WAGR syndrome

Other Names: Wilms tumor, Aniridia, Genitourinary anomalies, mental Retardation syndrome; WAGR Complex; Wilms Tumor-Aniridia-Gonadoblastoma-Mental Retardation syndrome; Chromosome 11p deletion syndrome; 11p deletion syndrome; AGR triad; Wilms tumor-aniridia-genitourinary anomalies-intellectual disability syndrome

WAGR syndrome is a rare genetic syndrome in which there is a predisposition to several conditions, including certain malignancies, distinctive eye abnormalities, and/or intellectual disability.

WAGR is an acronym for Wilms tumor, [[Aniridia[[, Genitourinary problems (such as undescended testicles or hypospadias in males, or internal genital or urinary anomalies in females), and Range of developmental delays. A combination of two or more of these conditions is usually present in most individuals with WAGR syndrome. File:WAGR syndrome.webm

Epidemiology

The prevalence of WAGR syndrome ranges from 1 in 500,000 to one million individuals. It is estimated that one-third of people with aniridia actually have WAGR syndrome. Approximately 7 in 1,000 cases of Wilms tumor can be attributed to WAGR syndrome.

Cause

WAGR syndrome is caused by a deletion of genetic material on the short (p) arm of chromosome 11. The size of the deletion varies among affected individuals.

The signs and symptoms of WAGR syndrome are related to the loss of multiple genes on the short arm of chromosome 11. WAGR syndrome is often described as a contiguous gene deletion syndrome because it results from the loss of several neighboring genes. The PAX6 and WT1 genes are always deleted in people with the typical signs and symptoms of this disorder. Because changes in the PAX6 gene can affect eye development, researchers think that the loss of the PAX6 gene is responsible for the characteristic eye features of WAGR syndrome. The PAX6 gene may also affect brain development. Wilms tumor and genitourinary abnormalities are often the result of mutations in the WT1 gene, so deletion of the WT1 gene is very likely the cause of these features in WAGR syndrome.

In people with WAGRO syndrome, the chromosome 11 deletion includes an additional gene, BDNF. This gene is active (expressed) in the brain and plays a role in the survival of nerve cells (neurons). The protein produced from the BDNF gene is thought to be involved in the management of eating, drinking, and body weight. Loss of the BDNF gene is likely responsible for childhood-onset obesity in people with WAGRO syndrome. People with WAGRO syndrome may be at greater risk of neurological problems such as intellectual disability and autism than those with WAGR syndrome. It is unclear whether this increased risk is due to the loss of the BDNF gene or other nearby genes.

Research is ongoing to identify additional genes deleted in people with WAGR syndrome and to determine how their loss leads to the other features of the disorder.

Inheritance

Most cases of WAGR syndrome are not inherited. They result from a chromosomal deletion that occurs as a random event during the formation of reproductive cells (eggs or sperm) or in early fetal development. Affected people typically have no history of the disorder in their family.

Some affected individuals inherit a chromosome 11 with a deleted segment from an unaffected parent. In these cases, the parent carries a chromosomal rearrangement called a balanced translocation, in which no genetic material is gained or lost. Balanced translocations usually do not cause any health problems; however, they can become unbalanced as they are passed to the next generation. Children who inherit an unbalanced translocation can have a chromosomal rearrangement with extra or missing genetic material. Individuals with WAGR syndrome who inherit an unbalanced translocation are missing genetic material from the short arm of chromosome 11, which results in an increased risk of Wilms tumor, aniridia, genitourinary anomalies, and intellectual disability.

Signs and symptoms

People with WAGR syndrome have a 45 to 60 percent chance of developing Wilms tumor, a rare form of kidney cancer. This type of cancer is most often diagnosed in children but is sometimes seen in adults.

Most people with WAGR syndrome have aniridia, an absence of the colored part of the eye (the iris). This can cause reduction in the sharpness of vision (visual acuity) and increased sensitivity to light (photophobia). Aniridia is typically the first noticeable sign of WAGR syndrome. Other eye problems may also develop, such as clouding of the lens of the eyes (cataracts), increased pressure in the eyes (glaucoma), and involuntary eye movements (nystagmus).

Abnormalities of the genitalia and urinary tract (genitourinary anomalies) are seen more frequently in males with WAGR syndrome than in affected females. The most common genitourinary anomaly in affected males is undescended testes (cryptorchidism). Females may not have functional ovaries and instead have undeveloped clumps of tissue called streak gonads. Females may also have a heart-shaped (bicornate) uterus, which makes it difficult to carry a pregnancy to term.

Another common feature of WAGR syndrome is intellectual disability. Affected individuals often have difficulty processing, learning, and properly responding to information. Some individuals with WAGR syndrome also have psychiatric or behavioral problems including depression, anxiety, attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), or a developmental disorder called autism spectrum disorder that affects communication and social interaction.

Other signs and symptoms of WAGR syndrome can include childhood-onset obesity, inflammation of the pancreas (pancreatitis), and kidney failure. When WAGR syndrome includes childhood-onset obesity, it is often referred to as WAGRO syndrome.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Aniridia(Absent iris)
• Aplasia/Hypoplasia of the iris(Absent/small iris)

30%-79% of people have these symptoms

• Abnormal vagina morphology
• Cataract(Clouding of the lens of the eye)
• Cryptorchidism(Undescended testes)
• Displacement of the urethral meatus
• Everted lower lip vermilion(Drooping lower lip)
• Hearing abnormality(Abnormal hearing)
• Hypospadias
• Intellectual disability(Mental deficiency)
• [[Microcephaly](Abnormally small skull)
• Micrognathia(Little lower jaw)
• Nephroblastoma
• Nystagmus(Involuntary, rapid, rhythmic eye movements)
• Ptosis(Drooping upper eyelid)
• Short stature(Decreased body height)
• Streak ovary
• Visual impairment(Impaired vision)

5%-29% of people have these symptoms

• Abnormality of the uterus(Uterine abnormalities)
• Ambiguous genitalia(Ambiguous external genitalia)
• Dysfunction of lateral corticospinal tracts
• Glaucoma
• Gonadoblastoma
• Obesity(Having too much body fat)
• Scoliosis
• 1%-4% of people have these symptoms
• Nephropathy
• Renal insufficiency(Renal failure)

Diagnosis

Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome should be suspected in individuals with aniridia and no family history of aniridia who also have at least one of the following findings:

• Wilms tumor (also known as nephroblastoma), a childhood kidney malignancy. Of children with WAGR who develop Wilms tumor, 90% do so by age four years and 98% by age seven years (see Wilms Tumor Predisposition).
• Genitourinary abnormalities.

In males: cryptorchidism, hypospadias, ambiguous genitalia;

in females: normal external female genitalia, but uterine abnormalities (heart-shaped bicornate uterus) and streak ovaries. In males and females: end-stage renal disease, ureteric abnormalities, and gonadoblastoma.

• Intellectual disability and/or behavior abnormalities including depression, anxiety, ADHD, obsessive-compulsive disorder, and autism.
• Childhood-onset obesity and pancreatitis

Establishing the Diagnosis The diagnosis of PAX6-related aniridia is established in a proband with one of the two following clinical and molecular genetic findings. Molecular genetic testing can establish the molecular basis of aniridia, and thus distinguish between isolated aniridia (no increased risk for Wilms tumor) and WAGR (markedly increased risk for Wilms tumor). In the following scenarios molecular genetic testing approaches are based on the individual's age, clinical findings, family history, and testing methods available.

Treatment

Wilms tumor, genital anomalies, and developmental delay / intellectual disability are managed as per standard practice.

Aniridia. Simple measures are often the most important:

• Regular eye examinations and correction of refractive errors. Refractive errors range from high myopia through emmetropia to high hypermetropia. Spectacle correction of refractive errors is usually recommended as use of contact lenses can be difficult in the presence of keratopathy and reduced tear production.
• Tinted or photochromic lenses to reduce light sensitivity associated with the large pupillary aperture. Colored, tinted, or artificial pupil contact lenses may reduce light sensitivity or restore a more normal appearance to the eye but, as above, may be difficult to wear because of a poor ocular surface and tear film.
• Occlusion therapy in childhood for anisometropic amblyopia or strabismic amblyopia
• Optical low-vision aids and other devices such as closed-circuit television systems to help adults and children of school age
• Advice and help with schooling
• Social support

Lens. Cataract extraction can significantly improve visual acuity in those with severe lens opacities. It should be remembered that in aniridia visual improvement after surgery is limited by foveal hypoplasia; thus, mild to moderate lens opacities may not require surgery:

• Children rarely require surgery (lensectomy).
• In adults, phacoemulsification and intraocular lens implantation can improve visual function if the cataract is severe.

Wilms tumor. The goal of surveillance in individuals with a genetic predisposition to Wilms tumor is to detect tumors while they are low-stage and require less treatment compared to advanced-stage tumors. Surveillance is not a one-time event and should continue through the period of risk, estimated to be until age five to eight years, depending on the underlying genetic condition. Wilms tumors can double in size every week , leading to the authors’ recommendation that evaluation with abdominal ultrasound be performed every three months. Because surveillance is associated with economic and psychosocial costs including missed work, anxiety associated with exams, and false-positive results leading to unnecessary interventions, the decision to pursue surveillance requires careful consideration. Weighing the risks and benefits of surveillance, Scott et al [2006] suggested that surveillance be pursued if the risk for tumor development is greater than 5%.

Aniridic fibrosis syndrome. Surgical intervention is recommended at the first sign of aniridic fibrosis syndrome

Genital abnormalities. This may need specialist care for functional and cosmetic management including endocrine therapy and surgical correction (e.g., hypospadias repair). There may be fertility issues that require support or active management.

Developmental delay / intellectual disability. There are a range of developmental, intellectual, psychiatric, and behavioral issues, as well as the challenges of visual impairment. Children may require:

Special educational support including extra or different teaching resources and a specialized educational setting, specialist teachers of the visually impaired, educational psychologists, and formal statements of educational needs;

Involvement of a pediatrician and sometimes a pediatric psychiatrist.

NIH genetic and rare disease info

• NIH info on WAGR syndrome

WAGR syndrome is a rare disease.

WAGR syndrome Resources
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