Beckwith-Wiedemann Syndrome (BWS) is the most common overgrowth syndrome. The condition was named after American pediatric pathologist John Bruce Beckwith in 1963, and German pediatrician Hans-Rudolf Wiedemann in 1964, reported the syndrome independently. Etiologically, BWS is a human imprinting disorder caused by genetic and epigenetic changes affecting the regulation of genes on chromosome 11p15 region. It presents with a wide and varied clinical spectrum, which can make the diagnosis challenging in some cases. Among the clinical signs, macrosomia, macroglossia, and abdominal wall defects stand out as the most common features. BWS is also a cancer predisposition syndrome. Thus, early recognition of the condition in the prenatal or neonatal period is critical for monitoring and timely treatment of complications.
The etiology of Beckwith-Wiedemann Syndrome is complex. About 80-90% of patients have a known molecular aberration that affects the regulation of a group of imprinted genes implicated in cell cycle progression and somatic growth control located in the chromosome 11p15.5. Genomic imprinting is an epigenetic-regulated process by which only one copy of a gene is expressed depending on the sex of the parent carrying the allele. Two imprinting control regions (IC1 and IC2) regulate the gene expression from the 11p15 region. Normally, methylation (silencing of gene expression) occurs in the paternal allele at IC1 and the maternal allele at IC2. In an individual with BWS, the molecular defects more commonly described are:
The incidence of BWS is estimated in 1:10,000 to 13,700 live births, a number that is likely underestimated due to subtle phenotypes. It affects all ethnic groups with a 1:1 sex ratio. There is a known positive correlation with assisted reproductive techniques with a 10-fold increase risk of BWS.
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.
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.
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.
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.
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:
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.
The management of patients with BWS entails a qualified lead health-care provider to oversee the coordination for the care of the patient, following a holistic approach. Once a diagnosis of BWS is made or even suspected, anticipatory medical management is required, as well as a comprehensive plan that includes standard supportive medical and surgical care, as necessary. Given the high heterogenicity and the variable degree of the features when present, treatment indications should be customized for each specific patient.
BWS is one of the multiple overgrowth syndromes along with isolated hemihyperplasia (IH), Sotos, Simpson-Golabi-Behmel, Costello, Perlman, Weaver, NF1-microdeletion, and Proteus syndromes, among others. The diagnosis is usually achieved with a comprehensive clinical assessment, including family history detailed documentation of physical findings, and confirmation with genetic/molecular analysis if needed. A particular consideration in the differential diagnosis of BWS should be isolated hemihyperplasia since they could share similar epigenetic alterations in 11p15, but this condition should not be reclassified as BWS solely on this finding.
Many other genetic syndromes and endocrine diseases may also share features with BWS, including mosaicism for trisomy 8, congenital hypothyroidism, mucopolysaccharidosis (Hurler, Hunter, and Maroteaux–Lamy syndromes), gangliosidosis, and Pompe disease which should be included in the differential diagnosis.
In the neonatal period, the finding of macrosomia, macroglossia, and hypoglycemia, should prompt a comprehensive evaluation, including maternal diabetes mellitus.
In children considered to have BWS and developmental delay with no chromosomal abnormalities, and no history of prematurity, birth trauma, or neonatal hypoglycemia, other causes of developmental delay need to be considered.
The prognosis varies depending on the severity of the clinical presentation, the molecular subtype, and the timely diagnosis of the condition. In general, most patients with BWS would have a normal life expectancy. Adults with BWS would present features related to their pediatric phenotype, with a good prognosis provided an early recognition of the disease, proper anticipatory guidance, and management of complications if they were to develop.
Patients and their families should be offered counseling, education, support, and guidance since the moment of diagnosis. As part of the holistic approach to the management of patients diagnosed with BWS, providers must facilitate contact information for BWS support groups and resources, including the entries on Beckwith-Wiedemann syndrome at the National Organization for Rare Disorders (NORD), the Beckwith-Wiedemann Children’s Foundation International (BWCFI), among others.
Beckwith-Weidemann syndrome (BWS) is a heterogeneous syndrome that could affect one or multiple systems. Classic features may or may not be obvious at birth. The etiology of BWS is complex. Most cases are sporadic molecular alterations of genes in the chromosome 11p15 region. The index of suspicion should be high when evaluating a case of BWS, with strong consideration of the use of genetic/molecular testing to confirm the diagnosis. Anticipatory guidance of the complications is fundamental in the care for these patients, with special consideration of a tumor protocol surveillance given the high risk of developing embryonal tumors during infancy and childhood. Early diagnosis and a holistic management approach with a multidisciplinary team are also indispensable to ensure a good prognosis for the patient.
In the management of BWS patients, it is fundamental to include different specialists to provide the best possible care. In order to coordinate this, an experienced lead health-care provider should work closely with the patients and their families to ensure the continuous monitoring and follow-up needed in this specific population. Specific treatment indications, including supportive medical and surgical care, should be personalized for each specific case depending on the clinical presentation and molecular subtype if known. Periodic evaluations and proper transition to adult health-care services are also tasks that the primary care provider should arrange.
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