WAGR Syndrome

Updated: Oct 21, 2022
Author: Jacquelyn N Crane, MD; Chief Editor: Max J Coppes, MD, PhD, MBA 

Overview

Background

Patients with an unusual complex of congenital developmental abnormalities, such as aniridia (see the image below), genitourinary (GU) malformations, and intellectual disability (previously termed mental retardation), are at high risk (>30%) of having a Wilms tumor. At birth, the association is aniridia, GU malformations, and intellectual disability (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 intellectual disability 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.

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 pathogenic germline deletion of varying lengths of chromosomal material along the short arm of chromosome 11, including WT1 and PAX6, is the underlying defect.[1]

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.[2] 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.[3]

The brain-derived neurotrophic factor (BDNF) gene is also located in the region of chromosomal loss associated with WAGR syndrome.[4] Loss of function of the BDNF gene in some patients with WAGR syndrome may produce obesity and hyperphagia.[5, 6] 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.

Etiology

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

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.[7, 8, 9]  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.

Patients with early bilateral Wilms Tumor suggests the possibility that they have a constitutional genetic defect that predisposes them to the development of a Wilms tumor, like that seen in WAGR syndrome.[10]  The prezygotic loss of one of the WT1 alleles is followed by the loss of the second allele in infancy or early childhood (somatic).

Epidemiology

Race- and age-related demographics

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. 

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.

Wilms in WAGR

About 10-15% of patients with Wilms tumor have an underlying germline predisposition.[11, 12]  In a US study of 3442 patients with Wilms tumor, only 26 (0.76%) presented with aniridia.[13]  Wilms tumor occurs in more than 40-65% of patients with 11p13 deletions.[12]

Prognosis

Patients with WAGR syndrome have an excellent prognosis for long-term survival. Early detection seems to improve the outcome.

Life-limiting abnormalities include GU anomalies in the first year of life. Lifelong disabilities may include vision loss and intellectual disability.

In the approximately 30% of patients with AGR syndrome in whom a Wilms tumor develops, the prognosis is related to the histologic features and the stage of the tumor.

Wilms in WAGR

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 and is completely removed by surgery.

  • In stage II, the disease extends beyond the kidney and is completley removed by surgery.

  • In stage III, there is residual non-hematogenous disease confined to the abdomen.

  • In stage IV, distinct metastases are present.

  • In stage V, bilateral kidney involvement is present.

Across all patients with Wilms Tumor, overall survival is approximately 90%. However, certain patients fare less well including patients with stage IV anaplastic Wilms, with overall survival of < 50%. On AREN0534, patients with stage V tumors, some of whom had WAGR syndrome, had an overall survival rate of approximately 94.9%.[14]

GU abnormalities in WAGR

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 WT1 disorder (which includes the sydnrome previously known as Denys-Drash syndrome), a distinct diagnosis resulting from constitutional WT1 mutations.

Renal function in WAGR

Patients with WAGR have an increased risk of end stage renal disease.[15, 16]

Aniridia in WAGR

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.

Intellectual disability in WAGR

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.

 

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.[17]

  • The family history is rarely helpful.

Physical Examination

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.[18]

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.

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.[19]  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 WT1 syndrome (includes the sydnromes previously known as Denys-Drash or Frasier syndromes), 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.

Intellectual disability

The presence and degree of intellectual disability widely vary among patients with WAGR syndrome.[20]  Generally, determining the degree of intellectual disability 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 intellectual disability.

 

DDx

Differential Diagnoses

  • Genital Anomalies

  • Wilms Tumor

  • WT disorder

    WT1 disorder describes various WT1 pathogenic variants resulting in a phenotypic spectrum which may including anomalies of the kidney and genitourinary tract, disorders of sexual development, risk of end stage renal disease and Wilms tumor. This includes the disorders previously known as Denys Drash syndrome and Frasier syndrome.

 

Workup

Laboratory Studies

GU abnormalities may lead to reduced renal function early in life. Renal function is rarely affected by nephroblastomatosis alone. 

Consider the following laboratory studies:

  • BUN and/or creatinine levels should be assessed in patients with WAGR syndrome.

  • Findings of protein in the urine should alert the clinician to the possibility of WT1 disorder (including Denys-Drash or Frasier syndromes), which are associated with declining renal function. Blood may be present in the urine when patients present with a Wilms tumor.

  • A CBC count with a platelet count may demonstrate anemia due to blood loss secondary to an enlarging renal mass.

  • Serum calcium levels should be measured.

  • Cytogenetic testing should be performed to confirm the diagnosis. Standard high-resolution chromosome studies may not be able to detect deletions in WT1. The addition of molecular cytogenetic fluorescence in situ hybridization techniques may define the extent of the deletion.

Imaging Studies

Ultrasonography

Renal ultrasonography is the initial study of choice to confirm the diagnosis of renal pathology in the neonatal period. Note the following:

  • Enlargement of the kidneys usually suggests nephroblastomatosis. The appearance of both kidneys should be documented.

  • Some (internal) GU abnormalities are usually best documented using ultrasonography, although additional imaging tests may be required.[21]

  • A follow-up examination of the kidneys should be performed every 3 months until the patient is aged 7-8 years. Physical examinations should be performed every 6 months until the patient's growth is complete. Baseline CT scanning may be indicated at the time of the initial diagnosis.

  • The presence of an enlarging renal mass suggests the development of a Wilms tumor.

  • Evaluation of the renal vein and inferior vena cava for the presence of tumor thrombi is important for staging, and the study is usually accomplished using renal ultrasonography and/or Doppler imaging.

Radiography

Chest radiography becomes important in the staging workup once Wilms tumor is diagnosed.

Computed tomography (CT) or magnetic resonance imaging (MRI)

CT scanning of the chest and CT or MRI abdomen may provide further information about the location and stage of the tumor.

Procedures

The role of a renal biopsy at the time of diagnosis of WAGR syndrome in the neonatal period is controversial. The presence of nephrogenic rests can be demonstrated histologically, but the risk of losing renal function as a result of the procedure may outweigh the need to confirm the diagnosis in a patient with AGR syndrome.

Biopsy findings of kidneys that contain nephrogenic rests or nephroblastomatosis reveal nests of developmentally immature renal parenchyma. Although these rests may be stable over a long period, they generally (1) die and produce a hyalinized remnant, (2) mature into normal renal parenchyma, or (3) produce a Wilms tumor.

In patients with WAGR syndrome presenting with a primary renal mass with clinical situation, age, and imaging highly suggestive of Wilms tumor, upfront chemotherapy without biopsy and surgical resection is recommended followed by delayed surgical resection.[14]

 

Treatment

Medical Care

Treatment considerations include the following:

  • Urology: After aniridia, GU abnormalities, and intellectual disability (AGR) syndrome or Wilms tumor, aniridia, GU abnormalities, and  intellectual disability (WAGR) syndrome is diagnosed, GU abnormalities must be evaluated immediately, and the patient should be referred to a pediatric urologist.

  • Genetics: Although the abnormality associated with WAGR syndrome may not be demonstrated by means of routine cytogenetic tests, the geneticist can help in assessing the 11p13 region using fluorescent in situ hybridization techniques. He or she can consult with the family regarding the likelihood of their having other affected children, and the geneticist can consult with patients regarding the risks to their children.

  • Oncology: Once a Wilms tumor is diagnosed in a patient with WAGR syndrome, the services of a pediatric oncologist are required for treatment and follow-up.

Surgical Care

Specific urologic intervention may be required early in patients with AGR syndrome.

If a Wilms tumor develops, multidisciplinary planning is required prior to surgery.

The National Wilms Tumor Studies (NWTS) and Children's Oncology Group Studies have demonstrated that preservation of renal parenchyma is possible following initial preoperative chemotherapy in patients with unilateral Wilms with WAGR or other underlying genetic predisposition syndromes or with bilateral Wilms.[22, 14]  Specifically, a report of patients with bilateral Wilms, including patients with WAGR, treated on the AREN0534 study through the Children's Oncology Group showed that pre-operative chemotherapy, surgical resection within 12 weeks of diagnosis, and post-operative chemotherapy based on histology resulted in improved preservation of renal parenchyma compared patients treated on the earlier NWTS trials.[14]  Further investigation is required to determine the need for earlier biopsy in nonresponsive tumors and earlier definitive surgery in patients with unfavorable histology.

Consultations

A pediatric ophthalmologist should be consulted early in the course of the disease to evaluate the ocular deformity, and this ophthalmologist should follow-up with the patient for long-term consequences (eg, vision loss, potential cataract development).

The potential for developmental delay in children with AGR or WAGR syndrome requires early evaluation and intervention by a pediatric developmental specialist.[23] On the basis of the findings from this evaluation, children with vision impairment and mental retardation can be appropriately referred to community resources.

A pediatric oncologist should be consulted if there are any concerns for Wilms Tumor development based on symptoms or on the routine surveillance abominal ultrasounds.

 

Medication

Medication Summary

Medical treatment of patients with Wilms tumor, aniridia, GU abnormalities, and intellectual disability (WAGR) syndrome depends on the appearance of Wilms tumor. The histologic features and the stage of the tumor determine the appropriate chemotherapeutic course. Refer to a pediatric oncologist for the most current chemotherapeutic regimen.

 

Follow-up

Further Outpatient Care

Oncologic follow-up care: After initial evaluation and treatment, the long-range plan for children with Wilms tumor, aniridia, GU abnormalities, and mental retardation (WAGR) syndrome includes regular follow-up. Note the following:

  • Abdominal ultrasonography should be performed every 3 months to examine the kidneys for the development of a Wilms tumor. The age at which these tests may be discontinued has not been established, although the general recommendation is to continue until the patient is aged 7-8 years old.

  • In a report of a cohort of 61 patients with WAGR syndrome, the oldest patient in whom Wilms tumor developed was aged 7 years 3 months.[24] Of the patients in whom tumors ultimately developed, 98% received the diagnosis before their seventh birthday. Reports of patients with AGR syndrome who develop Wilms tumor later in life, one of whom developed Wilms at age 25 years, suggest that further follow-up, by either physical examination or ultrasonography, may be recommended for older patients.

Ophthalmologic follow-up care: Patients with WAGR syndrome require routine ophthalmologic follow-up, both to evaluate and maximize their vision and to detect glaucoma or cataracts.

Nephrologic follow-up care: Patients with WAGR syndrome appear to have an increased risk of renal failure, which develops over many years. Note the following:

  • Long-term follow-up should include a regular evaluation of renal function with urinalysis and assessment of blood pressure and BUN and creatinine levels. Renal ultrasonography should be considered if abnormalities are suspected. Rare WAGR patients may develop focal segmental glomerular sclerosis with or without the development of Wilms tumor.

  • The NWTS found that the incidence of renal failure is 38% in patients with aniridia and Wilms tumor, compared with only 21 cases in 5358 patients without characteristic congenital GU abnormalities.[15]

  • The underlying reason for renal dysfunction may be multifactorial.

  • In one cohort of 54 patients with WAGR syndrome, 14 patients had some level of renal failure.[25]  Some of them had focal segmental glomerular sclerosis (FSGS) unrelated to the development of Wilms tumor. A study reported small glomeruli in patients with WAGR syndrome, suggesting that, in some cases, a structural explanation for the eventual appearance of end-stage renal disease is noted.[26]