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 a part of chromosome 11 is missing, or deleted.
Not everyone with WAGR has all of the symptoms, for example only about a 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.
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 in WAGR syndrome can include cataracts, which is a clouded lens,
glaucoma, or increased pressure in the eye, and nystagmus—abnormal rhythmic eye movements
of the eye.
Wilms’ tumor, also called nephroblastoma, is generally a malignant kidney tumor that
affects children.
Wilms’ tumor’s 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 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 can be a part of other syndromes like
Beckwith-Wiedemann syndrome.
Fortunately, Wilms’ tumor is also treatable and has a fairly high cure rate when it’s
treated with a combination of chemotherapy, radiation, and nephrectomy, which is removal
of the kidney.
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 undeveloped and
nonfunctional ovaries that are at an increased risk for developing a tumor called gonadoblastoma.
Finally, someone with WAGR syndrome might have ambiguous genitalia, meaning they don’t
appear to be either clearly male or clearly female.
Finally, intellectual disability is present in many but not all people with WAGR syndrome,
and it’s also associated with conditions like autism or ADHD, all of which are usually
recognized in childhood.
Now, WAGR is a great example of a contiguous gene deletion syndrome, contiguous means next
to each other, so it’s caused when two or more genes that are next to each other, along
the same chromosome arm 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 11.
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 1” 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 it’s considered
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 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’s technically autosomal dominant, but it’s usually sporadic, meaning that
it’s caused by a new mutation, rather than being inherited.
Diagnosis of WAGR syndrome is confirmed using FISH, or fluorescence in situ hybridization.
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 11s, so you would expect
two bright spots are seen in the 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’ll
only a single bright spot.
There’s no single treatment for WAGR syndrome; rather each problem is 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 so that there’s adequate
medical surveillance, like regular renal ultrasounds and blood pressure checks to look for Wilms’
tumor, as well as pelvic ultrasound in women to look for streak ovaries and the subsequent
possibility of gonadoblastoma.
All right, so quick recap: WAGR syndrome is a contiguous gene deletion syndrome caused
by a deletion of several genes on chromosome 11, including PAX6 and WT1.
The result is a risk for Wilms’ tumor, aniridia, genitourinary abnormalities, and intellectual
disability.