Rare parental gene mutation found to cause TTP in their children
Novel IKZF1 variant triggered rare blood disorder in 2 siblings in Israel
The cases of adult siblings in Israel, both diagnosed with infantile-onset acquired thrombotic thrombocytopenic purpura (TTP) as children, led to the discovery of a mutation in the IKZF1 gene that ultimately proved to be the cause of the rare blood disorder in both the sister and her younger brother.
According to the researchers, spontaneous parental mutations in IKZF1 — affecting some of the parent’s sperm or eggs but not other body cells — triggered TTP in the two siblings.
IKZF1 mutations affect a protein that regulates the development of certain immune cells in the body. These variants can lead to both immunodeficiency — a state in which the immune system’s ability to fight infections and cancer is compromised — and the generation of self-reactive antibodies against ADAMTS13, the underlying cause of acquired TTP.
“Our findings suggest an association between IKZF1 variants and autoimmune TTP,” the researchers wrote in a case study detailing their investigation into the siblings and their family.
The study, titled “IKAROS Associated Immunodeficiency and Thrombotic Thrombocytopenic Purpura,” was published in the journal Pediatric Blood & Cancer.
TTP is a rare and life-threatening blood disorder characterized by the formation of small blood clots throughout the body, which can block blood flow to organs such as the brain, kidneys, and heart. It’s caused by a deficiency of ADAMTS13, an enzyme that controls blood clotting.
Most cases of TTP are acquired and caused by self-reactive antibodies that target ADAMTS13, preventing it from working correctly. This form of TTP is classified as primary if there’s no apparent cause, or secondary if it’s associated with an underlying disease.
Brother and sister both diagnosed in childhood with rare blood disease
In this report, researchers from institutions in Haifa described the cases of two siblings with a rare mutation in the IKZF1 gene — both of whom were found to have early recurrent TTP. One of the siblings, the younger brother, also developed common variable immunodeficiency, which typically presents with hypogammaglobulinemia, or low antibody levels, recurrent infections, impaired vaccine response, and autoimmunity.
At the age of 1, the sister developed urinary tract infections and TTP. She was found to have low red blood cell counts, or anemia, and low platelet counts, called thrombocytopenia. Platelets are cell fragments in the blood that form clots and stop or prevent bleeding. The girl also had reduced ADAMTS13 activity and self-reactive antibodies against ADAMTS13.
Over a three-year period, she developed kidney and neurological complications that required intensive TTP therapy. This included corticosteroids, plasma exchange, intravenous immunoglobulin or IVIg, and immunosuppressive vincristine. She was also given multiple courses of rituximab.
Blood tests revealed a deficiency in the antibody immunoglobulin A (IgA) and variable levels of IgG. She also had a poor response to childhood vaccines, and a lack or low levels of certain types of immune T-cells and B-cells. These findings were consistent with immunodeficiency.
Her younger brother also experienced urinary tract infections with fever and persistent thrombocytopenia, mirroring the early findings of his older sister. During early childhood, he had recurrent TTP episodes, characterized by anemia, thrombocytopenia, low ADAMTS13 activity, and anti-ADAMTS13 antibodies. He also developed neurological complications, including headaches, seizures, brain bleeds, and strokes.
The boy underwent multiple courses of corticosteroids and plasma exchange, which partially controlled TTP episodes. Blood tests also showed an IgA deficiency, a gradual decrease in IgM, and low to normal IgG levels.
At age 9, further tests revealed hypogammaglobulinemia, alongside a loss of protective antibodies generated by childhood vaccines, and low B-cell counts. Based on these findings, he was diagnosed with common variable immunodeficiency and was started on IVIg therapy.
By age 12, the TTP episodes had resolved completely, and he has remained clinically stable on IVIg therapy for the past 25 years. Additional tests in adulthood revealed the continued absence of certain B-cells and reduced levels of T-cells.
Researchers investigate family, seeking cause of TTP in siblings
Because these health problems occurred in both siblings, the team investigated the family. The parents of the siblings were unaffected, the researchers found. The brother’s daughter was diagnosed with juvenile arthritis with uveitis, or inflammation inside the eye, while his other children were healthy.
A genetic analysis found no defects in the gene encoding ADAMTS13. However, a mutation in the IKZF1 gene — identified as p.His163Tyr — was found in both siblings, though not in their parents. This gene provides instructions for a protein that regulates the development of immune cells, primarily in early B-cells and T-cells.
According to the researchers, these results suggested germline mosaicism in one of the siblings’ parents, meaning a spontaneous mutation in some of the parent’s reproductive cells — sperm or eggs — but not in other body cells triggered TTP in both of their children.
“We report a pedigree with a novel IKZF1 variant (p.His163Tyr) associated with immunodeficiency and recurrent autoimmune TTP,” the researchers wrote, adding that the “recognition of this association is important for diagnosis, treatment, and genetic counseling.”
The findings “[highlight] the heterogeneity [diversity] of IKZF1-related disease,” the scientists wrote, noting that further study is needed into the mechanisms underlying this gene variant.
About the Author
