Wilms' tumor aniridia-genitourinary anomalies-mental retardation (WAGR) syndrome and genetics

ALSO KNOWN AS: 11p deletion syndrome; chromosome 11p deletion syndrome; WAGR complex; Wilms’ tumor-aniridia-gonadoblastoma-mental retardation syndrome

DEFINITION WAGR syndrome is a rare genetic condition. Children born with this syndrome often have an unusual group of developmental abnormalities. Generally, they have problems with their eyes, are at risk for developing certain types of cancer, and may be at risk for intellectual disability.

Risk Factors

WAGR syndrome usually occurs spontaneously during fetal development. Several genes on chromosome 11 have been linked to this condition. Therefore, individuals who have a deleted portion of chromosome 11 are at risk of developing WAGR syndrome. Wilms’ tumor occurs in approximately 8 per 1 million white children in the United States, and the incidence is somewhat higher in black children.

Etiology and Genetics

Several different disorders are associated with WAGR syndrome, each of which make up the acronym WAGR. Wilms’ tumor is the most common type of pediatric kidney cancer, and children with WAGR syndrome have a 50 percent chance of developing it. Aniridia is characterized by a missing iris, the colored part of the eye. Genitourinary anomalies include undesecended testes, abnormal locations of the opening for urination, and urinary problems in girls. Mental Retardation or intellectual disability may also occur and can vary in severity between individuals. The majority of children with WAGR syndrome experience at least two of these conditions, but they do not always have all the described conditions.

WAGR syndrome occurs when part of chromosome 11 is missing, and therefore it sometimes is referred to as a contiguous gene deletion syndrome. This designation means that WAGR syndrome develops when an individual does not have certain genes located on a specific part of chromosome 11 (11p13). In the majority of cases, this mutation is de novo, meaning that it occurs spontaneously during the early stages of fetal development. In other cases, this dysfunctional chromosome is passed from parent to offspring. This occurs when the chromosomes within a parent undergo a event. Translocation of two chromosomes (one being chromosome 11) can lead to a loss of some of the genes on the chromosome. When such a translocation event occurs and is passed on to a new generation, the offspring may contain normal cells and ones that have the 11p13 deletion, a condition referred to as mosaic WAGR syndrome.

It is not surprising that the severity of WAGR syndrome will depend on how large the chromosomal deletion is (how many and which genes are missing). Individuals with smaller deletions usually have aniridia and Wilms’ tumor. Larger deletions are responsible for genitourinary defects and intellectual disability. The deleted region of chromosome 11 contains an ocular development gene called PAX6. When absent, this gene causes aniridia. Some studies suggest that the PAX6 gene may also be responsible for pancreatic and brain deficiencies. The Wilms’ tumor-suppressor gene, WT1, also is deleted in individuals with WAGR syndrome. Although it is best known for causing Wilms’ tumor when it is missing, the WT1 gene also may be associated with some of the genitourinary manifestations of WAGR syndrome.

Symptoms

Symptoms of WAGR syndrome manifest soon after birth. Aniridia is commonly apparent first in both males and females. In boys, undescended testes also are noticeable soon after the baby is born. The specific symptoms experienced by each person who has WAGR syndrome depend on the combination of disorders that are present, since each individual may have varying physical and mental disorders.

Screening and Diagnosis

Aniridia is a rare symptom that manifests almost immediately and may indicate that a patient has WAGR syndrome. To diagnose WAGR syndrome definitively, genetic tests such as karyotyping are performed to analyze the chromosomes and determine whether the chromosome 11p13 deletion is present. Another test that may be employed during the genetic testing is a test, which also will evaluate whether the deletion is present.

Treatment and Therapy

Treatment of children with WAGR syndrome depends on the appearance of Wilms’ tumor. The features and the stage of the tumor determine the appropriate management for each individual. Close to 50 percent of Wilms’ tumors are diagnosed before reaching stage II, meaning that they are confined to the kidney and can be surgically excised. Approximately 90 percent of children with Wilms’ tumor are cured. Depending on how far the cancer has spread, chemotherapy and radiation may also be used.

Prevention and Outcomes

WAGR syndrome patients can survive long-term, and early detection of the disorder improves their prognosis. However, lifelong disabilities such as vision loss and intellectual disability may afflict these patients.

Bibliography

Chen, Juan, et al. "Autosomal Dominant Weill-Marchesani-Like Syndrome in a Chinese Family Due to Novel Haplotypic Mutations in LTBP2." Ophthalmic Research, vol. 67, no. 1, Jan.-Dec.-2024, doi.org/10.1159/000538844. Accessed 10 Sept. 2024.

Fischbach, Bernard V., et al. “WAGR Syndrome: A Clinical Review of 54 Cases.” Pediatrics116 (2005): 984–88. Print.

Kliegman, Robert M. Nelson Textbook of Pediatrics. 19th ed. Philadelphia: Saunders, 2011. Print.

Kumar, Vinay, Abul K. Abbas, and Jon C. Aster. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Philadelphia: Saunders Elsevier, 2015. Print.

Marzin, Pauline, et al. "Weill-Marchesani Syndrome: Natural History and Genotype-Phenotype Correlations from 18 News Cases and Review of Literature." Journal of Medical Frontiers, 2023, doi.org/10.1136/jmg-2023-109288. Accessed 10 Sept. 2024.

Rosenblum, Laurie. "Wilms' Tumor." Health Library. EBSCO Information Services, 28 May 2014. Web. 2 Sept. 2014.