Brothers with shared mutations develop different TMA patterns
Report finds overlapping genetic risks for aHUS and hereditary TTP
Written by |
Two brothers carrying identical genetic variants associated with atypical hemolytic uremic syndrome (aHUS) and hereditary thrombotic thrombocytopenic purpura (TTP) developed different disease manifestations, as reported in a case series.
TTP is a blood disorder, like aHUS, characterized by thrombotic microangiopathy (TMA), in which blood clots form in tiny blood vessels.
“Such insights are vital for guiding targeted therapies, anticipating complications, and providing accurate prognostic and genetic counseling for affected families,” the authors wrote.
The case series, “Dual pathogenic variants in ADAMTS13 and CFHR1/CFHR3 deletion: divergent thrombotic microangiopathy phenotypes in siblings,” was published in Pediatric Nephrology.
Shared variants linked to two rare TMA disorders
TMAs are a group of disorders that lead to destruction of red blood cells (hemolytic anemia), low levels of platelets (the cell fragments that help blood clot), and damage to organs, especially the kidneys.
Two TMA types include aHUS and hereditary TTP. aHUS is caused by abnormal activation of the alternative complement pathway, a part of the immune system, with many cases linked to mutations in complement-regulatory genes. TTP is caused by a deficiency of ADAMTS13, an enzyme that helps regulate blood clotting.
“The simultaneous occurrence of [disease-causing] variants in both pathways within a single family is exceptionally rare,” wrote the researchers who described the cases of two brothers, ages 15 and 13, who are the first and third children of parents in a consanguineous marriage.
Both brothers had a long history of anemia (low levels of hemoglobin, the protein that carries oxygen in red blood cells) and low platelet counts alongside unexplained enlargement of the liver and spleen. Since age 6, they had been treated with blood transfusions as needed. Despite extensive testing over the years, no definite diagnosis had been reached.
At age 15, the older brother suddenly developed pallor (pale skin), convulsions, and reduced consciousness, requiring admission to the intensive care unit. He had severely elevated blood pressure affecting the brain (hypertensive encephalopathy). Blood tests confirmed TMA alongside acute kidney injury.
His blood pressure was managed with medication, but the neurological symptoms persisted. Dialysis was started for the toxin buildup affecting the brain (uremic encephalopathy), which improved his level of consciousness. He was then moved to the nephrology (kidney) unit.
Brothers show different disease manifestations
Further TMA-specific testing showed that factor H, a protein that regulates the alternative complement pathway, was at the low end of the normal range, and that ADAMTS13 activity was reduced, at 66%. A kidney biopsy showed early scarring in some of the kidney’s filtering units, and a blood clot in a single small artery.
He showed marked improvement after treatment with therapeutic plasma exchange, a process that removes and replaces the liquid portion of the blood.
His 13-year-old brother presented with anemia and severely low platelets, but his kidney function was preserved. Although he also showed signs of hemolytic anemia, his factor H level was higher than his older brother’s, while his ADAMTS13 activity was very low at 10% of normal. His condition markedly improved after plasma transfusion.
Genetic testing identified the same genetic changes in both brothers. The first was a change in the ADAMTS13 gene that disrupts the body’s instructions for making a functional ADAMTS13 protein and was linked to hereditary TTP. The second finding was a deletion of the CFHR1 and CFHR3 genes, which are involved in regulating the complement system. That deletion is a well-established genetic risk factor for aHUS.
The authors noted that despite carrying the same genetic variants, the brothers developed markedly different disease manifestations. The older brother’s illness was dominated by kidney involvement consistent with aHUS, while the younger brother showed only blood-related features characteristic of hereditary TTP, with preserved kidney function.
The team suggested that these differences may be explained by epigenetic factors (changes that influence gene activity without altering the DNA itself) or environmental triggers, rather than by the underlying genetic changes alone.
“The coexistence of ADAMTS13 and CFHR1/3 variants in siblings from a consanguineous pedigree resulted in a wide clinical spectrum of TMA,” the authors concluded.
