Are You Confident of the Diagnosis?
Beckwith-Wiedemann syndrome (BWS) is a syndrome of somatic overgrowth and a susceptibility to embryonal tumors. Diagnosis is usually made on clinical grounds, given the extreme heterogeneity of possible presentations, ranging from mild cutaneous involvement to intrauterine death. Diagnosis, however, is often difficult and often is aided by molecular testing. And though molecular testing may be helpful in confirming the diagnosis, a negative result cannot, in fact, rule it out.
What you should be alert for in the history
First described by Beckwith and Wiedemann in 1969, BWS presents at birth. There may frequently be a history of polyhydramnios, an enlarged placenta or umbilical cord, or premature onset of labor. The immediate clue to the diagnosis, however, is the large size of the patient, frequently displaying a birth weight and length greater than the 90th percentile. Excessive growth usually begins during the second half of pregnancy and continues through the first few years of life, though adult height and weight usually end up remaining within the normal range.
Characteristic findings on physical examination
In one third of cases, this overgrowth may manifest as hemihypertrophy or macroglossia, the latter often leading to feeding, speech, and respiratory difficulties. Similarly, organomegaly, particularly hepatosplenomegaly, may be appreciated on examination; abdominal wall defects consisting of omphalocele, hernia, and diastasis recti may be present.
On the skin, patients may present with a capillary malformation on the mid-forehead, glabella, and upper eyelids, frequently extending down to the nose and superior lip. More subtle cutaneous findings may include a linear earlobe crease and circular depressions on the posterior helical rims. Rarely, a cleft palate is seen as well.
The differential diagnosis of BWS includes other conditions that predispose to overgrowth. Macrosomia secondary to maternal diabetes should be ruled out.
Genetic syndromes that share overlapping features of BWS include the following:
-Sotos syndrome (high forehead, long narrow face with a pointed chin, overgrowth, and delayed development)
-Costello syndrome (coarse facies with frequent facial warts, short stature, distinctive hand posture, severe feeding difficulty, failure to thrive, cardiac anomalies, developmental disability)
-Simpson-Golabi-Behmel syndrome (large protruding jaw, widened nasal bridge, upturned nasal tip, enlarged tongue, broad stocky appearance and broad, short hands and fingers, normal intelligence, congenital heart defects).
-Perlman syndrome (large birth size, bilateral renal hamartomas with or without nephroblastomatosis, hypertrophy of the islets of Langerhans, and characteristic facies with depressed nasal bridge and anteverted upper lip)
-Mucopolysaccaridosis type VI, also known as Maroteaux-Lamy syndrome (short stature, hepatosplenomegaly, stiff joints, corneal clouding, cardiac abnormalities, facial dysmorphism, normal intelligence)
Who is at Risk for Developing this Disease?
BWS appears in all ethnicities with an estimated incidence of 1 in 13,700, though this is likely an underestimate given that milder phenotypes go undiagnosed. It affects males and females equally except in the case of monozygotic twins in which there is striking female excess. There is an increased frequency of monozygotic twinning seen in BWS, and increased rates of BWS and other imprinting disorders are seen secondary to assisted reproductive technologies. Certain molecular alterations appear to occur with different frequencies in particular geographic/ethnic groups.
What is the Cause of the Disease?
BWS is classified as a genomic imprinting disorder, meaning that expression occurs in a parent-of-origin-specific manner and is regulated by epigenetic mechanisms. BWS usually occurs sporadically in 85% of cases, with the remaining 15% of cases being transmitted in a familial pattern. The genetic and epigenetic alterations that lead to BWS are complex and varied, with several different growth regulatory genes on chromosome 11p15.5 implicated.
This chromosomal region is divided into two imprinting clusters. One cluster is mutated less frequently (approximately 5% of BWS cases) and contains the genes H19 and IGF2; the second cluster is implicated more frequently (approximately 50% of BWS cases) and contains KCNQ1, KCNQ1OT1, and CDKN1C (p57kip2). IGF2 encodes an important growth factor while H19 may function as a tumor suppressor involved in growth restriction. CDKN1C (p57kip2) encodes a cyclin-dependent kinase inhibitor that negatively regulates cell proliferation, while KCNQ1 encodes part of a potassium channel.
Though the exact mechanisms that lead to BWS are unknown, it has been shown that it is the deregulated expression of these genes that causes BWS through varied mechanisms leading to changes in the normal ratio of contribution from each parental allele. An abnormality is found in the 11p15.5 region in 75% to 80% of cases, indicating that 20% to 25% of cases are caused by as yet to be determined molecular defects. Two genes, NALP2 on chromosome 19 and ZFP57 on chromosome 6, which modify imprinting in the second imprinting cluster on 11p15.5, may play a role.
Genotype-phenotype correlations may not only predict the clinical course but also give insight into the risk for future transmission. Finally, somatic mosaicism has been shown to be responsible for some of the clinical variability seen in BWS.
Systemic Implications and Complications
Beyond the features seen on physical examination, BWS patients are at risk for neonatal hypoglycemia (30% to 50% of cases), possibly due to pancreatic and subsequent islet cell hyperplasia and hyperinsulinemia, which may lead to neurologic sequelae if not recognized. In addition to the liver, spleen, and pancreas, the organomegaly can involve the kidneys, heart, and adrenals as well. Cardiac involvement occurs in approximately 20% and can evolve into a cardiomyopathy. Fetal adrenocortical cytomegaly is considered a pathognomonic finding for BWS.
Other major complications arise from the enhanced susceptibility to embryonal tumors. Numerous malignant and benign tumors have been associated with BWS, though the most common are Wilms tumor and hepatoblastoma. Others reported include rhabdomyosarcoma, adrenocortical carcinoma, and neuroblastoma. The risk of developing a neoplasm is approximately 7.5%; most tumors occur in the first 8 to10 years of life.
Treatment options are essentially supportive medical and surgical management: referral to a pediatric surgeon for any abdominal wall defects (omphalocele, hernia, etc); referral to a craniofacial team including plastic surgeons, speech therapists, and orthodontists for tongue reduction surgery if macroglossia is causing respiratory or feeding compromise.
Optimal Therapeutic Approach for this Disease
Aggressive monitoring of blood glucose and surveillance for underlying neoplasms are the mainstays of caring for these patients, even when the presenting phenotype appears mild.
If the diagnosis is even suspected, blood glucose should be monitored every 6 hours for the first three days. Regular screening for scoliosis should be undertaken if hemihypertrophy is present. Likewise, regular tumor surveillance is a must. Common imaging protocols call for a baseline MRI followed by quarterly abdominal ultrasounds to assess the kidneys, adrenals, liver, and pancreas. Any abnormalities should prompt a referral to the appropriate specialist as well as a pediatric oncologist. Cardiac ultrasound is also recommended to rule out cardiomyopathy, though this is somewhat rare.
Renal monitoring should continue into adolescence. Nephrocalcinosis and nephrolithiasis can appear later in the course with the development of medullary sponge kidney. Laboratory monitoring for tumor surveillance includes an alpha-fetoprotein (AFP) assay every 2 to 3 months for detection of possible hepatoblastoma and urine catecholamines quarterly to look for possible neuroblastoma.
Unusual Clinical Scenarios to Consider in Patient Management
BWS is just one of several conditions that has epigenetic and genetic alterations on chromosome 11p15. These include a spectrum of patients who do not completely fulfill clinical diagnostic criteria for BWS but may present with isolated hemihypertrophy or isolated Wilms tumor.
What is the Evidence?
Bliek, J, Verde, G, Callaway, J, Maas, SM, De Crescenzo, A, Sparago, A. “Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith–Wiedemann syndrome”. Eur J Hum Genet. vol. 17. 2009. pp. 611-9. (Established the role that epigenetic changes may play in BWS and phenotypic expression.)
Choufani, S, Shuman, C, Weksberg, R. “Beckwith-Wiedemann syndrome”. Am J Med Genet C Semin Med Genet. vol. 154C. 2010. pp. 343-54. (An outstanding up-to-date detailed review of the complex genetic underpinnings of BWS.)
Elliot, M, Bayly, R, Cole, T, Temple, IK, Maher, ER. “Clinical features and history of Beckwith-Wiedemann syndrome: presentation of 74 new cases”. Clin Genet. vol. 46. 1994. pp. 168-74. (One of the largest case series reported.)
Everman, DB, Shuman, C, Dzolganovski, B, O’Riordan, MA, Weksberg, R, Robin, NH. “Serum alpha-fetoprotein levels in Beckwith–Wiedemann syndrome”. J Pediatr. vol. 137. 2000. pp. 123-7. (Demonstrated that serum alpha-fetoprotein is abnormally elevated in BWS.)
Meyer, E, Lim, D, Pasha, S, Tee, LJ, Rahman, F, Yates, JR. “Germline mutation in NLRP2 (NALP2) in a familial imprinting disorder (Beckwith–Wiedemann syndrome)”. PLOS Genet. vol. 5. 2009. pp. 1-5. (Demonstrated that mutations at other loci may cause alterations of 11p15 and lead to BWS.)
Scott, RH, Douglas, J, Baskcomb, L, Huxter, N, Barker, K, Hanks, S. “Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor”. Nat Genet. vol. 40. 2008. pp. 1329-34. (Established that even non-syndromic Wilms tumor may be associated with imprinting defects in 11p15.)
Sparago, A, Cerrato, F, Vernucci, M, Ferrero, GB, Silengo, MC, Riccio, A. “Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome”. Nat Genet. vol. 36. 2004. pp. 958-60. (Seminal work establishing the mechanism of genomic alterations leading to methylation alterations and loss of function of the IGF2-H19 imprinting control element leading to BWS.)
Tomlinson, JK, Morse, SA, Bernard, SP, Greensmith, AL, Meara, JG. “Long-term outcomes of surgical tongue reduction in Beckwith–Wiedemann syndrome”. Plast Reconstr Surg. vol. 119. 2007. pp. 992-1002. (First study to address long-term outcomes following surgical tongue reduction in BWS.)
Weksberg, R, Nishikawa, J, Caluseriu, O, Fei, YL, Shuman, C, Wei, C. “Tumor development in the Beckwith-Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alternations including imprinting defects of KCNQ1OT1”. Hum Mol Genet. vol. 10. 2001. pp. 2989-3000. (One of the first studies to demonstrate genotype-phenotype relationships in terms of tumor susceptibility in BWS.)
Weksberg, R, Shuman, C, Beckwith, JB. “Beckwith-Wiedemann syndrome”. Eur J Hum Genet. vol. 18. 2010. pp. 8-14. (The best current review in the literature of BWS.)
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