Brothers found to have rare mix of 2 genetic blood-clotting disorders
Testing identifies unique overlap of TTP and aHUS after 1 sibling's health crisis
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Two teenage brothers in Egypt have been diagnosed with an extremely rare combination of two distinct genetic blood-clotting disorders.
The boys carry the genetic mutations for both thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS). Even though they’ve required medical treatment since early childhood, neither was accurately diagnosed until the older brother experienced a severe health crisis at age 15.
This case highlights the importance of rigorous genetic testing for people who experience blood-related health problems in childhood, researchers said.
The study, “Dual pathogenic variants in ADAMTS13 and CFHR1/CFHR3 deletion: divergent thrombotic microangiopathy phenotypes in siblings,” was published in Pediatric Nephrology.
Understanding TMAs and clotting disorders
Thrombotic microangiopathies (TMAs) are a group of disorders defined by tiny clots that form in blood vessels, leading to low blood cell counts and organ damage. TTP and aHUS are both TMAs that can be associated with underlying genetic mutations.
In TTP, the enzyme ADAMTS13, which normally helps prevent unneeded clotting, is absent or dysfunctional. This usually develops as a consequence of an immune disorder, but in a small number of cases, TTP is caused by mutations in the ADAMTS13 gene that provides instructions to make the enzyme.
Meanwhile, aHUS is marked by abnormal blood clots that form due to the abnormal activation of a group of immune proteins called the complement cascade. People with aHUS usually have an underlying mutation in a complement-related gene, such as CFHR1 or CFHR3; these mutations don’t cause the disease outright but set the stage for it to develop.
Since both TTP and aHUS are characterized by tiny blood clots, their symptoms and signs are similar. However, the biological causes are fundamentally distinct.
The two boys in this report are the first and third children of consanguineous parents (that is, parents who are close biological relatives). In early childhood, they both showed unexplained low blood cell counts and hepatosplenomegaly (enlargement of the liver and spleen). A battery of tests was performed when the two were young, but clinicians were unable to pinpoint a specific underlying cause for their symptoms.
Starting at age 6, both boys had been receiving regular blood transfusions to manage their disease. But then, when the older brother was 15, he suddenly developed abnormal paleness, convulsions, and loss of consciousness, prompting him to be brought to a specialty hospital. There, he showed features consistent with TMA, including low platelet counts, red blood cell breakdown, and acute kidney injury.
The older brother’s condition was ultimately managed with a combination of blood pressure medicines, dialysis, and plasma exchange. When he was hospitalized, genetic testing revealed he had a mutation in the ADAMTS13 gene — the cause of congenital TTP — and a genetic deletion encompassing the CFHR1 and CFHR3 genes, a well-established genetic variant that can set the stage for aHUS.
Testing of the younger brother, who was then 13 and had similar manifestations although his kidney function was preserved, revealed that he carried these same mutations. As such, both brothers were ultimately diagnosed with co-occurring TTP and aHUS.
“The coexistence of a [disease-causing mutation] in ADAMTS13 and deletion of CFHR1 and CFHR3 represents an exceptionally rare and complex overlap of two distinct TMAs,” the researchers concluded, adding that this complexity “necessitates a multidisciplinary approach focused on early genetic diagnosis” to facilitate optimal care.
