Charcot-Marie-tooth disease type 4D (CMT4D) is an early-onset, severe autosomal recessive demyelinating neuropathy, caused by mutations in the N-myc downstream-regulated gene 1 (NDRG1). Because of its rarity and predominance among specific ethnic groups, clinical knowledge remains limited. We report the case of two siblings of Romani ancestry, a 38-year-old man and a 40-year-old woman, with homozygous NM_006096.4:c.442C > T, p.(Arg148*) variant, and provide a review of the current literature.Both patients presented with severe distal-proximal sensorimotor neuropathy, muscle weakness and atrophy, generalized areflexia, and sensorineural deafness typical of CMT4D. Notably, they exhibited previously unreported features including severe dysphagia requiring PEG tube placement, bilateral vocal cord paralysis causing respiratory insufficiency necessitating non-invasive ventilation, and cognitive delay. Visual system involvement was demonstrated through abnormal visual evoked potentials with reduced P100 amplitude and absent responses, expanding the recognized phenotypic spectrum.Our systematic literature review identified 26 articles describing 72 patients with CMT4D. Twenty-two pathogenic NDRG1 variants were documented, with p.(Arg148*) being most frequent (64% of patients), predominantly in Roma populations. The median age of onset was 7 years, 96% of patients presented with lower limb involvement and all presented skeletal deformities were universal, including pes cavus (67%), claw hand (40%), and scoliosis (33%). Hearing impairment affected 61% of patients, while visual system involvement occurred in 17%.This study expands the clinical spectrum of CMT4D by documenting novel manifestations including severe bulbar dysfunction and respiratory involvement. These findings emphasize the importance of comprehensive assessment including swallowing evaluation, vocal cord examination, and pulmonary function testing in CMT4D patients, potentially impacting clinical management and prognosis.

During muscle contraction, increased influx of calcium from the myocyte cytosol into the mitochondrial matrix through the mitochondrial calcium uniporter (MCU) links calcium homeostasis with high ATP provision. The MCU is located at the inner mitochondrial membrane and one of its structural components, the mitochondrial calcium uniporter regulator 1 (MCUR1), promotes its activity. Although MCUR1 function has been studied in cell models, mutations have not yet been associated with human disease. Here, we present a patient with proximal muscle weakness and atrophy, showing histological features of autophagic vacuoles with sarcolemmal features, who carries a homozygous MCUR1 nonsense mutation. To investigate the underlying mechanisms of muscle pathology, we examined patient fibroblasts and quadriceps muscle specimens. MCUR1 deficiency compromised mtCa[2+] uptake, that had been stimulated both by histamine or rising extracellular calcium exposure. Autophagic flux and histologic markers for autophagy (LAMP2, LCB3) were increased in the patient. However, the MCUR1 mutation did not alter MCU-complex assembly or its subcellular location, nor the resting mitochondrial membrane potential. Our study associates MCUR1 deficiency with mitochondrial dysfunction and autophagic vacuolar myopathy, thereby highlighting the crucial role of mtCa[2+] uptake in regulating mitochondrial function and expanding the spectrum of mitochondrial disorders in humans.

Proximal lower extremity weakness in patients with diabetes mellitus presents a diagnostic challenge due to overlapping etiologies, including diabetic amyotrophy, lumbar radiculopathy, and chronic inflammatory demyelinating polyneuropathy (CIDP). This report presents the case of an 80-year-old male with a history of type 2 diabetes mellitus who experienced recurrent falls, progressive right thigh weakness, and muscle atrophy. Although the clinical presentation initially suggested diabetic amyotrophy, electrodiagnostic studies and imaging failed to support this diagnosis. Instead, findings were more consistent with peripheral neuropathy and possible focal L5 radiculopathy. This case highlights the limitations of current diagnostic frameworks for diabetic amyotrophy, particularly in atypical presentations that lack classic features such as pain and characteristic electromyographic abnormalities. The absence of standardized diagnostic criteria necessitated a diagnosis of exclusion, emphasizing the importance of clinical judgment. This report underscores a structured approach to evaluating diabetic patients with lower extremity weakness, including the role of a comprehensive workup, the exclusion of diagnoses with similar presentations, and the potential for recovery through supportive care.

Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a rare Anti-neutrophil cytoplasm antibodies (ANCA)-associated vasculitis with multi-organ involvement and eosinophilia. We present a 61-year-old male with a history of eosinophilic asthma who developed progressive weakness and muscle aches six weeks after his second COVID-19 booster. Four to six weeks post vaccination, he developed myal gias and weakness, especially in proximal muscles, leading to a severe decline in function. Lab results showed leukocytosis (29.54 cells/mm³); 54% eosinophils; and elevated erythrocyte sedimentation rate (ESR), C-reactive protein, and creatine kinase levels at 13 736 u/L. Anti-myeloperoxidase antibodies were positive, while PR-3, C-ANCA, and P-ANCA were negative. Magnetic resonance imaging of the lower extremities showed intramuscular edema. Muscle biopsies confirmed EGPA. Diagnosed per American College of Rheumatology (ACR)/ European Alliance of Associations for Rheumatology (EULAR) criteria, he received pulse dose IV methylprednisolone with significant improvement. He was discharged on 60 mg prednisone and started on mepolizumab (300 mg subcutaneous once every 4 weeks). Eosinophilic granulomatosis with polyangiitis progresses through stages: asthma, eosinophilia with organ involvement, and vasculitis. This case highlights a unique presentation of rapid myositis without significant involvement of any other organs and vasculitis post-mRNA vaccination. While environmental factors may trigger EGPA, the role of COVID-19 vaccines remains hypothesis-generating. This case underscores the importance of post-market surveillance for rare events, contributing to the understanding of vaccine-related rheumatic disease triggers Cite this article as: Memdani A, Busa V, Avula S, Ford A, Nesheiwat J. Unmasking Eosinophilic granulomatosis with polyangiitis: a case of rapid-onset myositis following COVID-19 booster in an eosinophilic asthma patient. Eur J Rheumatol. 2025, 13(1), 0016, doi:10.5152/eurjrheum.2026.25016.

BACKGROUND Kennedy disease, also known as spinal and bulbar muscular atrophy (SBMA), is a rare and incurable X-linked neuromuscular disorder mainly affecting men aged 30 to 60 years. Polymyositis can present similarly, but can be excluded by measuring muscle enzymes, performing muscle imaging, and electromyography. This report describes the case of a 52-year-old man with a 10-year history of progressive limb weakness due to Kennedy disease, established by genetic testing. CASE REPORT A 52-year-old man presented with a 10-year history of gradually progressive proximal limb weakness and persistently elevated creatine kinase levels ranging from 808-2300 U/L (normal 39-308 U/L). One year prior to this admission, the limb weakness had worsened, but initial electromyography, neuroimaging, and muscle biopsy showed no specific abnormalities. Despite a trial of immunosuppressive therapy due to suspected polymyositis, there was no clinical improvement. Neurological examination later revealed gynecomastia, proximal muscle atrophy, and bilateral tongue atrophy with tremor. Electromyography showed chronic neurogenic changes and reduced sensory nerve action potentials. Repeat expansion analysis identified a hemizygous pathogenic CAG repeat expansion in exon 1 of the androgen receptor gene using a short-read next-generation sequencing-based repeat detection algorithm (ExpansionHunter), with an estimated repeat number of 51 (range 50-53). At 6-month follow-up, the patient demonstrated mild progression of motor symptoms but remained functionally stable. CONCLUSIONS This report presents a rare case of Kennedy disease, initially diagnosed as polymyositis, and highlights the importance of follow-up with genetic testing when neurological and electromyography investigations are not typical for polymyositis. Early identification of Kennedy disease helps avoid unnecessary immunosuppressive treatments.

It is rare for two myositis-specific antibodies to co-exist in patients with immune-inflammatory myopathy. This overlap challenges the assumption of mutual exclusivity and may lead to conflicting diagnostic and therapeutic considerations. In this case, a 63-year-old female from the Philippines initially presented with chronic, progressive, and symmetrical proximal muscle weakness without cutaneous manifestations. Electrodiagnostic evaluation revealed a myopathic process while total creatine kinase levels were only mildly elevated. The myositis-specific antibody panel identified the presence of two distinct antibodies: anti-CN1A, which is a biomarker for inclusion body myositis, and anti-NXP2, which is specific to dermatomyositis. A muscle biopsy was performed, revealing fascicular atrophy, a characteristic feature of dermatomyositis. These findings presented a unique diagnostic challenge as dermatomyositis typically responds to immunosuppressive therapies, while inclusion body myositis is resistant to such treatments. This case illustrates the diagnostic complexity of overlapping myositis-specific antibodies and emphasizes the importance of integrating clinical, serological, and histopathological findings.

Dual ectopic secretion of adrenocorticotropic hormone (ACTH) and growth hormone-releasing hormone (GHRH) by a single neuroendocrine tumor (NET) is extremely rare. We report a 43-year-old woman presenting with acral enlargement, weight gain, hyperpigmentation, and proximal muscle weakness. Laboratory evaluation revealed elevated cortisol, ACTH, and insulin-like growth factor 1 (IGF-1), consistent with concurrent Cushing syndrome and acromegaly. Imaging demonstrated a left hilar mass, and biopsy confirmed a pulmonary NET with immunohistochemical (IHC) positivity for synaptophysin and chromogranin. Pituitary magnetic resonance imaging (MRI) showed diffuse hyperplasia, suggesting trophic stimulation rather than a primary pituitary adenoma. Surgical resection resulted in normalization of hormone levels, marked clinical improvement, and regression of pituitary enlargement. Although direct histologic confirmation of tumor-derived GHRH was unavailable, the reversible pituitary hyperplasia favors ectopic GHRH-mediated stimulation rather than primary ectopic GH secretion. IHC of the resected tumor demonstrated ACTH positivity, supporting ectopic ACTH secretion. This case highlights the importance of recognizing dual hormone-secreting NETs in patients presenting with overlapping endocrine syndromes, as early detection and complete resection can lead to remission.

Hamstring injuries are common injuries in recreational and professional athletes. Treatment of these injuries depends on various factors, including age, activity level, type of sport, and tear location such as proximal, myotendinous, muscle, or distal injuries. Proximal hamstring avulsion injuries are a different type of injury and symptoms can consist of cramping, pain, weakness, or even sciatic nerve symptoms. Over the last decade, Level III and IV retrospective cohort studies and case series have suggested an increasing role for operative repair, using either an open, endoscopic, or combined ("scopen") approach. More recently, studies have focused on ideal selection criteria for open repair and assessed factors such as age, retraction, activity level, partial versus complete tears, timing, failure of physical therapy, and whether the semimembranosus, semitendinosus, biceps femoris, or combination with conjoined tendon are involved. Overall, outcomes following surgical reattachment are encouraging and patient satisfaction is high with return to sports rates ranging between 60% and 100%. Emerging prospective cohort studies and randomized controlled trials with low crossover rates suggest that nonoperative treatment might lead to equivalent results to operative treatment, so a thorough discussion with patients on both treatments is important for these injuries.

Necrotizing dermatomyositis (NDM) represents a rare and severe inflammatory myopathy characterized by clinical features of dermatomyositis (DM) with histopathologic evidence of myofiber necrosis and minimal inflammatory infiltrates. Immune-mediated necrotizing myopathy is classically associated with anti-signal recognition particle (SRP) and anti-HMG-CoA reductase (HMGCR) antibodies; however, seronegative cases occur and may overlap with DM-specific autoantibodies such as anti-nuclear matrix protein 2 (anti-NXP2). Coexisting metabolic conditions, including hypothyroidism, may obscure the diagnosis. We report a 60-year-old woman with Hashimoto's thyroiditis who developed progressive proximal weakness and markedly elevated creatine kinase (CK) levels initially attributed to uncontrolled hypothyroidism. Despite thyroid hormone optimization, weakness persisted, and a progressive erythematous rash developed. Further evaluation revealed antinuclear antibody (ANA) positivity at 1:320, positive anti-Mi-2α/β, and markedly elevated anti-NXP2 antibodies, with negative anti-SRP and anti-HMGCR antibodies. Muscle biopsy demonstrated prominent myofiber necrosis with sparse inflammatory infiltrates, confirming NDM. High-dose corticosteroids and methotrexate resulted in gradual clinical improvement. Given the anti-NXP2 positivity, comprehensive malignancy screening was initiated. This case highlights the diagnostic challenge of distinguishing hypothyroid myopathy from inflammatory myopathy and expands the spectrum of anti-NXP2-associated disease to include SRP-negative necrotizing phenotypes. Persistent weakness or elevated CK levels despite thyroid correction should prompt evaluation for inflammatory myopathy, including myositis-specific antibodies and muscle biopsy.

Immune checkpoint inhibitors can produce severe immune-mediated toxicity involving multiple organ systems. A rare manifestation is the myocarditis, myositis, and myasthenia gravis (MMM) overlap syndrome, also referred to as triple M syndrome or immune-related MMM overlap syndrome, characterized by concurrent myocarditis, myositis, and myasthenia gravis and capable of rapid progression to life-threatening cardiac and neuromuscular complications. A 78-year-old man with metastatic melanoma developed palpitations, profound fatigue, proximal muscle weakness, diplopia, and ptosis two weeks after initiation of nivolumab and ipilimumab. Initial evaluation revealed marked elevations in high-sensitivity troponin (11,399 ng/L), creatine kinase (6,046 U/L), and transaminases, with sinus tachycardia on electrocardiography and preserved systolic function on echocardiography. Intravenous methylprednisolone was started, and immunotherapy was discontinued; however, his biomarkers continued to rise, and his condition rapidly deteriorated after transferring to a tertiary cardiac intensive care unit. He developed a complete heart block requiring transvenous pacing and subsequently demonstrated severe biventricular systolic dysfunction on cardiac imaging. Coronary angiography showed no obstructive disease. Despite escalation to pulse-dose steroids, his neuromuscular weakness worsened, and he progressed to respiratory failure requiring mechanical ventilation, followed by malignant ventricular arrhythmias and hemodynamic collapse before additional therapies, including plasmapheresis, could be initiated. Care was transitioned to comfort measures, and death occurred shortly thereafter. Endomyocardial biopsy confirmed lymphocytic myocarditis with myocyte necrosis. This case highlights that early neuromuscular symptoms accompanied by marked troponin and creatine kinase elevation may represent the first manifestations of MMM overlap syndrome and can precede rapid progression to life-threatening cardiac and respiratory complications.

Statins are among the most frequently prescribed agents in primary care for lipid control and cardiovascular risk reduction. Although generally safe, they are associated with muscle-related adverse effects, ranging from myalgia and self-limiting myopathy to the rare but clinically significant immune-mediated necrotizing myopathy (IMNM). We report a 52-year-old congenitally deaf and mute Chinese man with diabetes, hypertension, and dyslipidaemia who had been on atorvastatin since 2020 and presented with progressive proximal muscle weakness over one year, more prominent in the lower limbs, accompanied by unintentional weight loss. Communication barriers and the absence of classical features of rhabdomyolysis contributed to delayed recognition of an underlying inflammatory myopathy. Laboratory investigations revealed markedly elevated creatine kinase levels, and muscle biopsy confirmed IMNM with strong anti-HMG-CoA (anti-3-hydroxy-3-methylglutaryl-coenzyme A) reductase antibody positivity. The patient responded well to high-dose corticosteroids, with recovery of muscle strength and normalisation of enzyme levels. This case highlights a diagnostic challenge in primary care, where statin-induced myopathy is a common consideration, while statin-associated IMNM remains underrecognised in clinical practice.