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The Clinical Course of an Overgrowth Syndrome, From Diagnosis in Infancy Through Adulthood: The Case of Beckwith–Wiedemann Syndrome John G. Pappas, MD
Beckwith–Wiedemann syndrome (BWS) is the most common genetic overgrowth syndrome, and it is frequently clinically recognizable because of characteristic features. These features include macrosomia, hemihypertrophy, macroglossia, facial nevus flammeus, earlobe creases and pits, omphalocele, and organomegaly. The most common molecular cause is hypomethylation of the maternal imprinting control region 2 (ICR2) in 11p15. Other molecular causes include hypermethylation of the maternal ICR1 in 11p15, mutations in
CDKN1C, mosaic uniparental disomy 11p15, and chromosomal abnormalities involving 11p15. Some of these abnormalities are testable, and DNA methylation tests of 11p15 confirm about 60% of cases with BWS. The main management issues in pediatrics are hypoglycemia at birth, macroglossia, and surveillance for embryonal tumors, especially Wilms and hepatoblastoma.
Introduction
years of age. Most children have normal mental capabilities; the risk for developmental delays is slightly above the general population risk. The overgrowth is a feature of childhood with normal or slightly above normal adult height and weight. The diagnosis is clinical in many children with BWS since the common genetic tests have about 60% sensitivity and extensive genetic testing can reach about 80%.2–4
mong the genetic overgrowth syndromes, Beckwith–Wiedemann syndrome (BWS) is the most common, 1:13,700 births.1,2 Babies with BWS are large at birth, and either symmetric or asymmetric overgrowth continues throughout childhood. Characteristic features include eye proptosis with periorbital fullness, mid-glabellar capillary malformation (nevus flammeus), earlobe creases and pits, large mouth with large tongue (macroglossia), organomegaly, and omphalocele. Frequently, macroglossia is the sign that prompts the diagnosis in the nursery. Main pediatric management issues are hypoglycemia/ hypocalcemia at birth and the risk for embryonal tumors (primarily Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma). The hypoglycemia can be persistent in infancy and sometimes hard to treat. The risk for tumors is about 7.5% till 8 years of age and then gradually declines close to general population risk.2,3 This risk is addressed with tumor surveillance by abdominal ultrasound and peripheral blood alpha-fetoprotein levels every 3 months till 8
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From the Clinical Genetic Services, Department of Pediatrics, NYU School of Medicine, New York, NY. Curr Probl Pediatr Adolesc Health Care ]]]];]:]]]-]]] 1538-5442/$ - see front matter & 2015 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.cppeds.2015.03.001
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Clinical Diagnosis Beckwith and Wiedemann in 19695 described a syndrome with three cardinal features: exomphalos (omphalocele), macroglossia, and gigantism (EMG). The syndrome was renamed Beckwith–Wiedemann syndrome (BWS) and the associated phenotype expanded. BWS is quite variable and EMG is seen in some but not all of the children who have the BWS diagnosis. Clinical criteria have not been established. BWS experts including Dr. J Bruce Beckwith and Dr. Rossana Wecksberg published criteria in GeneReviews in 2010.3 Three major or one major and two minor criteria are diagnostic (Table). Differential diagnosis includes many overgrowth syndromes discussed by Yachelevich,6 as well as diabetic embryopathy. Boys with the rare X-linked recessive Simpson–Golabi–Behmel syndrome can present similarly to BWS and only molecular testing can provide the diagnosis.7
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TABLE. Major and Minor Findings Associated With Beckwith–Weidemann Syndrome (BWS)
Three major findings or one major and two minor findings are required to make the clinical diagnosis Caution: A child with isolated macroglossia or macrosomia or hemihypertrophy can be mosaic for a BWS related molecular abnormality and at risk for tumor similar to children with BWS diagnosis. Major findings Positive family history (one or more family members with a clinical diagnosis of BWS or a history or features suggestive of BWS) Macrosomia (traditionally defined as height and weight 497th centile) Anterior linear earlobe 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., Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma) in childhood Hemihyperplasia (asymmetric overgrowth of one or more regions of the body) Cytomegaly of the fetal adrenal cortex ascertained by pathology (It is pathognomonic and hence quite helpful in pathological analysis of abortuses16) Renal abnormalities including structural abnormalities, nephromegaly, nephrocalcinosis, later development of medullary sponge kidney Cleft palate (rare in BWS) Placental mesenchymal dysplasia10 Cardiomegaly Cardiomyopathy (rare in BWS) Minor findings Pregnancy-related findings including polyhydramnios and prematurity Neonatal hypoglycemia Facial nevus flammeus, other vascular malformations Characteristic facies, including midface hypoplasia, and infraorbital creases Structural cardiac anomalies Diastasis recti Advanced bone age (common in overgrowth/endocrine disorders)
Molecular Abnormalities Associated With BWS and Genetic Testing
modification, which do not change the DNA sequence but can change gene expression. The epigenetic abnormality in 11p15 involves loss or BWS is due to genetic or epigenetic abnormalities gain of DNA methylation that causes aberrant silenc(epimutations) involving 11p15.8 The segment 11p15 ing or activation of gene expression without a change is imprinted, which means that different genes are in the DNA sequence. Loss of methylation in the expressed or silenced in the maternal segment than maternal ICR2 is the most common molecular cause those in the homologous paternal segment. 'Maternal' of BWS.8–10 and 'paternal' refer to the parental origin of the ICR2 loss of methylation (hypomethylation) on chromosome and not to patterns that exist in the the maternal chromosome, found in 50% of persons chromosomes of the parents, with BWS, leads to reduced i.e., the paternal chromosome expression of CDKN1C.2,10 of the mother loses paternal A child with isolated macroThe CDKN1C gene is translated imprinting and becomes to the cyclin-dependent kinase glossia or macrosomia or maternal in her offspring. Im(CDK)-inhibitor 1C (CDKN1C) printed segments of the ge- hemihypertrophy can be mosaic protein that negatively regulates for a BWS related molecular nome like 11p15 include cell proliferation.8 Conceivably, imprinting control regions abnormality and at risk for reduced expression of CDK (ICR) that are chromosomal tumor similar to children with N1C upregulates cell proliferation regions that regulate the exunderlying overgrowth in BWS.8,9 BWS diagnosis. pression or silencing of imLoss-of-function mutations in printed genes. There are two CDKN1C are seen in 50% of ICRs in 11p15; ICR1 and ICR2. Epigenetic abnorfamilial BWS (about 15% of all cases are familial2,3) malities in ICR1 and ICR2 account for most of the and about 5% of the sporadic BWS.8 Interestingly, known causes of BWS. Epigenetic abnormalities are gain-of-function mutations in CDKN1C also have DNA modifications, usually methylation or histone clinical significance, as they are seen in the short-stature
2
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syndromes such as Russell–Silver syndrome and IMAGe syndrome.8 ICR1 gain of methylation (hypermethylation) on the maternal chromosome, found in approximately 5% of persons with BWS, leads to the biallelic expression of IGF2 and hence more IGF2 protein.2,3,9,10 The IGF2 protein (insulin-like growth factor 2) is a potent fetal growth factor. Loss of methylation (hypomethylation) in ICR1 accounts for about 40% of cases of Russell– Silver syndrome.9 In addition to epimutations in 11p15 and mutations in CDKN1C, chromosome abnormalities can also be associated with BWS. Approximately 20% of persons with BWS have somatic mosaicism of paternal uniparental disomy (UPD) of 11p15.2,3 Somatic mosaicism is due to a post-zygotic abnormality in cell division that creates two cell lines in the embryo: one normal and another with only paternal contribution in both 11p15.5 homologues. The UPD is usually segmental and involves only a part of chromosome 11 that includes 11p15.2,3,10 Since CDKN1C is expressed from the maternal allele and IGF2 from the paternal allele, lack of the maternal contribution and double the paternal contribution results in decreased expression of CDKN1C and increased expression of IGF2. Both of these changes in gene expression promote cell proliferation and growth. Other chromosome aberrations, either sub-microscopic or microscopically visible, can have similar effects to paternal UPD11p15. These aberrations include deletions, duplications, translocations, and inversions and account for about 1% of genetic abnormalities associated with BWS.2,3,10 Molecular abnormalities outside 11p15 may also cause BWS.10 The genetic tests used for BWS target the associated epigenetic and genetic abnormalities. The DNA
feature
macroglossia exomphalos (omphalocele) organomegaly macrosomia facial nevus flammeus hemihypertrophy hypoglycemia Score total
score
2.5 1.5 1 1 1 0.5 0.5
methylation test is designed to reveal abnormalities in ICR1 and ICR2, and it is positive in about 55% of cases.3 Sequencing of the CDKN1C is indicated if the DNA methylation test is normal and especially in familial cases. About 5% of cases will have mutations in CDKN1C.3,8 Testing for UPD11 is not sensitive because of the mosaicism that may not be detectable in blood samples.2,3,11 Skin and tumor samples may increase the sensitivity of the UPD11 test.2,3,11 Chromosome analysis with FISH for 11p15.5 and microarray may help the genetic diagnosis in about 1% of cases.2,3 A scoring system has been developed to predict the outcome of the DNA methylation test in children with possible BWS diagnosis.4 Specific clinical features are assigned weights: macroglossia 2.5 points, exomphalos (omphalocele) 1.5, organomegaly 1, macrosomia 1, facial nevus flammeus 1, hemihypertrophy 0.5, and hypoglycemia 0.5. Addition of the points in a particular patient provides a score that is associated with the likelihood of a positive BWS DNA methylation test; higher scores predict higher probability of an abnormal test result. The Figure summarizes the scoring system adapted from the ROC curve published by Ibrahim et al.4 Genotype—phenotype correlations to predict tumor risk have been reported, but their clinical utility is questionable since even those with lower-risk genotypes still have a clinically important risk of developing a tumor. As a result, these associations ultimately do not alter tumor surveillance recommendations. The highest risk for tumor, approximately 21%, is associated with UPD11p15 or gain of methylation at ICR1.3 The lowest risk for tumors, approximately 4%, is associated with loss of methylation at ICR2.3 A few individuals with BWS and neuroblastoma are reported to have mutation in CDKN1C.3
total score
1 2 3 4 5 6 7 8
probability of abnormal DNA methylaon test 16% 30% 50% 68% 83% 92% 95% 98%
FIG. Scoring system that calculates the probability of abnormal DNA methylation test for Beckwith–Wiedemann according to features of the patient.
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Natural History and Management
surgeons, orthodontists, and speech pathologists) can provide comprehensive evaluation and followThe Fetus With BWS up.3 Tongue reduction is sometimes needed. All infants with macroglossia benefit from speech therPrenatal manifestations of BWS include polyhydramapy evaluation and therapy. They may also benefit nios, increased abdominal circumference, enlarged pla3,12 from respiratory assessment including sleep studies centa, and omphalocele. The genetic tests for BWS if clinically indicated. The craniofacial team also are available prenatally, via an amniocentesis sample. coordinates the surgical repair in BWS babies with The Newborn With BWS palate and follows BWS an initially elevated AFP is not a cleft infants with facial hemihyBWS is associated with precause for alarm, as the trend in perplasia, for possible plastic maturity, macroglossia, macrosomia, and hypoglycemia at AFP level is the significant factor in surgery. In case of limb hemihyperplasia an evaluation birth.2,3 Assessment of the airmaking the diagnosis of and follow-up by orthopediway in the presence of macrohepatoblastoma. cians can provide the necesglossia may prompt intubation sary information for decision for ventilatory support. Equally about surgery in puberty. Surgery usually involves critical is the monitoring of blood glucose, electrolytes, epiphysiodesis for equalizing the final leg length. and adequacy of feeding. A long nipple is sometimes The risk for intellectual disabilities/developmental needed for feeding because of the large tongue. In case of delays is low in BWS and developmental screenprolonged hypoglycemia beyond the first 4 days, endoing that is part of routine pediatric care is sufficient.3 crine evaluation and management is warranted. Tumor In case of developmental delays, standard early surveillance with abdominal ultrasound and blood alphaintervention programs should be instituted. BWS fetoprotein [(AFP) for hepatoblastoma surveillance)] infants and children have a slightly higher risk should be initiated as soon as possible after birth. for hypothyroidism, hyperlipidemia/hypercholesterIncreased size of the kidneys with one kidney signifiolemia, and polycythemia, and screening for these cantly larger than the other is usually due to BWScan be easily incorporated to the regular pediatric associated hemihyperplasia (increased number of cells on care.3 one side of body) and is not alarming. Likewise, an initially elevated AFP is not a cause for alarm, as the trend in AFP level is the significant factor in making the The Child With BWS diagnosis of hepatoblastoma.13 The AFP will rise rapidly In childhood, surveillance and specialty follow-up on successive measurements in the case of a hepatoblasestablished in infancy should continue. If a tumor is toma, while an initially elevated AFP level will decline in ascertained, the treatment should follow the specific the absence of hepatoblastoma. An additional AFP tumor protocols. Tumor surveillance with abdominal measurement a month after the initial measurement ultrasound and blood AFP should continue till 8 years should establish the trend. If omphalocele is present, of age and then annual renal ultrasound till midcardiac evaluation is recommended prior to surgical adolescence.2,3 The renal ultrasound is primarily for correction. Measurement of urinary calcium/creatinine nephrocalcinosis. Annual measurement of urinary ratio and annual follow-up measurement should be 14 calcium/creatinine ratio should be instituted at the instituted to look for hypercalciuria. Cardiomyopathy time of the BWS diagnosis to look for hypercalciuria is reported in the medical literature but is rare and 3 even in the absence of nephrocalcinosis. Hypersometimes self-limited. Structural renal or gastrointesticalciuria with or without nephrocalcinosis prompts nal abnormalities require referrals to appropriate 3 an evaluation and treatment by nephrology. Disfigurspecialists. ing facial hemihyperplasia requires the multidisciplinary involvement of a craniofacial team for possible The Infant With BWS surgical correction. Clinical suspicion of cardiomyopathy requires a comprehensive cardiology If the macroglossia persists in infancy, then a evaluation. craniofacial team (otolaryngologists, plastic
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The Adult With BWS There are a few medical concerns for adults with BWS, i.e., renal medullary dysplasia and decreased fertility in males. These are rare complications and there is an association with a specific molecular abnormality.15 Suggested referrals include counseling for possible male infertility, offering referral for infertility assessment and semen evaluation as appropriate, echocardiography every 3–5 years, renal ultrasound once early in adulthood, renal function testing every 3–5 years, and evaluation of hearing every 2–3 years. These recommendations are based on a limited number of cases.15
Brief Case Reports Demonstrating Clinical and Molecular Diagnosis Case 1
not contributory. The clinical findings [three major findings: macrosomia, macroglossia, and earlobe pit and creases (Table)] suggested the diagnosis of BWS which was communicated with parents. Tumor surveillance was immediately initiated, consisting of abdominal ultrasound and serum alpha-fetoprotein assessment every 3 months till 8 years of age. Blood was drawn for DNA methylation test of 11p15. The likelihood of a positive result was 83% (2.5 for macroglosia, 1 for macrosomia, 1 for nevus flammeus, and 0.5 for hypoglycemia, total 5 associated with 83% chance of positive DNA methylation test; Figure). This revealed loss of methylation of ICR2 which established the BWS diagnosis. The patient was breast-fed and showed no episodes of hypoglycemia. He had uncomplicated orchiopexy in late infancy. He continued to grow above the 95th centile for height and weight in childhood. He followed regular school. He is currently 17 years old and his height and weight are at the 80th centile. He never developed a tumor or any other medical problem associated with BWS.
A full-term boy was born by vaginal delivery to 27year-old primigravida. The pregnancy was monitored closely by a high-risk obstetrician because of large Case 2 fetal abdominal circumference ascertained sonographically in the second trimester. Serial fetal ultrasounds A newborn girl was referred to us for genetic revealed accelerated fetal growth during the third evaluation because of omphalocele. She was conceived trimester. No structural abnormalities were found. by in vitro fertilization (donor ovum IVF) and was Elective cesarean section was discussed with the born at 30 weeks to a 44-year-old mother [gravida 3, mother, but she decided to wait for natural labor. para 0, abortions (spontaneous) 2] by vaginal delivery. Many maternal serum glucose measurements were The birth weight was 1600 g (þ1SD), the length was normal and two glucose tolerance tests were also 42 cm (þ1SD), and the head circumference was 28 cm normal. The vaginal delivery was uncomplicated and (at mean). She had respiratory insufficiency treated the baby boy weighed 4.6 kg and with ventilatory support throwas 58 cm in length; both weight ugh nasal prongs. She had Our differential included and length were above the 95th facial capillary malformations centile. The head circumference including the eyelids, macroBeckwith–Wiedemann synwas 37.5 cm at the 75th centile. drome because of IVF, prema- glossia, grooves behind on the The macrosomia prompted gluback of the earlobes, small turity and the clinical features, cose testing that revealed hypoomphalocele surgically corespecially macroglossia. glycemia; heel-stick glucose rected, loud murmur (patent 40 mg/dl. He was breast-fed freductus arteriosus as per cardiquently and the glucose normalology), palpable liver and ized. His electrolytes including calcium were normal. spleen, and mild generalized hypotonia. Chromosome He had macroglossia which along with the macrosomia analysis was reported normal 46,XX. Our differential prompted genetic evaluation. Dysmorphology examiincluded Beckwith–Wiedemann syndrome because of nation revealed mid-frontal/mid-glabellar flat capillary IVF,2,3,12 prematurity, and the clinical features [three malformation (nevous flammeus), pit and creases on major findings: macroglossia, omphalocele, and orgathe earlobes, the liver was palpable 2–3 cm below the nomegaly (Table)], especially macroglossia. BWS has costal margin, and the testes were undescended but been associated with IVF in the medical literature.2,3,12 palpable in the inguinal canals. The family history was Blood for DNA methylation test to evaluate for BWS Curr Probl PediatrAdolesc Health Care, Month ]]]]
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was sent, and tumor surveillance was initiated. Initial hypoglycemia was attributed to prematurity; however she continued to be hypoglycemic at 1 month and was treated by the endocrine service with glucose infusions. The probability of an abnormal DNA methylation test was between 83% and 92% [macroglossia 2.5, omphalocele 1.5, organomgaly 1, and hypoplycemia 0.5; total 5.5 (Figure)]. Indeed, the test revealed abnormal methylation in ICR2, confirming the BWS diagnosis. The tongue continued to enlarge and she required both tracheostomy and gastrostomy. She had tongue reduction surgery with subsequent decannulation and gastrostomy reversal. She is currently 3 years old with mild developmental delays and growth at the 95th centile. BWS has served as the prototype of syndromes with generalized overgrowth. The BWS tumor surveillance protocol is sometimes implemented for rare overgrowth syndromes that lack natural history studies. The frequency of the tumor surveillance (every 3 months) naturally puts the pediatrician at the steering wheel of the care. The pediatrician has to encourage the family to stay the course of surveillance, to help the parents endure the anxiety of every test, and to help the patient connect with naturally smaller classmates and to avoid situations that increased height and weight is judged as older age. Frequently, as the pediatrician pulls the family out the tunnel of anticipation of a tumor the patient is ready to enter puberty with fewer medical worries than in infancy. In case of tumor the outcome is quite variable depending on the type of tumor and the location. Unless there is a chromosome abnormality, which is a rare cause of BWS, the neurodevelopmental prognosis is good. Finally, a pediatrician can reasonably expect a BWS patient to graduate from the practice as an adult with ultimately normal growth and normal neurological development.
References 1. Thorburn MJ, Wright ES, Miller CG, Smith-Read EHM. Exomphalos–macroglossia–gigantism syndrome in Jamaican infants. Am J Dis Child 1970;119(4):316–21.
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2. Weksberg R, Shuman C, Beckwith JB. Beckwith–Wiedemann syndrome. Eur J Hum Genet 2010;18(1):8–14. 3. Shuman C, Beckwith JB, Smith AC, Weksberg R. Beckwith– Wiedemann Syndrome. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, (eds). GeneRev. Seattle (WA): University of Washington, 2010. http://www.ncbi.nlm.nih. gov/books/NBK1394/. [03 March 1993–2000, updated]. 4. Ibrahim A, Kirby G, Hardy C. Methylation analysis and diagnostics of Beckwith–Wiedemann syndrome in 1,000 subjects. Clin Epigenetics 2014;6(1):11. 5. Beckwith JB. Macroglossia, omphalocele, adrenal cytomegaly, gigantism, and hyperplastic visceromegaly, In Bergsma D, (ed). Birth Defects: Original Article Series. New York: National Foundation; 1969;5(2):pp.188–96. 6. Yachelevich N. (in this issue). 7. Knopp C, Rudnik-Schöneborn S, Zerres K, Gencik M, Spengler S, Eggermann T. Twenty-one years to the right diagnosis–clinical overlap of Simpson–Golabi–Behmel and Beckwith–Wiedemann syndrome. Am J Med Genet. 2014; 167A(1):151–5. 8. Eggermann T, Binder G, Brioude F. CDKN1C mutations: two sides of the same coin. Trends Mol Med 2014;20(11):614–22. 9. Eggermann T, Heilsberg AK, Bens S. Additional molecular findings in 11p15-associated imprinting disorders: an urgent need for multi-locus testing. J Mol Med (Berl) 2014;92 (7):769–77. 10. Choufani S, Shuman C, Weksberg R. Beckwith–Wiedemann syndrome. Am J Med Genet C Semin Med Genet 2010;154C (3):343–54. 11. Wilson M, Peters G, Bennetts B, et al. The clinical phenotype of mosaicism for genome-wide paternal uniparental disomy: two new reports. Am J Med Genet 2008;146A(2):137–48. 12. Wilkins-Haug L, Porter A, Hawley P, Benson CB. Isolated fetal omphalocele, Beckwith–Wiedemann syndrome, and assisted reproductive technologies. Birth Defects Res A Clin Mol Teratol 2009;85(1):58–62. 13. Everman DB, Shuman C, Dzolganovski B, O'riordan MA, Weksberg R, Robin NH. Serum alpha-fetoprotein levels in Beckwith–Wiedemann syndrome. J Pediatr 2000;137(1):123–7. 14. Goldman M, Shuman C, Weksberg R, Rosenblum ND. Hypercalciuria in Beckwith–Wiedemann syndrome. J Pediatr 2003;142(2):206–8. 15. Greer KJ, Kirkpatrick SJ, Weksberg R, Pauli RM. Beckwith– Wiedemann syndrome in adults: observations from one family and recommendations for care. Am J Med Genet A 2008;146A (13):1707–12. 16. Williams DH, Gauthier DW, Maizels M. Prenatal diagnosis of Beckwith–Wiedemann syndrome. Prenat Diagn 2005;25 (10):879–84.
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The Clinical Course of an Overgrowth Syndrome, From Diagnosis in Infancy Through Adulthood: The Case of Beckwith–Wiedemann Syndrome John G. Pappas, MD
Beckwith–Wiedemann syndrome (BWS) is the most common genetic overgrowth syndrome, and it is frequently clinically recognizable because of characteristic features. These features include macrosomia, hemihypertrophy, macroglossia, facial nevus flammeus, earlobe creases and pits, omphalocele, and organomegaly. The most common molecular cause is hypomethylation of the maternal imprinting control region 2 (ICR2) in 11p15. Other molecular causes include hypermethylation of the maternal ICR1 in 11p15, mutations in
CDKN1C, mosaic uniparental disomy 11p15, and chromosomal abnormalities involving 11p15. Some of these abnormalities are testable, and DNA methylation tests of 11p15 confirm about 60% of cases with BWS. The main management issues in pediatrics are hypoglycemia at birth, macroglossia, and surveillance for embryonal tumors, especially Wilms and hepatoblastoma.
Introduction
years of age. Most children have normal mental capabilities; the risk for developmental delays is slightly above the general population risk. The overgrowth is a feature of childhood with normal or slightly above normal adult height and weight. The diagnosis is clinical in many children with BWS since the common genetic tests have about 60% sensitivity and extensive genetic testing can reach about 80%.2–4
mong the genetic overgrowth syndromes, Beckwith–Wiedemann syndrome (BWS) is the most common, 1:13,700 births.1,2 Babies with BWS are large at birth, and either symmetric or asymmetric overgrowth continues throughout childhood. Characteristic features include eye proptosis with periorbital fullness, mid-glabellar capillary malformation (nevus flammeus), earlobe creases and pits, large mouth with large tongue (macroglossia), organomegaly, and omphalocele. Frequently, macroglossia is the sign that prompts the diagnosis in the nursery. Main pediatric management issues are hypoglycemia/ hypocalcemia at birth and the risk for embryonal tumors (primarily Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma). The hypoglycemia can be persistent in infancy and sometimes hard to treat. The risk for tumors is about 7.5% till 8 years of age and then gradually declines close to general population risk.2,3 This risk is addressed with tumor surveillance by abdominal ultrasound and peripheral blood alpha-fetoprotein levels every 3 months till 8
A
From the Clinical Genetic Services, Department of Pediatrics, NYU School of Medicine, New York, NY. Curr Probl Pediatr Adolesc Health Care ]]]];]:]]]-]]] 1538-5442/$ - see front matter & 2015 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.cppeds.2015.03.001
Curr Probl PediatrAdolesc Health Care, Month ]]]]
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Clinical Diagnosis Beckwith and Wiedemann in 19695 described a syndrome with three cardinal features: exomphalos (omphalocele), macroglossia, and gigantism (EMG). The syndrome was renamed Beckwith–Wiedemann syndrome (BWS) and the associated phenotype expanded. BWS is quite variable and EMG is seen in some but not all of the children who have the BWS diagnosis. Clinical criteria have not been established. BWS experts including Dr. J Bruce Beckwith and Dr. Rossana Wecksberg published criteria in GeneReviews in 2010.3 Three major or one major and two minor criteria are diagnostic (Table). Differential diagnosis includes many overgrowth syndromes discussed by Yachelevich,6 as well as diabetic embryopathy. Boys with the rare X-linked recessive Simpson–Golabi–Behmel syndrome can present similarly to BWS and only molecular testing can provide the diagnosis.7
1
TABLE. Major and Minor Findings Associated With Beckwith–Weidemann Syndrome (BWS)
Three major findings or one major and two minor findings are required to make the clinical diagnosis Caution: A child with isolated macroglossia or macrosomia or hemihypertrophy can be mosaic for a BWS related molecular abnormality and at risk for tumor similar to children with BWS diagnosis. Major findings Positive family history (one or more family members with a clinical diagnosis of BWS or a history or features suggestive of BWS) Macrosomia (traditionally defined as height and weight 497th centile) Anterior linear earlobe 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., Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma) in childhood Hemihyperplasia (asymmetric overgrowth of one or more regions of the body) Cytomegaly of the fetal adrenal cortex ascertained by pathology (It is pathognomonic and hence quite helpful in pathological analysis of abortuses16) Renal abnormalities including structural abnormalities, nephromegaly, nephrocalcinosis, later development of medullary sponge kidney Cleft palate (rare in BWS) Placental mesenchymal dysplasia10 Cardiomegaly Cardiomyopathy (rare in BWS) Minor findings Pregnancy-related findings including polyhydramnios and prematurity Neonatal hypoglycemia Facial nevus flammeus, other vascular malformations Characteristic facies, including midface hypoplasia, and infraorbital creases Structural cardiac anomalies Diastasis recti Advanced bone age (common in overgrowth/endocrine disorders)
Molecular Abnormalities Associated With BWS and Genetic Testing
modification, which do not change the DNA sequence but can change gene expression. The epigenetic abnormality in 11p15 involves loss or BWS is due to genetic or epigenetic abnormalities gain of DNA methylation that causes aberrant silenc(epimutations) involving 11p15.8 The segment 11p15 ing or activation of gene expression without a change is imprinted, which means that different genes are in the DNA sequence. Loss of methylation in the expressed or silenced in the maternal segment than maternal ICR2 is the most common molecular cause those in the homologous paternal segment. 'Maternal' of BWS.8–10 and 'paternal' refer to the parental origin of the ICR2 loss of methylation (hypomethylation) on chromosome and not to patterns that exist in the the maternal chromosome, found in 50% of persons chromosomes of the parents, with BWS, leads to reduced i.e., the paternal chromosome expression of CDKN1C.2,10 of the mother loses paternal A child with isolated macroThe CDKN1C gene is translated imprinting and becomes to the cyclin-dependent kinase glossia or macrosomia or maternal in her offspring. Im(CDK)-inhibitor 1C (CDKN1C) printed segments of the ge- hemihypertrophy can be mosaic protein that negatively regulates for a BWS related molecular nome like 11p15 include cell proliferation.8 Conceivably, imprinting control regions abnormality and at risk for reduced expression of CDK (ICR) that are chromosomal tumor similar to children with N1C upregulates cell proliferation regions that regulate the exunderlying overgrowth in BWS.8,9 BWS diagnosis. pression or silencing of imLoss-of-function mutations in printed genes. There are two CDKN1C are seen in 50% of ICRs in 11p15; ICR1 and ICR2. Epigenetic abnorfamilial BWS (about 15% of all cases are familial2,3) malities in ICR1 and ICR2 account for most of the and about 5% of the sporadic BWS.8 Interestingly, known causes of BWS. Epigenetic abnormalities are gain-of-function mutations in CDKN1C also have DNA modifications, usually methylation or histone clinical significance, as they are seen in the short-stature
2
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syndromes such as Russell–Silver syndrome and IMAGe syndrome.8 ICR1 gain of methylation (hypermethylation) on the maternal chromosome, found in approximately 5% of persons with BWS, leads to the biallelic expression of IGF2 and hence more IGF2 protein.2,3,9,10 The IGF2 protein (insulin-like growth factor 2) is a potent fetal growth factor. Loss of methylation (hypomethylation) in ICR1 accounts for about 40% of cases of Russell– Silver syndrome.9 In addition to epimutations in 11p15 and mutations in CDKN1C, chromosome abnormalities can also be associated with BWS. Approximately 20% of persons with BWS have somatic mosaicism of paternal uniparental disomy (UPD) of 11p15.2,3 Somatic mosaicism is due to a post-zygotic abnormality in cell division that creates two cell lines in the embryo: one normal and another with only paternal contribution in both 11p15.5 homologues. The UPD is usually segmental and involves only a part of chromosome 11 that includes 11p15.2,3,10 Since CDKN1C is expressed from the maternal allele and IGF2 from the paternal allele, lack of the maternal contribution and double the paternal contribution results in decreased expression of CDKN1C and increased expression of IGF2. Both of these changes in gene expression promote cell proliferation and growth. Other chromosome aberrations, either sub-microscopic or microscopically visible, can have similar effects to paternal UPD11p15. These aberrations include deletions, duplications, translocations, and inversions and account for about 1% of genetic abnormalities associated with BWS.2,3,10 Molecular abnormalities outside 11p15 may also cause BWS.10 The genetic tests used for BWS target the associated epigenetic and genetic abnormalities. The DNA
feature
macroglossia exomphalos (omphalocele) organomegaly macrosomia facial nevus flammeus hemihypertrophy hypoglycemia Score total
score
2.5 1.5 1 1 1 0.5 0.5
methylation test is designed to reveal abnormalities in ICR1 and ICR2, and it is positive in about 55% of cases.3 Sequencing of the CDKN1C is indicated if the DNA methylation test is normal and especially in familial cases. About 5% of cases will have mutations in CDKN1C.3,8 Testing for UPD11 is not sensitive because of the mosaicism that may not be detectable in blood samples.2,3,11 Skin and tumor samples may increase the sensitivity of the UPD11 test.2,3,11 Chromosome analysis with FISH for 11p15.5 and microarray may help the genetic diagnosis in about 1% of cases.2,3 A scoring system has been developed to predict the outcome of the DNA methylation test in children with possible BWS diagnosis.4 Specific clinical features are assigned weights: macroglossia 2.5 points, exomphalos (omphalocele) 1.5, organomegaly 1, macrosomia 1, facial nevus flammeus 1, hemihypertrophy 0.5, and hypoglycemia 0.5. Addition of the points in a particular patient provides a score that is associated with the likelihood of a positive BWS DNA methylation test; higher scores predict higher probability of an abnormal test result. The Figure summarizes the scoring system adapted from the ROC curve published by Ibrahim et al.4 Genotype—phenotype correlations to predict tumor risk have been reported, but their clinical utility is questionable since even those with lower-risk genotypes still have a clinically important risk of developing a tumor. As a result, these associations ultimately do not alter tumor surveillance recommendations. The highest risk for tumor, approximately 21%, is associated with UPD11p15 or gain of methylation at ICR1.3 The lowest risk for tumors, approximately 4%, is associated with loss of methylation at ICR2.3 A few individuals with BWS and neuroblastoma are reported to have mutation in CDKN1C.3
total score
1 2 3 4 5 6 7 8
probability of abnormal DNA methylaon test 16% 30% 50% 68% 83% 92% 95% 98%
FIG. Scoring system that calculates the probability of abnormal DNA methylation test for Beckwith–Wiedemann according to features of the patient.
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Natural History and Management
surgeons, orthodontists, and speech pathologists) can provide comprehensive evaluation and followThe Fetus With BWS up.3 Tongue reduction is sometimes needed. All infants with macroglossia benefit from speech therPrenatal manifestations of BWS include polyhydramapy evaluation and therapy. They may also benefit nios, increased abdominal circumference, enlarged pla3,12 from respiratory assessment including sleep studies centa, and omphalocele. The genetic tests for BWS if clinically indicated. The craniofacial team also are available prenatally, via an amniocentesis sample. coordinates the surgical repair in BWS babies with The Newborn With BWS palate and follows BWS an initially elevated AFP is not a cleft infants with facial hemihyBWS is associated with precause for alarm, as the trend in perplasia, for possible plastic maturity, macroglossia, macrosomia, and hypoglycemia at AFP level is the significant factor in surgery. In case of limb hemihyperplasia an evaluation birth.2,3 Assessment of the airmaking the diagnosis of and follow-up by orthopediway in the presence of macrohepatoblastoma. cians can provide the necesglossia may prompt intubation sary information for decision for ventilatory support. Equally about surgery in puberty. Surgery usually involves critical is the monitoring of blood glucose, electrolytes, epiphysiodesis for equalizing the final leg length. and adequacy of feeding. A long nipple is sometimes The risk for intellectual disabilities/developmental needed for feeding because of the large tongue. In case of delays is low in BWS and developmental screenprolonged hypoglycemia beyond the first 4 days, endoing that is part of routine pediatric care is sufficient.3 crine evaluation and management is warranted. Tumor In case of developmental delays, standard early surveillance with abdominal ultrasound and blood alphaintervention programs should be instituted. BWS fetoprotein [(AFP) for hepatoblastoma surveillance)] infants and children have a slightly higher risk should be initiated as soon as possible after birth. for hypothyroidism, hyperlipidemia/hypercholesterIncreased size of the kidneys with one kidney signifiolemia, and polycythemia, and screening for these cantly larger than the other is usually due to BWScan be easily incorporated to the regular pediatric associated hemihyperplasia (increased number of cells on care.3 one side of body) and is not alarming. Likewise, an initially elevated AFP is not a cause for alarm, as the trend in AFP level is the significant factor in making the The Child With BWS diagnosis of hepatoblastoma.13 The AFP will rise rapidly In childhood, surveillance and specialty follow-up on successive measurements in the case of a hepatoblasestablished in infancy should continue. If a tumor is toma, while an initially elevated AFP level will decline in ascertained, the treatment should follow the specific the absence of hepatoblastoma. An additional AFP tumor protocols. Tumor surveillance with abdominal measurement a month after the initial measurement ultrasound and blood AFP should continue till 8 years should establish the trend. If omphalocele is present, of age and then annual renal ultrasound till midcardiac evaluation is recommended prior to surgical adolescence.2,3 The renal ultrasound is primarily for correction. Measurement of urinary calcium/creatinine nephrocalcinosis. Annual measurement of urinary ratio and annual follow-up measurement should be 14 calcium/creatinine ratio should be instituted at the instituted to look for hypercalciuria. Cardiomyopathy time of the BWS diagnosis to look for hypercalciuria is reported in the medical literature but is rare and 3 even in the absence of nephrocalcinosis. Hypersometimes self-limited. Structural renal or gastrointesticalciuria with or without nephrocalcinosis prompts nal abnormalities require referrals to appropriate 3 an evaluation and treatment by nephrology. Disfigurspecialists. ing facial hemihyperplasia requires the multidisciplinary involvement of a craniofacial team for possible The Infant With BWS surgical correction. Clinical suspicion of cardiomyopathy requires a comprehensive cardiology If the macroglossia persists in infancy, then a evaluation. craniofacial team (otolaryngologists, plastic
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The Adult With BWS There are a few medical concerns for adults with BWS, i.e., renal medullary dysplasia and decreased fertility in males. These are rare complications and there is an association with a specific molecular abnormality.15 Suggested referrals include counseling for possible male infertility, offering referral for infertility assessment and semen evaluation as appropriate, echocardiography every 3–5 years, renal ultrasound once early in adulthood, renal function testing every 3–5 years, and evaluation of hearing every 2–3 years. These recommendations are based on a limited number of cases.15
Brief Case Reports Demonstrating Clinical and Molecular Diagnosis Case 1
not contributory. The clinical findings [three major findings: macrosomia, macroglossia, and earlobe pit and creases (Table)] suggested the diagnosis of BWS which was communicated with parents. Tumor surveillance was immediately initiated, consisting of abdominal ultrasound and serum alpha-fetoprotein assessment every 3 months till 8 years of age. Blood was drawn for DNA methylation test of 11p15. The likelihood of a positive result was 83% (2.5 for macroglosia, 1 for macrosomia, 1 for nevus flammeus, and 0.5 for hypoglycemia, total 5 associated with 83% chance of positive DNA methylation test; Figure). This revealed loss of methylation of ICR2 which established the BWS diagnosis. The patient was breast-fed and showed no episodes of hypoglycemia. He had uncomplicated orchiopexy in late infancy. He continued to grow above the 95th centile for height and weight in childhood. He followed regular school. He is currently 17 years old and his height and weight are at the 80th centile. He never developed a tumor or any other medical problem associated with BWS.
A full-term boy was born by vaginal delivery to 27year-old primigravida. The pregnancy was monitored closely by a high-risk obstetrician because of large Case 2 fetal abdominal circumference ascertained sonographically in the second trimester. Serial fetal ultrasounds A newborn girl was referred to us for genetic revealed accelerated fetal growth during the third evaluation because of omphalocele. She was conceived trimester. No structural abnormalities were found. by in vitro fertilization (donor ovum IVF) and was Elective cesarean section was discussed with the born at 30 weeks to a 44-year-old mother [gravida 3, mother, but she decided to wait for natural labor. para 0, abortions (spontaneous) 2] by vaginal delivery. Many maternal serum glucose measurements were The birth weight was 1600 g (þ1SD), the length was normal and two glucose tolerance tests were also 42 cm (þ1SD), and the head circumference was 28 cm normal. The vaginal delivery was uncomplicated and (at mean). She had respiratory insufficiency treated the baby boy weighed 4.6 kg and with ventilatory support throwas 58 cm in length; both weight ugh nasal prongs. She had Our differential included and length were above the 95th facial capillary malformations centile. The head circumference including the eyelids, macroBeckwith–Wiedemann synwas 37.5 cm at the 75th centile. drome because of IVF, prema- glossia, grooves behind on the The macrosomia prompted gluback of the earlobes, small turity and the clinical features, cose testing that revealed hypoomphalocele surgically corespecially macroglossia. glycemia; heel-stick glucose rected, loud murmur (patent 40 mg/dl. He was breast-fed freductus arteriosus as per cardiquently and the glucose normalology), palpable liver and ized. His electrolytes including calcium were normal. spleen, and mild generalized hypotonia. Chromosome He had macroglossia which along with the macrosomia analysis was reported normal 46,XX. Our differential prompted genetic evaluation. Dysmorphology examiincluded Beckwith–Wiedemann syndrome because of nation revealed mid-frontal/mid-glabellar flat capillary IVF,2,3,12 prematurity, and the clinical features [three malformation (nevous flammeus), pit and creases on major findings: macroglossia, omphalocele, and orgathe earlobes, the liver was palpable 2–3 cm below the nomegaly (Table)], especially macroglossia. BWS has costal margin, and the testes were undescended but been associated with IVF in the medical literature.2,3,12 palpable in the inguinal canals. The family history was Blood for DNA methylation test to evaluate for BWS Curr Probl PediatrAdolesc Health Care, Month ]]]]
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was sent, and tumor surveillance was initiated. Initial hypoglycemia was attributed to prematurity; however she continued to be hypoglycemic at 1 month and was treated by the endocrine service with glucose infusions. The probability of an abnormal DNA methylation test was between 83% and 92% [macroglossia 2.5, omphalocele 1.5, organomgaly 1, and hypoplycemia 0.5; total 5.5 (Figure)]. Indeed, the test revealed abnormal methylation in ICR2, confirming the BWS diagnosis. The tongue continued to enlarge and she required both tracheostomy and gastrostomy. She had tongue reduction surgery with subsequent decannulation and gastrostomy reversal. She is currently 3 years old with mild developmental delays and growth at the 95th centile. BWS has served as the prototype of syndromes with generalized overgrowth. The BWS tumor surveillance protocol is sometimes implemented for rare overgrowth syndromes that lack natural history studies. The frequency of the tumor surveillance (every 3 months) naturally puts the pediatrician at the steering wheel of the care. The pediatrician has to encourage the family to stay the course of surveillance, to help the parents endure the anxiety of every test, and to help the patient connect with naturally smaller classmates and to avoid situations that increased height and weight is judged as older age. Frequently, as the pediatrician pulls the family out the tunnel of anticipation of a tumor the patient is ready to enter puberty with fewer medical worries than in infancy. In case of tumor the outcome is quite variable depending on the type of tumor and the location. Unless there is a chromosome abnormality, which is a rare cause of BWS, the neurodevelopmental prognosis is good. Finally, a pediatrician can reasonably expect a BWS patient to graduate from the practice as an adult with ultimately normal growth and normal neurological development.
References 1. Thorburn MJ, Wright ES, Miller CG, Smith-Read EHM. Exomphalos–macroglossia–gigantism syndrome in Jamaican infants. Am J Dis Child 1970;119(4):316–21.
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2. Weksberg R, Shuman C, Beckwith JB. Beckwith–Wiedemann syndrome. Eur J Hum Genet 2010;18(1):8–14. 3. Shuman C, Beckwith JB, Smith AC, Weksberg R. Beckwith– Wiedemann Syndrome. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, (eds). GeneRev. Seattle (WA): University of Washington, 2010. http://www.ncbi.nlm.nih. gov/books/NBK1394/. [03 March 1993–2000, updated]. 4. Ibrahim A, Kirby G, Hardy C. Methylation analysis and diagnostics of Beckwith–Wiedemann syndrome in 1,000 subjects. Clin Epigenetics 2014;6(1):11. 5. Beckwith JB. Macroglossia, omphalocele, adrenal cytomegaly, gigantism, and hyperplastic visceromegaly, In Bergsma D, (ed). Birth Defects: Original Article Series. New York: National Foundation; 1969;5(2):pp.188–96. 6. Yachelevich N. (in this issue). 7. Knopp C, Rudnik-Schöneborn S, Zerres K, Gencik M, Spengler S, Eggermann T. Twenty-one years to the right diagnosis–clinical overlap of Simpson–Golabi–Behmel and Beckwith–Wiedemann syndrome. Am J Med Genet. 2014; 167A(1):151–5. 8. Eggermann T, Binder G, Brioude F. CDKN1C mutations: two sides of the same coin. Trends Mol Med 2014;20(11):614–22. 9. Eggermann T, Heilsberg AK, Bens S. Additional molecular findings in 11p15-associated imprinting disorders: an urgent need for multi-locus testing. J Mol Med (Berl) 2014;92 (7):769–77. 10. Choufani S, Shuman C, Weksberg R. Beckwith–Wiedemann syndrome. Am J Med Genet C Semin Med Genet 2010;154C (3):343–54. 11. Wilson M, Peters G, Bennetts B, et al. The clinical phenotype of mosaicism for genome-wide paternal uniparental disomy: two new reports. Am J Med Genet 2008;146A(2):137–48. 12. Wilkins-Haug L, Porter A, Hawley P, Benson CB. Isolated fetal omphalocele, Beckwith–Wiedemann syndrome, and assisted reproductive technologies. Birth Defects Res A Clin Mol Teratol 2009;85(1):58–62. 13. Everman DB, Shuman C, Dzolganovski B, O'riordan MA, Weksberg R, Robin NH. Serum alpha-fetoprotein levels in Beckwith–Wiedemann syndrome. J Pediatr 2000;137(1):123–7. 14. Goldman M, Shuman C, Weksberg R, Rosenblum ND. Hypercalciuria in Beckwith–Wiedemann syndrome. J Pediatr 2003;142(2):206–8. 15. Greer KJ, Kirkpatrick SJ, Weksberg R, Pauli RM. Beckwith– Wiedemann syndrome in adults: observations from one family and recommendations for care. Am J Med Genet A 2008;146A (13):1707–12. 16. Williams DH, Gauthier DW, Maizels M. Prenatal diagnosis of Beckwith–Wiedemann syndrome. Prenat Diagn 2005;25 (10):879–84.
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