Mutations in WT1 gene found in 4 children with aHUS
WT1 mutations known to cause rare kidney disorder Denys-Drash syndrome
Mutations in the Wilms’ tumor 1 (WT1) gene, known to cause a rare kidney disorder called Denys-Drash syndrome, were found in four children who had symptoms of atypical hemolytic uremic syndrome (aHUS), according to recent case series study.
“To our knowledge, this is the first report of a series of cases of WT1 mutations in pediatric patients presenting with clinical manifestations of aHUS,” researchers wrote, noting “this unique finding highlights an association between HUS and WT1 mutation.”
The study, “Association of Atypical Hemolytic Uremic Syndrome With Wilms’ Tumor 1 Gene Mutations: A Case Series and Literature Review,” was published in the journal Cureus.
aHUS is a rare disease marked by hemolytic anemia, or red blood cell destruction, low platelet counts, and kidney failure. It belongs to a larger group of disorders, called thrombotic microangiopathies (TMAs), where blood clots form inside small blood vessels, leading to organ damage.
The disease is typically associated with mutations in genes that regulate the function of the complement system, a part of the immune system that’s overactive in people with aHUS.
Denys-Drash syndrome often leads to kidney failure in childhood
Recently, several reports have also described mutations in the WT1 gene in patients with aHUS. Mutations in this gene are known to cause Denys-Drash syndrome, a rare kidney disorder that begins within the first few months of life. It causes scar tissue to form in the kidneys’ filtering units and often leads to kidney failure in childhood.
In the report, researchers in Saudi Arabia described the cases of four children with aHUS who had WT1 mutations.
The first case, an 18-month-old boy, had gastrointestinal bleeding, while the second, a one-year-old boy, experienced vomiting and diarrhea. Both had high blood pressure and low urine output by the time they arrived at the hospital.
The first boy was initially diagnosed with TMA and underwent a kidney biopsy, which confirmed the presence of severe scarring, including in the glomeruli, the kidneys’ filtering units. Despite intensive medical care, his condition worsened, and he had to undergo peritoneal dialysis, a procedure in which fluid is inserted into the abdomen to remove waste from the blood. No kidney biopsy was carried out in the second boy.
The first boy was treated with Ultomiris (ravulizumab), which works to block the activity of the complement system by targeting the C5 complement protein. However, because his kidney function failed to improve, he started hemodialysis.
The second boy received continuous kidney replacement therapy, a 24-hour nonstop form of dialysis. However, his blood parameters failed to improve so he underwent 10 sessions of plasma exchange therapy, but showed no improvement. He started treatment with Soliris (eculizumab), another complement inhibitor therapy, which caused his hemoglobin and platelet levels to normalize. Hemoglobin is the protein in red blood cells that’s responsible for oxygen transport.
Genetic testing revealed mutation in WT1 gene
In both boys, genetic testing revealed a mutation in the WT1 gene. Despite treatment, the first boy continued to have low urine output accompanied by high blood pressure, and required long-term dialysis. The second boy also didn’t recover his kidney function and became dependent on dialysis.
The two other reported cases were girls, who were 23 months old and 6 months old. Both had high blood pressure, along with anemia, low platelet counts, and acute kidney injury.
The first girl was admitted to the pediatric intensive care unit for suspected TMA and was started on continuous kidney replacement therapy, followed by Ultomiris. However, her kidney function failed to improve. The second girl required intubation and, after experiencing a high blood pressure crisis, also started continuous kidney replacement therapy.
A kidney biopsy in the first girl confirmed the presence of kidney alterations, and she received two more doses of Ultomiris. However, she continued to have low urine output and high blood pressure. She started hemodialysis five times per week.
The second girl received Soliris, but did not have any clinical improvement in urine output, although her hemoglobin and platelet levels normalized. She received two more doses of Soliris, but continued showing no improvements in kidney function.
Genetic testing in both cases revealed the presence of a mutation in the WT1 gene. Both patients underwent a kidney transplant that was successful, and showed no signs of aHUS recurrence.
“We report four cases of patients who presented initially with atypical hemolytic uremic syndrome … and whose genetic analysis reports showed pathogenic mutations in WT1,” the researchers wrote, adding future “studies of WT1 mutations are needed to elucidate the association between WT1 and aHUS and to develop possible treatments.”
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