Eight-year-old Miranda was born with WAGR syndrome, a genetic disorder with no cure. Because it is extremely rare — there are less than 450 documented cases worldwide — little research has been done on the condition. But in December 2021, researchers from Children’s Hospital of Philadelphia (CHOP) published the most comprehensive description to date of WAGR syndrome, providing guidance for both practitioners and families.

After Miranda was born, her eyes “didn’t really open much,” says her father, John. As a result, at first no one noticed a symptom of WAGR syndrome that’s often obvious in a newborn baby: aniridia, the complete or partial absence of the iris. Then when she was 2 months old, her eyes started darting all over the place. John and his wife, Beth, thought their daughter was having seizures. After their pediatrician watched a video of Miranda’s eye movements, it was decided that the family should be seen at CHOP. Once there, Miranda was diagnosed with aniridia, which led to genetic testing and a referral to genetics, where Miranda was seen by Elaine Zackai, MD, Director of Clinical Genetics. Test results identified WAGR syndrome.

The term “WAGR” is an acronym for the first letters of the physical and developmental problems associated with the condition:

• Wilms tumor, the most common form of kidney cancer in children
• Aniridia
• Genitourinary problems, such as testicles that are not descended or hypospadias (abnormal location of the opening for urination) in boys, or genital or urinary problems in girls
• Range of developmental delays

Most people who have WAGR syndrome have two or more of these conditions.

In Miranda’s case, the aniridia caused significant vision loss. Over the years, she developed cataracts and a detached retina that required surgery. She has developmental delays and is assessed annually by CHOP developmental pediatrician Carissa Jackel, MD. Every three months, she has an ultrasound to screen for Wilms tumor, and she is followed by a nephrologist because she’s at risk for chronic kidney disease. Her care team also includes Jennifer M. Kalish, MD, PhD, a pediatric geneticist with a special interest in rare diseases and cancer predisposition, and oncologist Garrett Brodeur, MD, Director of CHOP’s Cancer Predisposition Program. She undergoes physical therapy, occupational therapy, speech therapy, vision therapy, and orientation and mobility therapy to teach her how to navigate the world safely and confidently. “It’s a large team,” notes John — and it’s not necessarily the same team that another child with WAGR syndrome needs, as the CHOP study revealed.

More than the acronym

To help better understand the condition, the International WAGR Syndrome Association — of which John is a board member — established the WAGR Syndrome Patient Registry to collect clinical data on as many patients as possible. Dr. Kalish led a team of CHOP researchers to analyze the data from the 91 enrolled patients who self-reported their health issues. “Ninety-one doesn’t seem like a lot, but it’s more than 25% of the WAGR population,” John notes.

The analysis revealed how much of a spectrum disorder WAGR syndrome is. “The information that they are pulling out of the registry is wonderful,” says John.

“It gives healthcare practitioners a wider lens to look at WAGR — that it’s not just the four conditions that make up the acronym.”

For example, the thinking used to be that if a child needed a kidney removed because of Wilms tumor, having only one kidney could lead to the development of chronic kidney disease. But the research showed that the risk for chronic kidney disease in this population is just as high in the absence of Wilms. In addition, while every patient studied experienced some kind of eye issues, the types of problems varied wildly between patients. These variations in such a rare disease mean that no two patients are the same.

“By providing this more comprehensive picture of WAGR syndrome, we’re hopeful that these patients can receive the correct diagnosis as early as possible and establish a medical home so that parents and physicians can advocate for them,” says lead author Dr. Kalish. “Each child must have their own individualized care plan, and we hope that these recent findings help physicians develop those plans.”

Better understanding of the potential risks

Information like this helps families as well as clinicians. “Every family is often left with a lot of uncertainty,” John explains. “They know the acronym, but there are so many associated conditions. Someone might say, “My kid is exhibiting this — is this because of WAGR?’” Beth feels that this research helps people better understand what these children are at risk for, and what specialists should be on their medical team: “It shows the need for screening,” she explains, “because if you’re not looking for potential conditions early enough, you might not get medical management until it’s already progressed.”

When the WAGR community sees the results of the data, John hopes that even more families will enroll in the registry, further adding to what’s now known and improving the quality of life for patients with WAGR syndrome.