JPED Journal

Patient 1

An 8.5-year-old girl presented with new-onset symptoms of petechiae and hematomas. Her complete blood count was normal, other than a platelet count of 2000/µL. A peripheral blood smear suggested ITP. Intravenous immunoglobulin treatment was initiated. At age 3 years, she had been diagnosed clinically with NF1, based on multiple café ale spots and inguinal freckling, in the absence of a family history of NF1. Her birth history revealed normal at-term delivery and birth weight. She had mild gross motor delay, and started walking only at age 19 months. Due to fine motor delay, she required occupational therapy. Language development and intelligence were normal, yet learning disabilities and attention deficit hyperactivity disorder (ADHD) were diagnosed in childhood. Following therapy with intravenous immunoglobulin for ITP, her platelet count increased to 140,000/µL and then normalized. The acute ITP resolved with no recurrence during the subsequent 5 years.

Patient 2

A girl was diagnosed with ITP at age 4.5 years , following admission due to petechiae and purpura over her legs and arms. Her birth history and childhood milestones were normal. She had been diagnosed with familial NF1 at the age of one year. At diagnosis of ITP, her platelet count was 5000/μL. Bone marrow examination showed normal cellularity, no increased blasts, and an increased number of megakaryocytes, which was consistent with the diagnosis of ITP. Treatment with intravenous immunoglobulin was initiated, but the response was minimal. Over the years, she was treated for refractory ITP with intravenous immunoglobulin, corticosteroid and thrombopoietin agonists (eltrombopag and romiplostim), rituximab, and combinations of the above, without remission. Currently, she is 7.5 years old, has chronic ITP and is treated with intravenous immunoglobulin every other week. She is a good student. Other than skin manifestations, she did not have major bleeding, over the years.

Patient 3

A 12-year-old male with multiple café au lait spots, and an unremarkable medical history apart from learning disabilities and ADHD, was diagnosed with new onset ITP. Therapy with multiple therapeutic agents, including intravenous immunoglobulin, corticosteroids and various thrombopoietin agonists, showed minimal response. At the time of diagnosis of ITP, he was also diagnosed with Hashimoto’s thyroiditis requiring replacement therapy. Three years after the diagnosis of ITP he presented to our hospital with several hours of severe headache, dizziness, the inability to walk and worsening hemiparesis, with no report of trauma, fever or other illness. Initial examination showed confusion, facial asymmetry and left hemiparesis. His platelet count was 1000/μL, blood pressure 108/87 and heart rate 117 beats per minute. A brain computerized tomography and later magnetic resonance imaging (Figure 1) revealed a right thalamic haemorrhage.  He was treated in the intensive care unit with a high dose of corticosteroids, intravenous immunoglobulin, platelet transfusion and recombinant factor VII. Due to lack of improvement in platelet count and worsening clinical condition, he underwent emergent splenectomy within hours of admission. His platelet count rose to above 150,000μ/L within hours after surgery, and was above 1,000,000/μL at discharge. His neurological status improved and after rehabilitation, he has had no sequelae. Despite the clinical diagnosis of NF1 based on multiple café ale spots and inguinal freckling, no pathogenic NF1 variant was found.

Figure 1: Acute Rt.Thalamic Intracerebral Hemorrhage: (1) T1-weighted axial MRI (2) T2-weighted axial MRI. (1) On the T1-weighted image, the abnormality in the Rt thalamus, indicating acute hemorrhage is not well seen, as the signal is isointense.

However, on the T2-weighted image (2) The signal is dark, representing deoxyhemoglobin as well as significant surrounding vasogenic edema.

He was treated in the intensive care unit with a high dose of corticosteroids, intravenous immunoglobulin, platelet transfusion and recombinant factor VII. Due to lack of improvement in platelet count and worsening clinical condition, he underwent emergent splenectomy within hours of admission. His platelet count rose to above 150,000μ/L within hours after surgery, and was above 1,000,000/μL at discharge. His neurological status improved and after rehabilitation, he has had no sequelae. Despite the clinical diagnosis of NF1 based on multiple café ale spots and inguinal freckling, no pathogenic NF1 variant was found.

Discussion

In children, ITP is typically acute and short-lived. Complete remission has been reported in 69% of children within 6 months [6,7]. Among children with chronic ITP (defined as ongoing or active disease at 12-months follow-up), 28% were reported to achieve remission within 24 months [7]. Severe bleeding is very uncommon; the rate of intracranial haemorrhage was reported as 0.6-1% [8]. ITP is an immune-regulated disorder mediated by antiplatelet autoantibodies and antigen-specific T cells that lead to peripheral platelet destruction in the spleen and impaired platelet production in the bone marrow [9]. Since NF1 is not considered to have an autoimmune mechanism, the occurrence of ITP and NF1 could be coincidental. However, the appearance of autoimmune phenomena has been described in patients with NF1. Accordingly, Nanda et al. [10] reported a list of the most frequent autoimmune diseases that were found to be associated with NF1, mainly in adults. Possible mechanisms were suggested for the predisposition to autoimmunity in NF1 [4]. One is through unregulated RAS activity in T cells, which can result in lymphocytic proliferation, and regulation of T-cell activity [11]. The other is by autoimmunity that involves free DNA released from proliferating cells. This has been detected in association with both NF1 and systemic autoimmune diseases, triggering an antigenic response. In two of the three patients described in this report, ITP became chronic, and required frequent therapy. In one of these patients, the ITP was complicated by a severe adverse event, with intracranial bleeding.  Given the small sample size of patients described here, the significant proportion of chronic ITP observed in NF1 patients compared to the general population prompts the question of whether this truly represents a higher incidence or is merely a result of better detection in NF1 patients. A search for NF1 and ITP in the literature revealed a case report of an adolescent with NF1 and chronic ITP that was complicated by intracranial bleeding [12] and an  abnormal uterine bleeding in an adolescent girl having co-existent type-1 neurofibromatosis and ITP [13].^. The pathophysiology driving the development from acute ITP to chronicity remains undefined. However, factors that have been reported to be associated with a chronic course in ITP include an impaired bone marrow microenvironment, female gender, older age at presentation, gradual initiation of disease, frequent bleeding, immunological markers and higher platelets at baseline [14]. The pathogenic role of T-cells in ITP has also been investigated, including a potential focus on new therapies [15]. Intracranial haemorrhage is a rare complication of ITP in children, with 53% of the reported incidents occurring during the chronic phase. The main risk factor for intracranial haemorrhage is a platelet count less than 10,000/μL [16]. as was seen in our patient. The only definitive treatment that has been described in extreme instances is splenectomy, as performed in that patient.

Conclusion

Our study suggest that the incidence of  ITP is increased in NF1with  the possibility of persistent ITP and more severe bleeding complications. The limitation of this report is the small number of patients. Thus, further investigation should focus on the incidence of ITP in patients with NF1, the remission rate , the complication of intracranial haemorrhage and the  relation between NF1 and autoimmune phenomena.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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