Chronic Thrombocytopenia as the Initial Manifestation of STIM1-Related Disorders

Abstract

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.

STIM1/ORAI1 Loss-of-Function and Gain-of-Function Mutations Inversely Impact on SOCE and Calcium Homeostasis and Cause Multi-Systemic Mirror Diseases

“…While CRAC channelopathy is characterized by mydriasis, increased bone mineralization, immunodeficiency, splenomegaly, impaired platelet activation, and muscle hypotonia, TAM/STRMK patients typically present with miosis, decreased bone mineralization, hyposplenism, platelet pre-activation, and muscle cramping. A single TAM/STRMK patient was additionally diagnosed with lymphoproliferation ( Sura et al, 2020 ), indicating an over-active immune system. Investigations on TAM/STRMK mouse models confirmed a dysregulation of various immune system cells, which may account for the skin phenotype in humans and mice ( Silva-Rojas et al, 2019 ).…”

“…Of note, hematological analyses disclosed abnormal B, NK, and Treg counts in the STIM1 R304W mouse ( Silva-Rojas et al, 2019 ), indicating that disturbances of the immune system may also occur in TAM/STRMK patients and potentially contribute to the spleen, platelet, and skin anomalies. This is sustained by the detection of lymphoproliferation and circulating antibodies against platelets in a single patient with STIM1 R304W mutation ( Sura et al, 2020 ).…”

“…Pupillary dysfunction is a main clinical sign of CRAC channelopathy and TAM/STRMK. While CRAC channelopathy patients typically show iris dilatation (mydriasis) ( Feske et al, 2006 ; Picard et al, 2009 ; Fuchs et al, 2012 ; Lian et al, 2018 ), the inverse phenotype of light-insensitive iris hypercontraction (miosis) is a hallmark of TAM/STRMK, and results in migraine and reduced night vision ( Misceo et al, 2014 ; Morin et al, 2014 , 2020 ; Nesin et al, 2014 ; Markello et al, 2015 ; Bohm et al, 2017 ; Garibaldi et al, 2017 ; Harris et al, 2017 ; Alonso-Jimenez et al, 2018 ; Borsani et al, 2018 ; Claeys et al, 2020 ; Sura et al, 2020 ). Mydriasis and miosis have, however, not been described in murine models for CRAC channelopathy or TAM/STRMK.…”

“…In consequence of the overall reduction of Treg cells, high titers of anti-platelet autoantibodies are detectable in the serum of the patients, lead to hemolytic anemia, and contribute to mild or intermittent susceptibility to bleed in several affected individuals ( Picard et al, 2009 ; Byun et al, 2010 ; Fuchs et al, 2012 ; Lian et al, 2018 ). Bleeding diathesis associated with thrombocytopenia is a major clinical feature of TAM/STRMK ( Misceo et al, 2014 ; Morin et al, 2014 , 2020 ; Nesin et al, 2014 ; Markello et al, 2015 ; Bohm et al, 2017 ; Harris et al, 2017 ; Noury et al, 2017 ; Alonso-Jimenez et al, 2018 ; Borsani et al, 2018 ; Li et al, 2019 ; Claeys et al, 2020 ; Sura et al, 2020 ), and the analysis of blood samples from patients revealed increased platelet activation markers and enhanced secretion of alpha granules in unstimulated platelets ( Misceo et al, 2014 ). Despite this pre-activation state caused by elevated resting Ca 2+ , the platelet-platelet adhesion is impaired, and platelets often appeared with aberrant size and morphology ( Markello et al, 2015 ), suggesting that the coagulation defect in TAM/STRMK patients results from a combination of platelet loss and platelet dysfunction.…”

“…TAM and STRMK form a clinical continuum characterized by progressive muscle weakness and myalgia predominantly affecting the lower limbs ( Chevessier et al, 2005 ), and most patients manifest a varying degree of additional multi-systemic signs as miosis, ichthyosis, short stature, hyposplenism, thrombocytopenia, and dyslexia ( Endo et al, 2015 ; Markello et al, 2015 ; Walter et al, 2015 ; Bohm et al, 2017 ; Garibaldi et al, 2017 ; Noury et al, 2017 ; Bohm and Laporte, 2018 ; Morin et al, 2020 ). All GoF mutations are missense mutations affecting highly conserved amino acids in the Ca 2+ -binding EF hands (H72Q, N80T, G81D, D84G, D84E, S88G, L92V, L96V, Y98C, F108I, F108L; H109N, H109R, H109Y, I115F) ( Bohm et al, 2013 , 2014 ; Hedberg et al, 2014 ; Markello et al, 2015 ; Walter et al, 2015 ; Harris et al, 2017 ; Noury et al, 2017 ; Li et al, 2019 ; Claeys et al, 2020 ; Morin et al, 2020 ) or in the luminal coiled-coil domains of STIM1 (R304W, R304Q) ( Misceo et al, 2014 ; Morin et al, 2014 ; Nesin et al, 2014 ; Markello et al, 2015 ; Harris et al, 2017 ; Alonso-Jimenez et al, 2018 ; Borsani et al, 2018 ; Sura et al, 2020 ), or in the ORAI1 transmembrane domains forming the channel pore or concentric rings surrounding the pore (G97C, G98S, V107M, L138F, T184M, P245L) ( Nesin et al, 2014 ; Endo et al, 2015 ; Bohm et al, 2017 ; Garibaldi et al, 2017 ; Figure 1 ). Missense mutations in the muscle-specific SR Ca 2+ buffer calsequestrin ( CASQ1 ) have moreover been reported in patients with late-onset muscle weakness and myalgia, forming the mild end of the TAM/STRMK spectrum ( Barone et al, 2017 ; Bohm et al, 2018 ; Figure 1 ).…”