Pediatric thrombocytopenia has a wide differential diagnosis, and recently, 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, and a muscle biopsy was consistent with tubular aggregate myopathy. Ophthalmology evaluation noted photosensitivity, pupillary miosis, and iris hypoplasia. Genetic testing demonstrated a pathogenic variant in STIM1 consistent with autosomal dominant Stormorken syndrome. Our case is novel because of the overlap of phenotypes ascribed to both gain-of-function and loss-of-function pathogenic variants in STIM1, thereby blurring the distinctions between these previously described syndromes. Pediatricians should consider checking muscle enzymes when patients present with thrombocytopenia and arthralgia, myalgia, and/or muscle weakness. Our case highlights the importance of both multidisciplinary care and genetic testing in cases of chronic unexplained thrombocytopenia. By understanding the underlying genetic mechanism to a patient’s thrombocytopenia, providers are better equipped to make more precise medical management recommendations.

Thrombocytopenia, defined as a platelet count <150 000 K/μL, is a commonly found laboratory abnormality in childhood. Many cases of thrombocytopenia are spurious from improper handling or inadequate anticoagulation in the collection tube, contributing to platelet clumping. Other cases are attributable to commonly acquired etiologies, such as infections, medication exposures, malignancy, underlying disorders that promote immune-clearance, consumption, or inadequate production of platelets.

A smaller fraction of persistent or intermittent thrombocytopenia cases in childhood are due to genetic pathogenic variants that disrupt normal platelet development and/or platelet function.1  Traditionally, inherited thrombocytopenias have been classified on the basis of platelet size or by bleeding risk. However, because the bleeding risk associated with many of the hereditary thrombocytopenias is often of modest clinical impact, recent emphasis has been placed on managing the other associated congenital abnormalities, such as limb anomalies or hearing loss as well as their propensity for renal failure, bone marrow aplasia, immunodeficiency, and hematologic malignancy.2  Although there has been recent hesitation in using genetic testing for chronic childhood thrombocytopenia,3  careful clinical phenotyping in concert with genetic characterization of persistent thrombocytopenia is valuable to accurately gauge individual patient’s risks and ensure a comprehensive management plan (Table 1).

In this article, we describe a case of persistent moderate thrombocytopenia from infancy in a patient who presented with elevated muscle enzymes and inflammatory markers. Through collaborative multispecialty evaluation, he was determined to have previously unrecognized tubular aggregate myopathy (TAM), lymphadenopathy, asplenia, and subtle immunodeficiency with a unifying pathogenic variant in Stromal Interaction Molecule 1 (STIM1). This case highlights both the value of multispecialty care and genetic testing in patients with chronic thrombocytopenia while expanding the phenotype of STIM1 gene-related variants.

A 16-year-old Lebanese boy with a history of moderate thrombocytopenia (platelets ranging from 60 000–100 000 K/μL), first documented at age 2 months, presented with a sore throat, fatigue, back pain without muscle weakness, and acute edema of his dorsal hands after exposure to cold temperatures. His laboratory results were notable for leukocytosis (white blood count: 11.4–20.0 K/µL with unremarkable differential) and elevations in his inflammatory markers (erythrocyte sedimentation rate: 21–42 mm and C-reactive protein: 0.5–2.7 mg/dL) and creatine kinase (528–973 IU/L). His hand edema improved with naproxen. However, his laboratory abnormalities, initially presumed to be related to a viral process, persisted, prompting an evaluation for inflammatory myositis and a concurrent evaluation for the underlying etiology of his thrombocytopenia. MRI results of his lower extremities were negative for inflammatory myositis but demonstrated bilateral hip and knee effusions, notable inguinal lymphadenopathy (with many nodes measuring >1 cm), and hyperintense linear signal changes in the mid- and distal femurs with patchy red marrow signal. To further evaluate the elevated creatine kinase, a muscle biopsy was performed, which revealed large vacuoles consistent with TAM on both light and electron microscopies (Fig 1).

Bone marrow aspiration biopsy result was negative for malignancy but significant for toxic granulation of neutrophils, consistent with inflammation. Circulating antibodies against platelets (both immunoglobulin G and immunoglobulin A) were detected, consistent with immune-mediated thrombocytopenia, although abdominal ultrasound could not identify a definite spleen. α-β double-negative T cells were not elevated. The patient reported no recurrent or significant infections with unusual organisms nor other autoinflammatory features. Quantitative immunoglobulin levels for immunoglobulin G, immunoglobulin A, and immunoglobulin E were normal, whereas immunoglobulin M was mildly low (35 mg/dL; normal: 50–370 mg/dL). Flow cytometry demonstrated normal T, B, and natural killer (NK) cell absolute counts. Lymphocyte mitogen proliferation testing was normal. Lymphocyte antigen proliferation to tetanus was negative, despite adequate previous vaccination and post-revaccination, although he did demonstrate a response to Candida.

Genetic analysis via a 207-gene Primary Immunodeficiency Panel (Invitae clinical diagnostic laboratory) identified a pathogenic variant in STIM1 (c.910C>T, p.Arg304Trp [R304W]), consistent with a diagnosis of autosomal dominant STIM1-related conditions, including Stormorken syndrome. Of note, after the recognition of his STIM1-related variant, he was evaluated by ophthalmology and noted to have photosensitivity, miotic pupils that dilated poorly, and iris hypoplasia.

This patient, with chronic isolated thrombocytopenia of unknown etiology, received an extensive workup by a multidisciplinary team, including rheumatology, hematology, neurology, and genetics, to reveal a STIM1 pathogenic variant c.910C>T, p.Arg304Trp (R304W). If a hematologist was working alone to manage his thrombocytopenia, it is not likely that this etiology would have been discovered. In this case, the importance of both multidisciplinary care and genetic testing in cases of chronic unexplained thrombocytopenia is highlighted. By understanding the underlying genetic mechanism to a patient’s thrombocytopenia, providers are better equipped to make more precise medical management recommendations. By using our patient as an example, once the STIM1 pathogenic variant was identified, an ophthalmology evaluation, abdominal ultrasound, and neuropsychological testing were ordered. These evaluations led to diagnoses of photosensitivity, miotic pupils, iris hypoplasia, and asplenia. He will also be continually monitored for contractures, ophthalmoparesis, and cognitive delays and was counseled regarding the infection risk related to asplenia. Results of neuropsychological testing will guide whether further intervention is needed at school. Furthermore, individuals who know that they have a genetic variant causing their thrombocytopenia may make different reproductive choices (eg, deciding not to have children, adoption, in vitro fertilization with preimplantation diagnosis, or using a gamete donor), especially if they are at increased risk for malignancy.

The STIM1 protein, encoded by the STIM1 gene, is involved in calcium regulation in the endoplasmic and sarcoplasmic reticulum. Previously, distinct phenotypes have been reported with different gain-of-function (GOF) and loss-of-function (LOF) pathogenic variants in this gene. Our case is novel because of the overlap of phenotypes ascribed to both GOF and LOF pathogenic variants in STIM1, thereby blurring the distinctions between these previously described syndromes.

Our patient’s R304W genetic variant has been previously associated with Stormorken–York platelet syndrome, which has cardinal features of thrombocytopenia and/or thrombocytopathy, persistent pupillary constriction (miosis), and TAM. TAM is a clinically heterogeneous progressive muscle disorder with a variable age of onset. It may present with muscle cramps, myalgias, muscle stiffness, and with time, proximal muscle weakness. Muscle biopsy characteristically demonstrates tubular aggregates, with type II muscle fiber atrophy.4  In the literature, a 21-year-old Italian woman with a STIM1 pathogenic variant has been reported to have symptoms of diffuse myalgias during fever episodes,5  similar to our patient, who was only symptomatic with cold exposure. After genetic diagnosis, our patient was found to have asplenia, which has variably been reported in other previously published cases of the R304W variant. He also described difficulty with memory and information retention at school; learning difficulties and intellectual disability have been described in the R304W variant, as well.511 

The thrombocytopenia in the R304W GOF variant has previously been ascribed to abnormal platelet calcium regulation.12  However, our patient clearly had autoimmune thrombocytopenia, which is more consistent with previously described LOF variants in STIM1. Homozygous LOF pathogenic variants in STIM1 result in autosomal recessive immunodeficiency disorders with autoimmune cytopenias, lymphoproliferation, enamel defects, hypohidrosis and/or anhidrosis, iris hypoplasia, and nonprogressive muscular hypotonia. Although the initial cases of severe LOF had early onset and high mortality because of life-threatening infections, more recent reports describe hypomorphic variants with milder immunodeficiency.1315  Despite having a GOF genetic variant, our patient displays some phenotypic features previously attributed to the LOF variant, including autoimmune thrombocytopenia, lymphoproliferation, and iris hypoplasia.

Our patient expands the phenotypic spectrum of GOF and LOF STIM1 pathogenic variants.

Despite having a GOF pathogenic variant, our patient expressed phenotypic features previously attributed to both GOF and LOF variants of STIM1. Other variables such as epigenetic factors and polygenic inheritance patterns could be playing a role in this patient’s phenotype. These variables will hopefully be delineated as more individuals are diagnosed with STIM1-related disorder as whole exome and genome sequencing become more easily available.

Pediatricians should consider STIM1-related disease when patients present with thrombocytopenia (either with autoimmune etiology or not), along with elevated muscle enzymes. Along these lines, pediatricians should consider checking muscle enzymes when patients present with thrombocytopenia and arthralgia, myalgia, and/or muscle weakness. Also, hematologists managing thrombocytopenia of unknown etiology may benefit from involvement of a multidisciplinary team in workup when other organ systems are involved. Identifying previously unidentified STIM1 variants will lead to better preventive care and management of individual symptomatic manifestations, as in our patient.

More broadly, providers should consider genetic testing in cases of unexplained chronic thrombocytopenia associated with other hematologic manifestations or other organ abnormalities (such as hearing or vision impairment, significant dermatologic findings, skeletal dysplasia, developmental delay, etc). See Table 1 for a complete list of manifestations of genetic causes of thrombocytopenia. However, as can be seen in this table, some genetic causes of thrombocytopenia have no other significant manifestations at first, but individuals could be at risk for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) and require additional screening as is the case for ANKRD26-related thrombocytopenia. Therefore, genetic testing should still be considered even in the absence of other features if the chronic unexplained thrombocytopenia is very early onset, severe, or refractory to therapy.

Mr Jacher, Ms Sura, Ms Neil, Mr Hannibal, Ms McFadden, and Ms Walkovich all participated in literature review, drafted the initial manuscript, and then reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

AML

acute myeloid leukemia

GOF

gain-of-function

LOF

loss-of-function

MDS

myelodysplastic syndrome

NK

natural killer

R304W

c.910C>T, p.Arg304Trp

STIM1

Stromal Interaction Molecule 1

TAM

tubular aggregate myopathy

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: Mr Jacher is a current employee of Blueprint Genetics, and his affiliation during the drafting and submission of this article was as a full-time employee of the University of Michigan; the remaining authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.