Melorheostosis

Melorheostosis is a sporadic disease of uncertain etiology characterized by asymmetric bone overgrowth and functional impairment. Using whole exome sequencing, we identify somatic mosaic MAP2K1 mutations in affected, but not unaffected, bone of eight unrelated patients with melorheostosis. The activating mutations (Q56P, K57E and K57N) cluster tightly in the MEK1 negative regulatory domain. Affected bone displays a mosaic pattern of increased p-ERK1/2 in osteoblast immunohistochemistry. Osteoblasts cultured from affected bone comprise two populations with distinct p-ERK1/2 levels by flow cytometry, enhanced ERK1/2 activation, and increased cell proliferation. However, these MAP2K1 mutations inhibit BMP2-mediated osteoblast mineralization and differentiation in vitro, underlying the markedly increased osteoid detected in affected bone histology. Mosaicism is also detected in the skin overlying bone lesions in four of five patients tested. Our data show that the MAP2K1 oncogene is important in human bone formation and implicate MEK1 inhibition as a potential treatment avenue for melorheostosis.

Background and Objectives: Melorheostosis, also referred to in the literature as Leri's disease, is an unusual mesenchymal dysplasia with the clinical appearance of benign sclerosing bone dysplasia; it frequently occurs in late adolescence. Any bone in the skeletal system can be affected by this disease, though the long bones of the lower extremities are the most common, at any age. Melorheostosis has a chronic evolution, and symptoms are usually absent in the early stages. The etiopathogenesis is still unknown, however, numerous theories have been proposed that could explain the appearance of this lesion formation. An association with other benign or malignant bone lesions is also possible, and associations with osteosarcoma, malignant fibrous histiocytoma, or Buschke-Ollendorff syndrome have also been reported. There have also been reported cases of the malignant transformation of a pre-existing melorheostosis lesion into malignant fibrous histiocytoma or osteosarcoma. The diagnosis of melorheostosis can be made only based on radiological images, but, due to its polymorphism, additional imaging investigations are often necessary and sometimes only a biopsy can establish a definite diagnosis. Because there are currently no guidelines for treatment based on scientific evidence, due to the low number of cases diagnosed worldwide, our objective was to highlight the early recognition and specific surgical treatments for better prognosis and outcomes. Materials and Methods: We conducted a review of the literature consisting of original papers, case reports, and case series and presented the clinical and paraclinical characteristics of melorheostosis. We aimed to synthesize the treatment methods available in the literature as well as determine possible future directions related to the treatment of melorheostosis. Furthermore, we presented the results of a case of femoral melorheostosis admitted to the orthopedics department of the University Emergency Hospital of Bucharest in a 46-year-old female patient with severe pain in the left thigh and limitation of joint mobility. Following the clinical examination, the patient complained of pain in the middle third of the left thigh in the antero-medial compartment; the pain appeared spontaneously and was aggravated during physical activity. The pain started about two years prior, but the patient experienced complete pain relief after the administration of non-steroidal anti-inflammatory drugs. In the last six months, the patient presented an increase in pain intensity without significant improvement following the administration of non-steroidal anti-inflammatory drugs. The patient's symptoms were mainly determined by the increase in the volume of the tumor and the mass effect on the adjacent tissues, especially on the vessels and the femoral nerve. The CT examination and bone scintigraphy showed a unique lesion in the middle third of the left femur and no oncological changes in the thoracic, abdominal, and pelvic regions; however, at the level of the femoral shaft, there was a localized cortical and pericortical bone lesion formation that surrounded approximately 180 degrees of the femoral shaft (anterior, medial, and lateral). It had a predominantly sclerotic structure but was associated with lytic areas with thickening of the bone cortex and areas of periosteal reaction. The next therapeutic gesture was to perform an incisional biopsy using a lateral approach at the level of the thigh. The histopathological result supported the diagnosis of melorheostosis. Additionally, immunohistochemical tests completed the data obtained after the microscopic examination through the classic histopathological technique The patient was discharged and included in a full medical recovery program for eight weeks in a specialized medical center, during which she also received analgesic treatment in maximum doses, but without improvement regarding her symptoms. Taking into account the chronic evolution of the pain, the complete lack of response to conservative treatment after eight weeks, and the lack of treatment guidelines in the case of melorheostosis, a surgical approach needed to be considered. The surgical option in this case, considering the circumferential location of the lesion at the level of the femoral diaphysis, was a radical resection. The surgical approach consisted of segmental resection to healthy bone tissue and reconstruction of the remaining defect with a modular tumoral prosthesis. At the 45-day postoperative control, the patient no longer complained of pain in the operated-on limb and was mobile with full support without gait difficulties. The follow-up period was one year, and the patient presented complete pain relief and a very good functional outcome. Results: In the case of asymptomatic patients, conservative treatment seems to be a good option with optimal results. However, for benign tumors, it remains unclear whether radical surgery is a viable option. Conclusions: Melorheostosis remains an incompletely understood disease, given the limited number of cases worldwide, and thus, there is a lack of clinical guidelines regarding specialized treatment.

BackgroundA 20-year-old Danish woman with melorheostosis in her right femoral shaft and disabling pain in the affected area, whose symptoms did not in the long term respond to zoledronic acid, experienced continuous remission of pain after treatment with denosumab. To the best of our knowledge, this is the first case report on denosumab treatment for melorheostosis.Case presentationRadiologic findings and bone biopsy showed irregular cortical hyperostosis in the right femoral shaft with increased tracer uptake on Tc99-bone scan. The diagnosis of melorheostosis was made based on the radiological findings. There was a good initial response to zoledronic acid administration, but after relapse of pain, the second and third administrations had a poor effect. As a second line of treatment denosumab was administered at 8-week intervals, the frequency was based on our patient's symptoms and on biochemical markers of bone turnover.ConclusionThis is the first report indicating that denosumab has a place in the treatment of melorheostosis when the effect of bisphosphonate treatment is insufficient.

Melorheostosis is a rare sclerosing bone dysplasia that can clinically and radiologically mimic common bone disorders, particularly in atypical presentations. Its heterogeneous manifestations and limited awareness among clinicians frequently contribute to diagnostic delays or misdiagnosis. We report the case of a 34-year-old woman with chronic forearm pain and a longstanding subcutaneous mass. She was initially misdiagnosed as having a metabolic bone disorder based on imaging and histopathology. However, subsequent evaluation with MRI and bone scintigraphy demonstrated eccentric cortical thickening and longitudinal sclerotic lesions involving the radius, olecranon, and first metacarpal. Normal biochemical markers and the absence of systemic involvement further supported a diagnosis of melorheostosis. Histopathological re-examination confirmed lamellar cortical bone with osteoblastic rimming but remained nonspecific. This case underscores the importance of considering melorheostosis in the differential diagnosis of sclerosing bone disorders, especially when radiographic features are ambiguous. It highlights the critical role of multimodal imaging in establishing an accurate diagnosis, while histopathology provides complementary but not definitive evidence. Importantly, melorheostosis may also serve as a window into bone physiology, illustrating aberrant osteogenesis and dysregulated cortical remodeling. A better understanding of its molecular basis, particularly MAPK pathway alterations, may ultimately facilitate more targeted and effective treatments.