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Wilms Tumor - Aniridia Syndrome (WAGR Syndrome) - Implication for the Importance of Genetic Diagnosis and Prospective Tumor Screening

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Wilms Tumor - Aniridia Syndrome (WAGR Syndrome) - Implication for the Importance of Genetic Diagnosis and Prospective Tumor Screening Wilms Tumor - Aniridia Syndrome (WAGR Syndrome) - Implication for the Importance of Genetic Diagnosis and Prospective Tumor Screening - 1Akira Kikuchi MD, 2Hirofumi Ohashi MD, 1,5Daisuke Tomizawa MD, 3,6Tadashi Iwanaka MD, 4Eiji Oguma MD and 1Ryoji Hanada MD. 1Division of Hematology / Oncology, Saitama Children's Medical Center, 2Division of Medical Genetics, Saitama Children's Medical Center, 3Department of Surgery, Saitama Children's Medical Center, 4Department of Radiology, Saitama Children's Medical Center, 5Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan. 6Department of Pediatric Surgery, University of Tokyo, Tokyo, Japan. ABSTRACT Association between Wilms tumor and aniridia is well recognized as WAGR syndrome.1, 2 The responsible genes The association between Wilms tumor and aniridia is well for Wilms tumor (WT1)3, 4 and aniridia (PAX6)5 are located recognized. We performed FISH analysis of WT1 and PAX6 closely at p13 on the short arm of chromosome 11 within 1 genes in aniridia patients and prospective tumor screening in Mb distance and large interstitial deletion of 11p causes patients with WT1 germ line deletion. A two-month old girl Wilms tumor and aniridia simultaneously in affected with aniridia showing WT1 deletion underwent prospective patients. Generally, aniridia patients are at high risk for the abdominal ultrasonic echograms at two-month intervals and development of Wilms tumor. However, we previously bilateral renal tumors were detected four months later. She reported that the risk for Wilms tumor in aniridia patients remains well after chemotherapy and delayed primary surgery can be predicted by FISH analysis of WT1 gene and PAX6 at 48 months. FISH analysis of WT1 and PAX6 in aniridia gene.6 Based on this observation, we prospectively screened patients and prospective tumor screening for those with WT1 Wilms tumor in an aniridia patient with WT1 and PAX6 deletion are important for the prediction and early detection of deletion and successfully detected the tumor early. The Wilms tumor. treatment strategy for Wilms tumor in aniridia patients is also discussed. A two-month old girl was referred to our center because of abnormal eye appearance. She also had polydactylies of the lower limbs. She was diagnosed as having aniridia and FISH analysis revealed deletion of WT1 (Fig. 1) and PAX6. We started prospective tumor screening by abdominal ultrasonic echogram examinations at 2-month intervals. Key words: Wilms tumor, aniridia, WT1, FISH, tumor Four months later, bilateral renal tumors were detected screening (Fig. 2A). Distant metastasis was not detected. WAGR Correspondence to: Akira Kikuchi MD, Division of Hematology / Oncology, Saitama Children’s Medical Center, 2100 Magome Iwatsuki-ku Saitama-shi, Saitama 339-8551, Japan. 41 Tel: +81 48 7581811, Fax: +81 48 7581818, E-mail address: [email protected] Akira Kikuchi patients are at high risk for renal failure on long-term follow up and preservation of renal function is very important for these patients. Therefore, we started chemotherapy according to National Wilms’ Tumor Study (NWTS)-IV EE regimen7 without renal biopsy or nephrectomy. After six months of chemotherapy, renal tumors were markedly reduced (Fig. 2B) and tumor wedge resection was performed as a delayed primary operation. The histology of residual tumor only showed fibrosis and hypertrophic nephrogenic rest (data not shown). We did not add any further therapy and she currently remains well with no evidence of the tumor for 48 months. In this article, we reported a WAGR syndrome patient whose tumors were detected by prospective tumor screening based on genetic analysis for the WT1 gene. Generally, aniridia patients are at high risk for developing Wilms tumor and we previously reported the effectiveness of FISH analysis on WT1 and PAX6 genes for predicting the risk of Fig..1 FISH analysis with WT1gene (arrow) probe in white Wilms tumor development.6 In this report, Wilms tumor blood cells of the patient. Reference probes for chromosome 11 were only seen among aniridia patients with WT1 deletion are shown by arrows as control. WT1 gene (triangle) was deleted in one allele of the patient. (four of eight patients) and none among the patients without (zero of ten patients). Therefore it is unnecessary to consider the risk of Wilms tumor in aniridia patients without WT1 deletion. On the contrary, aniridia patients with WT1 deletion are at high risk for developing Wilms tumor and prospective tumor screening is needed because early detection of tumors allows the treatment to be minimized along with early and late complications associated with this disease. In this patient, we performed prospective abdominal ultrasonic echograms at 2-month intervals and bilateral renal tumors were detected four months later. Recently, Breslow et al. reported the treatment outcome of WAGR patients in NWTS Group.8 In their report, WAGR patients died of end stage renal disease, not tumor progression, on long-term follow up. Therefore, preservation of renal function is very important for WAGR patients. Based on these findings, we preceded chemotherapy rather than biopsy or nephrectomy and minimal wedge resection was performed after chemotherapy as delayed primary surgery. This strategy to avoid excessive loss of renal function was effective and feasible in our patient. For this purpose, genetic diagnosis of WT1 and PAX6 genes and prospective tumor screening by abdominal ultrasonic echograms are very useful. We propose the follow-up strategy described in this report for aniridia patients. At onset, all aniridia patients should receive genetic screening of WT1 and PAX6 gene deletions by FISH. If the patient is negative for WT1 gene deletion, further follow-up for Wilms tumor detection is not necessary. However, for the aniridia patients with WT1 deletion, we Fig. 2 Abdominal computed tomography of the patient before recommend abdominal ultrasonic echograms at 2-3-month (A) and after (B) chemotherapy. intervals to detect Wilms tumor in an early stage. We Austral - Asian Journal of Cancer ISSN-0972-2556, Vol. 8, No.1, January 2009 42 WAGR synd - FISH Diagnosis and Tumor Screening tentatively defined the upper limit of age for this screening imbalance in the Aniridia-Wilms’ tumor association: 11p as 8 years old because the mean plus 2 standard deviation interstitial deletion. Pediatrics 1978; 61: 604-610. 3 Call KM, Glaser T, Ito CY et al.: Isolation and characterization of onset age of WAGR syndrome was reported to be 89 of zinc finger polypeptide gene at the human chromosome-11 months old.8 Wilms tumor locus. Cell 1990; 60: 509-520. 4 Gessler M, Poustka A, Cavenee W et al.: Homozygous deletion We reported here a successful treatment of the bilateral in Wilms tumours of a zinc- finger gene identified by chromosomal jumping. Nature 1990; 343: 774-778 renal tumors by prospective abdominal ultrasonic echogram 5 Ton CCT, Hirvonen H, Miwa H et al.: Positional cloning and examinations in an aniridia patient with WT1 gene deletion characterization of a paired box-containing and homeobox- by FISH analysis. In conclusion, genetic analysis of WT1 containing gene from the aniridia region. Cell 1991; 67: and PAX6 genes in aniridia patients by the FISH method 1059-1074. 6 Muto R, Yamamori S, Ohashi H et al.: Prediction by FISH is important for the prediction of the development of Wilms analysis of the occurrence of Wilms tumor in aniridia patients. tumor and prospective abdominal ultrasonic echogram Am J Med Genet 2002;108: 285-289. examinations are also important for early tumor detection. 7 Green DM, Breslow JB, Beckwith JB et al.: Comparison between single-dose and divided-dose administration of dactinomycin and doxorubicin for patients with Wilms’ tumor. J Clin Oncol REFERENCES 1998;16: 237-245 8 Breslow NE, Norris R, Norkool PA et al.: Characteristics and 1 Miller RW, Fraumeni JF, Manning MD: Association of Wims’ outcome s of children with the Wilms tumor-Aniridia syndrome: tumor with aniridia, hemihypertrophy and other congenital a report from the National Wilms Tumor Study Group. J Clin malformations. N Engl J Med 1964; 270: 922-927. Oncol 2003;21: 4579-4585. 2 Riccardi VM, Sujansky E, Smith AC et al.: Chromosomal Austral - Asian Journal of Cancer ISSN-0972-2556, Vol. 8, No.1, January 2009 43.
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