Melorheostosis: Clinicopathological Features, Diagnosis, and Management

Vijay Kumar Jain, MS; Rajendra Kumar Arya, MS; Minakshi Bharadwaj, MD; Satish Kumar, MS

  • Orthopedics
  • July 2009 - Volume 32 · Issue 7

No abstract available for this article.

Melorheostosis is a rare, non-familial sclerosing bony dysplasia of poorly understood etiology. It was first described by Leri and Jonny1 in 1922. It is characterized by soft tissue contractures with overlying slowly evolving linear hyperostosis. It usually occurs in the limbs and frequently crosses synovial joints, and there is often ossification in local soft tissues.2-5

The term Melorheostosis is derived from the Greek melos, meaning limb, and rheos, which means flow. Melorheostosis is a mixed sclerosing dysplasia with disturbance of both endochondral and intramembranous ossification, in which disordered intramembranous ossification dominates.6

Melorheostosis has an incidence of 0.9 in 1 million and affects men and women equally.7,8

Clinical Features

The typical presentation is painless, asymmetric joint contracture prior to age 6 years, however, patients can present at any age with various symptoms, including pain, limb swelling, and restricted range of motion of extremity due to soft tissue contracture. The cause of pain associated with melorheostosis is not known. In children, unlike in adult patients, pain occurs infrequently and disease progression occurs more slowly.9 In 40% to 50% of cases, the disorder is evident by age 20 years.10 Age at presentation of melorheostosis varies widely, from 2 to 64 years.11,12

Although melorheostosis can affect any bone, the lower extremities are more frequently involved.2 Most reported cases involving the upper extremity are focused on the hand.13-22 Melorheostosis of the hand has been associated with bony spur formation and is complicated by an inflamed bursa.23 Other symptoms such as stiffness, swelling, numbness, tingling, carpal tunnel syndrome, and a slowly growing desmoid tumor of the soft tissues of the hand have also been reported.20,21,24 Involvement can encompass 1 bone (monostotic), more than 1 bone (polyostotic), or 1 extremity (monomelic).3 Involvement of the skull, facial bones,25-28 ribs,29,30 scapula,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, tense, erythematous, and shiny. Other changes in soft tissue include anomalous pigmentation, induration and edema of the subcutaneous tissues, periarticular fibrosis, weakness and atrophy of muscles, perivascular fibrosis with obliteration of blood vessels, and linear scleroderma.4,9,19,39-49 Soft tissue masses are a recognized feature of melorheostosis. Murray and McCredie50 reported mineralized soft tissue masses in 8 of 30 patients (27%) in their series. These masses are not always contiguous with hyperostotic cortex, nor are they always mineralized. These changes precede the bone abnormalities and may rarely be evident at birth. Because the abnormal ossifications frequently involve the soft tissues and extend into the joints, the latter often exhibit a restricted range of motion as the result of joint contracture and periarticular fibrosis and mechanical block.37

Judkiewicz et al51 reported that intra-articular extension of melorheostosis occurred in 35% of patients, and this finding may be associated with mineralization of the articular cartilage or with mechanical cartilage damage. It is also known that the longer the intervention is delayed, the more contracted the muscles become, and the articular cartilage may also degenerate. Synovitis of the joint further impairs joint motion.

Younge et al9 noted that the soft tissue contractures and periarticular fibrotic changes seen in patients with melorheostosis resemble those seen in patients with arthrogryposis multiplex congenita. Flexion contracture of the hip, knee, ankle, and fingers are most common. Other deformities are also common, including genu valgum, contractures of the Achilles tendon, varus or valgus deformities of the feet, overlapping toes, and patella dislocation.2,3,9 Limb-length discrepancy results from physeal abnormalities leading to shortening or, less commonly, lengthening of the affected limb. Growth disorders of the limbs are often the first sign in children. Younge et al9 reported a mean of 4 cm shortening in a study of 11 patients.

Table 1: Vascular and Lymphatic Lesions Associated With Melorheostosis

Melorheostosis with heterotopic ossification in the popliteal region without peroneal nerve involvement has been described.5 It has been suggested that contact with the nerve inhibits bone formation and subsequent invasion. It indicates that certain nerve structure or nerve secretions may inhibit bone growth into the nerve.

Kidney abnormalities, including minimal change disease and renovascular hypertension secondary to renal artery stenosis, have been described.52,53

Few isolated cases of osteosarcoma54-56 and a case of malignant fibrous histiocytoma57 have been reported with melorheostosis. Brennan et al55 reported a case of osteosarcoma superimposed on a mixed sclerosing dysplasia. Vascular lesions associated with melorheostosis include hemangiomas, vascular nevi, varices, glomus tumors, arteriovenous malformations, and aneurysms (Table 1).52,58-61 Anomalies associated with malformations of blood vessels or lymphatics are described with melorheostosis, suggesting an inherent defect in angiogenesis.59 Recently a case of melorheostosis in association with tricho-dento-osseous syndrome has been encountered.62 Neurofibromatosis, tuberous sclerosis, rheumatoid arthritis, and hypophosphatemic rickets have been described in patients with melorheostosis.63-66

Laboratory Findings

Serum calcium, phosphorus, and alkaline phosphatase levels have been reported to be within normal limits in melorheostosis.

Laboratory abnormalities reported in association with bone and soft tissue lesions of melorheostosis affect osteoblastic specific factor-2 (osf-2), osteonectin, fibronectin, transforming growth factor-β (TGF-β), and fibroblast growth factor-23 (FGF-23).67

Etiology

The etiology of this disorder is unknown. It ranges from vascular insufficiency to failure in intramembranous and, to a lesser extent, endochondral ossification. It has been observed that distribution of the lesions corresponds to sclerotomes that are supplied by individual spinal sensory nerve. Thus diseases of the spinal nerve lead to “bone scarring” along its segmental distribution.3,50,68 This hypothesis partially explains the peculiar tendency toward monomelic involvement in melorheostosis and its distribution in a linear track, regardless of the divisions of bone and joint. Freyschmidt2 suggested that it is a form of mosaicism rather than early embryonic infection of the sensory nerve, in which the disorder could be due to the action of a lethal gene that survives only in a mosaic state.

Mosaicism is a better explanation for the sporadic occurrence, the asymmetric “segmental” pattern with variable extent of involvement, and equal gender ratio of the disease. The sporadic occurrence of osteopoikilosis with melorheostosis has been reported and raises the possibility that 2 disorders may be related. This condition is also referred to as “overlap syndrome” or “mixed sclerosing bone dystrophy.”69-73 Alterations in adhesion proteins big-h3 expression appear to cause the skin and bone lesions in patients with melorheostosis in view of the downregulation of human transforming growth factor β induced gene product (betaig-h-3) in skin fibroblasts from affected regions.74

Other theories propose a vascular disorder, inflammation, a degenerative lesion of the connective tissue, and embryonic damage as etiopathogenic factors. Melorheostosis of sclerotome in association with synchronous multicentric fibromatosis has been reported in the literature, suggesting a similar underlying pathogenesis for both diseases.68

Figure 1A: Radiographs showing the ulna Figure 1B: A 26-year-old woman who had melorheostosis
Figure 1: Radiographs showing the ulna of a 26-year-old woman who had melorheostosis.

Recent studies have reported loss of function mutations in the LEMD3 gene, encoding an inner nuclear membrane protein that influences Smad signaling, as a cause of osteopoikilosis, Buschke-Ollendorff syndrome, and melorheostosis.75 Another group demonstrated that this gene codes for an inner nuclear membrane protein that normally inhibits both transforming growth factor and bone morphogenic protein, the upregulation of which could be responsible for the clinically observed phenotypes in these conditions. Loss-of-function mutation of MAN1 gene has also been reported for the pathogenesis.76 Hellemans et al,75 however, show that no such mutations were observed in isolated and sporadic cases of melorheostosis, which suggests that the genetic basis still remains unknown.

Radiographic Features

The lesions tend to be segmental and unilateral. In cases where the disease is bilateral, there have been no reports of symmetry. The classic radiographic feature of melorheostosis is asymmetrical bands of sclerosis in an irregular, linear pattern often described as molten wax dripping down from one side of a candle (Figure 1). Other patterns with extraosseous involvement (myositis ossificans type), osteopathia striata-like, an osteoma-like as well as a mixed pattern have been described. There is usually a distinct demarcation between the affected bone and normal bone. Most typically, the outer bony cortex is affected, but extension into the cancellous bone is also seen. In children the hyperostosis is endosteal, marked by streakiness of the long bones and spotting of the small bones, whereas in adults it is in an extracortical, subperiosteal location.9 Four types have been described depending on the clinical situation: monostotic, with only 1 bone; polyostotic, with multiple bones; monomelic, with 1 limb and generalized, with generalized skeletal involvement.2,3,6,9,12 Diaphyses of long bones are more commonly involved. Other sites include the pelvis and bones of hands and feet (Figure 2). The ribs, and the craniofacial complex are affected least often.25-30 Melorheostosis limited to the isolated spine is rare and is usually associated with multiple-rib involvement.

Figure 2A: Endosteal melorheostotic lesion in the first metatarsal Figure 2B: Endosteal melorheostotic lesion in the first metatarsal Figure 2C: Endosteal hyperostosis

Figure 2: Oblique (A) and AP (B) radiographs of the foot showing endosteal melorheostotic lesion in the first metatarsal in a patient with phalangeal fractures. AP radiograph of the hand reveals endosteal hyperostosis (C).

Melorheostosis affecting thoracic vertebrae with involvement of facet joints associated with back pain has been described recently.35 The epiphyses and the carpal and tarsal bones often exhibit hyperostosis in the form of more discrete rounded spots and patches similar to the changes observed in osteopoikilosis.3 In contrast to the irregular shape of lesions typically seen in long bones, nonmineralized soft tissue masses associated with melorheostosis can be difficult to assess on radiographs and bone scintigraphy and, if not recognized as a manifestation of this disease, may be confused with a more ominous soft tissue sarcoma.12

Figure 3: Characteristic candle wax lesion in the ulna
Figure 3: MRI of the forearm showing characteristic candle wax lesion in the ulna.

Radionuclide bone scanning is a useful method to distinguish a focus of melorheostosis from other lesions.77 In melorheostosis, focal increased radiopharmaceutical accumulation appeared in each radiographically abnormal area on Technetium-99m pyrophosphate bone scan. The factors responsible for uptake may include increased mass of the cortex, osteoblastic activity, local hyperemia, presence of immature collagen, and changes in capillary permeability.77-82

On magnetic resonance imaging (MRI), there is decreased signal intensity localized to affected bone on all pulse sequences (Figure 3).83 Computed tomographic (CT) scanning reveals its clear demarcation from normal bone more effectively (Figure 4).30 Computed tomography and MRI help confirm and accurately localize the zones of hyperostosis in the spine and provide assessment of the degrees of narrowing of the spinal canal and foramina.35 Further, although the MRI appearance of soft tissue masses associated with melorheostosis is variable, advanced imaging allows visualization of mineralized and nonmineralized soft tissue.83 Magnetic resonance images are useful in understanding the soft tissue pathoanatomy in melorheostosis and planning surgical correction. On MRI, an inflamed bursal collection adjacent to the spur can be seen.23 Ossification of the glenoid labrum and presence of a cartilage cap over a portion of the sclerotic bone seen on CT scan has been recently described.39

Figure 4A: Well-demarcated sclerotic thickening of the ulna Figure 4B: Well-demarcated sclerotic thickening of the ulna Figure 4C: Well-demarcated sclerotic thickening of the ulna Figure 4D: Well-demarcated sclerotic thickening of the ulna

Figure 4: CT scan showing well-demarcated sclerotic thickening of the ulna. Three-dimensional (A), coronal (B), axial (C), and sagittal view

Histopathology

Histological analysis reveals dense bone without distinctive cellular abnormalities; however, the microscopic appearance of lesions is not identical in all cases. Histologic findings include variable degrees of cortical thickening (Figure 5A) consisting of chondroid islands surrounded by woven or non-lamellar dense bone depending on stage of maturation with thickened, sclerotic, and irregular lamellae. An adjacent zone of fibrocartilage with irregular surface fibrillation is also observed. A large quantity of osteoid without mineralization suggests overproduction of bone matrix in affected bone. However, osteoclasts are more numerous, reflecting increased bone resorption (Figure 5B). This indicates that increased bone formation and bone resorption are combined processes in melorheostosis. Soft tissue abnormalities consisting of osseous, chondroid, vascular, and fibrocartilaginous tissue have been reported in 76% of cases of melorheostosis.3,84,85 Rarely, presence of a cartilage cap over a portion of the sclerotic bone has been described in intra-articular melorheostosis, and that could lead to misinterpreting the lesion as an osteochondroma, a bizarre parosteal osteochondromatous proliferation, or an even more concerning parosteal osteosarcoma.39

Figure 5A: Photomicrograph showing hyperostotic cortical bone trabeculae of varying thickness Figure 5B: Photomicrograph showing hyperostotic cortical bone trabeculae of varying thickness

Figure 5: Photomicrograph showing hyperostotic cortical bone trabeculae of varying thickness, hematoxylin-eosin ×40 (A), and osteoclastic activity, hematoxylin-eosin ×40 (B).

Cells immunopositive for TGF β and bFGF are densely present in melorheostotic bone. Both of these cytokines are osteogenic and angiogenic, so it is possible that these cytokines play a role in increased bone formation and increased angiogenesis.84 The bone marrow cavity can sometimes be compromised. Pathologically nonmineralized soft tissue masses associated with melorheostosis may contain osseous, chondroid, fibrolipomatous, and vascular components with a “cap” of hyaline cartilage covering portions of the lesion.39 Increased expression of procollagen alpha1 (I) mRNA expression and alpha1(I), alpha2(I), and alpha1(III) collagen secretion has been observed in dermal fibroblasts obtained from a skin biopsy overlying the involved bone.86

Differential Diagnosis

Radiologically, differential diagnoses of melorheostosis include chronic osteomyelitis, osteopetrosis, osteopoikilosis osteopathia striata, and infantile cortical hyperostosis (Table 2).3,6 Mixed sclerosing dysplasia or overlap syndrome comprises melorheostosis and osteopoikilosis and/or osteopathia striata in a single patient.87 Focal scleroderma may cause soft tissue fibrosis and contractures with radiologically normal bones. Single lesions may be mistaken for a mature focus of myositis ossificans, osteoma, or parosteal osteosarcoma (Table 3). Conditions that produce a calcified or ossified para-articular mass such as synovial osteochondromatosis, extraskeletal osteosarcoma, calcified synovial sarcoma, or tumoral sclerosis must also be kept in differential diagnosis.6

Table 2: Clinicoradiological Differences Between Hyperstotic Bone Conditions

Table 3: Differential Diagnosis of Melorheostosis

Treatment

There is no specific treatment for this condition. Therapy is mainly symptomatic. Patient symptoms vary considerably with melorheostosis, and consequently treatment should be individualized depending on the age and location. In children, presentation of melorheostosis is more likely to be limb-length discrepancy, deformity, or joint contractures, while adults typically present with pain, joint stiffness, or a progressive deformity.9 The primary goals of treatment are pain relief and restoration of full range of motion. Medical treatment is recommended to control bone pain. Conservative measures include analgesia, manipulation, braces, serial casting, physiotherapy and nerve blocks, and sympathectomy.3,9,88 Surgical treatment comprises soft tissue release, capsulotomies, fasciotomy, and tendon lengthening. Bony procedures involve correction of deformity by corrective osteotomy, arthroplasty, Ilizarov lengthening, epiphysiodesis, excision of hyperostotic bone, arthrodesis, and amputation.3,9,39,40,89-92

Several case reports with only 1 exclusive large study address the natural history and management of melorheostosis in children.9 Younge et al9 found only 1 soft tissue release resulting in permanent correction of 16 attempted on 12 pediatric patients. They emphasized that recurrence of deformity after soft tissue release or osteotomy is the rule, resulting in a short deformed limb. Soft tissue contracture and periarticular fibrosis in melorheostosis have been noted to be similar to those seen in arthrogryposis multiplex congenita. These tissues are stiff and do not stretch with growth, thus causing recurrence of deformity. Fixed contractures should be treated with radical release with wide capsulotomies and tendon resections rather than by tendon lengthening alone. Also the surgically treated limb should be braced throughout the growth period.9 Since melorheostosis is a progressive condition, surgical intervention should be deferred until the child approaches skeletal maturity to avoid additional procedures later.16

Campbell et al3 found recurrence of deformity in 5 of 8 joints in 5 patients.

Pruitt and Manske19 described 28 surgeries on a single patient to correct various deformity and complications with no success. The authors hypothesized that the patient should use the unaffected extremity as a dominant hand in the early course of the disease. Gradual correction of deformity with the Ilizarov technique is recommended by some authors.89-91 The Ilizarov technique has been used in a small number of children for lengthening and realignment of angular deformities and correction of joint contractures. Atar et al89 successfully treated the contracture of knee and limb-length discrepancies in a female child using this method. In addition, Choi et al91 treated a young patient with recurrent equinoplanovalgus deformity of the foot using the Ilizarov technique, including distraction osteotomy in the calcaneus.

Non-consolidation or pseudoarthrodesis has been reported as a complication by Griffet et al90 in a child after use of the Ilizarov technique. Epiphysiodesis of the opposite limb has been used to correct inequality in children. Discrepancy in limb length and inhibition of growth should be carefully recorded in a child so that epiphysiodesis may be planned at the appropriate time to correct the inequality.9 Younge et al9 concluded that shortening is the safer technique because of possible problems with distal ischemia. An epiphysiodesis for limb-length discrepancy is not indicated in cases where the discrepancy is <2>93 Incomplete correction or rapid recurrence of deformities are frequent and may necessitate amputation in children.3,9

Limb-length inequality has also been described in an adult patient. Marshall and Bradish94 performed callotasis to gain limb shortening in 1 patient. The regenerated bone had the radiological appearance of the original bone.

In adults, pain is common and is treated with analgesics. Peripheral vascular disturbances may be responsible for the pain associated with this disorder. Semble et al95 showed successful symptomatic improvement in pain and vasomotor function after treatment with nifedipine. Furthermore, those patients who presented with elevated serum alkaline phosphate and swelling reported relief with bisphosphonate. Pamidronate is used most commonly, followed by etidronate. Donath et al96 treated a polyostotic form of melorheostosis with intravenous pamidronate. Bisphosphonates are the most effective inhibitors of bone resorption. They inactivate osteoclasts, which then undergo apoptosis, resulting in reduced bone resorption, lower bone turnover, and a positive bone balance. Because bisphosphonates reduce elevated bone resorption regardless of cause, they are used to treat inflammation-related bone loss.96-98

Other symptoms such as joint stiffness or a progressive deformity are managed according to the site and extent of involvement. The results of an extensive search suggest that monomelic forms are treated commonly with conservative and surgical treatment by surgical debulking depending on the location of disease and type of symptoms. Polyostotic lesions should require conservative treatment, as the disease is progressive and extensive surgeries may lead to disability.

Bone pain and spinal stenosis with myelopathy and neurological involvement require decompression surgeries to relieve the pressure on the neural components, followed by arthodesis.37 Robertson et al36 treated lumbosacral melorheostosis by fusion. Recovery of neurologic function seems to be favorable in patients with melorheostosis-associated myelopathy.38

Melorheostosis of the hand is usually treated conservatively. Since it is a progressive condition, surgical intervention should be delayed and patients should be encouraged to use the unaffected extremity in a dominant fashion.16 Conservative treatment with pain management and daily life modifications seem to be all that is necessary for asymptomatic cases. Patients with severe and complicated forms of the disease may require surgery.

Positive results have been reported in cases where bone spur formation or soft tissue masses were responsible for the major complaints.23 Surgical debulking of the hyperostotic cortex resulted in correction of the deformity and relief of pain. Sharma and Burke16 successfully treated the pain by surgical debulking of the lesion in the proximal phalanx. Involvement of the median nerve in carpal tunnel requires decompression.21 Barfred and Ipsen20 successfully treated a case of congenital carpal tunnel syndrome associated with melorheostosis with a sural nerve graft after total degeneration of the median nerve.

Involvement of the foot usually requires corrective shoes and/or custom-made orthosis support to relieve pain and correct deformity.88,93 Severe cases may be treated with surgical debulking, contracture releases, plantar fasciectomy, tarsal osteotomy, triple arthrodesis, Ilizarov technique, and amputation of involved toes.3,9,91

Involvement of joints due to extension of cortical hyperostosis or a mass into adjacent joints have been described, resulting in contracture and mechanical block of the joint. Various procedures have been described with limited success. Moulder and Marsh40 described a patient with soft tissue contracture of the knee for which they used arthroscopic attempts. The patient was successfully treated with total knee arthroplasty, which resulted in good range of movement.

Gong et al99 successfully treated a case of elbow contracture with soft tissue release alone. Only 1 case described in the literature that had mechanical obstruction to shoulder joint motion from melorheostosis treated successfully with total joint arthroplasty.39 Rooney et al100 described the arthroscopic removal of a loose body causing locking symptoms in the knee. Involvement of ribs is rare with melorheostosis. Recently Chanda and Millner30 suggested that thoracic lesions are best dealt with surgical resection of the involved rib to relieve pain. Amputation has been used as a last resort for severe pain management and progressive and recurrent deformities.3,9,92

Prognosis

The prognosis of a patient with melorheostosis is variable and depends on the anatomical location, extension into the soft tissues, and soft tissue changes. Melorheostosis does not shorten life span, however, morbidity may be considerable. The disease exhibits a slow, chronic course, with periods of exacerbation and arrest. Recurrence usually is expected after operative excision.3,9

Conclusion

Although melorheostosis is benign in nature, chronic pain and deformity can be debilitating. Surgical intervention is advocated in chronic debilitating symptoms. Successful resection of these lesions can translate into near complete resolution of the symptoms.

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Authors

Messrs Jain, Arya, and Kumar and Dr Bharadwaj are from the Departments of Orthopedics and Pathology, Ram Manohar Lohia Hospital, New Delhi, India.

The material presented in any Vindico Medical Education continuing education activity does not necessarily reflect the views and opinions of Vindico Medical Education or Orthopedics. Neither Vindico Medical Education or Orthopedics nor the authors endorse or recommend any techniques, commercial products, or manufacturers. The authors may discuss the use of materials and/or products that have not yet been approved by the US Food and Drug Administration. All readers and continuing education participants should verify all information before treating patients or using any product.

The authors thank Dr S.C. Diwedi, Professor and Head, Department of Radiodiagnosis, Subharti Medical College, Meerut, and Dr Yashwant Singh, Department of Radiodiagnosis, Dr Ram Manohar Lohia Hospital, New Delhi, India, for providing radiology images.

Correspondence should be addressed to: Vijay Kumar Jain, MS, Department of Orthopedics, Dr Ram Manohar Lohia Hospital, New Delhi, 110001, India.

DOI: 10.3928/01477447-20090527-20

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