Intramuscular heterotopic ossification: an unusual presentation of juvenile-onset anti-NXP2-related myopathy

Abstract

Case Presentation: A 43-year-old woman was referred to investigate complaints of myalgia and weakness. Symptoms began at 8 years old, firstly in the right arm, followed by the right leg, both accompanied by localized warmth, erythema, allodynia, and edema, without preceding trauma. Two years later, the affected extremities developed painful, indurated plaques, deemed as subcutaneous, leading to restricted range of motion. Disease remained stable, with loss to follow-up at age 14. However, new clinical activity began at age of 38, mainly with myalgia at the left leg, followed by global weakness and myalgia, diaphoresis, hair loss, and intermittent dysphagia. Symptoms improved after 10 months of prednisone 80 mg/day. At the time of referral, neurological exam confirmed restriction of motion range due to prominent indurated subcutaneous nodules in her arms and thighs, with a MRC grade 4 for elbow and knee flexion and extension bilaterally. The highest registered serum CPK levels reached 950 IU/L. X-ray examination showed calcic deposition over limbs. Further imaging assessment through limb magnetic resonance demonstrated that those calcifications were within skeletal muscles rather than in the subcutaneous tissue, predominantly in her right biceps brachii and along the flexor, adductor, and extensor muscles of the thighs. Left biceps brachii open biopsy displayed mild dystrophic changes, with no marked inflammatory findings. A comprehensive myositis panel revealed nuclear matrix protein 2 (NXP2) antibody positivity. Immunosuppressive trial with prednisone and methotrexate failed to show any motor function improvement, although there was no disease progression over the last years. Discussion: Anti-NXP2 is one of most common myositis-specific antibodies detected in patients with juvenile dermatomyositis (DM) (about 20-25%), however it is also detected among adult population, with a large spectrum of clinical picture, still in need of further recognition. Classic skin presentations of DM such as Gottron papules and heliotrope rash are less common, with a more prominent feature of subcutaneous calcinosis in up to 37% of patients. In the current report, the patient developed marked calcinosis not under skin or soft tissues, but within the muscle fibers, probably contributing to the refractory pain and restricted motion. This atypical manifestation led to a noteworthy diagnostic delay, due to overlap with other causes of heterotopic ossification, such as systemic sclerosis, chronic kidney disease with calciphylaxis, hyperparathyroidism, and progressive fibrodysplasia ossificans. Aiming a higher disease awareness, intense myalgia with severe weakness, especially in proximal limb muscles, might be an important clue that should raise an anti-NXP2 myositis as one of the diagnostic hypotheses. Final Comments: This case report suggests that an intramuscular pattern of heterotopic ossification could guide clinicians towards an anti-NXP2 myopathy diagnosis.