Intractable thrombocytopenia in a patient with atypical ataxia-telangiectasia: a case report

Abstract

AbstractSection Background

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Ataxia-telangiectasia (A-T) is an infrequent autosomal recessive multisystemic disorder caused by ATM variants. It is characterized by progressive cerebellar ataxia, telangiectasia, susceptibility to malignancies and variable immunodeficiency. Patients have phenotypic heterogeneity, especially those with variant A-T form, posing challenges for early diagnosis and intervention.

AbstractSection Case presentation

Herein we describe an early-onset A-T patient with atypical symptoms, mainly manifested as immunodeficiency and isolated intractable thrombocytopenia, which led to the initial suspicion of immune thrombocytopenia. The patient did not receive a definitive diagnosis of variant A-T until genetic testing was performed and detected a compound heterozygous genotype in ATM. Anti-infective therapy, intravenous immunoglobulin, methylprednisolone as well as treatment of thrombopoietin were administered. The infection was controlled, but therapies had limited effect on the thrombocytopenia. Finally, patient was discharged voluntarily after 17 days of hospitalization with a last platelet count of 29 × 10⁹/L.

AbstractSection Conclusions

This case suggests that A-T should be considered among children with recurrent infections, immunodeficiency and/or thrombocytopenia, even in the absence of typical symptoms, for the sake of reducing incorrect or missed diagnosis. Genetic testing is an efficient tool for early identification and intervention. This report details the phenotype and management of secondary thrombocytopenia in A-T, enhancing clinicians’ insights into the disorder.

Background

Ataxia-telangiectasia (A-T, OMIM#208900) is a rare autosomal recessive multisystemic disease, with an estimated worldwide incidence of 1:40,000 to 1:100,000 [1]. Patients’ phenotypes are highly heterogeneous, mainly characterized by progressive cerebellar ataxia, oculo-cutaneous telangiectasia, variable immunodeficiency, radiosensitivity and predisposition to cancer, particularly lymphoid and breast malignancies [2]. Other observed abnormalities include unexplained granulomatous cutaneous lesions, growth failure and gonadal atrophy [3, 4]. Currently, no valid therapeutic strategy exists and patients typically succumb to malignancies or chronic pulmonary diseases [5].

A-T is caused by biallelic variants in the Ataxia-Telangiectasia Mutated (ATM, OMIM*607585) gene, which contains 66 exons and maps to chromosome 11q22.3-23.1 [6]. ATM protein is a high-molecular-weight nuclear serine/threonine protein kinase (~ 350 KDa) [7]. The kinase plays a critical role in cellular processes including DNA damaging repair, cell cycle regulation, oxidative stress and autophagy. The variable activity of ATM contributes to the phenotypic heterogeneity among A-T patients [8, 9]. Owing to atypical phenotypes, missed or incorrect diagnosis usually occur on A-T patients [10, 11]. Herein we report in detail the phenotype and management of thrombocytopenia in a patient with atypical A-T. The prominent immunological and hematologic abnormalities, alongside the absence of overt neurological phenotypes at initial presentation, complicated the diagnosis until genetic testing was performed.

Case presentation

The study was approved by the Ethics Committee of Tianjin Children’s Hospital, with the registration number 2024-LXKY-006. All investigations occurred clinically. Written informed consent for publication was obtained from the patient’s parents.

A 2-year-old boy was admitted with complains of recurrent fever and ecchymosis. He was born full term as the only child of healthy non-consanguineous parents. The perinatal history was unremarkable. To date, his developmental milestones including walking and speaking were normal. However, he has been admitted 4 times for unexplained fever since he was 11 months old. It was noteworthy that there was ecchymosis appearing 3 or 5 days after fever in the last two times.

Physical examination revealed ecchymosis over the body. There was no hepatosplenomegaly or superficial lymphadenopathy. Patient’s maximum body temperature was 41.3℃. The immunological testing (Table 1) indicated a combined T and B cell immunodeficiency, with markedly reduced B cell levels and an inverted CD4 +/CD8 + T cell ratio. Besides, serum IgA was severely deficient. Complete blood count revealed significant thrombocytopenia, contrasting with previous admissions (Table 1). This abnormality explained the ecchymosis in the patient. Bone marrow biopsy indicated impaired megakaryocyte maturation an decreased platelet production. Platelet autoantibodies were negative and the level of thrombopoietin was normal. In addition, the parents reported occasional convulsions accompanying fever, though none were observed during hospitalization. Ambulatory electroencephalogram, brain computed tomography and brain magnetic resonance imaging showed no abnormalities. Therefore, the convulsions were considered febrile. Etiological examinations ruled out Epstein-Barr virus, influenza virus and Mycoplasma pneumoniae infection. Other examinations including liver function tests, renal function tests and chest x-ray were normal.

Table 1 Complete blood count and immunological data at each admission of the present case

There was no history of thrombocytopenia during afebrile or non-infectious periods. Considering the history of recurrent fever, spontaneous bleeding and abnormal laboratory indicators, a clinical diagnosis of immune thrombocytopenia was considered. To further explore the genetic factors, whole exome sequencing was performed. Unexpectedly, no suspected or candidate variants in genes associated with thrombocytopenia were identified. But a compound heterozygous genotype was detected in ATM gene (NM_000051.4), consisting of two nonsense variants c.5692 C > T(p.Arg1898Ter) exhibited in Fig. 1 and c.2715T > A(p.Cys905Ter) in Fig. 2. Variants were inherited from the patient’s parents respectively, as shown in the pedigree chart (Fig. 3). Variant c.5692 C > T has been reported to be pathogenic in several A-T patients [12, 13]. The other one was novel and absent from the 1000 Genomes Project Database, National Heart, Lung, and Blood Institute Exome Sequencing Project and Human Gene Mutation Database. According to American College of Medical Genetics and Genomics variant classification guidance, it was classified as pathogenic (PVS1, PM2_Supporting, PM3). The variants have been submitted to Leiden Open Variation Database (URL: https://databases.lovd.nl/shared/individuals/00460352). There was no family genetic history of malignancy, inherited thrombocytopenia or other genetic diseases. Consequently, the patient received a definitive diagnosis of A-T. We strongly suspected the thrombocytopenia was induced by immune dysregulation and was the secondary symptom of A-T.

Fig. 1

Sanger sequencing of the ATM c.5692 position. Variant c.5692 C > T in ATM was confirmed by Sanger sequencing. The mother is a healthy heterozygous carrier. The position is indicated by red arrows

Fig. 2

Sanger sequencing of the ATM c.2715 position. Variant c.2715T > A in ATM was confirmed by Sanger sequencing. The father is a healthy heterozygous carrier. The position is indicated by red arrows

Fig. 3

Pedigree chart in this family. The proband’s mother (Ⅰ1) carried the heterozygous c.5692 C > T(p.Arg1898Ter) variant in ATM; The proband’s father (Ⅰ2) carried heterozygous c.2715T > A(p.Cys905Ter) variant. The proband (Ⅱ1) carried compound heterozygous variant of both sites

During the third hospitalization 5 months prior, the patient developed thrombocytopenia following an infection. That time platelet count normalized after high-dose immunoglobulin pulse therapy (1 g/kg). Thus during this admission (patient weight: 14.5 kg), intravenous immunoglobulin (15 g, approximately 1 g/kg) and anti-infective therapy of moxalactam (80 mg/kg) were administered empirically. The patient’s body temperature returned to normal, but the effect on platelet was minimal. On day 3, methylprednisolone (1.4 mg/kg) therapy was started. By day 8, platelet count remained low, prompting a 3-day high-dose methylprednisolone pulse therapy (300 mg, about 21 mg/kg). However, this yielded no significant improvement (platelet count: 35 × 10⁹/L). On day 12, treatment of thrombopoietin (7500U/d) was added. In any case, the therapy had limited effect, with platelet count fluctuating between 9 × 10⁹/L and 45 × 10⁹/L. After 17 days of hospitalization, the patient was voluntarily discharged with a last platelet count of 29 × 10⁹/L. Continued thrombopoietin (7500U/d) was recommended post-discharge. Two weeks later, telephone follow-up revealed that platelet counts gradually normalized with the subcutaneous injection of thrombopoietin. A detailed timeline of therapy and platelet responses was shown in Fig. 4. However, at the follow-up six month later, the patient’s platelet count decreased again (fluctuating between 40 × 10⁹/L and 60 × 10⁹/L) following an infection. At that time, unsteady gait, the manifestation associated with cerebellar ataxia, was present. Other typical phenotypes such as oculo-cutaneous telangiectasia, dysarthria, nystagmus or cerebellar atrophy were not observed yet.

Fig. 4

Timeline of therapy and platelet responses. Different dosed and therapies are distinguished by colored geometries. IVIG, intravenous immunoglobulin

Discussion and conclusions

A-T is classified into classical and variant forms based on the phenotypes, which are mainly determined by the expression and kinase activity of ATM protein [5]. Among classical form, loss-of-function alleles (the genotype usually be truncated variants) lead to early onset, severe typical phenotypes and even premature death (in the second decade of life). Progressive cerebellar degeneration, including ataxia, dystonia and dysphagia, are the main features, usually appearing between 6 and 18 months of age [14]. Variant A-T is usually caused by missense variants and characterized by milder, late-onset phenotypes. Among these patients, atypical manifestations like recurrent infections or immunodeficiency may predominate, while neurological symptoms are mild and appear late [15, 16].

In the present case, patient carried biallelic nonsense variants, which typically cause classical A-T. However, he initially presented predominantly with combined T and B cell immunodeficiency. The neurological symptoms only manifested mildly (unsteady gait) at the follow-up six month after discharge; other classic features such as oculo-cutaneous telangiectasia, dysarthria, nystagmus or cerebellar atrophy were not present yet. Similarly, in a pair of sisters we reported previously, null variants led to divergent of A-T forms: one exhibited progressive neurological degeneration and oculo-cutaneous telangiectasia, while the other initially presented only with immunodeficiency [17]. It suggests that the above findings on genotype-phenotype correlation in A-T are not absolute. Individual truncated variants may escape from the nonsense-mediated mRNA decay and retain partial function. Furthermore, some patients, as the present case, are too young for the full phenotypes to manifest. Regardless of variant type, clinicians should pay attention to multi-system involvement throughout the patient’s life cycle.

As disease progressed, the present patient developed an unusual atypical phenotype, intractable thrombocytopenia, which has never been reported as an isolated symptom. Considering that bone marrow biopsy showed no primitive lymphocytic cells, and the hemogram revealed no other abnormalities except for thrombocytopenia, diagnosis of lymphocytic leukemia was excluded. However, malignancy surveillance and management guidance were advised due to the lymphoid cancers predisposition in A-T [14, 18]. Excluding the factors of malignancy, infections, liver disease and specific medications, we strongly suspected secondary immune thrombocytopenia due to immune dysregulation. In a cohort containing 137 patients with monogenic syndromic combined immune deficiencies, 80 (58.4%) were diagnosis with A-T caused by ATM variants. Among them 6 suffered from immune thrombocytopenia [19]. It highlighted thrombocytopenia as a noteworthy secondary symptom of A-T. Whereas, there were few detail reports on the phenotypes and management. Regarding treatment, a retrospective cohort study of A-T patients showed that immunoglobulin replacement, glucocorticoid and anti-infective therapy may potentially prolonged the lifespan [20, 21]. However, with these therapy our patient only got short-term improvement. Anti-infective therapy and thrombopoietin provided some benefit for the immune thrombocytopenia. In Atm-deficient mice, bone marrow transplantation was proved to improve the phenotypes and outcomes via migration of ATM-competent cells [22]. While, more therapeutic trials are needed before clinical application.

Although our findings are informative, there were still limitations remaining to be improved in the future. First, the recruited sample of A-T patient with intractable thrombocytopenia was small. More patients are needed to determine the direct or secondary association between thrombocytopenia and ATM variants. In addition, no functional studies were conducted to demonstrate the expression and kinase activity of the variant ATM proteins.

In conclusion, we report an A-T patient with secondary intractable thrombocytopenia. The detailed description of the immune thrombocytopenia therapy timeline and platelet responses enhances the understanding and management of phenotypic heterogeneity of A-T among clinicians. Besides, it suggests that A-T tends to be misdiagnosed due to atypical and delayed symptoms. A-T should be considered among patients with recurrent infections and/or thrombocytopenia. Genetic testing can efficiently facilitate the early identification and intervention.