Idiopathic inflammatory myopathies represent a group of acquired and treatable myopathies characterized by distinct clinical features that should be distinguished from other neuromuscular diseases presenting with proximal muscle weakness or serum creatine kinase elevation. The approach to neuromuscular disorders requires a comprehensive evaluation of history and clinical phenotype. Depending on the presentation, diagnostic strategies vary from basic laboratory tests to complementary electrophysiological studies, muscle imaging, histopathology, and genomic tests. Since the approach to individualized treatments varies according to the accurate diagnosis, a close collaboration between pediatric neurologists and rheumatologists is crucial for the management and follow-up. This review aims to provide a structured diagnostic approach to pediatric myositis mimics, emphasizing the importance of accurate differential diagnosis and highlighting frequently overlooked conditions to improve clinical outcomes.

Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) immune-mediated necrotizing myopathy (IMNM) is a subtype of autoimmune necrotizing myopathy that presents with progressive proximal weakness and persistent creatine kinase (CK) elevation, which may continue despite statin discontinuation. Its relationship with hematologic malignancy is not well established. A 67-year-old woman developed markedly elevated CK levels after starting high-intensity statin. Despite statin withdrawal, CK levels remain persistently elevated, accompanied by progressive symmetrical proximal weakness. Anti-HMGCR IgG was strongly positive, while other autoimmune serologies were unrevealing. A diagnosis of statin-associated anti-HMGCR IMNM was established, and treatment with mycophenolate mofetil and intravenous immunoglobulin resulted in partial biochemical improvement. Five weeks after initiation of immunosuppressive therapy, routine laboratory testing showed rapidly rising leukocytosis. Further evaluation revealed mantle cell lymphoma with bone marrow involvement, IGH::CCND1 rearrangement, and TP53 deletion, consistent with high-risk disease. In this context, continued clinical and laboratory monitoring is appropriate in inflammatory myopathy, and new hematologic abnormalities warrant further evaluation.

Limb-Girdle Muscular Dystrophy Recessive type 4 (LGMDR4) is an autosomal recessive disorder caused by mutations in the SGCB gene and characterized by progressive proximal muscle weakness, often accompanied by respiratory and cardiac involvement. We generated two induced pluripotent stem cell (iPSC) lines from PBMCs of two related LGMDR4 patients carrying an eight-nucleotide duplication (c.377_384dupCAGTAGGA) in exon 3 of SGCB, resulting in a frameshift mutation (p.Gly129_Arg130insGlnTer). The iPSC lines exhibit typical undifferentiated morphology, express key stem cell-associated markers, differentiate into all three germ layers, and maintain a normal karyotype, providing a valuable model for studying disease mechanisms and developing therapies for LGMDR4.

Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) accounts for 8-18% of Cushing syndrome cases and is typically due to neuroendocrine tumors such as small cell lung carcinoma and bronchopulmonary neuroendocrine tumors. EAS arising from Ewing sarcoma (EwS) is rare, with only 9 pediatric and 5 adult cases reported to date. We present the case of a 40-year-old woman with refractory, metastatic EwS who developed progressive swelling, fatigue, hypokalemia, profound proximal muscle weakness, and intermittent confusion over 2 months. Physical examination revealed facial plethora, supraclavicular fat pads, hirsutism, ecchymoses, and bilateral lower extremity weakness. Laboratory evaluation was consistent with severe ACTH-dependent hypercortisolism, confirmed to be secondary to EAS after further evaluation, including the radiographic finding of rapid-onset bilateral adrenal hyperplasia. She started metyrapone, an 11-β hydroxylase inhibitor, which resulted in rapid biochemical improvement and allowed for discontinuation of insulin and potassium therapies. Due to the refractory, progressive EwS and the patient's poor performance status, she transitioned to palliative care at home, continuing metyrapone for hypercortisolism management until her death 4 months later. Herein, we summarize the existing literature of EAS in EwS, emphasize the importance of prompt recognition of the condition, and highlight the therapeutic challenges of managing paraneoplastic EAS.

With increased survival due to enzyme replacement therapy, children with classic infantile Pompe disease tend to develop a clinical phenotype with pronounced distal muscle weakness, while late-onset patients typically exhibit proximal muscle weakness. This MRI study aimed to characterize lower limb muscle involvement in classic infantile and young late-onset Pompe patients compared to healthy controls, and examine its relationship with motor function. Quantitative MRI (3-point Dixon and multi-echo spin-echo at 3T) was used to assess fat fraction (FF) and water T2 (T2water) in the leg muscles of eight classic infantile patients (6.6-15.0 years), 12 late-onset patients (6.8-27.3 years), and 13 healthy controls (6.5-26.9 years). Group comparisons were performed (Kruskal-Wallis, post hoc Dunn), and FF and T2water values were combined to identify the most frequently affected muscles. MRI findings were correlated with Quick Motor Function Test (QMFT) scores for thigh involvement and Medical Research Council (MRC) scores for foot dorsiflexion strength. MRI showed fat replacement and T2water abnormalities in numerous muscles in both patient groups. Fat replacement was generally mild (< 20%) but reached 69% in some cases. T2water values ranged from 21 to 37 ms. Classic infantile patients showed more frequent lower leg involvement (80% vs. 40%), while late-onset patients had predominant thigh involvement, particularly in the adductors. Extensive thigh involvement correlated with lower QMFT scores. Foot dorsiflexion weakness occurred only in classic infantile patients with tibialis anterior involvement. This data suggests a phenotype-specific pattern of muscle involvement and demonstrates the value of combining FF and T2water via quantitative MRI for detection of muscle involvement in Pompe disease.

The MYBPC1 gene, mapping to chromosome 12q23.2, encodes the slow myosin binding protein-C (sMyBP-C), a sarcomeric accessory protein, expressed mainly in slow skeletal muscle fibers, that aids in the regulation of actomyosin cross-bridges and provides thick filament stability. Biallelic molecular defects in MYBPC1 are associated with a lethal congenital form of myopathy (Lethal congenital contracture syndrome 4); meanwhile, heterozygous damaging variants lead to a form of distal arthrogryposis (distal arthrogryposis type 1B) and an early-onset congenital myopathy with tremor (congenital myopathy-16, CMYO16). To date, only 20 cases have been documented, all presenting a mild axial-proximal myopathy consistently coupled with a distinctive tremor phenotype. We report the case of a young Italian woman presenting with mild axial and proximal weakness, associated with a high-frequency postural tremor affecting the limbs and tongue, with apparent exacerbation of symptoms after hormonal stimulation. Laboratory tests showed normal creatine kinase levels. Electromyography revealed diffuse mild myopathic changes. Muscle MRI was substantially normal. Polygraphic tremor analysis confirmed the presence of a postural tremor at a frequency of 10-11 Hz. Muscle biopsy showed selective type 1 fiber hypotrophy. Clinical exome sequencing revealed the heterozygous c.788T>G p.(Leu263Arg) variant in exon 11 in the MYBPC1 gene. This variant has been previously reported in multiple independent subjects displaying skeletal muscle weakness and myogenic tremor. Our case helps further define the phenotypic spectrum of this disorder, providing additional clinical and pathologically relevant insides, including the possible influence of hormonal stimulation and a detailed characterization of muscle biopsy findings. Knowledge of this myopathic phenotype may allow identification of individuals with MYBPC1 variants without arthrogryposis.

Severe Cushing's syndrome (SCS) is a rare but potentially fatal endocrine emergency. We describe a woman in her fifties with a history of pituitary macroadenoma who presented with mood disturbance, proximal muscle weakness, and Cushingoid features. On admission to the intensive care unit (ICU) she was febrile, hypoxic, hypotensive, and disoriented, with imaging prior confirming recurrent pituitary macroadenoma and biochemical tests showing severe hypercortisolism. She was managed with intravenous etomidate, starting with a bolus followed by titrated infusion, which achieved rapid cortisol suppression. A block-and-replace strategy was then implemented, introducing physiological hydrocortisone once cortisol levels fell to the target range. Broad spectrum antimicrobial therapy and organ support were provided. Although biochemical control was achieved, her course was complicated by ventilator-associated pneumonia with multidrug-resistant organisms, culminating in refractory septic shock and death. This case underlines the diagnostic challenges of recognizing SCS in sepsis and the clinical value of etomidate-based block-and-replace therapy.

A man in his 60s presented with progressive, symmetric weakness of the shoulder and thigh girdles despite normal creatine kinase and electromyography findings. Lumbar spine MRI revealed only age-appropriate degenerative changes, insufficient to explain his symptoms. A targeted 60-gene next-generation sequencing panel identified a heterozygous MYOT c.179C>T (p.Ser60Phe) variant, confirming MYOT-related myofibrillar myopathy. Cardiac evaluation demonstrated mild aortic-root dilatation, mitral regurgitation and frequent premature atrial contractions. The patient underwent supervised eccentric-strengthening physiotherapy with stable function over 1 year. This case underscores that MYOT myopathy can present with preserved enzyme levels and normal electrodiagnostic studies, risking diagnostic delay if clinicians rely solely on conventional testing. Early gene-panel sequencing in patients with unexplained proximal weakness can expedite diagnosis, guide cardiac surveillance and inform family cascade testing.

Acute immune system-mediated neuropathy, referred to as Guillain-Barré syndrome, is a common etiology of acutely acquired weakness that often presents with proximally spreading initial distal extremity weakness and paralysis. Less common manifestations include delayed facial nerve palsy and weakness, occurring in approximately 15% of patients. This case report highlights a rarer initial presentation of Guillain-Barré syndrome in a 43-year-old man initially presenting with unilateral upper facial weakness whose symptoms progressed to bilateral hand and foot numbness over a 2-week period.

Immune checkpoint inhibitors (ICIs) are increasingly used as adjuvant therapy in high-risk renal cell carcinoma (RCC), but may cause serious immune-related adverse events, such as myocarditis. We report a rare case of myocarditis followed by steroid-induced myopathy during adjuvant pembrolizumab therapy. A 74-year-old man underwent partial and radical nephrectomy for bilateral clear cell RCC (pT1b and pT3a). Pembrolizumab was initiated postoperatively. On day 22, he developed exertional fatigue and cardiac enzyme levels were elevated. Myocardial biopsy confirmed myocarditis, and corticosteroid pulse therapy was started. Although cardiac markers improved initially, they rose again, requiring a second steroid pulse and higher maintenance doses. After 27 days of steroid therapy, the patient developed severe proximal muscle weakness. Myasthenia gravis and other autoimmune diseases were excluded. Steroid-induced myopathy was diagnosed, and steroid tapering plus rehabilitation led to functional recovery. He was later discharged without recurrence of myocarditis. This case highlights the importance of early detection and treatment of ICI-related myocarditis and awareness of secondary complications such as steroid myopathy. Multidisciplinary care is essential in managing these rare but serious conditions.

Bethlem myopathy is a rare collagen VI-related muscle disorder characterised by slowly progressive proximal weakness and joint contractures. Walking is usually preserved into adulthood and respiratory involvement is relatively mild. A 53-year-old woman had longstanding proximal limb weakness, early contractures and respiratory insufficiency. Despite an apparent clinical improvement on follow-up, initially attributed to immunotherapy, genetic testing ultimately identified a pathogenic COL6A1 mutation. This case highlights diagnostic challenges in late-presenting myopathies and emphasises the importance of genetic testing in atypical cases.

Pathogenic RYR1 variants are associated with a set of rare neuromuscular disorders termed RYR1 -related disorders (RYR1 -RD). Clinical manifestations of RYR1 -RD include proximal/axial muscle weakness, delayed motor milestones, impaired mobility, muscle pain, and fatigue. Muscle-specific microRNAs (miRNAs) are mostly expressed in muscle tissue and can be detected peripherally in plasma. Using a digital detection system, here we identified and quantified differential amounts of miRNAs in six adult (four monoallelic and two biallelic) RYR1 -RD patient plasma samples compared to controls. Overall, 51 differentially expressed miRNAs were identified and hsa-miR-4454+hsa-miR-7975, in particular, was significantly overexpressed relative to controls (+ 39-fold, P=0.00285). Exploration of these differentially expressed miRNAs warrant further investigation as potential biomarkers of RYR1 -RD.