Rare Childhood Bleeding Disorder Traced to Two New ADAMTS13 Gene Variants

Three children in southwestern China spent years caught in a diagnostic maze that is all too familiar to families dealing with rare blood disorders. They arrived at the hospital with recurring episodes of dangerously low platelet counts, sometimes accompanied by the telltale signs of red blood cells being destroyed in circulation. The initial working assumption, in many such cases, is immune thrombocytopenia, a condition in which the body’s own defenses mistakenly attack the platelets themselves. But these patients did not respond to the therapies that typically tame an immune attack, and that failure to improve became the first clue that something far rarer was at work. A team of pediatric hematologists at the Affiliated Hospital of Zunyi Medical University, also known as Guizhou Children’s Hospital, has now published a detailed account of these three cases, and their findings add two brand-new genetic variants to the world’s catalog of mutations behind hereditary thrombotic thrombocytopenic purpura, a disorder so uncommon that most physicians will never encounter a single case in their careers.

Hereditary thrombotic thrombocytopenic purpura, abbreviated hTTP, is caused by inherited defects in a gene called ADAMTS13, which carries the instructions for an enzyme with one of the most elegant jobs in the circulatory system. The enzyme patrols the bloodstream and slices up unusually long, sticky strands of von Willebrand factor, a protein that helps platelets clump together at sites of injury. When ADAMTS13 is missing or severely deficient, those ultra-large strands accumulate unchecked and spontaneously snag passing platelets, forming microscopic clots throughout the smallest blood vessels. The result is a cascade of problems: platelets are consumed faster than the bone marrow can replace them, red blood cells are sheared apart as they squeeze through partially blocked vessels, and vital organs, including the brain, kidneys, and heart, can be starved of oxygen by the clotting itself. Unlike the more common immune-mediated form of the disease, in which the body produces antibodies that disable a perfectly good enzyme, the hereditary form stems from mutations written directly into the genetic code.

The research team, led by Yeming Wan and Xiubin Guo as co-first authors with Mei Tan as corresponding author, retrospectively analyzed the clinical records, laboratory measurements, genetic testing results, family investigations, and treatment outcomes of the three pediatric patients. All three children presented with recurrent thrombocytopenia, meaning persistently or repeatedly low platelet counts, with or without hemolytic anemia, the destruction of red blood cells. These are precisely the features that make the disease so easy to mistake for more familiar conditions. The heterogeneous presentation of hTTP, the authors emphasize, is a central reason it is frequently misdiagnosed, and the consequences of that misdiagnosis can be serious, because the treatments for immune thrombocytopenia do nothing to address the underlying enzyme deficiency.

Laboratory testing told a decisive story once the right assays were ordered. In two of the three patients, designated Cases 2 and 3, ADAMTS13 activity measured below 5 percent of normal, a threshold that essentially rules out adequate enzyme function and points squarely toward either a hereditary defect or a severe immune-mediated shutdown of the enzyme. In Case 1, activity was recorded at 13 percent, though this measurement was taken after the patient had already received treatment, which may complicate interpretation of the value. Critically, testing for ADAMTS13 inhibitors, the autoantibodies that characterize the immune form of the disease, came back negative in all three children. That combination, profoundly reduced enzyme activity without any detectable inhibitor, is the biochemical signature of the hereditary form and provided the rationale for moving to genetic analysis.

Sequencing of the ADAMTS13 gene revealed three distinct variants across the three patients, and this is where the study makes its most durable contribution to medical knowledge. Two of the variants had never been reported before in the scientific literature. The first novel variant, written as c.1324 C>T, p.Gln442Ter, converts a codon specifying the amino acid glutamine at position 442 of the protein into a premature stop signal, a type of mutation that typically truncates the protein and destroys its function. The second novel variant, c.1459T>C, p.Cys487Arg, is subtler: it swaps a single amino acid, replacing a cysteine at position 487 with an arginine. Cysteine residues are often crucial for the three-dimensional folding of proteins because they form disulfide bonds that hold the molecular architecture together, so substituting a charged arginine for a cysteine can destabilize the enzyme or interfere with its catalytic machinery. The third variant, c.1192 C>T, p.Arg398Cys, had been reported previously and similarly replaces an arginine with a cysteine at position 398.

The inheritance patterns observed in the families add another layer of biological interest. Case 1 carried compound heterozygous mutations, meaning the child inherited two different defective copies of the ADAMTS13 gene, one from each parent: the novel nonsense variant p.Gln442Ter on one chromosome and the previously reported p.Arg398Cys on the other. Cases 2 and 3, by contrast, each carried homozygous mutations, meaning both copies of the gene carried the identical novel variant, p.Cys487Arg. Homozygosity for a rare disease-causing variant often raises the possibility of consanguinity in the family history, a pattern frequently seen in rare recessive disorders, and family investigations are a standard part of the workup for exactly this reason. Because ADAMTS13 deficiency is recessive, carriers with one normal copy typically produce enough enzyme to remain healthy, which is why these conditions can appear seemingly out of nowhere in a family with no prior history.

The clinical implications of the study reach well beyond the three patients described. The authors make an explicit recommendation that recurrent thrombocytopenia in children, particularly when there is a poor response to immune thrombocytopenia therapy, should prompt clinicians to consider evaluation for hereditary TTP. This is a message aimed at frontline pediatricians and emergency physicians, who are far more likely to see a child with low platelets than to suspect a defect in a single obscure enzyme. The diagnostic pathway the researchers describe, combining ADAMTS13 activity testing with inhibitor screening and confirmatory genetic analysis, is now the recognized gold standard for distinguishing the hereditary form from the immune form, and the distinction matters enormously for treatment decisions, prognosis, and family counseling.

Treatment of hereditary TTP has been transformed in recent years, although the source material for this case series focuses primarily on diagnosis rather than detailing long-term therapeutic regimens. Historically, the mainstay of care for acute TTP episodes of any cause was plasma exchange, in which the patient’s plasma, laden with ultra-large von Willebrand factor strands and deficient in functional enzyme, is replaced with donor plasma that supplies working ADAMTS13. For the hereditary form, regular plasma infusions can serve as prophylaxis, providing the missing enzyme on a scheduled basis. More recently, a recombinant form of the ADAMTS13 enzyme has been developed specifically for patients with the congenital form of the disease, offering a targeted replacement therapy that addresses the root cause rather than the symptoms. Immunosuppressive drugs, which are central to treating the immune form, have little role in the hereditary form because there is no antibody to suppress, underscoring why getting the diagnosis right is not an academic exercise but a decision that shapes the entire treatment strategy.

The study also highlights the practical value of expanding the global database of disease-causing variants. Every newly documented mutation, such as the p.Gln442Ter nonsense variant and the p.Cys487Arg missense variant reported here, improves the sensitivity of genetic screening, particularly for populations in which these variants may be enriched. For families who carry such variants, a precise molecular diagnosis enables informed reproductive planning, including the possibility of prenatal or preimplantation genetic testing. It also spares patients the ordeal of repeated ineffective treatments by closing the diagnostic loop early. The authors note that their findings provide additional clinical and genetic evidence for the molecular diagnosis of this rare disease, a modest phrasing that understates the real-world impact a confirmed genetic result can have on a family that has spent months or years without answers.

Published open access in BMC Pediatrics on 21 September 2026, the study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Affiliated Hospital of Zunyi Medical University, with written informed consent obtained from the legal guardians of all patients. The work was supported by the Master’s Student Research Initiation Fund of the Affiliated Hospital of Zunyi Medical University and the Guizhou Provincial Program on Commercialization of Scientific and Technological Achievements. For a disease this rare, case series like this one are the primary engine of medical knowledge, accumulating patient by patient and variant by variant. Each additional documented mutation sharpens the diagnostic lens for clinicians everywhere and brings the goal of early recognition, accurate genetic confirmation, and timely, correctly targeted treatment for children with hereditary thrombotic thrombocytopenic purpura one step closer to routine practice.

Subject of Research: Genetic variants underlying pediatric hereditary thrombotic thrombocytopenic purpura

Article Title: Clinical and genetic characteristics of pediatric hereditary thrombotic thrombocytopenic purpura: a case series of two novel ADAMTS13 variants and one previously reported variant

Article References: Wan, Y., Guo, X., Tian, R., Mao, Q., & Tan, M. (2026). Clinical and genetic characteristics of pediatric hereditary thrombotic thrombocytopenic purpura: a case series of two novel ADAMTS13 variants and one previously reported variant. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07704-7

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07704-7

Keywords: hereditary thrombotic thrombocytopenic purpura, ADAMTS13, novel variants, pediatric hematology, thrombocytopenia, von Willebrand factor, genetic diagnosis, rare disease, compound heterozygous, homozygous mutation, misdiagnosis, BMC Pediatrics