Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study

Abstract

Melorheostosis is a rare dysostosis involving cortical bone overgrowth that affects the appendicular skeleton. Patients present with pain, deformities, contractures, range of motion limitation(s), and limb swelling. It has been described in children as well as adults. We recently identified somatic mosaicism for gain-of-function mutations in MAP2K1 in patients with melorheostosis. Despite these advances in genetic understanding, there are no effective therapies or clinical guidelines to help clinicians and patients in disease management. In a study to better characterize the clinical and genetic aspects of the disease, we recruited 30 adults with a radiographic appearance of melorheostosis and corresponding increased uptake on ¹⁸F-NaF positron emission tomography (PET)/CT. Patients underwent physical exam, imaging studies, and laboratory assessment. All patients underwent nerve conduction studies and ultrasound imaging of the nerve in the anatomic distribution of melorheostosis. We found sensory deficits in approximately 77% of patients, with evidence of focal nerve entrapment in five patients. All patients reported pain; 53% of patients had changes in skin overlying the affected bone. No significant laboratory abnormalities were noted. Our findings suggest that patients with melorheostosis may benefit from a multidisciplinary team of dermatologists, neurologists, orthopedic surgeons, pain and palliative care specialists, and physical medicine and rehabilitation specialists. Future studies focused on disease management are needed. © 2019 The Authors. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Keywords: CANDLE‐WAX DISEASE; LERI'S DISEASE; MAP2K1; SCLEROTIC; SOMATIC MOSAIC.

Figure 1

Imaging appearance of melorheostosis. (i) 36‐year‐old woman (Melo‐22) with irregular radial growth of her left leg, (ii) demonstrating classic candle‐wax appearance of the left fibula and lateral three digits on radiograph. (iv) MIP PET ¹⁸F‐NaF image of her lower extremities showing three small foci of abnormal uptake in the left distal thigh (red arrows), and intensely increased activity in the left lateral femoral condyle (yellow arrow) as well as in the entire left fibula extending to the foot (black arrows). (v, vi) Axial CT and fused ¹⁸F‐NaF PET/CT images showing ¹⁸F‐NaF avid focal extraosseous lesions laterally (SUV_max: 5.32) and posteriorly (SUV_max: 15.8) to the femur. (v, vi) Axial and coronal CT and fused ¹⁸F‐NaF PET/CT images showing hyperostosis throughout the left fibula extending to the foot, associated with intensely increased ¹⁸F‐NaF activity (SUV_max: 42.5). MIP = maximum intensity projection.

Figure 2

Study design. Flowchart depicts the design for inclusion in the study. All adults with a radiographic appearance of melorheostosis and corresponding increased ¹⁸F‐NaF uptake were included in the study. MEL = melorheostosis.

Figure 3

Radiographic progression in melorheostosis. (A) Comparison of radiographs from 2004 (left) and 2014 (right) showing progression of both skeletal and extraosseous lesion of melorheostosis (Melo‐21; MAP2K1 mutation negative). (B) Comparison of radiographs from 2010 (left) and 2015 (right) showing evidence of disease progression in the extraosseous lesion around patient's right hip joint (Melo‐6; MAP2K1‐mutation positive).

Figure 4

Neurologic consequences of melorheostosis. (A) Ultrasonogram imaging showing hypervascularity of the hyperostotic bone cortex (white box). (B) Ultrasonogram imaging (Melo‐10) showing hyperostotic bone (white arrows) with focal entrapment of the saphenous nerve (blue circle). The entrapped nerve was the likely cause of patient's pain, numbness, and tingling.