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RENAL FINDINGS ON RADIOLOGICAL FOLLOWUP OF PATIENTS WITH BECKWITH-WIEDEMANN SYNDROME
Vol 161. 235-2:39. January 1999 Prrnlud In 1 1.9 A
RENAL FINDINGS ON RADIOLOGICAL FOLLOWUP OF PATIENTS WITH BECKWITH-WIEDEMA" SYNDROME JOSEPH G. BORER, MARTIN KAEFER, CAROL E. BARNEWOLT, ELLEN R. ELIAS, NEDDA HOBBS, ALAN B. RETIK AND CRAIG A. PETERS From the Departmerits of Urologv, Radiology and Coordrriated Care Serrwe. Chiidrerib Hosprtal and Harrsard Medical School. Boston. Massachusetts
ABSTRACT
Purpose: The Beckwith-Wiedemann syndrome is most commonly characterized by macroglossia and abdominal wall defectb), and it carries a predisposition to embryonal tumors, including Wilms tumor. We report our experience with the character and incidence of renal disease in patients with the Beckwith-Wiedemann syndrome, and discuss the role of radiological followup. Materials and Methods: We reviewed the medical records of all patients diagnosed with the Beckwith-Wiedemann syndrome who were treated a t our institution between March 1979 and February 1998. Radiological followup consisted of renal ultrasound a t approximately 3 to 6-month interval, with the addition of computerized tomography or magnetic resonance imaging (MRI) in patients with a n indeterminate lesion(s) or nephrogenic rest(s). Results: A total of 29 patients were identified. Of these cases renal ultrasound showed normal kidneys bilaterally in 19 (70%),simple cysts in 5 (19%),indeterminate lesion(s) in 2 (7%)and nephrocalcinosis in 1(4%). Nephrogenic rests were followed with MRI in 1patient, and 1in whom a 2 cm. mass was revealed by followup MRI underwent partial nephrectomy and chemotherapy for stage I Wilms tumor. Conclusions: The 3.7% incidence of Wilms tumor in our patients with the BeckwithWiedemann syndrome is similar to that in previously published reports. Aggressive followup by a sensitive radiological technique is warranted in cases of the Beckwith-Wiedemann syndrome, and associated hemihypertrophy a n d o r nephromegaly with or without evidence of a Wilms tumor precursor. The detection of suspected malignant disease a t a n early stage may permit curative nephron sparing surgery. KEY WORDS:nephroblastoma, Beckwith-Wiedemann s-yndrome, ludney The Beckwith-Wiedemann syndrome is a congenital overgrowth syndrome that was first described in 1963 by Beckwith' and independently in 1964 by Wiedemann.' The classic case of this syndrome involves macroglossia, an anterior abdominal wall defect (omphalocele or umbilical hernia) and macrosomia."4 Other associated features may but do not invariably include hemihypertrophy and/or organomegaly, and neonatal hyperinsulinemic hypoglycemia. Abnormal findings on renal imaging include nephromegaly, cortical and medullary cysts, and/or medullary dysplasia.""6 Patients with the Beckwith-Wiedemann syndrome have a predisposition toward embryonal tumor development in the kidney, adrenal glands and liver:3.'.7.8 Wilms tumor, adrenocortical carcinoma and hepatoblastoma are the most common lesions in these patients.'-9 The risk of Wilms tumor in the Beckwith-Wiedemann syndrome is reported to be approximately 0.8 to 3.6s.".7.10 This risk appears to increase significantly with associated hemihypertrophy and/or nephromegaly.7.". 11 Due t o the increased risk of tumor development radiological screening has been advocated in the BeckwithWiedemann syndrome.'-9.11-14 However, some groups believe that the available data are inconclusive15,16or do not support such screening.") We review our experience with patients with the Beckwith-Wiedemann syndrome in regard the character and incidence of renal imaging findings and the role of radiological screening. Accepted for publication August 21, 1998.
MATERIALS A N D METHODS
We reviewed the medical records of all patients diagnosed with the Beckwith-Wiedemann syndrome who were treated a t our institution between March 1979 and February 1998. A total of 16 female and 13 male patients were identified during this 20-year period. Radiological screening of these cases typically consisted of abdominal ultrasound, including pancreatic, hepatic and renal imaging every 3 to 6 months for the first 6 to 8 years of life. Imaging beyond age 8 years was performed for reasons other than routine screening. Findings on renal ultrasound were categorized as normal or by specific pathological findings. Two of the 29 patients had no documentation of renal imaging. One patient who underwent omphalocele repair as a newborn died of sepsis a t age 3 weeks and 1 was lost to followup before renal imaging. In addition to other manifestations of the Beckwith-Wiedemann syndrome, 3 of the 27 patients who underwent renal imaging had associated hemihypertrophy and nephromegaly, 2 had hemihypertrophy only and 2 had nephromegaly only. Also, computerized tomography (CT)or magnetic resonance imaging MiU)was done for further evaluation of indeterminate lesions, including those suspicious of a nephrogenic rest, nephroblastomatosis or medullary dysplasia. Serial MRI was performed in 1 patient with a nephrogenic rest. Any patient with a lesion suspicious of tumor on radiological imaging underwent surgical exploration. RESULTS
Radiological followup ranged from 4 months to 16.5 years (mean of 6.4 years, table 1). All 27 patients were evaluated 235
RENAL FINDINGS IN BECKWITH-WIEDEMA" SYNDROME
236 ~
~~
~
T . ~ I . E1. Radiological follotcap in the Beckwith- Wiedemann syndrome _ _ ~ ~~~~
Radiology Age at Fallowup
Yrs.
Study
Findings
Associated Findings
Less than 1 cm. simple cysts. rt. kidney
No hemihypertrophy or nephromegaly Hemihypertrophy
pt. No.
Sea
1
F
16
2
M
3
5.7
Ultrasound (fig. 21, CT
3
F
4
5.5
1
hl
12
16.2
Ultrasound, MRI (fig. 2, A and B . table 2 ) Ultrasound
5 6
hl
1
F
6.5
3.2 6.6
Ultrasound Ultrasound
7 6
F F M t8 pts.) F fllpts.)
9 5
8.9 5
Ultrasound Ultrasound
Bilat. nephrocalcinosis 1 Cm. simple cyst, upper pole rt. duplex kidney 0 . 5 Cm. simple cyst. It. kidney 1.3 x 1.9 Cm. simple cyst. It. kidney
03-10
Ultrasound
Normal kidneys
9-27
Followup 16.5
Ultrasound fig. 1 I. CT.*
h1RI' Bilat. mottled cartex, increased pyramid echogenicity. nephrogenic rests vs. medullary dysplasia 0.5 Nephrogenic rest, Wilms tumor Less than 1 cm. bilat. simple cysts
Hemihypertrophy + nephromegaly No hemihypertrophy or nephromegaly Nephromegaly No hemihypertrophy or nephromegaly Hemihypertrophy No hemihypertrophy or nephro megaly Hemihypertrophyhephromegaly t2 pts.) Nephromenalv ( 1 pt.)
* Performed to evaluate an enlarged pancreas shown on ultrasound
with abdominal ultrasound, which revealed normal kidneys bilaterally in 19 (70%).simple cysts in 5 (19%),indeterminate renal lesiods) in 2 (7%)and nephrocalcinosis in l ( 4 8 ) (fig. 1). In the 2 patients in whom a n indeterminate renal lesion was noted on ultrasound CT or MRI was performed for further evaluation. In patient 2 this lesion was believed to be consistent with medullary renal dysplasia on CT (fig. 1,A).In patient 3 with a n indeterminate renal lesion MRI showed a nephrogenic rest that subsequently developed into a 2 cm. mass, consistent with Wilms tumor (table 2, fig. 2, A and B). This patient underwent transabdominal exploration via a transverse supraumbilical skin incision. Partial nephrectomy with a 1 cm. tumor-free margin was performed for the lesion in the upper pole of the left kidney that was evident on preoperative MRI (fig. 2, C ) . In addition, Gerota's fascia of the contralateral kidney was opened and the kidney was examined under direct vision, and by digital palpation and intraoperative ultrasound. A radiologically undetected 2 mm. lesion palpated on the anterolateral surface of the contralatera1 kidney was excised. Microscopic examination demonstrated that the lesion excised from the left kidney was consistent with favorable histology Wilms tumor. The much smaller lesion of the contralateral kidney was positive for nephroblastomatosis, while nodal tissue was negative for tumor. The patient was treated with chemotherapy for stage I Wilms tumor according to the National Wilms Tumor Study protocol. She continues to do
well with no evidence of disease 2 years after surgery and chemotherapy. DISCUSSION
The Beckwith-Wiedemann syndrome is most commonly characterized by macroglossia, abdominal wall defects a n d macrosomia (birth weight or postnatal growth greater than the 90th percentile).3." In addition, children with this syndrome have a predisposition for embryonal tumors involving the kidney, adrenal cortex, liver and p a n ~ r e a s . ~ , ~ Tumors .~.* t h a t are primarily malignant arise in approximately 4 to 10% of cases.3.4.7 Wilms tumor i s t h e most common lesion, developing i n approximately 0.8 t o 3.6%of c a ~ e s . ~ . Preliminary ~.~O d a t a from the Beckwith-Wiedemann Syndrome Registry initiated at the National Cancer Institute indicate t h a t the peak incidence of Wilms tumor associated with t h e BeckwithWiedemann syndrome in childhood is 2,850/100,000 cases yearly between t h e first and second birthdays.I6 This rate of Wilms tumor represents a substantial increase over t h e annual incidence of 0.8/100,000 white children younger t h a n 15 years.17 The increased risk of Wilms tumor i n the BeckwithWiedemann syndrome appears to exist in children with partial or complete manifestations of the disease.* Renal imaging findings i n children with the BeckwithWiedemann syndrome include normal kidneys, nephromegaly, diffusely increased cortical echogenicity, a lobulated
FIG. 1. Renal ultrasound. A, less than 1 cm.simple cysts (arrow)in upper pole of right kidney in patient 1. B , diffuse mottled echo texture within cortex of right kidney in patient 2.
RENAL FINDINGS IN BECKWITH-WIEDEMANN SYNDROME
237
TAIM 2 . Radiological findings i n patient 3 with the Beckwith- Wiedemann syndrome, hemihypertrophy and Wilms tumor born July 8, I992 -
Study
___
Renal ultrasound
MRI tfig. 2, A ) Renal ultrasound or MRI Renal ultrasound MRI (fig. 2, B ) ~
RfRI~
~
_
_
_
Date
Findings
7/12/92 12/ 14/92 1/26/93 Every 343 mos.
5.6 Cm. rt. 6.8 cm. It. kidney, no masses Lt. kidney thickened parenchyma, no masses 2 Mm. nephrogenic rest at medial It. upper pole cortical margin, no enhancement with gadolinium Lt. kidney 0.8-1.3 cm. longer than rt. kidney maintained, appropriate bilat. interval growth. nephrogenic rest unchanged 7.7 Cm. rt. + 9.0 cm. It. kidney 2 Cm. mass at medial It. upper pole cortical margin No evidence of disease 5 mos. after resection of It. upper pole _ _ mass
u30/96 7/17/96 1/22/97 _ ~
.
es.3.32.18 In a detailed account of 76 patients Elliot et a1 noted nephromegaly in 45 (59%),multiple cysts in 10 (13%),hydronephrosis in 7 (9%),and medullary cysts and hydronephrosis in 4 (5%).3In other series associated nephromegaly has been reported in 28 and 90% of patients,11.12.18and it was present in 19% of our cases. The majority of our patients (70%)had normal kidneys on ultrasound. In 5 patients renal cysts developed relatively late at a mean age of 9.7 years. In contrast, a nephrogenic rest developed in only 1 case with subsequent development of Wilms tumor at ages 6 months and 4 years, respectively. Certainly some small renal masses are missed by ultrasound since Jamis-Dow et a1 reported that the approximately 79% detection rate for 20 to 25 mm. lesions decreases to 28% for 10 to 15 mm. lesions.19 They also reported that CT is much more sensitive for detecting small renal masses (75% detection rate for 10 to 15 mm. lesions). MRI appears to be particularly helpful for determining the character of renal lesions in patients with Wilms tumor and/or Wilms tumor precursor(s).‘o For example, on gadolinium enhanced T1weighted images Wilms tumor and nephrogenic rests were hypointense relative to normal renal tissue (fig. 2, A and B ) . Furthermore, on T2-weighted images nephrogenic rests were isointense or slightly hyperintense relative to the renal cortex, while sclerotic nephrogenic rests, which stabilize or decrease on followup imaging, were hypointense relative t o the renal cortex. Hemihypertrophy is an associated finding in approximately 12.5 to 24% of the children with the BeckwithWiedemann syndrome,J.4 which is consistent with our 19% rate (5 of 27 patients). Children with the BeckwithWiedemann syndrome and hemihypertrophy appear to be at greater risk for a neoplasm than those without associated hemihypertrophy.7 Wiedemann reported an analysis of the literature and personal observations in 388 children with the syndrome, ofwhom 29 (7.5%)had a tumor and 48 (12.5%)had associated hemihypertrophy.‘ Of the 29 cases of tumor at least 12 (41.44, that is greater than 40% of 29) had associated hemihypertrophy. Therefore, a lesion developed in at least 48 of the children with the Beckwith-Wiedemann syndrome and hemihypertrophy for an estimated 25% rate of tumor development in this specific subgroup. The specific number of Wilms tumors in this subgroup was not stated. An increased risk of Wilms tumor has also been noted in patients with the Beckwith-Wiedemann syndrome and nephromegaly versus those without nephromegaly. Choyke and DeBaun followed 81 patients with the BeckwithWiedemann syndrome, including 23 with nephromegaly, deFIG.2 . Patient 3, left kidney. A, post-gadolinium T1-weighted fined as a kidney greater than the 95th percentile for MRI shows 2 mm. nonenhancing lesion at medial upper pole cortical length.” Of the 23 patients with nephromegaly Wilms tumor margm consistent with nephrogenic rest ( N R ) .B , post-gadolinium T1-weighted MRI 3.5 years after part A reveals 2 cm. medial upper developed in an enlarged kidney in 16 (70%). However, 14 of pole mass with enhancement decreased relative to normal kidney. the 16 patients with nephromegaly had bilateral enlargeconsistent with Wilms tumor ( W n . C, intraoperative photograph ment. Therefore, of at least 37 enlarged kidneys theoretically demonstrates upper pole arterial branch CA) and Wilms tumor ( W T ) . at risk (unilateral versus bilateral disease was not designated in 7 cases) Wilms tumor developed in 16 (43%). The renal margin, cortical and medullary cysts, medullary dys- patient in our series with Wilms tumor had upper extremity plasia a n d o r pelvicaliceal dilatation.3.5.6 Renal abnormali- hemihypertrophy and ipsilateral nephromegaly, and the tuties are associated with the syndrome in 24 to 100% of cas- mor developed in the enlarged kidney. This patient was 1 of
238
RENAL FINDINGS IN BECKWITH-WIEDEMA" SYNDROME
which portends a n increased risk for metachronous Wilms 1 of 3 with both conditions. Therefore. in our small series tumor.23 We think, a s do Ritchey e t al,22t h a t the finding of Wilms tumor developed in 25% of the children with a n asso- nephrogenic rests or nephroblastomatosis is sufficient to ciated finding of hemihypertrophy or nephromegaly and in place a patient in a select group with unilateral Wilms tumor 33%with both conditions. Of the remaining 6 patients with in which parenchymal sparing surgery is indicated. To our hemihypertrophy and/or nephromegaly disease was benign knowledge there are no long-term data on or sufficient numin 3 who were 3 , 6 and 9 years old a t t h e last followup, while bers of patients with unilateral Wilms tumor treated with 3 with normal kidneys were 3, 4 and 10 years old, respec- parenchymal sparing surgery to date to determine any bentively. The available data do not indicate whether the asso- efit of such a practice. Notably there is a n increased incidence ciation of hemihypertrophy and nephromegaly place a pa- of local recurrence i n patients with bilateral Wilms tumor tient with the Beckwith-Wiedemann syndrome at even who have undergone parenchymal sparing surgery, although greater risk for tumor development over the already in- this does not adversely affect survival.24 Most cases of the Beckwith-Wiedemann syndrome occur creased risk coincident with either associated finding alone. The awareness of a n increased risk of Wilms tumor in sporadically (80%),while 20% are familial. Mutations of the children with the Beckwith-Wiedemann syndrome raises the l l p 1 5 gene are found in the syndrome, and only 1%or fewer issue of whether screening for Wilms tumor is appropriate genes actually have chromosomal rearrangement.25 Unipain this population. To date recommendations for and rental disomy and genetic imprinting have been implicated against screening have been based on expert o p i n i ~ n ,case ~ , ~ in t h e pathogenesis of the Beckwith-Wiedemann syndrome. seriesY-lx.1R and case reports.'", 14 However, these reports Loss of a tumor suppressor gene located on l l p 1 5 may exhave not included the rigorous quantitative techniques re- plain t h e predisposition to malignancy in this patient popuquired to address the benefit of screening. DeBaun et al lation. An interesting and provocative aspect of the recommended that the strongest evidence would be provided Beckwith-Wiedemann syndrome is that t h e phenotype apby a randomized screening trial.'6 Theoretically screening pears to abate with increasing patient age, as does t h e risk of would facilitate a downward shift from advanced stages 111 malignancy.s.25 This finding forms the basis of t h e cutoff and IV disease to more localized stages I and I1 disease. If point for ultrasound screening at age 8 years. However, it appreciated, this downward stage shift would minimize acute may be necessary t o continue surveillance beyond that age in and late sequelae as a result of decreased exposure to doxo- patients with multiple risk factors. rubicin chemotherapy and radiation therapy.'" Based on the CONCLUSIONS available data we recommend screening this at risk group using abdominal (renal, pancreatic and hepatic) ultrasound We believe t h a t regular followup with a sensitive radiologevery 3 months until age 6 or 8 years. Since ultrasound may ical technique is warranted in young patients with t h e not detect small lesions, this seems a reasonable compromise Beckwith-Wiedemann syndrome, especially in those with asbecause it is readily available, quickly performed, relatively sociated hemihypertrophy and/or a Wilms tumor precursor. less expensive, noninvasive, does not require sedation and As in our patient 3, screening should identify newly developavoids exposure to ionizing radiation. We strongly urge that ing suspicious lesions, allowing nephron sparing surgical CT or MRI be performed for further evaluation of any, even intervention at an early stage of suspected malignant dismildly suspicious or poorly characterized, ultrasound lesion ease. Our case of Wilms tumor identified at a n early stage with a high index of suspicion. and treated with minimal morbidity is at least anecdotal For this approach to be effective the radiologist must have evidence of the value of routine radiological screening in the expertise in pediatric sonography and patient-caregiver com- Beckwith-Wiedemann syndrome. The optimal method and pliance must be uncompromised. Although none of the pa- timing of screening remain to be determined. tients in our series had a negative outcome secondary to imperfect compliance, compliance issues have a significant REFERENCES bearing on the efficacy of any screening program. For example, Azouz et a1 reported that Wilms tumors greater than 11 1. Beckwith, J. B.: Extreme cytomegaly of the adrenal fetal cortex, omphalocele, hyperplasia of the kidneys and pancreas and and 4 cm. developed in patients 5 and 9 months, respectively, Leydig-cell hyperplasia: another syndrome? Read at Western after imaging studies were normal.13 Even perfect compliSociety of Pediatric Research, Los Angeles, California, Novemance with a 3-month imaging schedule does not guarantee ber 1963. detection of all Wilms tumors before significant growth.14 2. Wiedemann, H. R.: Complexe malformitif familial avec hernia Since Green et a1 clinically detected a n abdominal mass as ombilicale et macroglossie-un syndrome nouveau? J. Genet. early a s 48 days after radiographic screening was negative,'s Hum., 1 3 223, 1964. perhaps caregivers should be taught to palpate the abdomen 3. Elliot, M., Bayly, R. and Cole, T.: Clinical features and natural in the interval between ultrasound studies to supplement history of Beckwith-Wiedemann syndrome: presentation of 74 new cases. Clin. Genet., 46: 168, 1994. screening efforts. 4. Sotelo-Ada, C., Gonzalez-Crussi, F. and Fowler, J. W.: ComThe patient i n our series with a lesion consistent with plete and incomplete forms of Beckwith-Wiedemann synWilms tumor on radiographic screening underwent partial drome: their oncogenic potential. J. Ped., 96:47,1980. nephrectomy and contralateral excisional biopsy. We thought 5. Taybi, H. and Lachman, R. S.: Radiology of syndromes. In: Rat h a t she was an excellent candidate for parenchymal sparing diology of Syndromes, Metabolic Disorders, and Skeletal Dyssurgery based on small lesion size ( 2 cm.), and its polar and plasias, 3rd ed. Chicago: Year Book Medical Pub., pp. 46-49, superficial location. Wilimas et a1 proposed t h a t similar and 1990. additional radiological criteria, including no invasion of the 6. Brock, J. W. and Johnson, J.: Medullary renal dysplasia mimcollecting system or renal vein, and clear margins among the icking renal tumor in the Beckwith-Wiedemann syndrome. Urology, 44: 119, 1994. lesion, kidney and surrounding structures may be predictors 7. Wiedemann, H. R.: Tumours and hemihypertrophy associated of candidates for parenchymal sparing surgery who have with Wiedemann-Beckwith syndrome. Eur. J. Ped., 141: 129, Wilms tumor.2' The findings of Ritchey et a1 do not support a 1983. recommendation for parenchymal sparing surgery in pa8. Beckwith, J. B.: Certain conditions have an increased risk of tients with unilateral Wilms tumor and a normal contralatWilms tumor. AJR, 164 1294. 1995. era1 kidney based on a low incidence of renal failure in 9. Vaughan, W. G., Sanders, D. W. and Grosfeld, J. L.: Favorable similar patients treated with complete nephrectomy.22 Howoutcome in children with Beckwith-Wiedemann syndrome and ever, the contralateral kidney in our patient was in fact intraabdominal malignant tumors. J. Ped. Surg., 30: 1042, abnormal, based on the finding of nephroblastomatosis, 1995.
4 in our series with hemihypertrophy or nephromegaly, and
RENAL FINDINGS IN BECKWITH-WIEDEMA” SYNDROME 10. Craft, A. W., Parker, L. and Stiller, C.: Screening for Wilms tumour in patients with aniridia, Beckwith-Wiedemann syndrome or hemihypertrophy. Med. Ped. Oncol., 24: 231, 1995. 11. Choyke, P. L. and DeBaun, M. R.: Relation between nephromegaly and Wilms tumor in children with BeckwithWiedemann syndrome. Radiology, suppl., 201: 243, 1996. 12. Shah, K. J.:Beckwith-Wiedemann syndrome: role of ultrasound in its management. Clin. Rad., 3 4 313, 1983. 13. Azouz, E. M., Larson, E. J. and Patel, J.: Beckwith-Wiedemann syndrome: development of nephroblastoma during the surveillance period. Ped. Rad., 2 0 550, 1990. 14. Andrews, M. W. and Amparo, E. G.: Wilms tumor in a patient with Beckwith-Wiedemann syndrome: onset detected with 3-month serial sonography. AJR, 1 6 0 139, 1993. 15. Green, D. M., Breslow, N. E. and Beckwith, J. B.: Screening of children with hemihypertrophy, aniridia, and BeckwithWiedemann syndrome in patients with Wilms tumor: a report from the National Wilms Tumor Study. Med. Ped. Oncol., 21: 188, 1993. 16. DeBaun, M. R., Brown, M. and Kessler, L.: Screening for Wilms’ tumor in children with high-risk congenital syndromes: considerations for an intervention trial. Med. Ped. Oncol., 27: 415, 1996. 17. Green, D. M., D’Angio, G. J . and Beckwith, J . B.: Wilms tumor. CA, 4 6 46, 1996.
239
18. Engstrom, W., Lindham, S. and Schofield, P.: WiedemannBeckwith syndrome. Eur. J . Ped., 147: 450, 1988. 19. Jamis-Dow, C. A,, Choyke, P. L. and Jennings, S. B.: Small ( ~ 3 - c mrenal ) masses: detection with CT versus US and pathologic correlation. Radiology, 198: 785, 1996. 20. Gylys-Morin, V., Hoffer, F. A. and Kozakewich, H.: Wilms tumor and nephroblastomatosis: imaging characteristics at gadolinium-enhanced MR imaging. Radiology, 188: 517, 1993. 21. Wilimas, J. A., Magill, L. and Parham, D. M.: The potential for renal salvage in nonmetastatic unilateral Wilms’ tumor. h e r . J . Ped. Hemat. Oncol., 1 3 342, 1991. 22. Ritchey, M. L., Green, D. M. and Thomas, P. R. M.: Renal failure in Wilms tumor patients: a report from the National Wilms Tumor Study Group. Med. Ped. Oncol., 2 6 75, 1996. 23. DAngio, G. J., Rosenberg, H. and Sharples, K.: Position paper: imaging methods for primary renal tumors of childhood: costs versus benefits. Med. Ped. Oncol., 21: 205, 1993. 24. Horwitz, J. R., Ritchey, M. L. and Moksness, J.: Renal salvage procedures in patients with synchronous bilateral Wilms tumors: a report from the National Wilms Tumor Study Group. J . Ped. Surg., 31: 1020, 1996. 25. Elias, E. R., DeBaun, M. R. and Feinberg, A. P.: BeckwithWiedemann Syndrome. In: Principles of Molecular Medicine. Edited by J. L. Jameson. Totowa, New Jersey: Humana Press, 1998.
RENAL FINDINGS ON RADIOLOGICAL FOLLOWUP OF PATIENTS WITH BECKWITH-WIEDEMA" SYNDROME JOSEPH G. BORER, MARTIN KAEFER, CAROL E. BARNEWOLT, ELLEN R. ELIAS, NEDDA HOBBS, ALAN B. RETIK AND CRAIG A. PETERS From the Departmerits of Urologv, Radiology and Coordrriated Care Serrwe. Chiidrerib Hosprtal and Harrsard Medical School. Boston. Massachusetts
ABSTRACT
Purpose: The Beckwith-Wiedemann syndrome is most commonly characterized by macroglossia and abdominal wall defectb), and it carries a predisposition to embryonal tumors, including Wilms tumor. We report our experience with the character and incidence of renal disease in patients with the Beckwith-Wiedemann syndrome, and discuss the role of radiological followup. Materials and Methods: We reviewed the medical records of all patients diagnosed with the Beckwith-Wiedemann syndrome who were treated a t our institution between March 1979 and February 1998. Radiological followup consisted of renal ultrasound a t approximately 3 to 6-month interval, with the addition of computerized tomography or magnetic resonance imaging (MRI) in patients with a n indeterminate lesion(s) or nephrogenic rest(s). Results: A total of 29 patients were identified. Of these cases renal ultrasound showed normal kidneys bilaterally in 19 (70%),simple cysts in 5 (19%),indeterminate lesion(s) in 2 (7%)and nephrocalcinosis in 1(4%). Nephrogenic rests were followed with MRI in 1patient, and 1in whom a 2 cm. mass was revealed by followup MRI underwent partial nephrectomy and chemotherapy for stage I Wilms tumor. Conclusions: The 3.7% incidence of Wilms tumor in our patients with the BeckwithWiedemann syndrome is similar to that in previously published reports. Aggressive followup by a sensitive radiological technique is warranted in cases of the Beckwith-Wiedemann syndrome, and associated hemihypertrophy a n d o r nephromegaly with or without evidence of a Wilms tumor precursor. The detection of suspected malignant disease a t a n early stage may permit curative nephron sparing surgery. KEY WORDS:nephroblastoma, Beckwith-Wiedemann s-yndrome, ludney The Beckwith-Wiedemann syndrome is a congenital overgrowth syndrome that was first described in 1963 by Beckwith' and independently in 1964 by Wiedemann.' The classic case of this syndrome involves macroglossia, an anterior abdominal wall defect (omphalocele or umbilical hernia) and macrosomia."4 Other associated features may but do not invariably include hemihypertrophy and/or organomegaly, and neonatal hyperinsulinemic hypoglycemia. Abnormal findings on renal imaging include nephromegaly, cortical and medullary cysts, and/or medullary dysplasia.""6 Patients with the Beckwith-Wiedemann syndrome have a predisposition toward embryonal tumor development in the kidney, adrenal glands and liver:3.'.7.8 Wilms tumor, adrenocortical carcinoma and hepatoblastoma are the most common lesions in these patients.'-9 The risk of Wilms tumor in the Beckwith-Wiedemann syndrome is reported to be approximately 0.8 to 3.6s.".7.10 This risk appears to increase significantly with associated hemihypertrophy and/or nephromegaly.7.". 11 Due t o the increased risk of tumor development radiological screening has been advocated in the BeckwithWiedemann syndrome.'-9.11-14 However, some groups believe that the available data are inconclusive15,16or do not support such screening.") We review our experience with patients with the Beckwith-Wiedemann syndrome in regard the character and incidence of renal imaging findings and the role of radiological screening. Accepted for publication August 21, 1998.
MATERIALS A N D METHODS
We reviewed the medical records of all patients diagnosed with the Beckwith-Wiedemann syndrome who were treated a t our institution between March 1979 and February 1998. A total of 16 female and 13 male patients were identified during this 20-year period. Radiological screening of these cases typically consisted of abdominal ultrasound, including pancreatic, hepatic and renal imaging every 3 to 6 months for the first 6 to 8 years of life. Imaging beyond age 8 years was performed for reasons other than routine screening. Findings on renal ultrasound were categorized as normal or by specific pathological findings. Two of the 29 patients had no documentation of renal imaging. One patient who underwent omphalocele repair as a newborn died of sepsis a t age 3 weeks and 1 was lost to followup before renal imaging. In addition to other manifestations of the Beckwith-Wiedemann syndrome, 3 of the 27 patients who underwent renal imaging had associated hemihypertrophy and nephromegaly, 2 had hemihypertrophy only and 2 had nephromegaly only. Also, computerized tomography (CT)or magnetic resonance imaging MiU)was done for further evaluation of indeterminate lesions, including those suspicious of a nephrogenic rest, nephroblastomatosis or medullary dysplasia. Serial MRI was performed in 1 patient with a nephrogenic rest. Any patient with a lesion suspicious of tumor on radiological imaging underwent surgical exploration. RESULTS
Radiological followup ranged from 4 months to 16.5 years (mean of 6.4 years, table 1). All 27 patients were evaluated 235
RENAL FINDINGS IN BECKWITH-WIEDEMA" SYNDROME
236 ~
~~
~
T . ~ I . E1. Radiological follotcap in the Beckwith- Wiedemann syndrome _ _ ~ ~~~~
Radiology Age at Fallowup
Yrs.
Study
Findings
Associated Findings
Less than 1 cm. simple cysts. rt. kidney
No hemihypertrophy or nephromegaly Hemihypertrophy
pt. No.
Sea
1
F
16
2
M
3
5.7
Ultrasound (fig. 21, CT
3
F
4
5.5
1
hl
12
16.2
Ultrasound, MRI (fig. 2, A and B . table 2 ) Ultrasound
5 6
hl
1
F
6.5
3.2 6.6
Ultrasound Ultrasound
7 6
F F M t8 pts.) F fllpts.)
9 5
8.9 5
Ultrasound Ultrasound
Bilat. nephrocalcinosis 1 Cm. simple cyst, upper pole rt. duplex kidney 0 . 5 Cm. simple cyst. It. kidney 1.3 x 1.9 Cm. simple cyst. It. kidney
03-10
Ultrasound
Normal kidneys
9-27
Followup 16.5
Ultrasound fig. 1 I. CT.*
h1RI' Bilat. mottled cartex, increased pyramid echogenicity. nephrogenic rests vs. medullary dysplasia 0.5 Nephrogenic rest, Wilms tumor Less than 1 cm. bilat. simple cysts
Hemihypertrophy + nephromegaly No hemihypertrophy or nephromegaly Nephromegaly No hemihypertrophy or nephromegaly Hemihypertrophy No hemihypertrophy or nephro megaly Hemihypertrophyhephromegaly t2 pts.) Nephromenalv ( 1 pt.)
* Performed to evaluate an enlarged pancreas shown on ultrasound
with abdominal ultrasound, which revealed normal kidneys bilaterally in 19 (70%).simple cysts in 5 (19%),indeterminate renal lesiods) in 2 (7%)and nephrocalcinosis in l ( 4 8 ) (fig. 1). In the 2 patients in whom a n indeterminate renal lesion was noted on ultrasound CT or MRI was performed for further evaluation. In patient 2 this lesion was believed to be consistent with medullary renal dysplasia on CT (fig. 1,A).In patient 3 with a n indeterminate renal lesion MRI showed a nephrogenic rest that subsequently developed into a 2 cm. mass, consistent with Wilms tumor (table 2, fig. 2, A and B). This patient underwent transabdominal exploration via a transverse supraumbilical skin incision. Partial nephrectomy with a 1 cm. tumor-free margin was performed for the lesion in the upper pole of the left kidney that was evident on preoperative MRI (fig. 2, C ) . In addition, Gerota's fascia of the contralateral kidney was opened and the kidney was examined under direct vision, and by digital palpation and intraoperative ultrasound. A radiologically undetected 2 mm. lesion palpated on the anterolateral surface of the contralatera1 kidney was excised. Microscopic examination demonstrated that the lesion excised from the left kidney was consistent with favorable histology Wilms tumor. The much smaller lesion of the contralateral kidney was positive for nephroblastomatosis, while nodal tissue was negative for tumor. The patient was treated with chemotherapy for stage I Wilms tumor according to the National Wilms Tumor Study protocol. She continues to do
well with no evidence of disease 2 years after surgery and chemotherapy. DISCUSSION
The Beckwith-Wiedemann syndrome is most commonly characterized by macroglossia, abdominal wall defects a n d macrosomia (birth weight or postnatal growth greater than the 90th percentile).3." In addition, children with this syndrome have a predisposition for embryonal tumors involving the kidney, adrenal cortex, liver and p a n ~ r e a s . ~ , ~ Tumors .~.* t h a t are primarily malignant arise in approximately 4 to 10% of cases.3.4.7 Wilms tumor i s t h e most common lesion, developing i n approximately 0.8 t o 3.6%of c a ~ e s . ~ . Preliminary ~.~O d a t a from the Beckwith-Wiedemann Syndrome Registry initiated at the National Cancer Institute indicate t h a t the peak incidence of Wilms tumor associated with t h e BeckwithWiedemann syndrome in childhood is 2,850/100,000 cases yearly between t h e first and second birthdays.I6 This rate of Wilms tumor represents a substantial increase over t h e annual incidence of 0.8/100,000 white children younger t h a n 15 years.17 The increased risk of Wilms tumor i n the BeckwithWiedemann syndrome appears to exist in children with partial or complete manifestations of the disease.* Renal imaging findings i n children with the BeckwithWiedemann syndrome include normal kidneys, nephromegaly, diffusely increased cortical echogenicity, a lobulated
FIG. 1. Renal ultrasound. A, less than 1 cm.simple cysts (arrow)in upper pole of right kidney in patient 1. B , diffuse mottled echo texture within cortex of right kidney in patient 2.
RENAL FINDINGS IN BECKWITH-WIEDEMANN SYNDROME
237
TAIM 2 . Radiological findings i n patient 3 with the Beckwith- Wiedemann syndrome, hemihypertrophy and Wilms tumor born July 8, I992 -
Study
___
Renal ultrasound
MRI tfig. 2, A ) Renal ultrasound or MRI Renal ultrasound MRI (fig. 2, B ) ~
RfRI~
~
_
_
_
Date
Findings
7/12/92 12/ 14/92 1/26/93 Every 343 mos.
5.6 Cm. rt. 6.8 cm. It. kidney, no masses Lt. kidney thickened parenchyma, no masses 2 Mm. nephrogenic rest at medial It. upper pole cortical margin, no enhancement with gadolinium Lt. kidney 0.8-1.3 cm. longer than rt. kidney maintained, appropriate bilat. interval growth. nephrogenic rest unchanged 7.7 Cm. rt. + 9.0 cm. It. kidney 2 Cm. mass at medial It. upper pole cortical margin No evidence of disease 5 mos. after resection of It. upper pole _ _ mass
u30/96 7/17/96 1/22/97 _ ~
.
es.3.32.18 In a detailed account of 76 patients Elliot et a1 noted nephromegaly in 45 (59%),multiple cysts in 10 (13%),hydronephrosis in 7 (9%),and medullary cysts and hydronephrosis in 4 (5%).3In other series associated nephromegaly has been reported in 28 and 90% of patients,11.12.18and it was present in 19% of our cases. The majority of our patients (70%)had normal kidneys on ultrasound. In 5 patients renal cysts developed relatively late at a mean age of 9.7 years. In contrast, a nephrogenic rest developed in only 1 case with subsequent development of Wilms tumor at ages 6 months and 4 years, respectively. Certainly some small renal masses are missed by ultrasound since Jamis-Dow et a1 reported that the approximately 79% detection rate for 20 to 25 mm. lesions decreases to 28% for 10 to 15 mm. lesions.19 They also reported that CT is much more sensitive for detecting small renal masses (75% detection rate for 10 to 15 mm. lesions). MRI appears to be particularly helpful for determining the character of renal lesions in patients with Wilms tumor and/or Wilms tumor precursor(s).‘o For example, on gadolinium enhanced T1weighted images Wilms tumor and nephrogenic rests were hypointense relative to normal renal tissue (fig. 2, A and B ) . Furthermore, on T2-weighted images nephrogenic rests were isointense or slightly hyperintense relative to the renal cortex, while sclerotic nephrogenic rests, which stabilize or decrease on followup imaging, were hypointense relative t o the renal cortex. Hemihypertrophy is an associated finding in approximately 12.5 to 24% of the children with the BeckwithWiedemann syndrome,J.4 which is consistent with our 19% rate (5 of 27 patients). Children with the BeckwithWiedemann syndrome and hemihypertrophy appear to be at greater risk for a neoplasm than those without associated hemihypertrophy.7 Wiedemann reported an analysis of the literature and personal observations in 388 children with the syndrome, ofwhom 29 (7.5%)had a tumor and 48 (12.5%)had associated hemihypertrophy.‘ Of the 29 cases of tumor at least 12 (41.44, that is greater than 40% of 29) had associated hemihypertrophy. Therefore, a lesion developed in at least 48 of the children with the Beckwith-Wiedemann syndrome and hemihypertrophy for an estimated 25% rate of tumor development in this specific subgroup. The specific number of Wilms tumors in this subgroup was not stated. An increased risk of Wilms tumor has also been noted in patients with the Beckwith-Wiedemann syndrome and nephromegaly versus those without nephromegaly. Choyke and DeBaun followed 81 patients with the BeckwithWiedemann syndrome, including 23 with nephromegaly, deFIG.2 . Patient 3, left kidney. A, post-gadolinium T1-weighted fined as a kidney greater than the 95th percentile for MRI shows 2 mm. nonenhancing lesion at medial upper pole cortical length.” Of the 23 patients with nephromegaly Wilms tumor margm consistent with nephrogenic rest ( N R ) .B , post-gadolinium T1-weighted MRI 3.5 years after part A reveals 2 cm. medial upper developed in an enlarged kidney in 16 (70%). However, 14 of pole mass with enhancement decreased relative to normal kidney. the 16 patients with nephromegaly had bilateral enlargeconsistent with Wilms tumor ( W n . C, intraoperative photograph ment. Therefore, of at least 37 enlarged kidneys theoretically demonstrates upper pole arterial branch CA) and Wilms tumor ( W T ) . at risk (unilateral versus bilateral disease was not designated in 7 cases) Wilms tumor developed in 16 (43%). The renal margin, cortical and medullary cysts, medullary dys- patient in our series with Wilms tumor had upper extremity plasia a n d o r pelvicaliceal dilatation.3.5.6 Renal abnormali- hemihypertrophy and ipsilateral nephromegaly, and the tuties are associated with the syndrome in 24 to 100% of cas- mor developed in the enlarged kidney. This patient was 1 of
238
RENAL FINDINGS IN BECKWITH-WIEDEMA" SYNDROME
which portends a n increased risk for metachronous Wilms 1 of 3 with both conditions. Therefore. in our small series tumor.23 We think, a s do Ritchey e t al,22t h a t the finding of Wilms tumor developed in 25% of the children with a n asso- nephrogenic rests or nephroblastomatosis is sufficient to ciated finding of hemihypertrophy or nephromegaly and in place a patient in a select group with unilateral Wilms tumor 33%with both conditions. Of the remaining 6 patients with in which parenchymal sparing surgery is indicated. To our hemihypertrophy and/or nephromegaly disease was benign knowledge there are no long-term data on or sufficient numin 3 who were 3 , 6 and 9 years old a t t h e last followup, while bers of patients with unilateral Wilms tumor treated with 3 with normal kidneys were 3, 4 and 10 years old, respec- parenchymal sparing surgery to date to determine any bentively. The available data do not indicate whether the asso- efit of such a practice. Notably there is a n increased incidence ciation of hemihypertrophy and nephromegaly place a pa- of local recurrence i n patients with bilateral Wilms tumor tient with the Beckwith-Wiedemann syndrome at even who have undergone parenchymal sparing surgery, although greater risk for tumor development over the already in- this does not adversely affect survival.24 Most cases of the Beckwith-Wiedemann syndrome occur creased risk coincident with either associated finding alone. The awareness of a n increased risk of Wilms tumor in sporadically (80%),while 20% are familial. Mutations of the children with the Beckwith-Wiedemann syndrome raises the l l p 1 5 gene are found in the syndrome, and only 1%or fewer issue of whether screening for Wilms tumor is appropriate genes actually have chromosomal rearrangement.25 Unipain this population. To date recommendations for and rental disomy and genetic imprinting have been implicated against screening have been based on expert o p i n i ~ n ,case ~ , ~ in t h e pathogenesis of the Beckwith-Wiedemann syndrome. seriesY-lx.1R and case reports.'", 14 However, these reports Loss of a tumor suppressor gene located on l l p 1 5 may exhave not included the rigorous quantitative techniques re- plain t h e predisposition to malignancy in this patient popuquired to address the benefit of screening. DeBaun et al lation. An interesting and provocative aspect of the recommended that the strongest evidence would be provided Beckwith-Wiedemann syndrome is that t h e phenotype apby a randomized screening trial.'6 Theoretically screening pears to abate with increasing patient age, as does t h e risk of would facilitate a downward shift from advanced stages 111 malignancy.s.25 This finding forms the basis of t h e cutoff and IV disease to more localized stages I and I1 disease. If point for ultrasound screening at age 8 years. However, it appreciated, this downward stage shift would minimize acute may be necessary t o continue surveillance beyond that age in and late sequelae as a result of decreased exposure to doxo- patients with multiple risk factors. rubicin chemotherapy and radiation therapy.'" Based on the CONCLUSIONS available data we recommend screening this at risk group using abdominal (renal, pancreatic and hepatic) ultrasound We believe t h a t regular followup with a sensitive radiologevery 3 months until age 6 or 8 years. Since ultrasound may ical technique is warranted in young patients with t h e not detect small lesions, this seems a reasonable compromise Beckwith-Wiedemann syndrome, especially in those with asbecause it is readily available, quickly performed, relatively sociated hemihypertrophy and/or a Wilms tumor precursor. less expensive, noninvasive, does not require sedation and As in our patient 3, screening should identify newly developavoids exposure to ionizing radiation. We strongly urge that ing suspicious lesions, allowing nephron sparing surgical CT or MRI be performed for further evaluation of any, even intervention at an early stage of suspected malignant dismildly suspicious or poorly characterized, ultrasound lesion ease. Our case of Wilms tumor identified at a n early stage with a high index of suspicion. and treated with minimal morbidity is at least anecdotal For this approach to be effective the radiologist must have evidence of the value of routine radiological screening in the expertise in pediatric sonography and patient-caregiver com- Beckwith-Wiedemann syndrome. The optimal method and pliance must be uncompromised. Although none of the pa- timing of screening remain to be determined. tients in our series had a negative outcome secondary to imperfect compliance, compliance issues have a significant REFERENCES bearing on the efficacy of any screening program. For example, Azouz et a1 reported that Wilms tumors greater than 11 1. Beckwith, J. B.: Extreme cytomegaly of the adrenal fetal cortex, omphalocele, hyperplasia of the kidneys and pancreas and and 4 cm. developed in patients 5 and 9 months, respectively, Leydig-cell hyperplasia: another syndrome? Read at Western after imaging studies were normal.13 Even perfect compliSociety of Pediatric Research, Los Angeles, California, Novemance with a 3-month imaging schedule does not guarantee ber 1963. detection of all Wilms tumors before significant growth.14 2. Wiedemann, H. R.: Complexe malformitif familial avec hernia Since Green et a1 clinically detected a n abdominal mass as ombilicale et macroglossie-un syndrome nouveau? J. Genet. early a s 48 days after radiographic screening was negative,'s Hum., 1 3 223, 1964. perhaps caregivers should be taught to palpate the abdomen 3. Elliot, M., Bayly, R. and Cole, T.: Clinical features and natural in the interval between ultrasound studies to supplement history of Beckwith-Wiedemann syndrome: presentation of 74 new cases. Clin. Genet., 46: 168, 1994. screening efforts. 4. Sotelo-Ada, C., Gonzalez-Crussi, F. and Fowler, J. W.: ComThe patient i n our series with a lesion consistent with plete and incomplete forms of Beckwith-Wiedemann synWilms tumor on radiographic screening underwent partial drome: their oncogenic potential. J. Ped., 96:47,1980. nephrectomy and contralateral excisional biopsy. We thought 5. Taybi, H. and Lachman, R. S.: Radiology of syndromes. In: Rat h a t she was an excellent candidate for parenchymal sparing diology of Syndromes, Metabolic Disorders, and Skeletal Dyssurgery based on small lesion size ( 2 cm.), and its polar and plasias, 3rd ed. Chicago: Year Book Medical Pub., pp. 46-49, superficial location. Wilimas et a1 proposed t h a t similar and 1990. additional radiological criteria, including no invasion of the 6. Brock, J. W. and Johnson, J.: Medullary renal dysplasia mimcollecting system or renal vein, and clear margins among the icking renal tumor in the Beckwith-Wiedemann syndrome. Urology, 44: 119, 1994. lesion, kidney and surrounding structures may be predictors 7. Wiedemann, H. R.: Tumours and hemihypertrophy associated of candidates for parenchymal sparing surgery who have with Wiedemann-Beckwith syndrome. Eur. J. Ped., 141: 129, Wilms tumor.2' The findings of Ritchey et a1 do not support a 1983. recommendation for parenchymal sparing surgery in pa8. Beckwith, J. B.: Certain conditions have an increased risk of tients with unilateral Wilms tumor and a normal contralatWilms tumor. AJR, 164 1294. 1995. era1 kidney based on a low incidence of renal failure in 9. Vaughan, W. G., Sanders, D. W. and Grosfeld, J. L.: Favorable similar patients treated with complete nephrectomy.22 Howoutcome in children with Beckwith-Wiedemann syndrome and ever, the contralateral kidney in our patient was in fact intraabdominal malignant tumors. J. Ped. Surg., 30: 1042, abnormal, based on the finding of nephroblastomatosis, 1995.
4 in our series with hemihypertrophy or nephromegaly, and
RENAL FINDINGS IN BECKWITH-WIEDEMA” SYNDROME 10. Craft, A. W., Parker, L. and Stiller, C.: Screening for Wilms tumour in patients with aniridia, Beckwith-Wiedemann syndrome or hemihypertrophy. Med. Ped. Oncol., 24: 231, 1995. 11. Choyke, P. L. and DeBaun, M. R.: Relation between nephromegaly and Wilms tumor in children with BeckwithWiedemann syndrome. Radiology, suppl., 201: 243, 1996. 12. Shah, K. J.:Beckwith-Wiedemann syndrome: role of ultrasound in its management. Clin. Rad., 3 4 313, 1983. 13. Azouz, E. M., Larson, E. J. and Patel, J.: Beckwith-Wiedemann syndrome: development of nephroblastoma during the surveillance period. Ped. Rad., 2 0 550, 1990. 14. Andrews, M. W. and Amparo, E. G.: Wilms tumor in a patient with Beckwith-Wiedemann syndrome: onset detected with 3-month serial sonography. AJR, 1 6 0 139, 1993. 15. Green, D. M., Breslow, N. E. and Beckwith, J. B.: Screening of children with hemihypertrophy, aniridia, and BeckwithWiedemann syndrome in patients with Wilms tumor: a report from the National Wilms Tumor Study. Med. Ped. Oncol., 21: 188, 1993. 16. DeBaun, M. R., Brown, M. and Kessler, L.: Screening for Wilms’ tumor in children with high-risk congenital syndromes: considerations for an intervention trial. Med. Ped. Oncol., 27: 415, 1996. 17. Green, D. M., D’Angio, G. J . and Beckwith, J . B.: Wilms tumor. CA, 4 6 46, 1996.
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18. Engstrom, W., Lindham, S. and Schofield, P.: WiedemannBeckwith syndrome. Eur. J . Ped., 147: 450, 1988. 19. Jamis-Dow, C. A,, Choyke, P. L. and Jennings, S. B.: Small ( ~ 3 - c mrenal ) masses: detection with CT versus US and pathologic correlation. Radiology, 198: 785, 1996. 20. Gylys-Morin, V., Hoffer, F. A. and Kozakewich, H.: Wilms tumor and nephroblastomatosis: imaging characteristics at gadolinium-enhanced MR imaging. Radiology, 188: 517, 1993. 21. Wilimas, J. A., Magill, L. and Parham, D. M.: The potential for renal salvage in nonmetastatic unilateral Wilms’ tumor. h e r . J . Ped. Hemat. Oncol., 1 3 342, 1991. 22. Ritchey, M. L., Green, D. M. and Thomas, P. R. M.: Renal failure in Wilms tumor patients: a report from the National Wilms Tumor Study Group. Med. Ped. Oncol., 2 6 75, 1996. 23. DAngio, G. J., Rosenberg, H. and Sharples, K.: Position paper: imaging methods for primary renal tumors of childhood: costs versus benefits. Med. Ped. Oncol., 21: 205, 1993. 24. Horwitz, J. R., Ritchey, M. L. and Moksness, J.: Renal salvage procedures in patients with synchronous bilateral Wilms tumors: a report from the National Wilms Tumor Study Group. J . Ped. Surg., 31: 1020, 1996. 25. Elias, E. R., DeBaun, M. R. and Feinberg, A. P.: BeckwithWiedemann Syndrome. In: Principles of Molecular Medicine. Edited by J. L. Jameson. Totowa, New Jersey: Humana Press, 1998.