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Beckwith-Wiedemann Syndrome

BWS

Beckwith-Wiedemann Syndrome is defined as an overgrowth disorder which is mainly characterized by an unusual growth pattern in infants together with an increased risk of getting cancer.


Presentation

The patients of Beckwith Wiedemann Syndrome manifest the intrauterine signs and symptoms, but the pregnancy continues uncomplicated. Some important signs during pregnancy are a large abdominal circumference, raised volume of amniotic fluid, protruding tongue, and large placenta for gestational age baby. At birth, the baby is identified by the presence of a large body and large organs. Beckwith Wiedemann Syndrome manifests as macroglossia, midline abdominal wall defects such as omphalocele, exomphalos, umbilical hernia, and diastasis recti and macrosomia [5]. Macroglossia can lead to problems with breathing, eating, and speech. It has been seen that patients are prone to sleep with disordered breathing, which is due to multiple factors, including macroglossia [6]. The commonest feature is neonatal hypoglycemia which is also feared to cause death. The mental retardation is also due to hypoglycemia during infancy making it a significant etiologic factor. The other features of Beckwith Wiedemann Syndrome are large, prominent eyes, ear creases, ear pits, nevus flammeus, prominent occiput, midface hypoplasia, hemihypertrophy, and hearing loss. The overgrowth also extends to the internal organs particularly causing hepatomegaly and nephromegaly. 5% to 20% of the patients may develop embryonal tumors most frequently Wilm’s tumor and hepatoblastoma. The other tumors are rhabdomyosarcoma and adrenocortical carcinoma. These tumors mostly occur in the first 8 to 10 years of life. The patients of Beckwith Wiedemann Syndrome continue to grow and gain weight throughout infancy and childhood at an unusual rate resulting in all the features that have been indicated.

Down Syndrome
  • Prune belly anomalies in a girl with Down syndrome. Pediatr Nephrol. 2003;18:1191-92. Wisanuyotin S, Dell KM, Vogt BA, et al. Complications of peritoneal dialysis in children with Eagle-Barrett syndrome. Pediatr Nephrol. 2003;18:159-63.[rarediseases.org]
Pediatric Disorder
  • Initial management of complex pediatric disorders: prune belly syndrome, posterior urethral valves. Urol Clin North Am. 2004;31:399-415. Summaria V, Minordi LM, Canade A, et al. Megaureter and ureteral valves. Rays. 2002;27:89-91. Cromie WJ.[rarediseases.org]
Macroglossia
  • Cold surgical techniques are commonly used in treating macroglossia. We presented tongue reduction with laser and its early result on a child with Beckwith-Wiedemann syndrome for macroglossia.[ncbi.nlm.nih.gov]
  • Its most common feature is macroglossia, being present in most cases. Clinically macroglossia can compromise the airway, cause dysphagia, drooling and poor cosmesis.[ncbi.nlm.nih.gov]
  • Macroglossia is present in the majority of patients with Beckwith-Wiedemann syndrome (BWS) and surgical treatment may be indicated.[ncbi.nlm.nih.gov]
  • Macroglossia is observed in the majority of patients with Beckwith-Wiedemann syndrome (BWS), a congenital condition with characteristic anomalies.[ncbi.nlm.nih.gov]
  • KEYWORDS: Sleep apnea; child; infant; macroglossia; obstructive; syndrome[ncbi.nlm.nih.gov]
Cardiomegaly
  • Although cardiomegaly is common, it usually resolves on its own. Childhood malignancies and renal anomalies pose large health threats and mortality risks. After childhood, the complications for patients with BWS are infrequent.[en.wikibooks.org]
  • Cardiac malformations are found in 9-34% of cases and about half of these have spontaneously-resolving cardiomegaly. Cardiomyopathy is rare.[orpha.net]
  • 1977 Am J Dis Child. 1977;131(3):293-294. doi:10.1001/archpedi.1977.02120160047007 Full Text • Twelve of 13 patients with BeckwithWiedemann syndrome were found to have cardiovascular abnormalities: congenital heart disease in 7 of the 12 and isolated cardiomegaly[jamanetwork.com]
  • […] 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[en.wikipedia.org]
  • Cardiomegaly is frequently present, but usually resolves without treatment. Non-malignant kidney abnormalities, including renal cysts and hydronephrosis, occur in approximately 25% of patients.[encyclopedia.com]
Hepatomegaly
  • Posterior helical ear pits Polydactyly of right hand and photo of ear with creases / pits Case of BWS with an enlarged tongue and omphalocele Gross images Images hosted on other servers: Large lobulated adrenal glands Placental mesenchymal dysplasia Hepatomegaly[pathologyoutlines.com]
  • (hypoglycemia), enlarged kidney (renomegaly), asymmetrical body (one body side/part, is bigger than the other) Apart from these, the infant may have large eyes, undescended testicles (cryptorchidism), small head size (microcephaly), enlarged liver (hepatomegaly[dovemed.com]
  • The overgrowth also extends to the internal organs particularly causing hepatomegaly and nephromegaly. 5% to 20% of the patients may develop embryonal tumors most frequently Wilm’s tumor and hepatoblastoma.[symptoma.com]
Hepatosplenomegaly
  • […] unique set of features that can consist of: macroglossia : most common clinical finding 4 otic dysplasia ref omphalocoele localized gigantism / macrosomia hemihypertrophy cardiac anomalies pancreatic islet cell hyperplasia organomegaly nephromegaly hepatosplenomegaly[radiopaedia.org]
Placental Disorder
  • Placental mesenchymal dysplasia (PMD) is a distinct placental disorder that may coexist with a normal fetus. In one-third of cases, the fetus exhibits Beckwith-Wiedemann Syndrome (BWS).[ncbi.nlm.nih.gov]
Ear Lobe Crease
  • Clinical overlap exists between Simpson-Golabi-Behmel syndrome (SGBS) and Beckwith-Wiedemann syndrome (BWS) which share pre- and postnatal overgrowth, macroglossia, umbilical hernia, organomegaly, ear lobe creases, and occurrence of embryonal tumors as[ncbi.nlm.nih.gov]
  • Children with BWS may have one or several of the following symptoms: Abdominal wall defects Ear lobe creases Enlargement of some organs and tissues External ear abnormalities Large size Large, prominent eyes Large tongue, sometimes protruding Lethargy[kidspot.com.au]
  • 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[en.wikibooks.org]
  • lobe creases / posterior helical ear pits Anterior abdominal wall defects Omphalocele / exomphalos Umbilical hernia Diastasis recti Visceromegaly involving liver, spleen, kidneys, adrenals and pancreas Renal abnormalities ( nephrocalcinosis , medullary[pathologyoutlines.com]
  • lobe creases or pits Visceromegaly, which is the enlargement of 1 or more abdominal organ Embryonal tumor ( Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma ) Adrenocortical tumor ( adrenal gland tumor ) Kidney abnormalities Cleft palate,[cancer.net]
Prominent Occiput
  • Raised fontanelle, prominent occiput. Metopic ridge, prominent on forehead due to early closure of fontanelle. Others: Seizures. Cryptorchidism. Early bone maturation. Naevus flammeus - stork bite mark over eyelids and forehead.[patient.info]
  • A prominent occiput Hypoplasia of the midface Hemihypertrophy Kidney enlargement Heart abnormalities Musculokeletal abnormalities Hearing loss Adrenal enlargement Beckwith-wiedemann syndrome is also characterized by childhood tumor formations such as:[syndromespedia.com]
  • The other features of Beckwith Wiedemann Syndrome are large, prominent eyes, ear creases, ear pits, nevus flammeus, prominent occiput, midface hypoplasia, hemihypertrophy, and hearing loss.[symptoma.com]
Renomegaly
  • […] large-sized tongue that causes breathing and feeding problems, abnormally large body at birth Minor features: Creases at the earlobes, blood vessel defect called port-wine stain (often seen as a red birthmark), low blood sugar (hypoglycemia), enlarged kidney (renomegaly[dovemed.com]

Workup

The diagnosis of Beckwith Wiedemann Syndrome is usually done on the basis of the presenting signs and symptoms. However, a prenatal diagnosis of the syndrome is possible too. The ultrasound will make evident the large, protruding tongue as well as the presence of large kidneys [7]. MRI scans of the fetus can be used to confirm the same. An amniotic fluid sample can be obtained for genetic analysis of the disorder. At birth and thereafter regular tests to assess hypoglycemia are mandatory. The use of a glucometer is useful in measuring the blood sugar levels and documentation of sugars less than 60mg/dl should be done. Whenever the blood is being tested for sugars, plasma ketones must also be obtained. Patients must be screened for hypercalciuria by obtaining a random, non-fasting urine sample at every follow up visit. Imaging studies are helpful in screening and diagnosing embryonal tumors and picking up malignancies at the earliest. X-ray of the chest can pick up thoracic neuroblastoma and X-ray of the long bones is also helpful. Abdominal ultrasound, CT scan, and MRI can pick up Wilm’s tumor, adrenocortical neoplasias and other tumors [8]. As described by Dr. Wiedemann several years back, it is advisable to conduct abdominal ultrasound every 3 months till 3 years of age and then every 6 months thereafter.

Visceromegaly
  • Most common manifestations are exomphalos, macroglossia, gigantism, and visceromegaly.[ncbi.nlm.nih.gov]
  • The main features of Wiedemann-Beckwith syndrome (WBS) include macroglossia, abdominal wall defects, visceromegaly, gigantism, hypoglycemia, ear creases, nevus flammeus, and mid-face hypoplasia.[ncbi.nlm.nih.gov]
  • Features characteristic of the BWS phenotype include both physical attributes, such as macroglossia, abdominal wall defects, gigantism, nevus flammeus, visceromegaly, and mid-face hypoplasia, as well as biochemical abnormalities such as hypoglycemia.[ncbi.nlm.nih.gov]
  • Perlman syndrome is an overgrowth syndrome with high perinatal mortality, most frequent antenatal findings include polyhydramnios, macrosomia, visceromegaly, nephromegaly and foetal ascites.[ncbi.nlm.nih.gov]
  • This syndrome consists of various abnormalities, including macroglossia, visceromegaly, omphalocele, and gigantism. These abnormalities frequently require operative correction during the neonatal period.[ncbi.nlm.nih.gov]
Hepatocellular Carcinoma
  • A patient with Simpson-Golabi-Behmel syndrome and hepatocellular carcinoma. J Med Genet 1998; 35 (2) 153-156 33 Morris MR, Astuti D, Maher ER. Perlman syndrome: overgrowth, Wilms tumor predisposition and DIS3L2.[doi.org]

Treatment

The goal of treatment of Beckwith Wiedemann Syndrome is to maintain a state of euglycemia and to pick up tumors at the earliest to provide appropriate and timely treatment. In order to maintain the sugars above the level of 60mg/dl, it is very important to regularly check sugars. Also, the ability to maintain normal blood sugar levels during a certain period of fasting of the duration appropriate for that particular age needs to be assessed. This ability depends on the body mass of the patient and the maturity of the counter regulatory responses to hypoglycemia. The first mode of treatment for hypoglycemia is subcutaneous infusion or injection of glucagon which shows a rise of 30mg/dl of the blood sugar within 30 minutes from the administration. If the patient cannot be weaned from regular glucagon injections, the second option is to use of the diazoxide. Diazoxide is an insulin secretion inhibiting agent. Further, long acting Octreotide, an octapeptide and a more potent inhibitor of insulin, can be successfully used to maintain euglycemia in patients who do not tolerate diazoxide [9]. Beckwith Wiedemann Syndrome may also require references to pediatric oncologists and pediatric surgeons to diagnose and treat embryonal tumors. Appropriate modalities of treatment of cancers need to be evaluated which may also include surgery. An early stage Wilm’s tumor can be treated with partial nephrectomy. Hepatoblastoma can be adequately treated by chemotherapy and surgery and the outcome is seen to be good with an overall survival rate being high. This means that caution and attention by the physician to diagnose at the beginning stages can help provide optimum management. Apart from tumors other surgeries also may be required for structural anomalies. A large tongue may require resection for the maintenance of a patent airway and avoid breathing complications [10]. Similarly, the abdominal wall defects like omphalocele may need to be repaired.

Prognosis

Beckwith Wiedemann Syndrome is one of the major causes of intrauterine, neonatal, and infant mortality. With the development in the diagnostic and treatment modalities this mortality has gone down drastically. Death later in childhood occurs due to complications arising from hypoglycemia, cardiomyopathy, macroglossia, and tumors. [4] The patients who usually do survive infancy well ahead in life and the prognosis is good. The prognosis mostly depends on the status of the airway and appropriate and aggressive management of hypoglycemia. Also, treatment of tumors with chemotherapy and surgery has been found to show positive outcome with a good survival rate.

Etiology

The basic genetic cause of Beckwith Wiedemann Syndrome is the abnormal regulation of the chromosome 11 at 11p15.5. [1] About half the cases arise from the disruption in a process called methylation. The most common breakpoint cluster regions are BWS CR1, KvLQT1 (KCNQ1), BWS CR2 and BWS CR3 that encompass the maternally derived rearrangements associated with the condition. In 20% of the cases, genetic change called paternal uniparental disomy (UPD) causes to have 2 active copies of paternally expressed imprinted genes instead of one from each parent leading to mosaicism. Around 1% of the patients have been found to have translocation or duplication of genetic material from chromosome 11. DNA sequencing done in the patients has detected genomic alterations in CDKN1C. The CDKN1C (p57kip2) mutations are seen both sporadically (5%) and in patients having parental transmission of autosomal dominant origin.

Epidemiology

The occurrence is mostly sporadic in 85% of the cases, but it has been seen that in 15% of the cases the transmission is familial. Being a congenital disorder, it is manifested since birth. The incidence is seen to be 1 in 13,700 births with around 300 children being born with this syndrome every year in the United States. There is equal incidence in both males and females. However, an exception has been observed with female monozygotic twins being more affected. An increasing association of Beckwith Wiedemann Syndrome has been seen with children born to parents with sub fertility who have undergone assisted reproductive techniques like IVF [2].

Sex distribution
Age distribution

Pathophysiology

The manifestation of Beckwith Wiedemann Syndrome is primarily due to a genetic cause and hence, the inheritance of the abnormal chromosome 11 from any parent leads to this syndrome. The occurrence of Beckwith Wiedemann Syndrome in a child is unpredictable with neither of the parents showing any genetic abnormality, but often a familial association has been seen. The exact manner of inheritance is too complex to comprehend, but what has been reported most often is autosomal dominant inheritance, though a variable expression has also been seen. The gene duplication at band 11p.15.5 is  derived from the father, while translocation and inversion are invariably derived from the mother [3]. This has been associated with structural modifications of certain processes such as methylation or lack of acetylation. The gene for insulin-like growth factor-2 [IGF-2]), the gene for insulin, and H19 seem to be the most commonly imprinted genes. H19 appears to be particularly critical for proper imprinting and evidence reveals that H19 mRNA binds IGF-2 mRNA binding protein, which may be one of the mechanisms by which it affects IGF-2. The overgrowth associated with Beckwith Wiedemann Syndrome appears to be most often the result of increased IGF-2 with other features a result of primarily an aberrant genome imprint and microdeletions.

Prevention

Beckwith Wiedemann syndrome is a genetic disorder and hence it cannot be prevented. Genetic counseling should be done to help parents decide whether they would want a second child. Once the syndrome has been diagnosed, it is more important to prevent its complications. The complications that can be prevented are advancement of tumors and improvement of life quality. The screening of tumors can not only detect them when they are small in size, but also greatly contributes in improved survival and decreased morbidity. The commonest tumors encountered in patients with the condition are Wilm’s tumor and hepatoblastoma. Not all patients develop cancer. 1 in 10 children with the condition develop a tumor. Regular screenings by means of abdominal ultrasound have been found to diagnose Wilm’s tumor when it is very small in size. A USG at an interval of less than 4 months can bring to the notice of the physician a tumor of the size as small as 3 cms. This helps in early diagnosis through further imaging and prompt treatment. Hepatoblastoma can be detected as early as possible by continuous monitoring of the levels of alpha-fetoprotein (AFP) in the blood [11]. It has been seen that at birth the AFP levels are high and tend to regularize only by the age of 10 to 11 months. However, in patients of the syndrome with hepatoblastoma, these levels normalize at a slower rate. Further, in children with hepatoblastoma these levels may not normalize at all and in fact keep rising. If these abnormal levels or the rising level of AFP is picked at a very early age, the patient can be treated adequately with the right treatment modality and better survival chances.

Summary

In 1964, Dr. H. R. Wiedemann described a set of symptoms and then in 1969 Dr. J. B. Beckwith introduced a similar set of symptoms. This constellation of symptoms came to be known as Beckwith Wiedemann Syndrome which is one of the most common genetic overgrowth disorders of infancy. The syndrome consists of various symptoms which characterize a large body, large organs, certain midline abdominal wall defects, and an increased rate of cancer development. The syndrome is caused by certain abnormalities in the chromosome number 11 which mostly is an autosomal dominant disorder. It has been seen that the children born through IVF and other such technologies tend to be at a higher risk of developing Beckwith Wiedemann Syndrome . There is an increased risk of early childhood death due to complications arising from large organs and hypoglycemia. Once childhood is surpassed by adequate management of the complications the patients do well further in life.

Patient Information

Beckwith Wiedemann Syndrome is a disorder comprising of a group of symptoms having a genetic cause. An aberration in the chromosome number 11 has been found to be the etiology and mostly transmitted from parents to their child. However, many times both the parents might not be affected and yet have a child with the syndrome. Fortunately, a child with the condition can be identified while in the mother’s womb during routine abdominal ultrasounds by the presence of its characteristic features. This syndrome is characterized by a large body, large tongue, prominent head, prominent eyes, creases over the ears, and defects in the abdominal wall like protrusions of the intestines out of the body through a hole. Beckwith Wiedemann Syndrome also presents with large organs like the liver and the kidney. Children of the disorder grow at a very unusual rate and usually suffer from hypoglycemia which needs to be treated aggressively with dextrose injections or other drugs to keep blood sugars at a normal level. The large tongue can give rise to speech and feeding problems and severe respiratory troubles. Patients are more prone to develop cancer especially of the kidney and the liver. The syndrome cannot be cured but the complications can be managed by caution on the part of the physician as well as parents. Regular feedings to prevent low blood sugar, regular ultrasounds to detect tumors at the earliest, and correction and repair of structural defects can greatly help in keeping the symptoms under control. The children who survive the complications in childhood do very well later in terms of disappearance of facial features and a relatively healthy life.

References

Article

  1. Slavotinek A, Gaunt L, Donnai DJ et al. Paternally inherited duplications of 11p15.5 and Beckwith-Wiedemann syndrome. Med Genet. 1997 Oct;34(10):819-26.
  2. Alders M, Maas SM, Kadouch DJ, et al. Methylation analysis in tongue tissue of Beckwith Wiedemann syndrome patients identifies the (EPI)genetic cause in 3 patients with normal methylation levels in blood. Eur J Med Genet. 2014 May-Jun;57(6):293-7. doi: 10.1016/j.ejmg.2014.03.011. Epub 2014 Apr 2.
  3. Odom LN, Segars J. Imprinting disorders and assisted reproductive technology. Endocrinol Diabetes Obes. 2010 Dec;17(6):517-22. 
  4. Gaston V, Le Bouc Y, Soupre V, et al. Analysis of the methylation status of the KCNQ1OT and H19 genes in leukocyte DNA for the diagnosis and prognosis of Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2001 Jun;9(6):409-18.
  5. Elliott M, Bayly R, Cole T, et al. Clinical features and natural history of Beckwith-Wiedemann syndrome: presentation of 74 new cases. Clin Genet. 1994 Aug;46(2):168-74.
  6. Follmar A, Dentino K, Abramowicz S, et al. Prevalence of sleep-disordered breathing in patients with Beckwith-Wiedemann syndrome. Craniofac Surg. 2014 Sep;25(5):1814-7. 
  7. Storm DW, Hirselj DA, Rink B, et al. The prenatal diagnosis of Beckwith-Wiedemann syndrome using ultrasound and magnetic resonance imaging. Urology. 2011 Jan;77(1):208-10. 
  8. Ortiz-Neira CL, Traubici J, Alan D, et al. Sonographic assessment of renal growth in patients with Beckwith-Wiedemann syndrome: the Beckwith-Wiedemann syndrome renal nomogram. Clinics (Sao Paulo). 2009;64(1):41-4.
  9. Al-Zubeidi H, Gottschalk ME, Newfield RS, et al. Successful use of long acting octreotide in two cases with Beckwith-Wiedemann syndrome and severe hypoglycemia. Pediatr Endocrinol. 2014;2014(1):18. 
  10. Heggie AA, Vujcich NJ, Portnof JE, et al. Tongue reduction for macroglossia in Beckwith Wiedemann syndrome: review and application of new technique. Int J Oral Maxillofac Surg. 2013 Feb;42(2):185-91. 
  11. Cajaiba MM, Sarita-Reyes C, Zambrano E, et al. Mesenchymal hamartoma of the liver associated with features of Beckwith-Wiedemann syndrome and high serum alpha-fetoprotein levels. Pediatr Dev Pathol. 2007 May-Jun;10(3):233-8.

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Last updated: 2019-07-11 20:24