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CASE BASED REVIEW
Ahead of print publication  

Essential Thrombocythemia Masquerading as Henoch–Schonlein Purpura in a 9-year-old Child


1 Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
2 Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India

Correspondence Address:
CG Delhikumar,
Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry - 605 006
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_115_19

  Abstract 


Leukocytoclastic vasculitis (LCV) is a complex group of conditions which are characterized by vascular damage and neutrophilic infiltrates. LCV in children is usually considered as a part of connective tissue diseases, autoimmune disorders, and primary systemic vasculitis such as systemic lupus erythematosus (SLE) or Henoch–Schonlein purpura (HSP). We herein describe a 9-year-old child with fever, arthritis, diffuse abdominal pain, and palpable purpura over the lower limbs, who was initially diagnosed to have HSP based on the European League Against Rheumatism criteria. He also had thrombocytosis which was attributed to HSP. The skin biopsy showed LCV, providing corroborative evidence of HSP in this setting. Due to severe abdominal pain, prednisolone was prescribed, and resolution of symptoms occurred. There was no hepatosplenomegaly, anemia, polycythemia, or lymphadenopathy at this juncture. On follow-up, however, the thrombocytosis worsened (2000 × 109/L) with appearance of a palpable spleen. Further investigations revealed essential thrombocythemia (ET) as the etiology of LCV in this child. The learning point in this case report is the emphasis on consideration of inclusion of malignancies in the spectrum of LCV in children, besides the usual differential diagnosis such as HSP or SLE, especially when accompanied by worsening thrombocytosis. ET has not been reported in the constellation of malignancies described in association with LCV in the literature.

Keywords: Essential thrombocythemia, leukocytoclastic vasculitis, thrombocytosis



How to cite this URL:
Sivamurukan P, Krishnamurthy S, Delhikumar C G, Jagadeesh A, Srinivas BH, Basu D. Essential Thrombocythemia Masquerading as Henoch–Schonlein Purpura in a 9-year-old Child. Indian J Rheumatol [Epub ahead of print] [cited 2019 Dec 8]. Available from: http://www.indianjrheumatol.com/preprintarticle.asp?id=271908




  Introduction Top


Leukocytoclastic vasculitis (LCV) is a complex group of Conditions which are characterized by vascular damage and neutrophilic infiltrates of small blood vessels. LCV in children is usually considered as a part of connective tissue diseases, autoimmune disorders, and primary systemic vasculitis such as systemic lupus erythematosus (SLE) or Henoch–Schonlein purpura (HSP). ET (Essential thrombocythemia) is a type of myeloproliferative neoplasm (MPN) characterized by increased and abnormal megakaryopoiesis causing persistent thrombocytosis. ET is very rare in children and its presentation as LCV has not been reported in pediatric age group to our best knowledge.


  Case Report Top


In June 2016, a 9-year-old boy presented with fever and arthritis involving multiple joints (ankle, knees, elbows, and small joints of hand). There was no history of breathlessness, palpitations, choreiform movements, convulsions, altered behavior, vomiting, hematochezia, or melena. On examination, there was no pallor, rash, lymphadenopathy, organomegaly, small joint involvement, or subcutaneous nodules. On day 4 of illness, he developed diffuse severe abdominal pain and palpable purpuric rashes over the lower limbs [Figure 1]. He satisfied the European League Against Rheumatism diagnostic criteria for Henoch–Schonlein purpura (HSP). His complete blood count performed on day 4 of illness revealed hemoglobin of 11.8 g/dL, total counts of 20.4 × 109/L, and platelet count of 700 × 109/L, and peripheral smear showed normocytic, normochromic red blood cell, normal distribution of white blood cell without any atypical cells, and increased thrombocytes. The initial urine analysis was normal. The skin biopsy histopathology showed leukocytoclastic vasculitis (LCV), and the direct immunofluorescence was negative for all immunoglobulins [Figure 2]. Other investigations were as follows: blood urea – 25 mg/dL, serum creatinine – 0.4 mg/dL (normal for age), erythrocyte sedimentation rate 18 mm in 1st h, C-reactive protein – 8 mg/dl, C3 was 93 mg/dl, and antinuclear antibodies were negative done by immunofluorescence. Due to severe abdominal pain, prednisolone was prescribed at a dose of 2 mg/kg for 2 weeks, followed by tapering over next 2 weeks; resolution of abdominal pain, arthritis, and rashes occurred. He was discharged on day 7 and advised to come for follow-up for serial monitoring of platelets and screening for microscopic hematuria and proteinuria.
Figure 1: Palpable purpuric rash mimicking Henoch–Schonlein purpura in the child

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Figure 2: Skin biopsy showing leukocytoclastic vasculitis. (a) Histopathological examination of skin biopsy showing perivascular inflammation and subepidermal bulla filled with neutrophils (H and E, ×100). (b) Histopathological examination of skin biopsy showing perivascular and transmural neutrophilic infiltrate with red cell extravasation (H and E, ×200)

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During the follow-up (2 weeks after discharge) in the pediatric outpatient department, he continued to be asymptomatic without reappearance of fever, arthritis, abdominal pain, or rashes (platelet count was 850 × 109/L; no microscopic hematuria or albuminuria). The platelet count subsequently increased 2000 × 109/L at the end of 2 months. At the end of the 2nd month, a palpable spleen of 3 cm size was appreciated. There were no neurological deficits. At this juncture, the child was rehospitalized for bone marrow aspiration and biopsy which revealed markedly increased megakaryocytes which were loosely clustered with topographic disorganization and paratrabecular location. Many were enlarged with dyspoietic lobes. Erythropoiesis and myelopoiesis were normal. Fibrosis was not increased. Iron stores were replete (Grade 2 WHO). Overall, the features were consistent with the diagnosis of essential thrombocythemia (ET) [Figure 3]. The diagnostic criteria for ET were fulfilled. Genetic analysis of myeloproliferative leukemia (MPL) virus, Janus kinase 2 (JAK2), and calreticulin (CALR) genes was negative for any mutations. During the hospital stay, the platelet count increased to 3200 × 109/L and thereafter progressively decreased to 400 × 109/L after 2 months of initiation of treatment with hydroxyurea. He continues to be asymptomatic on hydroxyurea, with no palpable spleen now. The current platelet count is 400 × 109/L.
Figure 3: Bone marrow showing increased megakaryopoiesis, with normal erythropoiesis and myelopoiesis. (a) Histopathological examination of bone marrow showing normocellular to hypocellular marrow (low power view). (b) Histopathological examination of bone marrow showing clustering of megakaryocytes with few bizarre forms (high-power view)

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  Discussion Top


LCV in children is a complex group of conditions with various etiologies. The incidence of biopsy-proven LCV is 3–4.5/100,000 persons per year.[1] LCV is a histopathological term used to describe small-vessel vasculitis which is characterized by disruption of small vessels by inflammatory cells (mostly neutrophilic), deposition of fibrin within the lumen, and/or vessel wall coupled with nuclear debris. Based on a retrospective study done in 56 children with clinical features and cutaneous biopsy consistent with LCV, it was found that IgA vasculitis (HSP) was the most common cause, followed by cutaneous small-vessel vasculitis, urticarial vasculitis, antineutrophil cytoplasmic antibody-associated vasculitis, and acute hemorrhagic edema of infancy. Usually, LCV is considered to be a manifestation of connective tissue disorder, autoimmune disorders, and small-vessel vasculitis. Rarely, LCV has been described in literature in association with ulcerative colitis, insect bite, influenza A infection and in association with antitubercular drugs in children.

However, the occurrence of malignancies in association with LCV has been reported in <8% of adult cases, as a paraneoplastic manifestation.[2],[3] Moreover, various forms of vasculitis such as LCV, polyarteritis nodosa, Wegener's granulomatosis, microscopic polyangiitis, HSP, and granulomatosis cutaneous vasculitis have been reported in association with malignancies (in adults). Out of these, the most frequently observed vasculitis was LCV.[4] Nevertheless, there is a paucity of similar statistical information in children. The list of malignancies associated with LCV includes squamous cell carcinoma, acute myeloblastic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, malignant pleural mesothelioma, and Epstein–Barr virus-positive diffuse large B-cell lymphoma. All these cases pertain to adults. No reports of pediatric malignancies (including ET) in association with LCV could be found on a literature search.

ET is a type of myeloproliferative neoplasm (MPN). ET is characterized by increased and abnormal megakaryopoiesis, persistent thrombocytosis, risk of vascular complications, and risk of leukemic transformation. About 19% of patients were found to have splenomegaly.[5] ET-related cutaneous manifestations were found in 22% of cases in one study.[6] These cutaneous manifestations have been attributed to paraneoplastic manifestation of the underlying malignancy.[2] ET is a disorder commonly seen in elderly people; it is very rarely seen in children. The incidence of ET is 0.09 per million children in 0–14 year of age.[7] Unlike adults, children with ET are usually asymptomatic and do not develop any thrombotic events or leukemic transformation. So far, there are five mutations for ET, which have been described as causative in the adult population, namely JAK2 V617F, MPL, CALR, THPO, and TET2. Among these, JAK2 and V617F mutations were seen in 40%–50%, followed by MPL. However, in children, CALR mutations were found with ET with lower incidence of JAK 2 mutation.[8] The diagnosis of ET requires four diagnostic criteria as per the World Health Organization,[9] namely (a) elevated platelet count >450,000 cell/l, (b) megakaryopoiesis with typical morphology on bone marrow, (c) not meeting criteria for other MPNs, and (d) demonstration of clonal markers – JAK2, V617F, MPL, CALR, or first three (a, b, and c) plus absence of reactive thrombocytosis/presence of a clonal marker. Although the genetic analysis for JAK2, V617F, CALR, and MPL genes was negative in our case, THPO and TET2 genes could not be analyzed. Moreover, even after the steroids had been discontinued, the platelet counts continued to rise, which along with appearance of splenomegaly, led us to suspect an alternative diagnosis, e.g., MPN. ET in association with LCV has been reported in sporadic instances in adults; Brostoff et al. reported an adult patient with HSP developed ET due to deficient Smad4 expression.[10] To the best of our knowledge, there are no such reports in children.

In our patient, the initial elevated platelet count was attributed, probably to HSP which has been reported in many studies during the acute phase.[11],[12],[13] However, there was worsening of thrombocytosis in our patient. This led us to further evaluate the child for an alternative diagnosis, following which a diagnosis of ET was made.

To conclude, we emphasize that although rare, malignancies (including ET) should be considered as a possibility in children with LCV complicated by persistent or worsening thrombocytosis, in order to initiate timely therapeutic strategies. This report has the merit to add ET to the spectrum of malignancies associated with LCV in the pediatric population.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Arora A, Wetter DA, Gonzalez-Santiago TM, Davis MD, Lohse CM. Incidence of leukocytoclastic vasculitis, 1996 to 2010: A population-based study in olmsted county, minnesota. Mayo Clin Proc 2014;89:1515-24.  Back to cited text no. 1
    
2.
Loricera J, Calvo-Río V, Ortiz-Sanjuán F, González-López MA, Fernández-Llaca H, Rueda-Gotor J, et al. The spectrum of paraneoplastic cutaneous vasculitis in a defined population: Incidence and clinical features. Medicine (Baltimore) 2013;92:331-43.  Back to cited text no. 2
    
3.
Jayachandran NV, Thomas J, Chandrasekhara PK, Kanchinadham S, Kadel JK, Narsimulu G. Cutaneous vasculitis as a presenting manifestation of acute myeloid leukemia. Int J Rheum Dis 2009;12:70-3.  Back to cited text no. 3
    
4.
Fain O, Hamidou M, Cacoub P, Godeau B, Wechsler B, Pariès J, et al. Vasculitides associated with malignancies: Analysis of sixty patients. Arthritis Rheum 2007;57:1473-80.  Back to cited text no. 4
    
5.
Hofmann I. Myeloproliferative neoplasms in children. J Hematop 2015;8:143-57.  Back to cited text no. 5
    
6.
Itin PH, Winkelmann RK. Cutaneous manifestations in patients with essential thrombocythemia. J Am Acad Dermatol 1991;24:59-63.  Back to cited text no. 6
    
7.
Hasle H. Incidence of essential thrombocythaemia in children. Br J Haematol 2000;110:751.  Back to cited text no. 7
    
8.
Karow A, Nienhold R, Lundberg P, Peroni E, Putti MC, Randi ML, et al. Mutational profile of childhood myeloproliferative neoplasms. Leukemia 2015;29:2407-9.  Back to cited text no. 8
    
9.
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the world health organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127:2391-405.  Back to cited text no. 9
    
10.
Brostoff JM, Ranganna GM, Colaco CB. Henoch-Schonlein purpura with thrombocythaemia: An abnormality in smad4 expression? Rheumatol Int 2009;29:587-9.  Back to cited text no. 10
    
11.
Lin SJ, Huang JL, Hsieh KH. Clinical and laboratory correlation of acute Henoch-Schönlein purpura in children. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 1998;39:94-8.  Back to cited text no. 11
    
12.
Lin SJ, Huang JL. Henoch-schönlein purpura in Chinese children and adults. Asian Pac J Allergy Immunol 1998;16:21-5.  Back to cited text no. 12
    
13.
Uppal SS, Hussain MA, Al-Raqum HA, Nampoory MR, Al-Saeid K, Al-Assousi A, et al. Henoch-schönlein's purpura in adults versus children/adolescents: A comparative study. Clin Exp Rheumatol 2006;24:S26-30.  Back to cited text no. 13
    


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