Symptom onset often occurs in childhood or adolescence and complaints typically aggravate over time. Eventually, patients may seek medical attention for pain, diminished motion ranges of affected joints, and/or deformities. MRO usually affects hands or feet; more proximal parts of the limbs are the second most commonly affected anatomical structures. However, MRO has also been described in bones forming parts of the axial skeleton, namely the vertebral column, sternum, ribs and pelvis [9]. In some patients, one single bone shows pathological alterations. In other cases, symptoms are more diffuse and arise from lesions of multiple bones. Unilateral complaints are more frequently registered than bilateral MRO.

Pain may be persistent or intermittent, dull or sharp, and is often the first symptom noted. It may worsen with exercise. Compromised joints become increasingly stiff, may swell, and contractures of the respective tendons, ligaments and muscles may occur. Deformities develop slowly and may be striking. Patients may present with limbs of distinct length, twisted hands, feet, fingers or toes. Additionally, physical examination may reveal scleroderma and edema, whereby the latter results from either primary or secondary vascular anomalies. Affected skin may be hyperpigmented. Structural alterations of adjacent soft tissues may not only interfere with vessel function but can also compress nerves. This occurs rarely but may cause severe complications. In the United Kingdom, a case of disabling radiculopathy due to nerve root compression has been described [10].

• Pain

  She was regularly reviewed at both orthopaedic and pain management clinics. However, her pain worsened and in her own words she was “utterly miserable”. [doi.org]

  Dramatic pain and disability reduction occurred following lumbosacral fusion. Histologic examination was consistent with melorheostosis. Melorheostosis rarely causes severe low back pain that can respond favorably to fusion surgery. [ncbi.nlm.nih.gov]

• Asymptomatic

  It may be asymptomatic, but pain and limb deformity may occur and can be very debilitating. Different reports have indicated efficacy of bisphosphonates (pamidronate and etidronate) on symptoms. [ncbi.nlm.nih.gov]

  Patients may be asymptomatic or may experience symptoms such as stiffness, pain (typically worsened by activity), impaired joint mobility, altered limb length, deformity, and various other orthopedic, dermatologic, vascular, lymphatic, and soft-tissue [ispub.com]

  The condition, especially in childhood, is usually asymptomatic, being diagnosed as an incidental finding on radiographs obtained for another purpose 1,3. [radiopaedia.org]

• Swelling

  The swelling and periarticular fibrosis may precede the classical bony sclerosis and “dripping candle wax” appearance of radiographs. [humpath.com]

  Following treatment with bisphosphonate (30 mg/day of pamidronate for 6 days) infusion, the pain and swelling of his right foot showed improvement and his elevated serum alkaline phosphatase decreased. [ncbi.nlm.nih.gov]

• Soft Tissue Mass

  Mineralized or nonmineralized soft tissue masses should be recognized as another manifestation of this disease as opposed to a more ominous finding, making biopsy unwarrranted. [ncbi.nlm.nih.gov]

  Mineralized soft tissue masses can also have increased uptake, but nonmineralized or minimally mineralized soft tissue masses can be occult on bone scintigraphy. References Judkiewicz AM, Murphey MD, Resnik CS, Newberg AH, Temple HT, Smith WS. [roentgenrayreader.blogspot.com]

• Lymphedema

  LEMD3 gene, 12q14.3 (OMIM gene/locus number #607844 ) Phenotype Joint contractures, contractures over affected bones, sclerodermatous skin lesions, skin atrophy over affected bones, sclerotic soft tissue over affected bones, muscle atrophy, hemangiomas, lymphedema [iofbonehealth.org]

  31 pelvic bone, 32 and spine has been reported only sporadically. 33-38 Involvement of the spine is usually asymptomatic, but patients may present with severe low back pain and neurological deficits. 35-38 The overlying skin may be thickened due to lymphedema [healio.com]

• Skin Lesion

  Gene LEMD3 gene, 12q14.3 (OMIM gene/locus number #607844 ) Phenotype Joint contractures, contractures over affected bones, sclerodermatous skin lesions, skin atrophy over affected bones, sclerotic soft tissue over affected bones, muscle atrophy, hemangiomas [iofbonehealth.org]

  The skin overlying the involved bone lesion is often tense, shiny, erythematous, and scleodermatous. [ncbi.nlm.nih.gov]

• Skin Atrophy

  Gene LEMD3 gene, 12q14.3 (OMIM gene/locus number #607844 ) Phenotype Joint contractures, contractures over affected bones, sclerodermatous skin lesions, skin atrophy over affected bones, sclerotic soft tissue over affected bones, muscle atrophy, hemangiomas [iofbonehealth.org]

  They may be accompanied by abnormalities of adjacent soft tissue, including joint contractures, sclerodermatous skin lesions, muscle atrophy, or hemangiomas (review by Hellemans et al., 2004). [omim.org]

• Bone Disorder

  Melorheostosis is a non-hereditary disorder involving the bones in a segmental pattern, whereas osteopoikilosis is a rather mild disseminated bone disorder inherited as an autosomal dominant trait. [ncbi.nlm.nih.gov]

• Joint Deformity

  With adult onset, the patients most often present with pain, deformity, or limitation of joint motion. The lesion may involve one or many bones. Ectopic bone may be present in para-articular locations. [humpath.com]

  Soft tissue contracture of the limb and subsequent joint deformities were reported to represent clinical manifestations of pediatric melorheostosis. [ncbi.nlm.nih.gov]

  Usually, the initial manifestations are pain (from dull to sharp and penetrating), stiffness, limitation of joint movement or joint deformity. Pain is present in almost all cases and is usually aggravated by activity but it is rarely constant. [orpha.net]

  People with melorheostosis may also have a joint deformity (contracture) or pain. As bone tissue grows, you may also notice skin changes, including skin thickening or shininess. [my.clevelandclinic.org]

• Osteoporosis

  The book details the pathologic and radiologic characteristics of all bone and joint diseases, including arthritis, metastatic bone disease, osteoporosis, trauma, osteomyelitis, developmental bone disorders, and tumor-like lesions. [books.google.ro]

  Igor Fijalkowski, Eveline Boudin, Geert Mortier and Wim Van Hul, Sclerosing Bone Dysplasias: Leads Toward Novel Osteoporosis Treatments, Current Osteoporosis Reports, 10.1007/s11914-014-0220-5, 12, 3, (243-251), (2014). Annelise L. Dawson, Joshua M. [doi.org]

  It can be confused with arthritis, osteoporosis, spinal stenosis, or other changes that come with age. Some people only find out they have it because of an X-ray or blood test taken for a different reason. [webmd.com]

• Flexion Contracture

  We present a case of an 8-year-old boy diagnosed with melorheostosis who was suffering from severe genu valgum, permanent dislocation of the patella, knee flexion contracture and leg length shortening. [ncbi.nlm.nih.gov]

  Age Typically presents as a painless contracture before age 6 Gender Presentation Flexion contracures are common. Flexion contracture of knee is most common, followed by the ankle, hip, and fingers. [orthopaedicsone.com]

  She had significant flexion contractures of some fingers and her right elbow. An 8-year-old boy had congenital deformity of his left leg and foot caused by progressive MEL; skin atrophy affected the foot. [omim.org]

  Flexion contracture of the hip, knee, ankle, and fingers are most common. [healio.com]

• Muscular Atrophy

  Clinically, patients affected may have pain and stiffness of the involved bones, contractures when the osseous abnormality involves a joint, muscular atrophy and overlying skin changes. [iofbonehealth.org]

  Sensibility in the fingers was intact with no muscular atrophy. Laboratory tests, including complete blood count, serum phosphorus, alkaline phosphatase, calcium level, erythrocyte sedimentation rate, and C-reactive protein, were normal. [consultant360.com]

• Suggestibility

  The co-occurrence of both rare bone disorders suggests that both conditions might be related as suggested previously by Butkus et al. [1997: Am J Med Genet 72:43-46] and Nevin et al. [1999: Am J Med Genet 82:409-414]. [ncbi.nlm.nih.gov]

  Plain radiographs of pelvis and left lower limb showed peripherally located hyperostosis with ‘flowing candle wax dripping ‘ appearance in left hip and bones of left lower limb, suggestive of melorheostosis (Fig. 1-4). [ispub.com]

Plain radiography is the technique of choice to diagnose MRO. Characteristic findings are undulating bone surfaces, cortical hyperostosis and general deformities resulting from growth defects. Cortical bone typically resembles a candle marked by numerous wax droplets and this appearance has lead to alternative designations like candle bone disease or melting wax syndrome. Contrary to an ordinary candle, MRO-associated cortical defects are generally one-sided and segmental. Furthermore and as has been indicated above, unilateral MRO is much more common than bilateral bone dysplasia. In fact, the distribution pattern of sclerotic bone lesions generally corresponds to a single sclerotome. Of note, retrospective analyses have shown that only minor shares of patients show the classical, candle wax-like appearance on radiographic images [3]. In other cases, anomalies rather reminded those of osteoma, osteopathia striata or myositis ossificans. Mixed patterns were also observed. Moreover, calcifications of the overlying soft tissue are frequently seen in plain radiography.

Magnetic resonance imaging and computed tomography scans may be conducted but provide little additional information unless MRO affects the spine. Here, precise localization of MRO lesions can be much more easily achieved with those techniques than with plain radiography. Magnetic resonance imaging may also be helpful if patients present extensive soft tissue lesions. If bone scintigraphy is carried out, focal accumulation of technetium-99m has to be expected.

Laboratory analyses of blood samples, i.e., measurement of calcium, phosphorus and alkaline phosphatase, has been proven little helpful in MRO diagnosis. Those parameters are usually within reference ranges. However, more specific parameters like transforming growth factor β, osteonectin, fibronectin and fibroblast growth factor-23 may be altered [11]. This may be partially explained by the fact that MRO patients carry a LEMD3 gene which encodes for a defective protein that is unable to adequately regulate transforming growth factor β and bone morphogenic protein signaling.

• Soft Tissue Calcification

  Soft tissue calcification or ossification may be seen. Scintigraphy Scintigraphy reveals abnormal increased tracer uptake in the bone and soft tissue lesions. It may be instrumental in confriming the diagnosis in equivocal cases. [flipper.diff.org]

  Differential diagnosis includes osteosarcoma in localised forms, myositis ossificans or calcified haematoma in cases associated with soft tissue calcifications. [iofbonehealth.org]

  tissue calcifications that may resemble myositis ossificans. [roentgenrayreader.blogspot.com]

  Soft tissue calcifications are not infrequent, especially in the para-articular regions. These calcifications may progress to joint ankylosis. [ispub.com]

Specific treatment for MRO is not available, but patients may benefit considerably from symptomatic therapy. Only general recommendations can be given to this end since MRO patients may report very different complaints. These largely depend on the affected bone(s), compromised joints and soft tissues, and on the overall severity of the disease.

• Most patients require analgesics, at least during episodes of intense pain. Non-steroidal anti-inflammatory drugs are most commonly prescribed, but tend to lose efficacy over time. Steroids and opioid analgesics may constitute alternatives, but possible side effects should be considered before resorting to these compounds. In the case of intractable pain, nerve blocks or sympathectomy may become necessary [12]. The need for amputation because of MRO-induced pain has been described.
• Physiotherapy is probably helpful in all cases; it may not be sufficient if people suffer from severe MRO, though. This measure aims at improving joint motion ranges and long-term therapeutic approaches may even reduce contractures.
• In the case of severe lesions, more invasive interventions may be required. This applies particularly to patients who present with shortened limbs, deformities or contractures. Surgery may considerably improve life quality and prevent from a progression of secondary orthopedic issues like joint disorders.
• Casts, braces, and other orthopedic devices are recommended if needed.

In most cases, MRO-associated symptoms worsen over time. Causative treatment is not available. Nevertheless, medical and surgical care, physiotherapy and use of orthopedic devices usually cause symptomatic relieve and improve life quality. Despite considerable morbidity, MRO does not diminish life expectancy. Osteosarcoma and malignant fibrous histiocytoma have been reported to develop in melorheostotic bones, but due to low case numbers, a mere coincidence cannot be ruled out. Fatal outcomes have been reported very rarely. The death of a young woman diagnosed with MRO occurred after respiratory failure [8]. This patient did suffer from multiple additional pathologies, though.

Retrospective analysis of reported MRO cases revealed that most patients suffer from unilateral bone lesions that are typically restricted to a particular segment of the appendicular or axial skeleton - namely to determined sclerotomes. A sclerotome comprises those parts of a bone that are innervated by a single spinal nerve [2]. If a patient suffers from more extensive lesions, these may correspond to an involvement of multiple, generally neighboring sclerotomes. These observations imply developmental defects to account for MRO. To date, it is not known why such defects are restricted to determined sclerotomes. Mosaicism and nerve infection during embryonic development have been proposed as possible triggers [3]. These events may be related to defective intramembranous or endochondral ossification or vascular malformations. The fact that MRO patients may suffer from edema due to vascular function impairment argues for the latter hypothesis.

More recently, mutations in the LEMD3 gene have been associated with MRO. This gene encodes for an eponymous protein which fulfills regulatory functions. In detail, the LEMD3 protein is located at the inner surface of the nuclear membrane and affects transforming growth factor β, bone morphogenic protein and subsequent SMAD protein signaling [4]. These pathways regulate gene expression and thus influence cell growth, differentiation, and proliferation as well as apoptosis. Of note, LEMD3 gene mutations have also been related to other sclerosing dysplasias such as osteopoikilosis and Buschke-Ollendorff syndrome [5]. Either of those diseases may co-occur with MRO. It has to be noted though that the same authors that first described LEMD3 mutations in MRO patients refuted their own theory in a later study. The vast majority of cases is sporadic and LEMD3 mutations could no be detected in 12 unrelated patients suffering from MRO; LEMD3 germline mutations have been identified only in patients diagnosed with concurrent MRO and Buschke-Ollendorff syndrome [6].

Despite an estimated annual incidence of 0.9 per 1,000,000 inhabitants [7], only a few hundred cases have been reported to date. This apparent contradiction cannot be explained by a large share of asymptomatic patients since according to current knowledge, about 50% of affected individuals manifest symptoms during their first two decades of life.

No gender predilection has been reported.

MRO is a type of sclerosing bone dysplasia that additionally affects adjacent soft tissues. According to the above-described hypothesis, transforming growth factor β and bone morphogenic protein signaling are dysregulated due to a defective LEMD3 protein. In general, transforming growth factor β favors differentiation over proliferation and has a proapoptotic effect. Bone morphogenic proteins play important roles in embryonic skeletal formation. These facts seem to agree with a potential modification of intramembranous and endochondral ossification, but according to latest findings, LEMD3 mutations only play a minor role in MRO pathogenesis [6]. Disturbed signaling pathways are apparently not restricted to osseous tissues, and MRO patients may present considerable vascular and dermatological lesions. Unfortunately, this still leaves massive room for speculation about signaling cascades implied in MRO pathogenesis. Histopathological analyses have been conducted and may narrow down the possibilities. Respective studies revealed increases in both bone formation and bone resorption. There is abundant non-mineralized osteoid in MRO bone specimens, but osteoclast counts are also incremented. Further target-oriented research regarding MRO pathophysiology is largely dependent on the identification of the causative factors of the disease.

No specific measures can be recommended to prevent MRO.

Melorheostosis (MRO) is a rare type of bone dysplasia. Only a few hundred cases have been described so far, with first reports dating back to the early 20th century. French neurologist André Léri and his colleague Joanny published their description of a "flowing hyperostosis comprising the whole length of a member" and suggested the name that's still used today [1].

Pathologic alterations in bone structure are the most characteristic signs of MRO. Cortical thickening and superficial irregularities that remind of dripping candle wax are most typical. However, MRO does also affect the overlying soft tissues, namely tendons, muscles, vessels, loose connective tissue, and skin. Bones of hands and feet are most frequently affected and lesions generally span joints. In fact, MRO typically shows a sclerotomal distribution pattern, i.e., only parts of the skeleton innervated by a single, sensory spinal nerve show the above-described lesions.

Affected individuals suffer from muscle and joint contractures, deformities of the respective parts of the skeleton and consequent orthopedic problems and disability. Circumscribed or linear scleroderma and hyperpigmentation are also readily palpable and observable. Such signs may be noted in infants, as early as during the first few days of life, but generally manifest during childhood or adolescence. In some cases, symptom onset does not occur until adulthood.

The etiology of the disease is still unclear. The aforementioned sclerotomal distribution pattern indicates a developmental defect restricted to an individual spinal nerve. Distinct hypotheses regarding possible triggers have been proposed and recently, MRO has been related to a gene defect. However, MRO is a non-hereditary disease and if gene mutations contribute to MRO pathogenesis, they are most likely not germline mutations.

Causative treatment is not available. Depending on the severity of the disease, patients may receive analgesics, may be referred to physiotherapy or surgery. Orthopedic measures may be indicated.

Melorheostosis (MRO) is a rare type of bone dysplasia. Its precise causes are unknown, but disturbances in embryonic development are assumed to contribute to osseous lesions.

Symptom onset typically occurs during childhood or adolescence but may be observed at any age. In detail, affected individuals may claim persistent or intermittent chronic pain as well as decreased mobility of compromised joints. In more severe cases, these processes result in considerable deformities like an unequal length of limbs. These complaints result from pathological alterations of determined bones and overlying soft tissue. With regards to the latter, tendon and muscle contractures, hardening of the skin and hyperpigmentation are frequently observed.

The limbs are most frequently affected, but MRO may also account for lesions of the axial skeleton, namely the vertebral column, sternum, ribs, and pelvis. In most cases, MRO patients present unilateral symptoms that are restricted to a well-defined part of the arm or leg.

MRO diagnosis is based on plain radiography. In fact, affected bones may resemble a candle marked by numerous wax droplets - a very characteristic finding that led to the alternative denomination candle bone disease.

Treatment is symptomatic and has to be adjusted to the needs of each individual patient. In general, medication may be prescribed to relieve pain, surgery may be necessary to correct deformities. Most patients will be referred to physiotherapy in order to improve joint motion ranges.

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