WAGR Syndrome

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

Background

Patients with an unusual complex of congenital developmental abnormalities, such as aniridia (see the image below), 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. Note the almost complete absence of the Aniridia. Note the almost complete absence of the iris.

Aniridia, GU malformations, and 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.

See Wilms Tumor: A Pediatric Oncology Success Story, a Critical Images slideshow, to help identify the clinical features, staging evaluation, prognostic factors, and therapeutic options for this tumor.

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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. [1] 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. [2]

The brain-derived neurotrophic factor (BDNF) gene is also located in the region of chromosomal loss associated with WAGR syndrome. [3] Loss of function of the BDNF gene in some patients with WAGR syndrome may produce obesity and hyperphagia. [4, 5] See the image below.

Subjects were categorized as BDNF haploinsufficien 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.
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Epidemiology

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. [6] Wilms tumor occurs in more than 30% of patients with 11p13 deletions.

Mortality/Morbidity

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, as follows:

  • 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. [6] Patients with stage V tumors, some of whom had WAGR syndrome, had an overall survival rate of approximately 87%.

Aniridia results in decreased visual acuity, although the amount of vision loss varies. 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. Over time, scanning nystagmus develops in infants who are visually impaired. Other ocular abnormalities seen in these patients include corneal pannus and optic nerve hypoplasia.

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.

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.

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