• Disease Overview
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
  • Programs & Resources
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Melorheostosis

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Last updated: 01/09/2024
Years published: 2006, 2014, 2017, 2021


Acknowledgment

NORD gratefully acknowledges Kristina Bundra, Pharm. D, NORD Editorial Intern, and Geert Mortier, MD, PhD, Chair, Department of Medical Genetics, University Hospital Antwerp and Professor of Medical Genetics, University of Antwerp, Belgium, for assistance in the preparation of this report.


Disease Overview

Melorheostosis is a rare and progressive disease characterized by thickening or widening (hyperostosis) of the outer layers of the bone (cortical bone).

Melorheostosis affects both bone and soft tissue growth and development. This disorder is benign (noncancerous), but it often results in severe functional limitation; chronic pain; joint contractures and/or stiff muscles, tendons or ligaments and limb, hand, or foot deformities.

Melorheostosis can be an isolated disorder or can be part of several genetic syndromes.

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Signs & Symptoms

Melorheostosis usually affects a single arm or leg (segment of the appendicular skeleton) and rarely affects both sides of the body. This condition is usually restricted to the inside (medial) or outside (lateral) of the bones. The disease can also affect the axial skeleton: pelvis, sternum, ribs and, more rarely, the spine and skull. Symptoms may progressively worsen over time. Signs and symptoms of melorheostosis may include:

  • Irregular bone growth, including cortical thickening and “dripping candle wax” appearance on x-ray images (this sign appears as irregular hyperostosis of the cortical bone which looks like melted wax flowing down one side of a candle)
  • Limb-length discrepancy (when one leg or arm is shorter than the other leg or arm)
  • Soft tissue abnormalities including:
    • Shortening of tendons and ligaments
    • Absent or abnormal muscles
    • Calcium buildup in tissues (subcutaneous calcification)
    • Joint swelling and contractures leading to malformed or immobilized joints
  • Limited range of motion
  • Pain and stiffness
  • Swelling (edema) of the legs and arms (extremities)
  • Vascular anomalies
  • Nerve compression from bone injuries (less common but serious)

In children, the most obvious symptom is the limb-length discrepancy with deformed joints and joint contractures.

In adults, symptoms of pain, joint stiffness and progressive deformity are more evident.

Melorheostosis has a chronic course. The severity of onset and symptoms varies greatly in children and adults but in general, symptoms begin in young children and may even manifest in the first days of life. About 50% of people affected with melorheostosis will develop symptoms by age 20.

Complications are related to the extension of the injury to the adjacent soft tissues and to the bone deformity and damage of the bone structure. The risk of tissue cells becoming cancerous (secondary malignant transformation) has also been reported.

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Causes

Melorheostosis is usually an isolated disorder. However, it has also been observed in some families with osteopoikilosis or Buschke-Ollendorff syndrome due to a change (mutation or pathogenic variant) in the LEMD3 gene.

Because melorheostosis appears sporadically without reports of being passed down from parents to children and because there is a localized distribution of bone lesions, this disease may be due to a somatic mutation. Somatic mutations are changes in DNA that occur after conception, so they are not present in eggs or sperm and are not passed down from parent to child.

Somatic mutations have been identified in the MAP2K1 gene and the SMAD3 gene. There are also indications that somatic mutations in other unknown genes may be responsible for the disorder.

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Affected populations

The estimated incidence of melorheostosis is 1 in 1,000,000. Approximately 400 cases have been reported. Males and Females are affected in equal numbers.

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Diagnosis

Diagnosis is based on radiological images.  Plain X-ray images are the preferred diagnostic tool for melorheostosis.

On plain radiographs, melorheostosis appears as linear lesions of increased bone density along the main axis (body or diaphysis) of the tubular bones. The lesions result in increased thickness of the cortex of the bone and can expand to the outer surface of the bones, giving the appearance of wax dripping down a candle. When there is polyostotic involvement, the linear lesions are typically continuous along the same side of the affected limb and ‘jump’ over the joints. Soft tissue calcification and formation of bone outside the normal location may be observed. CT images are similar to radiographic images.

Magnetic resonance imaging (MRI) contributes to the evaluation of soft tissue injuries. MRI is not routinely done to diagnosis melorheostosis, but it may reveal bone marrow invasion.

Radioactive isotope bone examination or bone scans can help distinguish melorheostosis from other bone lesions. This test detects differences in bone metabolism highlighted by a radioactive tracer in the body.

A biopsy shows varying degrees of fibrosis of the bone marrow (the part inside the body’s bones, where blood cells are made) along with extremely irregular bones with mixed areas of lamellar and woven bone. A mixture of bone and cartilaginous, fibrovascular and fatty tissue is observed in soft tissue masses.

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Standard Therapies

Treatments are currently limited and mostly aimed at reducing symptoms.

Currently there are no treatment guidelines based on scientific evidence because of the small number of patients diagnosed worldwide. What may be useful for one person may be ineffective or even harmful for another. Therefore, treatment must be adapted to each affected person and requires a multidisciplinary team of specialists who work together. Treatment decisions should be made based on the severity of symptoms, areas of skeletal involvement and therapeutic possibilities. Treatment options may include surgery, physical and occupational therapy, hydrotherapy and medications aiming to alter the bone remodeling process.

Because this disease is benign in many people, nonsurgical treatment is often sufficient to improve symptoms and restore function.

Pain management can be challenging. Prescription pain medications may include nonsteroidal anti-inflammatory drugs (NSAIDs), steroids or rarely, narcotics. These medications are sometimes helpful in the early stages of the chronic progression of the disease, but may be less so for people who are severely affected. However, medications have reduced the symptoms and resulted in improved bone scans for some patients.

Other alternative therapies have also been used, such as nerve blocks, an anesthetic and/or anti-inflammatory injection that targets a specific nerve or group of nerves to treat pain, serial casting, manipulations and sympathectomies, a procedure to cut or block a nerve found in the middle of the body.

In isolated cases, drugs called zolendronate and denosumab showed improvement in symptoms.

Patients with severe symptoms and significantly limited joint mobility may benefit from surgery. Surgical treatment can be divided into adjuvant surgical treatment aimed at improving the complications of the disease and curative treatment, which consists of resection of the bone lesion and reconstruction.

In some patients, due to massive extension to adjacent tissues and complications related to the growth of the lesion pressing on the vessels and nerves, radical interventions may be necessary such as resection and reconstruction of the bone segment with tumor prostheses, arthroplasty or even amputation.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

Kasper, DL, Fauci AS, Longo DL, et al., eds. Harrison’s Principles of Internal Medicine. 16th ed. McGraw-Hill Companies. New York, NY; 2005:2283.

James WD, Berger T, Elston DM, eds. Andrew’s Diseases of the Skin: Clinical Dermatology. 10th ed. Saunders Elsevier. Philadelphia, PA. 2006:171.

Beighton P, ed. Mckusick’s Heritable Disorders of Connective Tissue. 5th ed. St. Louis, MO: Mosby-Year Book, Inc; 1993:657.

Slimani S, Nezzar A, Makhloufi H. Successful treatment of pain in melorheostosis with zoledronate, with improvement on bone scintigraphy. BMJ Case Rep. 2013 Jun 21;2013.

Motimaya AM, Meyers SP. Melorheostosis Involving the Cervical and Upper Thoracic Spine: Radiographic, CT, and MR Imaging Findings. AJNR Am J Neuroradiol. 2006;27:1198-1200.

Zeiler SC, Vaccaro AR, Wimberley DW, Albert TJ, Harrop JS, Hilibrand AS. Severe myelopathy resulting from melorheostosis of the cervicothoracic spine. A case report. J Bone Joint Surg Am. 2005;87:2759-62.

Wollridge B, Stone NC, Denic N. Melorheostosis isolated to the calcaneus: a case report and review of the literature. Foot Ankle Int. 2005;26:660-63.

Reznik M, Fried GW. Myelopathy associated with melorheostosis: a case report. Arch Phys Med Rehabil. 2005;86:1495-97.

Schreck MA. Melorheostosis in a pediatric patient. J Am Podiatr Med Assoc. 2005;95:167-70.

Ethunandan M, Khosla N, Tilley E, Webb A. Melorheostosis involving the craniofacial skeleton. J Craniofac Surg. 2004;11:1062-65.

Shivanand G. Srivastava DN. Melorheostosis with scleroderma. Clin Imaging. 2004;28:214-15.

Hellemans J, Preobrazhenska O, Willaert A, et al. Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. Nat Genet. 2004;36:1213-18.

Happle R. Melorheostosis may originate as a type 2 segmental manifestation of osteopoikilosis. Am J Med Genet A. 2004;15:221-23.

McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Melorheostosis. Entry Number;155950. Last Update 06/22/2020. Available at: https://omim.org/entry/155950 Accessed March 25, 2021.

Azouz EM, Greenspan A. Melorhesostosis. Orphanet Encyclopedia. February 2005. Available at: https://www.orpha.net/data/patho/GB/uk-Melorheostosis.pdf Accessed March 25, 2021.

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