WAGR Syndrome Clinical Presentation

Updated: Sep 12, 2018
  • Author: Steven K Bergstrom, MD; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
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Presentation

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. [7]

  • 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. [8]

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. [9] 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. [10]  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. [11] 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. [12, 13, 14]  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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