Chronic Thrombocytopenia as the Initial Manifestation of STIM1-Related Disorders Anjali Sura, MD,a Joseph Jacher, MS,b Erin Neil, DO,c Kathryn McFadden, MD,d Kelly Walkovich, MD,e Mark Hannibal, MD, PhDb Pediatric thrombocytopenia has a wide differential diagnosis, and recently, abstract genetic testing to identify its etiology has become more common. We present a case of a 16-year-old boy with a history of chronic moderate thrombocytopenia, who later developed constitutional symptoms and bilateral hand edema with cold exposure. Laboratory evaluation revealed evidence both of inflammation and elevated muscle enzymes. These abnormalities persisted over months. His thrombocytopenia was determined to be immune mediated. Imaging revealed lymphadenopathy and asplenia, Divisions of aPediatric Rheumatology, bPediatric Genetics, and a muscle biopsy was consistent with tubular aggregate myopathy. cPediatric Neurology, and ePediatric Hematology-Oncology d Ophthalmology evaluation noted photosensitivity, pupillary miosis, and iris and Department of Pathology, University of Michigan, Ann Arbor, Michigan hypoplasia. Genetic testing demonstrated a pathogenic variant in STIM1 consistent with autosomal dominant Stormorken syndrome. Our case is novel Mr Jacher, Ms Sura, Ms Neil, Mr Hannibal, Ms McFadden, and Ms Walkovich all participated in because of the overlap of phenotypes ascribed to both gain-of-function and literature review, drafted the initial manuscript, and loss-of-function pathogenic variants in STIM1, thereby blurring the then reviewed and revised the manuscript; and all distinctions between these previously described syndromes. Pediatricians authors approved the final manuscript as submitted and agree to be accountable for all aspects of should consider checking muscle enzymes when patients present with the work. thrombocytopenia and arthralgia, myalgia, and/or muscle weakness. Our case DOI: https://doi.org/10.1542/peds.2019-2081 highlights the importance of both multidisciplinary care and genetic testing in Accepted for publication Oct 28, 2019 cases of chronic unexplained thrombocytopenia. By understanding the ’ Address correspondence to Anjali Sura, MD, underlying genetic mechanism to a patient s thrombocytopenia, providers are Pediatric Rheumatology, SUNY Upstate, 725 Irving better equipped to make more precise medical management Ave, Suite 805, Syracuse, NY 13210. E-mail: suraa@ recommendations. upstate.edu PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2020 by the American Academy of Thrombocytopenia, defined as a platelet childhood are due to genetic pathogenic Pediatrics count ,150 000 K/mL, is a commonly variants that disrupt normal platelet FINANCIAL DISCLOSURE: The authors have indicated found laboratory abnormality in development and/or platelet function.1 they have no financial relationships relevant to this childhood. Many cases of Traditionally, inherited article to disclose. thrombocytopenia are spurious from thrombocytopenias have been FUNDING: No external funding. improper handling or inadequate classified on the basis of platelet size or POTENTIAL CONFLICT OF INTEREST: Mr Jacher is anticoagulation in the collection tube, by bleeding risk. However, because the a current employee of Blueprint Genetics, and his fi contributing to platelet clumping. Other bleeding risk associated with many of af liation during the drafting and submission of this cases are attributable to commonly article was as a full-time employee of the University the hereditary thrombocytopenias is of Michigan; the remaining authors have indicated acquired etiologies, such as infections, often of modest clinical impact, recent they have no potential conflicts of interest to medication exposures, malignancy, emphasis has been placed on managing disclose. underlying disorders that promote the other associated congenital immune-clearance, consumption, or abnormalities, such as limb anomalies To cite: Sura A, Jacher J, Neil E, et al. Chronic inadequate production of platelets. or hearing loss as well as their Thrombocytopenia as the Initial Manifestation of A smaller fraction of persistent or propensity for renal failure, bone STIM1-Related Disorders. Pediatrics. 2020;145(4): e20192081 intermittent thrombocytopenia cases in marrow aplasia, immunodeficiency, and Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 145, number 4, April 2020:e20192081 CASE REPORT hematologic malignancy.2 Although persisted, prompting an evaluation (Invitae clinical diagnostic there has been recent hesitation in for inflammatory myositis and laboratory) identified a pathogenic using genetic testing for chronic a concurrent evaluation for the variant in STIM1 (c.910C.T, childhood thrombocytopenia,3 careful underlying etiology of his p.Arg304Trp [R304W]), consistent clinical phenotyping in concert with thrombocytopenia. MRI results of his with a diagnosis of autosomal genetic characterization of persistent lower extremities were negative for dominant STIM1-related conditions, thrombocytopenia is valuable to inflammatory myositis but including Stormorken syndrome. Of accurately gauge individual patient’s demonstrated bilateral hip and knee note, after the recognition of his risks and ensure a comprehensive effusions, notable inguinal STIM1-related variant, he was management plan (Table 1). lymphadenopathy (with many nodes evaluated by ophthalmology and measuring .1 cm), and hyperintense noted to have photosensitivity, miotic In this article, we describe a case of linear signal changes in the mid- and pupils that dilated poorly, and iris persistent moderate distal femurs with patchy red marrow hypoplasia. thrombocytopenia from infancy in signal. To further evaluate the a patient who presented with elevated creatine kinase, a muscle DISCUSSION elevated muscle enzymes and biopsy was performed, which fl in ammatory markers. Through revealed large vacuoles consistent This patient, with chronic isolated collaborative multispecialty with TAM on both light and electron thrombocytopenia of unknown evaluation, he was determined to microscopies (Fig 1). etiology, received an extensive have previously unrecognized tubular workup by a multidisciplinary team, Bone marrow aspiration biopsy result aggregate myopathy (TAM), including rheumatology, hematology, was negative for malignancy but lymphadenopathy, asplenia, and neurology, and genetics, to reveal fi significant for toxic granulation of subtle immunode ciency with a STIM1 pathogenic variant neutrophils, consistent with a unifying pathogenic variant in c.910C.T, p.Arg304Trp (R304W). If Stromal Interaction Molecule 1 inflammation. Circulating antibodies a hematologist was working alone to STIM1 against platelets (both ( ). This case highlights both the manage his thrombocytopenia, it is immunoglobulin G and value of multispecialty care and not likely that this etiology would immunoglobulin A) were detected, genetic testing in patients with have been discovered. In this case, the consistent with immune-mediated chronic thrombocytopenia while importance of both multidisciplinary STIM1 thrombocytopenia, although expanding the phenotype of care and genetic testing in cases of abdominal ultrasound could not gene-related variants. chronic unexplained identify a definite spleen. a-b double- thrombocytopenia is highlighted. By negative T cells were not elevated. understanding the underlying genetic PATIENT PRESENTATION The patient reported no recurrent or mechanism to a patient’s significant infections with unusual A 16-year-old Lebanese boy with thrombocytopenia, providers are organisms nor other a history of moderate better equipped to make more autoinflammatory features. thrombocytopenia (platelets ranging precise medical management Quantitative immunoglobulin levels from 60 000–100 000 K/mL), first recommendations. By using our for immunoglobulin G, documented at age 2 months, patient as an example, once the STIM1 immunoglobulin A, and presented with a sore throat, fatigue, pathogenic variant was identified, an immunoglobulin E were normal, back pain without muscle weakness, ophthalmology evaluation, abdominal whereas immunoglobulin M was and acute edema of his dorsal hands ultrasound, and neuropsychological mildly low (35 mg/dL; normal: after exposure to cold temperatures. testing were ordered. These 50–370 mg/dL). Flow cytometry His laboratory results were notable evaluations led to diagnoses of demonstrated normal T, B, and for leukocytosis (white blood count: photosensitivity, miotic pupils, iris natural killer (NK) cell absolute 11.4–20.0 K/µL with unremarkable hypoplasia, and asplenia. He will also counts. Lymphocyte mitogen differential) and elevations in his be continually monitored for proliferation testing was normal. inflammatory markers (erythrocyte contractures, ophthalmoparesis, and Lymphocyte antigen proliferation to sedimentation rate: 21–42 mm and cognitive delays and was counseled tetanus was negative, despite C-reactive protein: 0.5–2.7 mg/dL) regarding the infection risk related to adequate previous vaccination and and creatine kinase (528–973 IU/L). asplenia. Results of post-revaccination, although he did His hand edema improved with neuropsychological testing will guide demonstrate a response to Candida. naproxen. However, his laboratory whether further intervention is abnormalities, initially presumed to Genetic analysis via a 207-gene needed at school. Furthermore, be related to a viral process, Primary Immunodeficiency Panel individuals who know that they