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WAGR Syndrome

Author: Steven K Bergstrom, MD, Assistant to the Chairman, Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland
Contributor Information and Disclosures

Updated: Dec 6, 2007

Introduction

Background

Patients with an unusual complex of congenital developmental abnormalities, such as aniridia, genitourinary (GU) malformations, and mental retardation, are at high risk (>30%) of having a Wilms tumor. At birth, the association is aniridia, GU malformations, and mental retardation (AGR) syndrome. With the discovery of a Wilms tumor in these patients, the association is referred to as WAGR syndrome. These syndromes result from the loss of chromosomal material from the short arm of chromosome 11.

Aniridia, GU malformations, and/or mental retardation are usually detected in the perinatal period, and patients with these conditions require careful long-term follow-up, both because of the consequences of the congenital defects and because of the potential development of a Wilms tumor. Early tumor detection has improved the long-term disease-free survival of children with WAGR syndrome.

Pathophysiology

WAGR syndrome affects the development of seemingly disparate areas of the body, including the kidney, the GU system, the iris of the eye, and the CNS. The deletion of varying lengths of chromosomal material along the short arm of chromosome 11 is the underlying defect, and developmental abnormalities are related to the contiguous loss of neighboring genes.

The constitutional loss of one allele of the Wilms tumor gene (WT1) results in GU anomalies and forms the first of 2 genetic events in the development of a Wilms tumor. The product of the WT1 gene has zinc finger arrays that bind to specific DNA sequences, whereas the amino terminus appears to regulate transcription. Alterations to the remaining allele result in the development of a Wilms tumor, usually in early childhood. Meanwhile, the deletion of one copy of the PAX6 gene is responsible for aniridia. PAX6 plays a role in CNS development as well and may be responsible for the mental retardation seen in a reported 75% of children with WAGR syndrome.

Frequency

United States

• The incidence of WAGR syndrome has not been determined.
• Wilms tumor occurs in approximately 8 per 1 million white children in the United States; the incidence is somewhat higher in blacks. Only 2% of patients with Wilms tumor have an associated genetic disorder.
• In a US study of 3442 patients with Wilms tumor, only 26 (0.76%) presented with aniridia.¹
• Wilms tumor occurs in more than 30% of patients with 11p13 deletions.

Mortality/Morbidity

• Wilms tumor
  • The overall survival rate of patients with Wilms tumor is excellent and is related to the histologic features of the tumor (favorable vs unfavorable) and the stage of the disease.
    • In stage I, the disease is localized to the kidney.
    • In stage II, the disease extends through the capsule of the kidney.
    • In stage III, the disease extends to ipsilateral structures or beyond the line connecting the poles.
    • In stage IV, the distinct metastases are present.
    • In stage V, bilateral kidney involvement is present.
  • In the third National Wilms Tumor Study (NWTS), the survival rate ranged from 95% for stage I to almost 80% for stage IV.¹ Patients with stage V tumors, some of whom had WAGR syndrome, had an overall survival rate of approximately 87%.
• Aniridia: Aniridia results in decreased visual acuity, although the amount of vision loss is variable. Aniridia has been associated with the development of glaucoma, probably due to the structural abnormalities of the anterior chamber of the eye. Cataracts have also been reported in these patients.
• GU abnormalities: A wide variety of GU abnormalities are associated with WAGR syndrome; these include cryptorchidism, hypospadias, and renal and ureteral malformations. Streak ovaries and bicornuate uterus have been reported in females with AGR syndrome. The presence of pseudohermaphroditism should alert the clinician to the possibility of Denys-Drash syndrome, a distinct diagnosis resulting from constitutional WT1 mutations.
• Mental retardation: The cognitive function of patients with WAGR syndrome widely varies. The appearance of retardation is correlated with the amount and position of genetic material lost from chromosome 11. Cognitive testing must be performed carefully and is more difficult to evaluate in children with vision loss.

Race

Wilms tumor occurs in approximately 8 per 1 million white children in the United States; the incidence is somewhat higher in blacks.

Age

Aniridia and/or GU abnormalities are usually detected while the baby is in the newborn nursery, and the diagnosis of AGR syndrome is considered at that time.

Clinical

History

Symptoms suggestive of AGR syndrome are usually noted in the perinatal period.

• 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.

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.²
  • 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.
• 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 vary greatly among patients with WAGR syndrome.
  • 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, and it is required for the diagnosis of mental retardation.

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.³ 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.
  • 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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