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WAGR Syndrome Clinical Presentation

  • Author: Steven K Bergstrom, MD; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
 
Updated: Dec 02, 2015
 

History

Symptoms suggestive of aniridia, GU malformations, and mental retardation (AGR) syndrome are usually noted in the perinatal period. Note the following:

  • The mother's pregnancy and the patient's birth history are generally unremarkable.
  • Nephromegaly may be revealed using prenatal ultrasonography.
  • The family history is rarely helpful.
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Physical

Wilms tumor

The development of Wilms tumor in patients with Wilms tumor, aniridia, GU abnormalities, and mental retardation (WAGR) syndrome is more rapid than in patients with a sporadic Wilms tumor. In one cohort, the average age of tumor diagnosis was 17-27 months compared with 38 months in patients who did not have WAGR syndrome.[7]

If AGR syndrome has been diagnosed, the tumor may be detected with routine ultrasonographic screening. Otherwise, the presence of a new or enlarging abdominal mass, hematuria, abdominal pain, or hypertension may indicate the development of malignancy. A palpable mass that is located in either flank and immobile on respiration is suggestive of a Wilms tumor.

Occasionally, patients may have a varicocele, which is due to obstruction of the spermatic vein by a thrombus in the inferior vena cava.

Aniridia

The congenital absence of the iris is usually the first and most striking feature. Although generally absent in the newborn period, scanning nystagmus may be present in infancy. The degree of vision loss varies among patients.

In a recent study of 125 patients who presented with aniridia, 74 were classified as sporadic, 24 were classified as familial, and 14 were classified as having WAGR syndrome.[8] The 11p13 chromosomal analysis of these patients revealed that 10 of the 14 (71%) patients with WAGR syndrome had deletions (2 cryptic and 8 visible).

GU abnormalities

A range of GU abnormalities may be present at birth. Cryptorchidism and hypospadias are commonly observed in association with AGR and WAGR syndromes. The presence of pseudohermaphroditism should alert the clinician to the possibility of Denys-Drash or Frasier syndromes, both of which result from mutations in the WT1 gene. Nephroblastomatosis, or the enlargement of one or both kidneys related to the presence of nephrogenic rests, may be detected by means of prenatal ultrasonography or careful palpation of the abdomen during the neonatal period.

Mental retardation

The presence and degree of mental retardation widely vary among patients with WAGR syndrome.[9]  Generally, determining the degree of retardation is impossible in the newborn period, although parents should be alerted to the possibility.

As the patient ages, the reliability of neuropsychometric testing improves, and baseline testing should be performed. The presence of vision loss may complicate the testing process because children with vision difficulties may acquire developmental milestones differently from children with normal vision. Thorough developmental screening appropriate in individuals with visual impairment is required for the diagnosis of mental retardation.

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Causes

WAGR syndrome is caused by the contiguous loss of chromosomal material from the short arm of chromosome 11.

The appearance of early bilateral disease in some children suggests the possibility that these patients have a constitutional genetic defect that predisposes them to the development of a Wilms tumor.[10] The prezygotic loss of one of the alleles is followed by the loss of the second allele in infancy or early childhood (somatic).

The identification of the gene responsible for Wilms tumor did not occur until 1990, when 3 groups independently identified the WT1 gene on band 11p13.[11, 12, 13]  Note the following:

  • The genetic structure includes 4 zinc-finger regions, which suggest that WT1 may be important in controlling the expression of other genes. Both the GU abnormalities and the development of a Wilms tumor in patients with WAGR syndrome are related to the loss of WT1 gene function. In adults, WT1 isoforms continue to be expressed in some kidney tissue.
  • A neighboring gene, PAX6, is responsible for the development of the iris. Deletion of the PAX6 gene as part of the band 11p13 deletion in patients with AGR or WAGR syndrome results in aniridia.
  • Deletion of the PAX6 gene, which plays a role in myelinization of the cerebral hemispheres during CNS development, may also be responsible for the mental retardation seen in the WAGR association. An association between PAX6 abnormalities and diabetes may indicate that it plays a role in pancreatic development as well.
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Contributor Information and Disclosures
Author

Steven K Bergstrom, MD Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland

Steven K Bergstrom, MD is a member of the following medical societies: Alpha Omega Alpha, Children's Oncology Group, American Society of Clinical Oncology, International Society for Experimental Hematology, American Society of Hematology, American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Timothy P Cripe, MD, PhD, FAAP Chief, Division of Hematology/Oncology/BMT, Gordon Teter Endowed Chair in Pediatric Cancer, Nationwide Children's Hospital; Professor of Pediatrics, Ohio State University College of Medicine

Timothy P Cripe, MD, PhD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American Association for Cancer Research, American Pediatric Society, American Society of Gene and Cell Therapy, American Society of Pediatric Hematology/Oncology, Connective Tissue Oncology Society, Society for Pediatric Research, Children's Oncology Group

Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA Executive Vice President, Chief Medical and Academic Officer, Renown Heath

Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American College of Healthcare Executives, American Society of Pediatric Hematology/Oncology, Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

Stephan A Grupp, MD, PhD Director, Stem Cell Biology Program, Department of Pediatrics, Division of Oncology, Children's Hospital of Philadelphia; Associate Professor of Pediatrics, University of Pennsylvania School of Medicine

Stephan A Grupp, MD, PhD is a member of the following medical societies: American Association for Cancer Research, Society for Pediatric Research, American Society for Blood and Marrow Transplantation, American Society of Hematology, American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

References
  1. Al-Hussain T, Ali A, Akhtar M. Wilms tumor: an update. Adv Anat Pathol. 2014 May. 21 (3):166-73. [Medline].

  2. Yamamoto T, Togawa M, Shimada S, Sangu N, Shimojima K, Okamoto N. Narrowing of the responsible region for severe developmental delay and autistic behaviors in WAGR syndrome down to 1.6 Mb including PAX6, WT1, and PRRG4. Am J Med Genet A. 2014 Mar. 164A (3):634-8. [Medline].

  3. Han JC, Thurm A, Golden Williams C, et al. Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome. Cortex. 2013 Feb 19. [Medline]. [Full Text].

  4. Han JC, Liu QR, Jones M, et al. Brain-derived neurotrophic factor and obesity in the WAGR syndrome. N Engl J Med. Aug 2008. 359:918-927. [Medline].

  5. Rodriguez-Lopez R, Perez JM, Balsera AM, et al. The modifier effect of the BDNF gene in the phenotype of the WAGRO syndrome. Gene. 2013 Mar 10. 516(2):285-90. [Medline].

  6. D'Angio GJ, Breslow N, Beckwith JB, et al. Treatment of Wilms' tumor. Results of the Third National Wilms' Tumor Study. Cancer. 1989 Jul 15. 64(2):349-60. [Medline].

  7. Breslow N, Olshan A Beckwith JB. Epidemiology of Wilms tumor. Med Ped Oncol. 1993. 21:172-181.

  8. Robinson DO, Howarth RJ, Williamson KA, van Hyningen V, Beal SJ, Crolla JA. Genetic analysis of chromosome 11p13 and the PAX6 gene in a series of 125 cases referred with aniridia. Am J Med Genet A. Mar 2008. 164A:558-569. [Medline].

  9. Termine C, Parigi G, Rossi M, Romano P, Balotin U. WAGR syndrome: is the 'R' always justified?. Clin Dysmorphol. Jan 2007. 16:69-70. [Medline].

  10. Knudson AG, Strong LC. Mutation and cancer: a model for Wilms tumor of the kidney. J Natl Cancer Inst. Feb 1972. 48:313-324.

  11. Call KM, Glaser T, Ito CY. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms tumor locus. Cell. Feb 1990. 60:509-520.

  12. Ton CCT, Hirvonen H, Miwa H. Positional cloning and characterization of a paired box- and homeobox-containing gene from the aniridia region. Cell. 1991. 67:1059-1074.

  13. Haber DA, Oshn RL, Buckler AJ. Alternative splicing and alternative structure of the Wilms tumor gene WT1. Proc Natl Acad Sci USA. 1991. 88:9618-9622.

  14. Tezcan B, Rich P, Bhide A. Prenatal Diagnosis of WAGR Syndrome. Case Rep Obstet Gynecol. 2015. 2015:928585. [Medline].

  15. Hamilton TE, Ritchey ML, Haase GM,et al. The management of synchronous bilateral wilms tumor: a report from the national wilms tumor study group. Ann Surg. 2011 May. 253(5):1004-10. [Medline].

  16. Beckwith JB. Precursor lesions of Wilms tumor: clinical and biological impications. Med Pediatr Oncol. 1993. 21:158-168.

  17. Fischbach BV, Trout KL, Lewis J. WAGR syndrome: A clinical review of 54 cases. Pediatrics. Oct 2005. 116:984-988.

  18. Dahan K, Kamal M, Noel LH, et al. Small glomeruli in WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies and mental retardation) syndrome. Am J Kidney Dis. June 2007. 49:522-527.

 
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Subjects were categorized as BDNF haploinsufficient by comparative genomic hybridization. Subject A has a large deletion on chromosome 11 that removes one copy of the BDNF gene. Subject B has a smaller deletion that does not remove BDNF.
Aniridia. Note the almost complete absence of the iris.
 
 
 
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