Ataxia telangiectasia (AT; Louis-Bar syndrome) is a rare autosomal recessive genetic disorder caused by variants in the ATM gene, with an estimated prevalence of 1–9/100,000 (1). The ATM gene is located at chromosome 11q22-23, comprises 63 exons, and encodes a 3,056-amino-acid serine/threonine kinase belonging to the phosphoinositide 3-kinase (PI3K)-related kinase family. ATM plays a central role in the DNA damage response, particularly in signaling following double-strand DNA breaks. Loss of functional ATM impairs multiple nuclear and cytoplasmic signaling pathways, resulting in multisystem manifestations. The cardinal clinical features include progressive cerebellar ataxia, oculocutaneous telangiectasia, ionizing radiation sensitivity, immunodeficiency, and cancer susceptibility. We present a case of classic AT complicated by recurrent, progressive hematuria due to bladder wall telangiectasia.

AT is typically classified as classic or variant based on age at onset, disease progression, and residual ATM activity. The diagnosis of classic AT rests on a constellation of features including early-onset progressive cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, and cancer predisposition. Our patient had a typical history of early-onset ataxia, cerebellar atrophy on imaging, scleral telangiectasia, immunoglobulin deficiency, and a history of leukemia consistent with classic AT.

Most pathogenic ATM genotypes involve homozygous or compound heterozygous variants; nearly 1,000 different pathogenic variants have been cataloged. In classic AT, truncating (nonsense and frameshift) variants are common. We evaluated the variants according to the 2015 ACMG/AMP guidelines: Both variants are absent from control populations in the Exome Sequencing Project and 1000 Genomes Project, and are exceedingly rare in the gnomAD database (v4.0.0), with a combined allele frequency of <0.0001% (PM2). Multiple computational predictions support a deleterious effect (PP3). Although these variants are currently classified as variants of uncertain significance (VUS) due to lack of prior reports and functional data, the patient's clinical phenotype strongly supports their pathogenicity.

Defects in DNA repair and immunodeficiency contribute to increased cancer susceptibility in AT patients. Approximately one-third of AT patients develop malignancies, a risk about 25% higher than that of the general population (2). Children with AT are more susceptible to leukemia and lymphoma, while adults are prone to solid tumors. The prognosis of AT-associated tumors is often poor. This patient achieved complete remission after chemotherapy, though long-term surveillance is required.

Hematuria was the most prominent clinical feature in this case, characterized by (1) intermittent occurrence without an obvious trigger; (2) the presence of blood clots; (3) unremarkable upper urinary tract imaging; (4) isomorphic urinary red blood cells; and (5) normal coagulation and renal function. These findings strongly suggested a bladder origin. Cystoscopy confirmed multiple telangiectasias with active bleeding in the bladder wall, establishing the diagnosis of hemorrhagic cystitis.

Hemorrhagic cystitis may arise from several causes, most commonly viral infection (adenovirus, BK or JC polyomavirus) or exposure to alkylating agents such as CTX or IFO. Severe bladder hemorrhage is a rare complication of AT. Suzuki et al. reported the first case of vesical varices in an AT patient. To date, only 19 cases of hemorrhagic cystitis in AT patients have been reported across 10 articles (Table 1), most with prior CTX exposure. AT patients also have immunodeficiency, predisposing them to viral infections. For example, Christmann et al. reported a 14-year-old AT patient who developed severe hematuria 4 years after CTX treatment for B-cell lymphoma; cystoscopy showed bladder telangiectasia, and JC virus infection was confirmed (9). This was the first report of hemorrhage cystitis accompanied by JC virus infection in AT patients. However, viral-induced cystitis is typically self-limiting. Many experts attribute hemorrhagic cystitis in AT patients primarily to CTX toxicity—even at low doses—exacerbated by impaired DNA repair mechanisms. The latency between CTX exposure and hematuria can range from days to years (7). Furthermore, standard prophylaxis with hyperhydration and mesna appears insufficient to prevent this late-onset complication in AT patients (12). In our case, hematuria appeared 1.5 years after CTX treatment, suggesting that CTX may induce progressive telangiectatic changes in the bladder wall, leading to delayed, potentially massive hemorrhage.

The ATM gene plays critical roles in preventing cellular senescence and tumorigenesis. At the same time, this gene is essential for the formation of immature vessels in response to accumulation of reactive oxygen species (ROS), as well as for maintaining vascular stability, which is through oxidative activation of p38α rather than through the DNA repair pathway (14). As previously mentioned, most cases of severe hemorrhagic cystitis involve the use of CTX. It is well known that CTX causes hemorrhagic cystitis, primarily due to accumulation of its metabolite acrolein in the urine. Oxidative stress is one of the key mechanisms underlying the toxic effects of acrolein, which may contribute to vascular endothelium and blood vessel damage in the bladder wall. Although direct evidence is lacking, we speculate that defects in the ATM gene may limit the ability of affected individuals to repair the vascular damage caused by CTX, thereby laying the groundwork for recurrent bladder bleeding in the future.

Management of hemorrhagic cystitis depends on severity. Conservative measures and bladder irrigation with hemostatic agents may suffice for mild cases. Persistent or severe hemorrhage may be life-threatening and require surgical treatment, which may include cystoscopic electrocoagulation, laser therapy (e.g., Nd:YAG), transarterial embolization of the bladder artery, or, rarely, cystectomy (3). In this patient, cystoscopic electrocoagulation achieved hemostasis.

The c.8357G>T and IVS54+3A>C variants in the ATM gene are pathogenic for AT. Patients with AT are at risk for hemorrhagic cystitis due to bladder wall telangiectasia, which can lead to life-threatening hemorrhage. This complication may be associated with prior chemotherapy but can present with significant latency. Cystoscopy is essential for diagnosis and enables early intervention. Surgical treatment, such as electrocoagulation, may be necessary for severe cases.