WAGR syndrome

Definitions & Key takeaways

WAGR syndrome is a rare genetic disorder caused by a deletion or mutation of certain genes on chromosome 11. It is characterized by four main features: Wilms tumor, aniridia, genitourinary abnormalities, and intellectual disability. People with WAGR syndrome can also present with cataracts, glaucoma, and nystagmus. The severity and range of symptoms can vary widely among affected individuals. Treatment usually involves a multidisciplinary approach, including surgical intervention for Wilms tumor, management of developmental and intellectual issues, and regular monitoring for potential health issues.

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Introduction0:00–0:38

[Osmosis sound logo] WAGR Syndrome stands for Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation, which is now called intellectual disability.
And this is a genetic disorder that's caused when part of chromosome eleven is missing or deleted. Not everyone with WAGR has all these symptoms.
For example, only about half of the individuals have Wilms' tumor. On the flip side, some have additional symptoms, too: like progressive kidney failure, growth retardation, small head size, and obesity.

Aniridia and eye features0:38–1:25

The most specific feature of WAGR syndrome is aniridia, which is the complete or partial absence of the iris --the colored part of the eye.
And this is an easily noticeable feature, and it's present at birth, so it's usually the first thing to raise suspicion of WAGR syndrome.
Now, a normal iris controls how much light enters the eye; and it constricts the pupil, when there's a lot of light around, to keep the vision sharp.
With aniridia, too much light gets into the eye, which leads to blurry vision and photophobia --which is discomfort when the eyes are exposed to light.
Additional eye features of WAGR syndrome can include: cataracts--which is a clouded lens; glaucoma --or increased pressure in the eye; and nystagmus --abnormal, rhythmic movements of the eye.

Wilms tumor1:25–2:34

Wilms' tumor --also called nephroblastoma-- is generally a malignant kidney tumor that affects children. Wilms' tumor is composed of metanephric blastema --which is a cell type that's seen in the developing kidney; stromal cells --which are part of the connective tissue; and epithelial cells --which self-organize into primitive glomeruli and tubules.
Children with Wilms' tumor often develop a large flank mass, as well as hematuria --which is blood in the urine-- and hypertension.
Now that hypertension is a result of an increased renin secretion, which either comes from the tumor itself or from healthy kidney tissue that secretes renin because it's physically compressed by the tumor.
It's worth noting that Wilms' tumor isn't specific for WAGR syndrome; in fact, it most commonly happens in otherwise healthy children.
And it can also be part of other syndromes, like Beckwith-Wiedemann syndrome. Fortunately, Wilms' tumor is also treatable.
It has a fairly high cure rate when it's treated with a combination of chemotherapy, radiation, and nephrectomy --which is removal the kidney.

Genitourinary anomalies2:34–3:09

The most common genital defect in boys with WAGR syndrome is undescended testes --also called cryptorchidism-- as well as hypospadias --where the urethra exits the penis on the underside, instead of at the tip.
The most common genital defect in girls is streak ovaries --which are underdeveloped and non-functional ovaries that are at an increased risk for developing a tumor called gonadoblastoma.
Finally, someone with WAGR syndrome might also have ambiguous genitalia --meaning they don't appear to be either clearly male or clearly female.

Intellectual Disability3:09–3:24

Finally, intellectual disability is present in many --but not all-- people with WAGR syndrome, And it's also associated with other conditions --like autism or ADHD-- all of which are usually recognized in childhood.

Causes3:24–4:48

Now, WAGR syndrome is an example of a contiguous gene deletion syndrome. Contiguous means "next to each other" so it's caused when two or more genes are next to each other, along the same chromosome arm, and are deleted at the same time.
In the case of WAGR syndrome, it's a heterozygous deletion of a small part of the short --or 'p'-- arm of chromosome eleven.
There are two particularly important genes within the deleted region: the PAX6 gene --which causes the aniridia-- and the WT1 gene --or the Wilms' tumor one gene-- which causes the increased risk of Wilms' tumor as well as the genitourinary abnormalities.
If deleting or disrupting a gene results in an increased tumor risk, then that gene's considered to be a tumor suppressor gene.
So WT1 is an example of a tumor suppressor gene. Finally, the specific gene responsible for intellectual disability in WAGR syndrome is not known.
Sometimes that deletion is also extra large and also includes the gene BDNF --which is named for brain-derived neurotrophic factor.
Deletion of BDNF causes the obesity seen in some patients with WAGR syndrome --a phenotype called WAGRO ('O' for obesity).
WAGR syndrome is technically autosomal dominant, but it's usually sporadic --meaning that it's caused by a new mutation, rather than being inherited.

Diagnosis4:48–5:20

Diagnosis of WAGR syndrome is confirmed using FISH --or fluorescence in situ hybridization-- and this involves a fluorescently labeled probe --made of DNA-- that's complementary to the WAGR region.
In a normal cell, the probes can base pair to both chromosome elevens, so you would expect two bright spots to be seen in a microscope, when the cell is viewed under fluorescent light.
If a WAGR deletion is present though, one of those WAGR regions is missing, so you [will] only see a single bright spot.

Treatment5:20–5:51

Now, there's no single treatment for WAGR syndrome. Rather, each problem is usually addressed individually.
For example: for photophobia, you might use tinted lenses, or for Wilms' tumor, you might use chemotherapy. The most important thing is to have a timely diagnosis of WAGR syndrome, so that there's adequate medical surveillance: like regular renal ultrasounds and blood pressure checks --to look for Wilms' tumor; as well as pelvic ultrasounds in women --to look for streak ovaries and the subsequent possibility of a gonadoblastoma.

Review5:51–6:35

All right! As a quick recap: WAGR syndrome is a contiguous gene deletion syndrome caused by the deletion of several genes on chromosome eleven, including PAX6 and WT1.
The result of this is: a risk for Wilms' tumor, aniridia, genitourinary abnormalities, and intellectual disability. [Osmosis' closing sound logo] What's up guys!
Thanks for watching! Just want to give a little shout-out to Phil in Boston who is one of our awesome script writers.
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Thanks a lot guys. Bye.