Beckwith–Wiedemann syndrome (BWS), the most prevalent epigenetic disorder, has a variety of clinical symptoms, including overgrowth, abdominal wall defects, and predisposition to embryonal tumors.
It is a human genomic imprinting disorder linked with changes in chromosome 11. The clinical symptoms of BWS range in severity and are commonly identified neonatally or in early childhood.
Beckwith-Wiedemann syndrome is linked to genetic and epigenetic alterations in the 11p15 region of chromosome 11, which contains imprinted genes that control fetal and postnatal development.
In the 11p15.5 region, growth-inhibitory genes like Cyclin-Dependent Kinase Inhibitor 1C (CDKN1C) and H19 coexist with growth promoters like Insulin-like Growth Factor 2 (IGF2). The 11p15.5 gene cluster is functionally separated into two domains, each controlled independently by an imprinting center (IC) methylated in a parent-of-origin way on only one parental chromosome.
The genetic errors that cause BWS are diverse, but they always damage the 11p15.5 region, which leads to uneven expression of imprinted genes in roughly 80% of cases. Most molecularly verified BWS cases (>90%) are sporadic.
The remaining 10% of cases have an autosomal dominant inheritance with penetrance dependent on the parent of origin.
Patients with BWS can present with a spectrum of clinical features, including macroglossia (enlarged tongue), abdominal wall defects, organomegaly (enlarged organs), ear creases/pits, nephrological anomalies, macrosomia (excessive birth weight), and lateralized overgrowth.
The syndrome is defined by the association of multiple symptoms that might present with varying degrees of severity, defining the disorder's clinical spectrum. The most common symptom of BWS is macroglossia, which affects 90-97 percent of patients.
Only about half of all cases of macrosomia are apparent at birth. Omphalocele, umbilical hernia, and diastasis recti are all abdominal wall abnormalities. Hemihyperplasia is the feature that has the strongest link to tumor growth, indicating that it is a reliable clinical predictor of malignancy.
The liver, kidneys, pancreas, spleen, thymus, heart, and adrenal glands are among the organs that can expand due to organomegaly. A pathognomonic histologic finding is fetal adrenocortical cytomegaly. Organ enlargement is linked to the development of cancer. In 28-61% of BWS patients, nephrological anomalies are present.
The most prevalent abnormalities in infants and early infancy include nephromegaly, cortical or pyramidal hyperechogenicity, and kidney anomalies. Polyhydramnios during pregnancy may be linked to ureteral enlargement caused by vesicoureteral reflux.
Infections in newborns and early childhood can be caused by severe forms, which are one of the most common childhood complications. Hypoglycemia affects about half of BWS neonates, with the majority of cases resolving on their own.
Midface hypoplasia, infraorbital creases, macroglossia, and relative microcephaly with metopic ridge are some features associated with facial defects. Cardiac anomalies are found in 20% of children with BWS. The most common is cardiomegaly or mild to severe anatomic malformations such as patent ductus arteriosus or foramen ovale.
These flaws normally go away on their own. Polydactyly, genital anomalies, extra nipples, and cleft palate are other traits. BWS children's neuropsychomotor development is often normal. Duplications of chromosome 11p15.5 inherited from the father are frequently linked to intellectual impairment. Overgrowth affects 43–65 percent of BWS patients, with lateralized overgrowth occurring when one side of the body is larger.
During the first decade of life, the probability of developing an embryonal tumor is believed to be 8-10%. Neoplasms most commonly form during childhood, with risk peaking at birth and gradually decreasing throughout the first ten years of life to the risk seen in the general population.
The most prevalent histotype is Wilms' tumor (43%). This is followed by hepatoblastoma (20%), adrenal adenoma/carcinoma (7%), neuroblastoma, rhabdomyosarcoma, pancreatoblastoma, and leukemia. Significant differences in cancer risk and histotype incidence distinguish BWS molecular subgroups.
The frequency of cases with a definite diagnosis is estimated to be one in 10,500 live births. The prevalence is nearly equal in both sexes, with a pan-ethnic distribution. Although no proven risk factor exists, mounting data suggests that BWS is more common among children created by Artificial Reproductive Techniques (ART).
These are connected with a one in 1,100 increase in risk. According to a study, outwardly recognized characteristics of BWS (omphalocele and macroglossia) appear more common in Caucasian individuals, whereas less visually prominent features appear more common in non-Caucasian patients (hyperinsulinism, nephromegaly).
Diagnosis and management
BWS is a clinical diagnosis based on criteria that have evolved. It is widely accepted that a diagnosis can be made if the patient meets three major or at least two major plus one minor criterion.
Recently, a new scoring system was published to assist clinicians in proposing molecular tests. Macroglossia and abdominal wall abnormalities are given far more weight in this approach than other BWS traits. In people with BWS, molecular genetic testing can detect epigenetic and genomic changes on chromosome 11p15.
Molecular tests can help confirm a diagnosis, assist a geneticist in providing appropriate counseling, and assist a clinician in determining cancer risk. BWS can be detected through standard prenatal ultrasounds at various stages of pregnancy or after an abnormal biochemical screen for Down's syndrome. At various stages of pregnancy, routine screening for fetal abnormalities is usually performed.
All patients with BWS should be referred to and preferably followed up with regularly at the Centers for Rare Diseases to evaluate and track disease patterns and set up necessary diagnostic tests and supplementary procedures.
Treatment of manifestations involves treatment of hypoglycemia, repair of the abdominal wall, managing feeding difficulties occurring as a result of macroglossia, and speech therapy. Management of other symptoms may also help the patients.
- Wang KH, Kupa J, Duffy KA, et al. (2020). Diagnosis and Management of Beckwith-Wiedemann Syndrome. Frontiers in pediatrics, 7, 562. doi:10.3389/fped.2019.00562. https://www.frontiersin.org/articles/10.3389/fped.2019.00562/full
- Duffy KA, Sajorda BJ, Yu AC, et al. (2019). Beckwith-Wiedemann syndrome in diverse populations. American journal of medical genetics. Part A, 179(4), 525–533. doi:10.1002/ajmg.a.61053. https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.61053
- Brioude F, Kalish JM, Mussa A, et al. (2018). Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nature reviews. Endocrinology, 14(4), 229–249. doi:10.1038/nrendo.2017.166. https://www.nature.com/articles/nrendo.2017.166
- Mussa A, Molinatto C, Cerrato F, et al. (2017). Assisted Reproductive Techniques and Risk of Beckwith-Wiedemann Syndrome. Pediatrics, 140(1), e20164311. doi:10.1542/peds.2016-4311. https://publications.aap.org/pediatrics/article-abstract/140/1/e20164311/37961/Assisted-Reproductive-Techniques-and-Risk-of?redirectedFrom=fulltext
- Mussa A, Di Candia S, Russo S, et al. (2016). Recommendations of the Scientific Committee of the Italian Beckwith-Wiedemann Syndrome Association on the diagnosis, management and follow-up of the syndrome. European journal of medical genetics, 59(1), 52–64. doi:10.1016/j.ejmg.2015.11.008. https://www.sciencedirect.com/science/article/abs/pii/S176972121530046X?via%3Dihub
- All Genetic Disorder Content
- What are Genetic Disorders?
- Genetic Disorder Comorbidities
- Multifactorial And Polygenic (Complex) Genetic Disorder
- Single Gene Genetic Disorder
Last Updated: Aug 29, 2023