WAGR syndrome is a complex and rare genetic disorder affecting multiple body systems. Its name is an acronym referring to its primary features: Wilms tumor, Aniridia, Genitourinary anomalies, and a Range of developmental delays. The condition is classified as a syndrome because it involves a collection of symptoms and abnormalities that consistently occur together. WAGR syndrome is estimated to affect between 1 in 500,000 to 1 million births, requiring specialized, coordinated medical support from diagnosis.
Genetic Foundation of the Syndrome
WAGR syndrome is a contiguous gene deletion syndrome, meaning it is caused by the loss of a segment of genetic material containing multiple adjacent genes on a single chromosome. Specifically, the disorder results from a deletion on the short arm of chromosome 11, in the region designated as 11p13. This chromosomal deletion is typically a de novo event, occurring randomly during the formation of reproductive cells or early fetal development, rather than being inherited from a parent.
The resulting loss of multiple genes in this region accounts for the syndrome’s diverse effects on the body. Two genes that are consistently deleted in people with the syndrome are WT1 and PAX6. The WT1 gene, an abbreviation for Wilms Tumor 1, is a tumor suppressor gene that plays a role in the development of the kidneys and the genitourinary system. The deletion of one copy of WT1 significantly increases the lifetime risk for Wilms tumor and is strongly linked to the genitourinary abnormalities seen in the syndrome.
The PAX6 gene, also located in the 11p13 region, is important for the syndrome’s manifestation. This gene regulates eye development, and its deletion causes Aniridia, the near-complete or partial absence of the iris. PAX6 is also involved in the formation of the central nervous system, and its loss contributes to the cognitive and developmental challenges characteristic of the syndrome. The size of the deleted segment varies between individuals, explaining the differences in the severity and spectrum of symptoms.
Defining Clinical Features
The clinical presentation of WAGR syndrome is highly variable, but it is defined by the four components of its acronym, the first of which is Wilms tumor (W). This is a malignant kidney tumor that develops in up to 50% of children with the syndrome, typically appearing between the ages of one and three years old. The presence of abnormal cell clusters in the kidney, called nephrogenic rests, is common in affected individuals and represents a precursor lesion that can transform into a tumor.
Aniridia (A) is the most common and often the first noticeable sign of the syndrome, present in nearly all affected individuals. This condition involves the partial or total absence of the iris, leading to reduced visual acuity and extreme sensitivity to light (photophobia). Affected eyes frequently develop other complications, including cataracts, glaucoma, and nystagmus.
Genitourinary anomalies (G) encompass a range of defects affecting the reproductive and urinary systems, which are more common in males. Males frequently present with undescended testes (cryptorchidism) or a misplaced urinary opening (hypospadias). In females, the anomalies can include underdeveloped ovaries, often referred to as streak gonads, and malformations of the uterus, such as a bicornuate (heart-shaped) uterus.
The final component, Range of developmental delays (R), describes the cognitive and behavioral challenges that vary significantly in severity. Individuals may experience intellectual disability ranging from mild to moderate, along with delays in speech and language development. Many affected individuals also experience psychiatric and behavioral issues, which can include anxiety, depression, attention-deficit/hyperactivity disorder (ADHD), and features of Autism Spectrum Disorder.
Beyond the core WAGR features, the deletion often includes other nearby genes, leading to associated conditions. Childhood-onset obesity is common and is often linked to the co-deletion of the BDNF gene, which is involved in appetite regulation and neurological function. Other issues include chronic kidney disease, which can progress to kidney failure, auditory and sensory processing disorders, and various neurological and metabolic abnormalities.
Lifelong Management and Supportive Care
The management of WAGR syndrome requires a comprehensive, multidisciplinary approach involving numerous medical specialists. Proactive surveillance for Wilms tumor is necessary, as early detection significantly improves long-term survival. This typically involves regular abdominal ultrasounds, performed every three months from birth until at least eight years of age, to monitor the kidneys for tumor development.
Ophthalmological care is continuous and focuses on preserving vision and managing the effects of Aniridia and related eye conditions. Patients often require visual aids and protection from bright light to manage photophobia and may undergo treatment for secondary complications like cataracts and glaucoma. Surgical and medical interventions are utilized to maintain intraocular pressure and address corneal and lens abnormalities that can further impair sight.
Developmental and behavioral support is customized to the individual’s specific needs and often begins with early intervention programs. Speech, physical, and occupational therapies are routinely employed to address developmental delays and improve functional skills. For school-aged children, educational support plans are often necessary to accommodate learning differences and ensure access to appropriate resources.
Endocrinology and nephrology specialists monitor for metabolic and kidney issues. The risk of chronic kidney disease requires ongoing assessment of kidney function, extending into adolescence and adulthood. Nutritional counseling and lifestyle modifications are often necessary to manage childhood-onset obesity, particularly when the BDNF gene is involved. Regular consultation with a pediatric urologist is also needed to manage genitourinary anomalies, which may require surgical correction early in life.