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 25, 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 have

Downloaded from www.aappublications.org/news by guest on September 25, 2021 2 SURA et al TABLE 1 Known Genetic Causes of Thrombocytopenia, Arranged by Platelet Size and Their Association With Malignancy Disorder (OMIM ID) Gene (OMIM ID) Inheritance Other Hematologic Manifestations Nonhematologic Manifestations Pattern Macrothrombocytopenias Not associated with malignancy Autosomal dominant deafness DIAPH1 (602121) AD None Hearing loss with thrombocytopenia (124900) Bernard–Soulier syndrome GP1BA (606672) AD or AR Hemolytic anemia, erythrocyte Splenomegaly (231200) hypocellularity, neutropenia, gastrointestinal hemorrhage GP1BB (138720) AR Gastrointestinal hemorrhage None GP9 (173515) Bleeding disorder, platelet-type, ACTN1 (102575) AD Anisocytosis None 15 (615193) Bleeding disorder, platelet-type, ITGA2B (607759) AD or AR Intracranial and gastrointestinal None 16 (187800) and autosomal ITGB3 (173470) hemorrhage recessive Glanzmann thrombasthenia (273800) Bleeding disorder, platelet-type, GFI1B (604383) AD or AR (1 Myelofibrosis, red cell anisopoikilocytosis None 17 (187900) family) Bleeding disorder, platelet-type, PRKACG (176893) AR Anemia None 19 (616176) Bleeding disorder, platelet-type, SLFN14 (614958) AD Decreased ATP secretion None 20 (616913) Bleeding disorder, platelet-type, FLI1 (193067) AD or AR (1 None Eczema, psoriasis, alopecia, and 21 (617443) family) recurrent viral infections Gray platelet syndrome (139090) NBEAL2 (614169) AR Gray polymorphonuclear neutrophils and Splenomegaly myelofibrosis MYH9-related disorders (155100) MYH9 (160775) AD Leukocyte inclusions Deafness, cataracts, and kidney disease Periventricular nodular FLNA (300017) XL None Skeletal dysplasia, intellectual heterotopia (300049) disability, and congenital malformations of the heart and kidneys Platelet glycoprotein IV CD36 (173510) AR None Susceptibility to malaria and coronary deficiency (608404) artery disease Sitosterolemia (210250) ABCG5 (605459) AR Hemolytic anemia and stomatocyte Splenomegaly, atherosclerosis, ABCG8 (605460) formation xanthomas, arthralgia Thrombocytopenia 6 (616937) SRC (190090) AD None Dysmorphic facial features, osteoporosis TUBB1-related TUBB1 (612901) AD None None macrothrombocytopenia (613112) XL thrombocytopenia with or GATA1 (305371) XL Dyserythrocytic anemia, neutropenia, and Splenomegaly without dyserythropoietic congenital erythropoietic porphyria anemia (300367) Microthrombocytopenia Associated with malignancy XL thrombocytopenia (313900) WAS (300392) XL Hemolytic anemia, lymphopenia, decreased Nephropathy, inflammatory bowel No. NK cells, risk of transformation to disease, recurrent infections, severe MDS and AML eczema Not associated with malignancy Platelet abnormalities with ARPC1B (604223) AR None Failure to thrive, immunodeficiency, eosinophilia and immune- vasculitis, lymphadenopathy mediated inflammatory disease (617718) Thrombocytopenia 3 (273900) FYB1 (602731) AR None None

Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 145, number 4, April 2020 3 TABLE 1 Continued Disorder (OMIM ID) Gene (OMIM ID) Inheritance Other Hematologic Manifestations Nonhematologic Manifestations Pattern Thrombocytopenias with normally sized platelets Associated with malignancy Bone marrow failure syndrome 3 DNAJC21 (617048) AR Aplastic anemia, pancytopenia, shortened Pancreatic insufficiency, atrophic (617052) telomeres, bone marrow failure, risk of pancreas, recurrent infections, transformation to MDS and AML short stature, IUGR, dysmorphic facial features, retinal dystrophy, skeletal abnormalities, nail dystrophy, developmental delays Congenital amegakaryocytic MPL (159530) AR Aplastic anemia, pancytopenia, risk of Hypoplastic cerebellar vermis thrombocytopenia (604498) transformation to AML Dyskeratosis congenita ACD (609377) AD or AR Bone marrow failure, Shortened telomeres in leukocytes, (PS127550) DKC1 (300126) XL hypogammaglobulinemia, leukopenia, abnormal skin pigmentation, NOLA2 (606470) AR risk of transformation to MDS and AML dystrophic nails, oral leukoplakia, NOLA3 (606471) AR pulmonary fibrosis, dental and eye PARN (604212) AR abnormalities RTEL1 (608833) AD or AR TERC (602322) AD TERT (187270) AD or AR TINF2 (604319) AD WRAP53 (612661) AR Familial platelet disorder with RUNX1 (151385) AD Risk of transformation to MDS and AML None associated myeloid malignancy (601399) Fanconi anemia (PS227650) BRCA1 (113705) AR Anemia, neutropenia, bone marrow failure, Microcephaly, renal and heart BRCA2 (600185) AR risk of transformation to MDS and AML abnormalities, short stature, radial BRIP1 (605882) AR ray anomalies, thumb deformity ERCC4 (133520) AR FANCA (607139) AR FANCB (300515) XLR FANCC (613899) AR FANCD2 (613984) AR FANCE (613976) AR FANCF (613897) AR FANCG (602956) AR FANCI (611360) AR FANCL (608111) AR FANCM (609644) AR MAD2L2 (604094) AR PALB2 (610355) AR PHF9 (608111) AR RAD51A (179617) AD RAD51C (602774) AR RFWD3 (614151) AR SLX4 (613278) AR UBE2T (610538) AR XRCC2 (600375) AR XRCC9 (602956) AR Shwachman-Diamond syndrome EFL1 (617538) AR Anemia, neutropenia, hypocellular bone Hepatomegaly, pancreatic (PS260400) marrow, risk of transformation to MDS insufficiency, myocardial necrosis, and AML skeletal abnormalities, short stature, recurrent infections SBDS (607444) AR Anemia, neutropenia, bone marrow failure, Hepatomegaly, pancreatic risk of transformation to MDS and AML insufficiency, steatorrhea, skeletal abnormalities, short stature, developmental delay, elevated transaminases SRP54-related bone marrow SRP54 (604857) AD Congenital neutropenia, hypocellular bone Pancreatic insufficiency, failure marrow, bone marrow failure, risk of developmental delay, IUGR, transformation to MDS and AML recurrent infections

Downloaded from www.aappublications.org/news by guest on September 25, 2021 4 SURA et al TABLE 1 Continued Disorder (OMIM ID) Gene (OMIM ID) Inheritance Other Hematologic Manifestations Nonhematologic Manifestations Pattern Thrombocytopenia 2 (188000) ANKRD26 (610855) AD Increased total white blood count, risk of None transformation to MDS and AML Thrombocytopenia 5 (616216) ETV6 (600618) AD Anemia, neutropenia, risk of None transformation to MDS and AML Not associated with malignancy Chediak-Higashi syndrome LYST (606897) AR Large lysosomal inclusion bodies in Oculocutaneous albinism, progressive (214500) granulocytes, decreased phagocyte neurologic dysfunction, recurrent chemotaxic response, defective NK cell infections, dysmorphic facial function, risk of hemophagocytic features lymphohistocytosis Congenital amegakaryocytic MPL (159530) AR Pancytopenia, bone marrow failure Hypoplastic cerebellar vermis thrombocytopenia (604498) Hermansky-Pudlak syndrome 2 AP3B1 (603401) AR Bleeding diathesis, immunodeficiency, Oculocutaneous albinism, pulmonary (608233) neutropenia fibrosis, hepatosplenomegaly, intellectual disability Hermansky-Pudlak syndrome 9 BLOC1S6 (604310) AR Leukopenia Oculocutaneous albinism, recurrent (614171) cutaneous infections Hemolytic-uretic syndrome C3 (120700) AD Microangiopathic hemolytic anemia Renal failure, neurologic dysfunction, (PS235400) CFB (138470) AD recurrent fever, hypertension CFH (134370) AD or AR CFHR1 (134371) AD or AR Microangiopathic hemolytic anemia Renal failure, recurrent fever, CFHR3 (605336) AD or AR hypertension CFI (217030) AD DGKE (601440) AR MCP (120920) AD or AR THBD (188040) AD Radioulnar synostosis with HOXA11 (142958) AD Aplastic anemia, pancytopenia, bone Hearing loss, proximal radioulnar amegakaryocytic marrow failure synostosis, digital abnormalities, thrombocytopenia 1 (605432) shallow acetabulae Radioulnar synostosis with MECOM (165215) AD Severe congenital anemia, neutropenia, Hearing loss, proximal radioulnar amegakaryocytic bone marrow failure synostosis, digital abnormalities thrombocytopenia 2 (616738) STIM1-related disorder including STIM1 (605921) AD or AR Anemia, bone marrow failure Developmental delay, muscle pain, Stormorken syndrome, TAM, proximal muscle weakness, tubular and immunodeficiency 10 aggregates seen on muscle biopsy, syndrome (185070, 160565, elevated creatine kinase levels, 612783) asplenia, ophthalmoplegia, contractures, recurrent infections, lymphadenopathy, intermittent fevers, defective enamel development Thrombocytopenia 4 (612004) CYCS (123970) AD None None Thrombocytopenia with absent RBM8A (605313) AR Anemia, hypercellular bone marrow, Bilateral absent radii, present thumbs, radius syndrome (27400) eosinophilia congenital heart abnormalities, spina bifida, congenital brain malformations, Meckel diverticulum, pancreatic cysts, dysmorphic facial features, short stature Thrombotic thrombocytopenic ADAMTS13 AR Hemolytic anemia, platelet thrombi Neonatal jaundice, renal dysfunction, purpura (274150) (604134) neurologic symptoms (tremor, confusion), periodic fever AD, autosomal dominant; AR, autosomal recessive; ATP, adenosine triphosphate; IUGR, intrauterine growth restriction; OMIM ID, Online Mendelian Inheritance in Man identifier; XL, X-linked; XLR, X-linked recessive.

a genetic variant causing their adoption, in vitro fertilization with The STIM1 protein, encoded by the thrombocytopenia may make preimplantation diagnosis, or using STIM1 gene, is involved in calcium different reproductive choices (eg, a gamete donor), especially if they are regulation in the endoplasmic and deciding not to have children, at increased risk for malignancy. sarcoplasmic reticulum. Previously,

Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 145, number 4, April 2020 5 FIGURE 1 A, Hematoxylin and eosin stain shows central and subsarcolemmal aggregates of basophilic, granular material. B, Gomori trichrome stain shows accumulated red, granular material. C, This material stains darkly on nicotinamide adenine dinucleotide-tetrazolium reductase. D, Aggregates are dark on esterase-reacted sections. E and F, Electron micrographs show each tubule contains an inner tubule (type I).

distinct phenotypes have been Our patient’s R304W genetic variant It may present with muscle cramps, reported with different gain-of- has been previously associated with myalgias, muscle stiffness, and with function (GOF) and loss-of-function Stormorken–York platelet syndrome, time, proximal muscle weakness. (LOF) pathogenic variants in this which has cardinal features of Muscle biopsy characteristically gene. Our case is novel because of the thrombocytopenia and/or demonstrates tubular aggregates, overlap of phenotypes ascribed to thrombocytopathy, persistent with type II muscle fiber atrophy.4 In both GOF and LOF pathogenic pupillary constriction (miosis), and the literature, a 21-year-old Italian variants in STIM1, thereby blurring TAM. TAM is a clinically woman with a STIM1 pathogenic the distinctions between these heterogeneous progressive muscle variant has been reported to have previously described syndromes. disorder with a variable age of onset. symptoms of diffuse myalgias during

Downloaded from www.aappublications.org/news by guest on September 25, 2021 6 SURA et al 5 fever episodes, similar to our phenotype. These variables will ABBREVIATIONS patient, who was only symptomatic hopefully be delineated as more with cold exposure. After genetic individuals are diagnosed with AML: acute myeloid leukemia diagnosis, our patient was found to STIM1-related disorder as whole GOF: gain-of-function have asplenia, which has variably exome and genome sequencing LOF: loss-of-function been reported in other previously become more easily available. MDS: myelodysplastic syndrome published cases of the R304W NK: natural killer Pediatricians should consider STIM1- variant. He also described difficulty R304W: c.910C.T, p.Arg304Trp related disease when patients present with memory and information STIM1: Stromal Interaction with thrombocytopenia (either with retention at school; learning Molecule 1 autoimmune etiology or not), along difficulties and intellectual disability TAM: tubular aggregate myopathy with elevated muscle enzymes. Along have been described in the R304W – these lines, pediatricians should variant, as well.5 11 consider checking muscle enzymes The thrombocytopenia in the R304W when patients present with REFERENCES thrombocytopenia and arthralgia, GOF variant has previously been 1. Noris P, Pecci A. Hereditary ascribed to abnormal platelet calcium myalgia, and/or muscle weakness. thrombocytopenias: a growing list of 12 regulation. However, our patient Also, hematologists managing disorders. 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