WAGR syndrome (ORPHA:893)
A rare genetic disorder characterized by the association of complete or partial congenital aniridia (and associated eyes abnormalities), genitourinary anomalies (ranging from sexual ambiguity to ectopic testis), variable degrees of intellectual disability and an increased risk of developing Wilms tumors. A minority of patients develop kidney failure. Other variable findings may include obesity and duplicated halluces.
Epidemiology
The prevalence of WAGR syndrome is approximately 1/500,000-1,000,000 people. There is no male or female predominance.
Clinical description
The disease has a broad range of clinical manifestations; most affected patients present with ≥ 2 clinical features. Onset is at birth, but it may be diagnosed at a later age, as clinical features can be hard to detect or do not show in many patients. Congenital aniridia of variable severity is almost systematically present at birth, and is often associated with other eye abnormalities such as cataract, glaucoma, limbal insufficiency, optic nerve hypoplasia, and corneal opacification/vascularization, leading to visual impairment. Some patients are at risk of developing end-stage renal disease, especially when presenting with Wilms tumor (45-60% of patients). Bilateral synchronous kidney tumors are the most common (4-7% of all Wilms tumors) and generally present at a younger age than unilateral tumors (< 5 years old). Patients may also present with genitourinary anomalies or neurological abnormalities, and variable intellectual disability or behavioral abnormalities. A large number of affected patients develops obesity. However, WAGR syndrome with childhood-onset obesity is called WAGRO syndrome.
Etiology
WAGR syndrome is a contiguous gene deletion syndrome involving an interstitial de novo 11p13 microdeletion of variable size (from 1 million to 26.5 million base pairs), which explains the variability of clinical signs. The affected genes include PAX6 and WT1. BDNF deletion can be included and is associated to the WAGRO phenotype.
Diagnostic methods
Diagnosis is based on clinical signs and may be delayed as some manifestation develop late or are easier to detect in the adult. Congenital aniridia in infants should prompt genetic testing to detect the specific deletions associated with the patient's phenotype and invalidate or confirm WAGR syndrome.
Differential diagnosis
The main differential diagnoses are isolated aniridia, anterior segment developmental abnormalities of the eye (e.g. Axenfeld-Rieger syndrome, coloboma of iris), aniridia-cerebellar ataxia-intellectual disability syndrome (also called Gillespie syndrome), Frasier syndrome, and Denys-Drash syndrome.
Antenatal diagnosis
Prenatal diagnosis is possible in very rare familial cases when mutations/deletions have been identified.
Genetic counseling
Most cases are sporadic. In rare cases, the syndrome can be inherited in an autosomal dominant manner. In such cases, affected individuals should be offered genetic counseling informing them of the 50% risk of having an affected child at each pregnancy.
Management and treatment
Management and treatment are complex and require a multidisciplinary approach. Supportive measures should be provided for visual impairment and light sensitivity. Medical or surgical intervention may be required for eye abnormalities such as cataract, glaucoma or corneal complications. Surgery, chemotherapy and radiotherapy can be recommended for the treatment of tumors. Patients require lifelong oncological and ophthalmologic monitoring. Transplantation may be required for renal disease. The management of obesity has no specificity. Patients and their family often need psychological support, and patients may be enrolled in special education program.
Prognosis
WAGR syndrome is associated with significant morbidity (vision loss and intellectual disability). The development of Wilms tumors is the main factor of early mortality. With early detection and appropriate treatment, the prognosis is improved.

                            Last update: 
                            September 2023


                            - Expert reviewer(s): 
                            Pr Dominique BREMOND-GIGNAC | ERN-EYE*


                                * European Reference Network