Pediatric Essential Thrombocythemia With a Novel CALR Mutation: A Case Report

ABSTRACT

Pediatric essential thrombocythemia (ET) is extremely rare and frequently lacks identifiable driver mutations. We report a case of a 5‐year‐old male with ET harboring a novel CALR exon 9 frameshift mutation complicated by acquired von Willebrand syndrome. The patient presented with purpura, extreme thrombocytosis (1900 × 10⁹ /L), and reduced von Willebrand factor activity. Antiplatelet therapy was avoided because of bleeding risk, and anagrelide was initiated. Treatment was associated with reduction in platelet count and improvement in von Willebrand factor activity. This case expands the molecular spectrum of pediatric CALR‐mutated ET and highlights the importance of individualized management in children with extreme thrombocytosis.

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1. Introduction

Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm characterized by sustained thrombocytosis and megakaryocytic proliferation [1]. In myeloproliferative neoplasms, CALR mutations, which were first identified in 2013, are typically insertions or deletions in exon 9 that result in a frameshift and the generation of a novel C‐terminal domain [2, 3]. Approximately 85% of CALR mutations are represented by Type 1 or Type 2 variants, whereas most of the remaining variants can be classified as Type 1‐like or Type 2‐like based on their structural features. CALR‐mutated ET is characterized by higher platelet counts and a lower risk of thrombosis compared with JAK2‐mutated disease [2, 3, 4].

Pediatric ET is extremely rare, and its diagnosis is often challenging due to the high prevalence of reactive thrombocytosis in children [5, 6]. Compared with adult ET, pediatric ET has a lower reported incidence of thrombotic complications and a higher proportion of triple‐negative cases [7, 8, 9]. Considering the rarity of this condition, clinical data are limited, and treatment strategies are largely extrapolated from adult experience.

2. Case

A previously healthy 5‐year‐old male presented with purpura involving the lower extremities, abdomen, and back. There was no significant past medical or family history. Physical examination revealed splenomegaly, measuring 10.8 × 3.0 cm on ultrasonography. Laboratory data revealed marked thrombocytosis, with a platelet count of 1900 × 10⁹ /L. The patient's hemoglobin level and white blood cell count were within normal ranges. The prothrombin time–international normalized ratio and activated partial thromboplastin time were normal. In contrast, the von Willebrand factor (vWF) activity was markedly decreased to 28%, and the vWF antigen level was 61%. Other coagulation parameters were within normal limits. Bone marrow examination revealed an increased number of megakaryocytes (51/µL). Bone marrow clot sections showed increased numbers of enlarged, mature megakaryocytes without a significant increase in granulopoiesis or erythropoiesis (Figure 1A). No evidence of fibrosis was observed on bone marrow biopsy. G‐banding demonstrated a normal karyotype. Molecular analysis identified a CALR mutation (NM_004343.4:c.1127_1132delinsTTTGCGTTTCT; NP_004334.1:p.(Arg376LeufsTer56)), which was predicted to cause a frameshift in exon 9 (Figure 1B). This variant has not been previously reported in public databases, including ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) and COSMIC (https://cancer.sanger.ac.uk/cosmic/login). However, it is located within exon 9 of CALR, a well‐established mutational hotspot in myeloproliferative neoplasms [2, 3]. Frameshift mutations in this region generate a novel C‐terminal domain with altered physicochemical properties, which is a known pathogenic mechanism in CALR‐mutated disease [2, 3]. Based on the above findings, the patient was diagnosed with ET harboring the novel CALR exon 9 frameshift mutation. The observed bleeding tendency was consistent with acquired von Willebrand syndrome (AVWS) secondary to extreme thrombocytosis.

FIGURE 1.

(A) Bone marrow clot sections showing increased numbers of enlarged, mature megakaryocytes. (B) Reverse Sanger sequencing chromatogram of CALR exon 9 revealing the novel frameshift mutation (NM_004343.4:c.1127_1132delinsTTTGCGTTTCT; NP_004334.1:p.(Arg376LeufsTer56)). (C) Clinical course illustrating changes in platelet count and anagrelide dose.

Despite the absence of thrombotic events, the presence of extreme thrombocytosis complicated by AVWS prompted initiation of cytoreductive therapy. Antiplatelet therapy was avoided because of the associated bleeding risk. Anagrelide was started at a dose of 0.25 mg/day and gradually escalated to 1.0 mg/day (Figure 1C). Following treatment initiation, the platelet count gradually decreased. At the most recent follow‐up, vWF activity had increased from 28% to 70%, and vWF antigen was 83% compared with 61% at diagnosis. Splenomegaly was no longer evident on ultrasonography. During two years of follow‐up, no thrombotic events, major bleeding, or treatment‐related adverse events were observed.

3. Discussion

In this report, we describe a pediatric case of ET harboring a novel CALR exon 9 frameshift mutation complicated by AVWS that was successfully managed with cytoreductive therapy using anagrelide.

The presence of a CALR mutation in this young patient is notable, considering the relatively low frequency of such mutations in pediatric ET, in which a substantial proportion of cases lack identifiable driver mutations. The variant identified in this case (p.Arg376LeufsTer56) is a frameshift variant in exon 9 of CALR that results in alteration of the C‐terminal domain, a characteristic feature of pathogenic CALR mutations in myeloproliferative neoplasms [2, 3]. This variant has not been previously reported.

Clinically, CALR‐mutated ET has been associated with higher platelet counts and a lower risk of thrombosis compared with JAK2‐mutated disease [2, 3, 4]. In addition, pediatric ET has a lower incidence of thrombotic complications than adult ET [10]. Consistent with these findings, thrombotic events were not observed in the present case despite extreme thrombocytosis.

In contrast, the patient presented with bleeding manifestations attributed to AVWS associated with extreme thrombocytosis. AVWS is a recognized complication of ET and is thought to result from increased adsorption and proteolytic degradation of vWF under conditions of markedly elevated platelet counts [11]. A previous report suggested that AVWS may occur relatively frequently in pediatric ET, thereby emphasizing the importance of evaluating hemostatic function, particularly in patients with extreme thrombocytosis [10]. Given the presence of AVWS and the associated bleeding risk, antiplatelet therapy was avoided in this case. Previous studies have suggested that aspirin may increase bleeding complications in patients with CALR‐mutated ET, particularly in the presence of extreme thrombocytosis [12].

Thus, cytoreductive therapy with anagrelide was initiated to reduce platelet counts and improve hemostatic abnormalities. Evidence regarding optimal cytoreductive therapy in pediatric ET remains limited. However, previous reports have demonstrated that anagrelide can achieve effective platelet control with acceptable tolerability in children with ET [13, 14]. In addition, compared with hydroxyurea, anagrelide may represent an attractive option in younger patients because concerns remain regarding the potential long‐term toxicity of prolonged hydroxyurea exposure [10, 13]. Nevertheless, long‐term safety data for anagrelide in pediatric patients remain limited, and progressive anemia has been observed during prolonged anagrelide therapy in young adult patients with ET, particularly in those with CALR mutations [13, 15]. Therefore, careful long‐term monitoring is warranted. In the present case, anagrelide therapy was associated with a reduction in platelet count and improvement in vWF activity without treatment‐related toxicity during follow‐up.

In conclusion, we report a rare pediatric case of ET harboring a novel CALR exon 9 frameshift mutation complicated by AVWS. Although the functional consequences of the novel CALR variant were not experimentally assessed, this case expands the molecular and clinical spectrum of pediatric CALR‐mutated ET and highlights the importance of careful bleeding risk assessment and individualized treatment strategies in children with extreme thrombocytosis.

Funding

The authors have nothing to report.

Ethics Statement

The study was conducted in accordance with the Declaration of Helsinki and the institutional review board's guidelines. The present study was approved by the Institutional Review Board of Kobe Children's Hospital (R3‑62; Kobe, Japan).

Consent

Informed consent was obtained for this report from the guardian of the patient.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.