.gif)
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’ tumors are 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 to WAGR
syndrome; in fact, it most commonly happens in otherwise-healthy children and
can be a part of other syndromes like Beckwith-Weidman 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 the 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, undeveloped and nonfunctional ovaries 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 unknown. 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 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 have 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.
Helping current and future
clinicians focus to learn to retain and thrive
Thank You