anterior ear creases, posterior helical pits, cleft palate, nevus flammeus | – |
| Kidney abnormalities (cytomegaly of the adrenal fetal cortex, medullary dysplasia, delayed development of medullary sponge kidney), increased risk of cancer | Adrenal insufficiency |
| Neonatal hypoglycemia | – |
| Structural cardiac defects | – |
| Advanced bone age | Delayed endochondral ossification associated with osteopenia, hypercalcemia, and/or hypercalciuria |
| Fetal macrosomia (LGA), polyhydramnios, large/dysplastic placenta, long and thickened umbilical cord, increased risk for premature delivery | Intrauterine growth restriction |
| – | Metaphyseal dysplasia |
| – | Micropenis, undescended testes, and varying severity of hypospadias |
Symptoms
The phenotypic features of BWS vary greatly from person to person, which can make a clinical diagnosis based on physical exam findings and molecular diagnoses based on genetic testing challenging. Sometimes, the clinical and molecular diagnoses do not match because clinically the patients may not have many salient physical features of BWS even if they have changed in the BWS critical region based on genetic testing. Some individuals may appear mildly affected while others appear more significantly affected. Affected individuals may not have all of the symptoms listed. The range of clinical features due to changes on chromosome 11p15.5 has been redefined as the Beckwith-Wiedemann spectrum.
Diagnosis of BWS can be challenging because patients are often mosaic as the genetic abnormalities characteristic of BWS may occur in some cells or parts of the body but not others). For this reason, it may be helpful to perform genetic testing on multiple tissues (such as skin biopsies or removed tumors, or pancreas tissue).
Some infants with BWS are born prematurely, but still have an excessive birth weight (large for gestational age). Over half of infants with BWS are above the 97th percentile in weight for gestational age. Overgrowth can continue throughout childhood (macrosomia). Abnormal enlargement of one side or structure of the body (lateralized overgrowth) may occur, resulting in asymmetric growth. Lateralized overgrowth or isolated lateralized overgrowth (ILO) is a new term used to describe what was previously termed hemihypertrophy or hemihyperplasia. ILO is defined as an asymmetric overgrowth of the body. ILO is not limited to one side of the body and it does not specify what part or tissue is displaying overgrowth. For example, a patient may have a larger left arm and a larger right leg.
Abdominal wall defects can include an omphalocele (also known as exomphalos), in which part of an infant’s intestines and abdominal organs are outside of the body because of an opening in the belly button. The intestines and other organs are covered by a thin membrane. Less severe abdominal defects can include protrusion of part of the intestines through an abnormal opening in the muscular wall of the abdomen near the umbilical cord (umbilical hernia), or weakness and separation of the left and right muscles of the abdominal wall (diastasis recti). Additionally, the internal organs of affected individuals can become abnormally enlarged (organomegaly). Any or all of the following organs may be affected: liver, spleen, pancreas, kidneys, or adrenal glands.
Some newborns with BWS may have low blood sugar (neonatal hypoglycemia or hyperinsulinism) due to overgrowth and excessive secretion of the hormone insulin by the pancreas. Insulin helps regulate blood glucose levels by promoting the movement of glucose into cells. Most infants with neonatal hypoglycemia associated with BWS have mild and transient symptoms. However, without proper detection and appropriate treatment, neurological complications may result. Congenital hyperinsulinism is the most common cause of persistent and severe low blood sugar.
Patients with BWS may have an enlarged tongue (macroglossia), which can cause difficulties in speaking, feeding, and breathing. In addition to macroglossia, BWS may be characterized by other abnormalities of the skull and facial (craniofacial) region. Such features may include distinctive slit-like grooves or creases in the ear lobes and dimples on the back of the ears (ear creases or pits), prominent eyes with relative underdevelopment of the bony cavity of the eyes (intraorbital hypoplasia), and/or a prominent back region of the skull (occiput). Some infants may have flat, pale red, or reddish-purple facial marks at birth, most commonly on the eyelids and forehead, which consist of abnormal clusters of small blood vessels (facial nevus simplex). Such marks typically become less apparent during the first year of life. In patients with lateralized overgrowth, one side of the face may appear larger than the other. Due to the mosaic nature of BWS, some patients have eyes with multiple colors. Additionally, in some affected patients, there may be improper contact of the teeth of the upper and lower jaws (malocclusion) and abnormal protrusion of the lower jaw (mandibular prognathism), features that may occur secondary to macroglossia.
A variety of kidney (renal) abnormalities can occur in individuals with BWS, including abnormally large kidneys (nephromegaly), improper development of the innermost tissues of the kidney (renal medullary dysplasia), and the formation of calcium deposits in the kidney (nephrocalcinosis), which could potentially impair kidney function. Additional abnormalities include duplication of the series of tubes and ducts through which the kidneys reabsorb water and sodium (duplicated collecting system), widening of some of the small tubes and collecting ducts (medullary sponge kidney), and the presence of small pouches (diverticula) on the kidneys. Kidney stones have been reported to occur in adolescents and adults with BWS.
Patients with BWS may have an increased risk of developing certain childhood cancers. Embryonal cancers occur in approximately 8% of patients with BWS. The most common types of tumors are Wilms tumor (a kidney tumor), hepatoblastoma (a liver tumor), neuroblastoma (a nerve cell tumor), and rhabdomyosarcoma (a soft tissue tumor), and adrenal carcinoma (an adrenal gland tumor). The overall tumor risk is highest during the first two years of life.
Many clinical features of BWS become less evident with increasing age and many adults experience normal growth and appearance. Neurological (brain) development appears to be unaffected in BWS unless associated with prolonged, untreated neonatal hypoglycemia, extreme prematurity, or a chromosomal duplication. Adult patients may present with medical issues related to these clinical features or have required surgical intervention in early childhood. Most features in adults with BWS, such as renal issues and back pain, are consequences of pediatric issues. However, more research is needed to determine the relationship between features of adults with BWS and pediatric symptoms.
Causes
Genetics is the study of genes whereas epigenetics is the study of how those genes are turned on or off (gene expression). BWS results from various abnormalities affecting the proper expression of genes that control growth within a specific region of chromosome 11(11p15.5). This region is referred to as the BWS critical region.
Approximately 80% of people with BWS have no family history of this syndrome. For these people, BWS is usually caused by epigenetic changes that appear to occur randomly (sporadically). More rarely, BWS is caused by genetic changes that are passed down from a parent (inherited). Approximately 5-10% of patients have BWS due to a family history of the syndrome. About 14% of patients with BWS have an unknown cause for diagnosis.
Everyone has two copies of every gene, one received from the father and one received from the mother. In most people, both genes are “turned on” or active. However, some genes are “turned off” or preferentially silenced based upon which parent that gene came from (a process known as genomic imprinting). Genomic imprinting is controlled by marks on the DNA called methylation. Proper genomic imprinting is necessary for normal development and defective imprinting on chromosome 11 can lead to BWS. Several genes that control growth on chromosome 11 are imprinted, which means that the gene is only active from the mother’s chromosome or the father’s chromosome but not both.
Imprinted genes tend to be clustered or grouped. Chromosome 11p15.5 has two imprinting cluster regions known as imprinting centers 1 and 2 (IC1 and IC2). Several specific imprinted genes are located in these regions. The improper imprinting of these two regions leads to the improper expression of the genes located within the regions, playing a role in the development of BWS. These genes include H19 (a gene that signals not to grow), IGF2 (insulin-like growth factor II), KCNQ10T1 (LIT1), and CDKN1C (p57[KIP2])(a gene that signals not to grow).
H19 is a long noncoding RNA thought to play a role in inhibiting growth. IGF2 is a growth factor. KCNQ10T1 is a noncoding RNA and CDKN1C is a cell cycle regulator and tumor suppressor. Researchers believe that the paternally-expressed genes promote growth and that the maternally-expressed genes act as tumor suppressor genes or inhibit growth. Normally, H19 and CDKN1C are expressed from the maternal chromosome, and IGF2 and KCNQ1OT1 are expressed from the paternal chromosome. Improper methylation in the BWS critical region can lead to an imbalance of the “grow” and “don’t grow” signals, leading to overgrowth.
Gain of methylation (hypermethylation) at imprinting center 1 (IC1 GOM) occurs in about 5% of patients with BWS. This leads to decreased H19 expression and increased IGF2 expression.
Imprinting center 2 (IC2) is associated with KvDMR, a chemical switch found on the KCNQ1 gene. Loss of methylation (hypomethylation) at KvDMR of imprinting center 2 (IC2 LOM) occurs in about 50% of people with BWS. This leads to increased KCNQ10T1 (long QT intronic transcript 1 [LIT1]) expression and decreased CDKN1C expression.
Imprinting errors may also be caused by a chromosomal abnormality known as uniparental disomy (UPD). UPD occurs when a person receives both copies of a chromosome (or part of a chromosome) from one parent instead of receiving one copy from each parent. Approximately 20% of people with BWS have UPD. In BWS, both copies of chromosome 11 are received from the father (paternal uniparental disomy (PD)). As a result, there are too many active paternally-expressed genes (IGF2) in this region and not enough maternally-expressed genes (H19, CDKN1C). Uniparental paternal disomy occurs after fertilization (post-zygotic), and therefore the risk of recurrence is extremely low.
Mosaic genome-wide paternal uniparental isodisomy (GWpUPD) occurs in about 10% of BWS due to PD (approximately 2% of all patients with BWS). In the case of GWpUPD, every chromosome is inherited from the father in the cells that carry the abnormality, instead of just chromosome 11 as in PD. GWpUPD is associated with greater tumor risk. The severity of GWpUPD varies according to the number of cells affected and where the affected cells are located within the patient.
Abnormal changes (mutations) of the CDKN1C gene have been detected in some individuals with BWS. The loss of proper expression or “underexpression” of the gene is thought to play an important role in causing the disorder. Approximately 5% of people with BWS are found to have mutations of the CDKN1C gene. The mutation is inherited as an autosomal dominant trait, which means that only one copy of the mutated gene is needed to pass down the disorder. However, CDKN1C is normally only maternally expressed, and therefore, the offspring will only be affected (i.e. have BWS) if the mutation is passed from mother to offspring. Approximately 40% of individuals with a family history of BWS have mutations of the CDKN1C gene. Mutations in CDKN1C can also occur randomly without the mother carrying the change (de novo mutation). Patients with BWS due to CDKN1C changes have a 50% risk of passing the mutation to their children.
Research has shown that small deletions (microdeletions) affecting imprinting center 1 (IC1) of chromosome 11p15.5 may be the cause of familial BWS in some people. Approximately 1-2% of patients with BWS have deletions involving 11p15.5. Microdeletions of the KCNQ10T1 (LIT1) gene have also been identified in some people with BWS. These microdeletions appear to cause BWS when inherited maternally; when inherited paternally, the disorder does not develop. Small duplications (microduplications), affecting imprinting center 1 (IC1) of chromosome 11p15.5 inherited from the father can also cause BWS. These microduplications can also occur randomly (de novo).
Approximately 2-4% of cases of BWS are due to various chromosomal abnormalities involving the 11p15.5 chromosomal region. This includes chromosomal inversions or rearrangements (translocations) or the presence of extrachromosomal material (duplications).
Phenotype genotype correlation: Researchers are investigating if specific causes of BWS are associated with specific symptoms (genotype-phenotype correlation). Research indicates that omphalocele and macroglossia are more common in individuals with defects of IC2 or a mutation of the CDKN1C gene. Patients with PD are at a greater risk for lateralized overgrowth and hyperinsulinism. Individuals with defects of IC1 or PD appear to be at a greater risk of developing an associated tumor such as Wilms tumor. Patients with PD also have a greater risk of developing a liver tumor (hepatoblastoma). The different molecular types of BWS each carry a different tumor risk. More research is necessary to determine how the specific causes of BWS correlate with the various symptoms of the disorder.
Diagnosis
Patients with BWS can be diagnosed both before and after birth (prenatally and postnatally) either by physical evaluation (clinical diagnosis) and/or genetic testing (molecular diagnosis).
History and Physical
BWS is a complex multisystem disorder that presents in a wide and varied clinical spectrum. For a better understanding of the historical features and physical findings likely to encounter in BWS patients, this section is divided according to the presentation of the syndrome in the different stages of life.
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Prenatal stage: common complications in pregnancies with BWS fetuses usually start after the 22 weeks of gestation with gestational hypertension, pre-eclampsia, gestational diabetes mellitus, vaginal bleeding, polyhydramnios, macrosomic fetus, increased alpha-fetoprotein, and ultrasonographic findings of organomegaly. During birth, patients may present with macrosomia-related complications (e.g., cephalohematoma, brachial plexus injury), premature birth, and placentomegaly. A positive family history of BWS is another important consideration since approximately 15% of cases could be attributed to familial transmission, although it is important to point out that most cases are sporadic.[rx][rx]
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Neonatal period: neonates with BWS may present with macrosomia, whole body hemihypertrophy, limb length discrepancy, distinctive facial appearance, abdominal wall defects (omphalocele, umbilical hernia, or diastasis recti), organomegaly (could involve liver, kidneys, spleen, pancreas, thymus, heart, and adrenal glands), nephrological abnormalities (kidney malformations +/- hydronephrosis), cardiac anomalies (patent ductus arteriosus, patent foramen ovale, and congenital long QT syndrome), and hypotonia. Typical dysmorphic facies in BWS include prominent eyes, infraorbital creases, midfacial hypoplasia, macroglossia (most common feature), prognathism, and anterior earlobe creases, posterior helical pits, and nevus flammeus at the glabella. Other physical findings are cleft palate, supernumerary nipples, polydactyly, and genital abnormalities (cryptorchidism). Neonatal BWS is also characterized by hypoglycemia, most likely secondary to islet cell hyperplasia and hyperinsulinism.[rx][rx][rx]
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Infancy, childhood, and Adolescence: typical features of BWS facies are usually lost in later childhood. Regarding growth parameters, height and weight usually remain around the 90th percentile while head circumference remains around the 50th percentile. Development is, most of the time, not affected unless specific 11p15.5 duplication or perinatal complications were present. Nephrocalcinosis, nephrolithiasis, renal cysts, and recurrent urinary tract infections are common nephrological complications that could develop during infancy to adolescence. Predisposition to embryonal tumor development is one of the most feared characteristics of BWS, for which long-term monitoring is warranted. The most common malignancies reported are Wilms tumor and hepatoblastoma, while others include neuroblastoma, adrenocortical carcinoma, and rhabdomyosarcoma.[rx][rx][rx]
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Adulthood: Most of the features are derived from their pediatric phenotype. Adult height usually ends in the normal range, although some studies report an increased mean adult height in the BWS population. Limb length discrepancy can persist or even worsen, leading to scoliosis. Fertility issues have been reported in males as a primary testicular dysfunction or consequence of cryptorchidism; insufficient data is available for females.[rx][rx]
The diagnosis of BWS is established based on clinical criteria and may be confirmed by molecular/cytogenetic testing. However, given the heterogeneous presentation of this disorder, no consensus exists, and most experts agree that these criteria should not replace clinical judgment on a case-by-case basis. In the same line, negative diagnostic testing cannot rule out BWS.
Clinical Diagnosis
There are several published diagnosis criteria for BWS. Recent reviews consider it acceptable to guide the clinical diagnosis based on the presence of major and minor findings of BWS. The presence of at least three major findings, or two major and one or more minor findings would support the diagnosis of BWS.[rx][rx][rx]
Major Findings
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Abdominal wall defect: omphalocele or umbilical hernia
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Macroglossia
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Neonatal macrosomia (birth weight more than 90 percentile)
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Postnatal overgrowth (height/length more than 90 percentile)
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Embryonal tumors (Wilms tumor, hepatoblastoma, adrenal tumors, neuroblastoma)
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Outer ear malformations (anterior ear creases, posterior helical pits)
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Visceromegaly
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Cytomegaly of the adrenal fetal cortex
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Hemihypertrophy
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Anomalies of the kidney and ureter (e.g., medullary dysplasia, nephrocalcinosis, medullary sponge kidney, and nephromegaly)
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Positive family history of BWS
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Cleft palate
Minor Findings
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Polyhydramnios
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Enlarged placenta, placental mesenchymal dysplasia
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Thickened umbilical cord
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Prematurity
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Neonatal hypoglycemia
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Nevus flammeus at the glabella
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Distinctive facies
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Cardiomegaly, cardiac anomalies, hypertrophic cardiomyopathy
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Diastasis recti
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Polydactyly
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Supernumerary nipples
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Advanced bone age
Novel diagnostic criteria consider the predictive value of each BWS feature. Brioude et al. (2018) proposed a clinical scoring system based on cardinal features (macroglossia, omphalocele, lateralized overgrowth, bilateral Wilms tumor, hyperinsulinism, adrenal cytomegaly or placental mesenchymal dysplasia) and suggestive features (birth weight greater than two standard deviations above the mean, facial nevus simplex, polyhydramnios or placentomegaly, ear creases or pits, transient hypoglycemia, embryonal tumors, nephromegaly or hepatomegaly, and umbilical hernia or diastasis recti). The scoring consist of adding 2 points for each cardinal feature present, and 1 point for each suggestive feature. A total score of 4 or more would confirm a diagnosis of BWS even without the need for testing. A score of 2 or 3 would warrant genetic testing. Finally, a score of less than two would not meet the criteria for testing.[rx][rx]
Molecular Diagnosis
As previously stated, given the wide variety of molecular aberrations that are behind the etiology of BWS, as well as the mosaicism affecting different tissues in the same individual, the molecular diagnosis of this condition requires a multistep approach, and a negative test cannot exclude the diagnosis. Testing is usually performed on DNA derived from blood leukocytes; however, samples from buccal swabs, skin fibroblasts, or mesenchymal-derived cells from surgical resections and/or excisions of hyperplastic tissues, could be used to improve the detection. Different testing approaches have been recommended. The most widely used tests are the following:[rx][rx]
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Methylation analysis: consider first-line testing since methylation alteration could be detected in most cases of BWS with known molecular etiology. Further studies such as copy number variant (CNV) testing might be needed to determine the exact molecular mechanism.
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Sequencing analysis, or gene-targeted sequencing: test to be considered if methylation analysis is negative. Useful in the detection of pathogenic variants of genes in the 11p.15 region, specially CDKN1C mutations.
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Chromosomal microarray, SNP array, or microsatellite analysis: could detect microdeletions, microduplications, or length of paternal uniparental disomy region of chromosome 11.
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Karyotype or FISH: could detect chromosomal defects associated with BWS such as duplication, inversion, or translocation of 11p15.5.
Genetic Testing
Genetic testing approaches can include DNA methylation studies, single-gene testing, copy number analysis for (sequences within) 11p15.5, chromosomal microarray, karyotype, and use of multigene panels that include genes in the BWS critical region:
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DNA methylation studies – of IC1 and IC2 should be performed simultaneously. Methylation alterations at both IC1 and IC2 suggest uniparental disomy. For recurrence risk purposes, further genetic studies can be undertaken to define the mechanism that leads to the methylation abnormality (see Genetic Counseling).
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Single-gene testing – Sequence analysis followed by gene-targeted deletion/duplication analysis of CDKN1C should be considered in familial cases, in individuals with BWS and midline anomalies (cleft palate, posterior fossa abnormalities, omphalocele, or hypospadias [rx]), or in individuals for whom a strong clinical suspicion for BWS exists but no detectable chromosome 11p15.5 cytogenetic abnormalities, copy number variants, methylation abnormalities, or UPD has been identified.
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Chromosomal microarray (CMA) – using oligonucleotide arrays or SNP genotyping arrays can detect a deletion or duplication in a proband. CMA may be considered first in a proband with intellectual disability. The ability to size the deletion depends on the type of microarray used and the density of probes in the 11p15.5 region [rx, RX, rx]. SNP array analysis can also detect segmental paternal uniparental disomy.
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Karyotype – A karyotype may be considered to test for an inversion or translocation involving 11p15.5. This accounts for fewer than 1% of individuals with BWS.
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A multigene panel – that includes CDKN1C and other genes of interest may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting the identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
Prenatal Diagnosis
If there is a positive family history of BWS or the presence of prenatal features, genetic counseling is warranted, and testing could be offered. Methylation analysis and CDKN1C sequencing are the preferred diagnostic tests in these situations. Regardless of any positive or negative result, postnatal testing is needed for confirmation.[rx][rx]
A BWS consensus scoring system has been established to help with the clinical diagnosis of BWS and to determine the need for molecular testing. Features that will more likely lead to a positive diagnosis of BWS are termed “cardinal features” (including macroglossia, omphalocele, lateralized overgrowth, multiple Wilms tumors, hyperinsulinism, and specific pathology findings including adrenal cytomegaly (enlargement of the cells in the adrenal gland) and placental mesenchymal dysplasia (enlargement of cells in the placenta)). As such, cardinal features are given two points each in the scoring system. Features that are seen in BWS but are also present in the general population are termed “suggestive features” (including large birth weight, macrosomia, facial nevus simplex, polyhydramnios or placentamegaly, ear creases or pits, hypoglycemia, embryonal tumors such as single Wilms tumors or hepatoblastomas, nephromegaly or hepatomegaly, umbilical hernia, and diastasis recti). Suggestive features are given one point each. A total of four or more points, two of which should be due to a cardinal feature, is consistent with a clinical diagnosis of BWS. A total of two or more points indicates the need for molecular testing, especially if a cardinal feature is present.
Genetic testing looks for changes in the BWS critical region. This includes looking at the methylation marks (11p15.5 methylation analysis) on the DNA followed by looking at the number of copies of the imprinting control regions (11p15.5 copy number analysis) that are present in that region (normally there should be two copies). This will detect if there are deletions or duplications of the region. Additionally, if the previous testing is normal, CDKN1C sequencing is performed to detect any changes in the CDKN1C gene. Additional testing that looks at all of the chromosomes is recommended for patients determined to have UPD based on the methylation analysis. A chromosome microarray or a single nucleotide polymorphism (SNP) array is used to detect the extent of the region of UPD.
Not every patient with a clinical diagnosis of BWS will have positive confirmatory molecular testing of the syndrome. This is because most of the genetic and epigenetic changes that occur to cause BWS are not present in every cell. This is termed “mosaicism.” For this reason, testing multiple tissues can increase the likelihood of finding the cause of BWS. Negative testing on blood, for example, may not necessarily exclude a diagnosis. A recent study demonstrated that testing multiple tissues increased molecular diagnostic yield from 70% to 82%.
Treatment
The treatment of BWS is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Geneticists, pediatricians, plastic surgeons, endocrinologists, nephrologists (kidney specialists), orthodontists (dental specialists), pulmonologists (lung specialists), speech pathologists, pediatric oncologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment.
Given the high heterogenicity and the variable degree of the features when present, treatment indications should be customized for each specific patient.[rx][rx][rx][rx]
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Prenatal management: in suspected or confirmed cases, it is important to anticipate possible fetal or maternal complications (maternal pre-eclampsia, congenital anomalies, macrosomia-related complications, postnatal hypoglycemia), and provide adequate care. Delivery should be planned to occur in an institution with a neonatal intensive care unit.
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Management of hypoglycemia: glucose monitoring should be performed for the first 48 hours of life. If hypoglycemia is detected, the newborn should be transferred to a neonatal intensive care unit for management as per general guidelines. If no hypoglycemia is detected, fasting tests, including glucose, insulin, and ketones, are recommended at 48 hours of life and before nursery discharge. Severe persistent hyperinsulinism warrants further investigation.
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Management of growth anomalies: growth should be routinely monitored using growth charts specifically modified for BWS patients. Interventions for possible tall stature could be considered. Lateralized overgrowth should be monitored clinically, at least once a year. If a leg-length discrepancy is encountered, referral to a pediatric orthopedic surgeon is warranted; on the contrary, an arm-length discrepancy is generally monitored clinically with no indication for surgical correction.
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Management of macroglossia: feeding problems require the involvement of feeding specialists and dietitians. For suspected airway obstruction, careful evaluation, including sleep studies and consultations with pulmonologists and ear, nose, and throat specialists, are needed. Tongue-reduction surgery is indicated if there are macroglossia-related complications such as feeding difficulties, persistent drooling, speech difficulties, dental malocclusion, and appearance-related psychosocial problems, usually performed after the age of 1 year, or earlier in cases of severe airway obstruction.
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Management of abdominal wall defects: there are no additional specific recommendations than the general guidelines for these conditions.
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Management of cardiac anomalies: a baseline clinical cardiovascular examination is necessary at diagnosis. If anomalies are detected or suspected, referral to a cardiologist specialist for assessment and echocardiography is required. Annual evaluation and electrocardiogram are recommended for patients with a known molecular aberration involving the IC2 region.
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Management of renal complications: clinical and ultrasonographic evaluation for nephrological anomalies is needed at diagnosis and at the time of adult transition. If anomalies are detected, referral to a nephrologist and urologist is necessary. Nephrocalcinosis and renal stones should also be monitored along with abdominal surveillance for tumor screening.[rx][rx]
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Management and monitoring of embryonal tumors: BWS is a recognized cancer predisposition syndrome, with an estimated tumor risk of 8 to 10% in the first decade of life, with the highest incidence during the first 2 years of life. Different tumor screening protocols have been proposed with common goals of early detection, reducing morbidity, and increasing survival. The protocol of tumor surveillance used in the USA includes the performance of abdominal ultrasound and serum alpha-fetoprotein (AFP) at diagnosis, then every 3 months until age 4 years. Thereafter, only ultrasound screening should be continued every 3 to 4 months until the age of 7 years. Abdominal ultrasound screening covers the most common associated tumors, including Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma, and adrenal carcinoma. AFP is specifically used for monitoring hepatoblastoma; however, it has been involved in recent controversies due to the presence of higher levels of this marker in BWS infants which obscure its interpretation, and the implications of repeated venipuncture. Even though certain molecular defects have more predisposition to certain types of cancer, it is recommended to apply the protocol to all BWS patients regardless of the molecular subtype.[rx]
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Management of neurological features: cognitive development is usually normal, but monitoring by a pediatrician is recommended, especially if perinatal complications (prematurity, birth trauma, neonatal hypoglycemia) or chromosomal anomalies are present.
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Monitoring of late-onset complications: a comprehensive evaluation at age 16 to 18 years is recommended to detect any complications that would require follow-up by adult healthcare services. Genetic counseling should be offered for family-planning advice.
Similar to other features associated with BWS, macroglossia can vary in severity. Patients with macroglossia are at an increased risk for obstructive sleep apnea, feeding difficulties, speech difficulties, and potential jaw development issues. Patients with macroglossia require the support of a multidisciplinary team. They should undergo feeding evaluation and sleep studies in addition to consultations with plastic surgeons and pulmonologists if needed. Feeding difficulties caused by macroglossia may require the support of feeding specialists or dieticians. Treatment may include the use of specialized nipples or the temporary insertion of a nasogastric tube. Speech difficulties may require the support of speech therapy. A pulmonologist can evaluate the degree to which macroglossia affects a patient’s breathing and sleeping. Polysomnography (sleep study) may be used to assess for obstructive sleep apnea, airway obstruction, airway resistance, severe desaturation, sleep-disordered breathing, and snoring. Continuous positive airway pressure (CPAP) is a method used to support children with obstructive sleep apnea. Some patients may undergo tongue reduction surgery to improve breathing, feeding, and jaw or dental malformations due to macroglossia. Patients with macroglossia should be followed closely by a multidisciplinary team.
Regular orthopedic evaluation is recommended for patients with lateralized overgrowth. Some patients with significant lateralized overgrowth of the limbs may require shoe lifts and in some cases, surgical correction may be needed.
In addition, infants and patients with BWS should undergo regular abdominal and renal ultrasounds, and measurement of serum alpha-fetoprotein levels as recommended enabling early detection and treatment of certain malignancies that may occur in association with BWS (e.g., Wilms tumor, hepatoblastoma).
Alpha-fetoprotein (AFP) is a protein produced by the liver. AFP levels typically decline during infancy; however, AFP may be abnormally elevated in blood if certain tumors are present (hepatoblastoma). The trend in AFP levels over time should be followed in patients with BWS and normal AFP values for children with BWS are available to aid in the interpretation of results. There have been recent discussions regarding the utility of AFP screening in young children. While some suggest that the invasiveness of a regular blood draw may be stressful for many families, AFP has proven to be a useful early indicator for hepatoblastoma.
According to the United States-based guidelines, screening is recommended for all patients with a clinical or molecular diagnosis of BWS by AFP analysis and a full abdominal ultrasound every three months until the 4th birthday (to screen for hepatoblastoma and Wilms tumor) followed by renal ultrasounds every 3 months until 7th birthday (to screen for Wilms tumor). Additional screening by urine analysis for neuroblastoma is recommended for patients with CDKN1C mutations. Also, screening for patients with BWS due to GWpUPD may extend beyond the 7th birthday.
If a tumor develops in association with BWS, the appropriate treatment measures vary depending on the specific tumor present, the stage and/or extent of disease, and/or other factors. Treatment methods may include surgery (for example, nephron-sparing kidney resection in the case of a Wilms tumor), use of certain anticancer drugs (chemotherapy), radiation therapy, and/or other measures. (For more information on Wilms tumor, choose “Wilms” as your search term in the Rare Disease Database.)
Patients with cardiac, gastrointestinal, and renal abnormalities may require certain medications, surgery, or other medical interventions. These patients should be referred to appropriate specialists. Genetic counseling may be of benefit for affected individuals and their families. Another treatment is symptomatic and supportive.
Late-onset complications with BWS may require continued follow-up in adulthood. More research is needed to understand the features and associated treatments for adults with BWS.
Complications
The following are some of the complications seen in patients with BWS
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Perinatal complications: gestational hypertension, pre-eclampsia, gestational diabetes mellitus, vaginal bleeding, polyhydramnios, prematurity, and macrosomia-related complications (cephalohematoma, brachial plexus injury, or other birth trauma).
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Neonatal complications: increased risk for mortality mainly as a result of complications of prematurity, macroglossia (breathing and feeding difficulties), hypoglycemia, and, rarely, cardiomyopathy.[rx]
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Other complications: speech issues related to macroglossia, cognitive impairment related to specific chromosomal anomalies and/or perinatal complications, high risk to develop embryonal tumors (especially Wilms tumor and hepatoblastoma), nephrocalcinosis, nephrolithiasis, renal cysts, recurrent urinary tract infections, scoliosis related to the leg-length discrepancy, fertility issues from cryptorchidism, and psychosocial issues related to the fear for the condition and complications.[rx][rx]
References
