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Melorheostosis is an uncommon and progressively deteriorating disease. It can be indicated by the thickening or widening (hyperostosis) of the bones’ outermost layers (cortical bone). With this disease, the maturation and development of both the bone and soft tissue are affected. Although this disease is non-cancerous in nature, it imposes some lasting and damaging functional effects, which include, but are not limited to: chronic pain; joint contractures; stiff muscles, tendons/ligaments; and deformities of the extremities.

It is also a medical developmental disorder and mesenchymal dysplasia in which the bony cortex widens and also becomes hyper-dense in a sclerotomal distribution. The onset of this condition begins in childhood. Pain is a frequent symptom and the bone can have the appearance of dripping candle wax.

Signs and Symptoms
There are several signs and symptoms that suggest that an individual may have melorheostosis. These signs and symptoms are comprised of irregular bone growth (this includes cortical thickening and “dripping candle wax” that may appear on x-ray imaging); limbs that grow unequally, the shortening of tendons or ligaments (soft tissue abnormalities); abnormal muscles; subcutaneous calcification, joint swelling and contractures that result in malformed immobilized joints; limitations within a person’s range of motion; pain and stiffness; edema and vascular deformities. While rare, another sign/symptom where the surrounding nerves may be compressed by the bone lesion, has been proven to be severe.

Melorheostosis tends to affect only a certain portion of the appendicular skeleton, which includes the arms and legs. It isn’t usually a bilaterally affecting disease, meaning that it tends to affect one side or the medial side of the body. The pelvis, sternum, and ribs are the most commonly affected, although the spine and skull are more rarely inflicted.

This condition presents itself in children with disproportionate limb length, deformities, or other joint contractures. In adults, this disease presents itself in the form of joint stiffness and general progressive deformities.

The onset of this disease is often in early childhood. Generally, patients with this disease will present with signs and symptoms by the age of 20.

Cause
The exact cause of Melorheostosis is unknown. However, the current hypothesis is that melorheostosis is caused by a somatic mutation in the LEMD3 gene that is only present in the affected tissues.

Mechanism/Pathophysiology
in a modest number of melorheostosis patients, who also have osteopoikilosis or Buschke-Ollendorff syndrome, a mutation in the LEMD3 gene has been identified. The LEMD3 gene codes for a protein that is part of the nuclear membrane. This membrane protein plays an inhibitory role in bone formation. However, the vast majority of sporadic patients with melorheostosis do not have a LEMD3 germline (egg or sperm) mutation.

The disorder tends to be unilateral and monostotic (i.e. affecting a single bone), with only one limb typically involved. Cases with involvement of multiple limbs, ribs, and bones in the spine have also been reported. There are no reported cases of involvement of skull or facial bones. Melorheostosis can be associated with pain, physical deformity, skin and circulation problems, contractures, and functional limitation. It is also associated with a benign inner ear dysplasia known as  osteosclerosis.

Paraspinal soft-tissue mass lesions and intrathecal lipoma have been found in various patients with axial melorheostosis, and linear cutaneous vascular malformation was found in another patient with peripheral involvement; Once again, it's important to note that the disease affects mesenchymal tissue generally, rather than being confined to bone. Some reports show melorheostosis in association with hypophosphatemic rickets, minimal change nephrotic syndrome with mesenteric fibromatosis, and capillary hemangioma or renal artery stenosis.

Diagnosis
Melorheostosis is a mesenchymal dysplasia manifesting as regions of dripping wax appearance or flowing candle wax appearance. The disorder can be detected by radiograph due to thickening of bony cortex resembling "dripping candle wax." It is included on the spectrum of developmental bone dysplasias including pycnodysostosis and osteopoikilosis. The estimated incidence of melorheostosis is 1 in 1,000,000. Both sexes are affected and approximately 400 cases have been reported.

In melorheostosis, bone scans appear to be positive. However, on magnetic resonance imaging (MRI) there is usually a low signal. X-ray imaging is the chosen diagnostic mechanism for melorheostosis. X-rays often reveal a pattern of thickened bone (sclerotic bone lesions) that resembles dripping candle wax.

Symptoms of the following disorders are related to and can mirror those of melorheostosis. Comparison is useful for a differential diagnosis:

Osteopoikilosis is an uncommon and benign bone disorder that can be distinguished by multiple round or oval areas of increased bone density at the ends of the long bones. They are usually present bilaterally on the body.

Buschke-Ollendorff syndrome is a rare, hereditary disorder that affects connective tissue. It is characterized by the combination of skin growths (called connective tissue nevi) with osteopoikilosis.

Osteopathia Striata is a benign bone disorder categorized by longitudinal bands of increased density in the affected bones.

Linear Scleroderma presents as a band-like thickening of skin on the extremities. Typically, this disorder initially appears during early childhood and is identified by the failure of one limb to grow as rapidly as its counterpart.

Desmoid Tumors commonly develop in the fibrous (connective) tissue of the body that forms tendons and ligaments, typically in the extremities or midsection, and also in the head and neck. Desmoid tumors can be invasive to surrounding tissues and difficult to control.

Hemangiomas appear in early infancy and are growths made up of small blood vessels.

Treatment
Treatment options are narrowly defined at the present time and are prevalently aimed at symptom reduction. No treatment option has been proven to be fully effective, and is contingent upon an individual basis. Treatment options may include surgery, physical and occupational therapy, hydrotherapy, and medications to adjust the bone remodeling process.

Pain management may be formidable. Medications are typically used to control the pain. Medications such as: non-steroidal anti-inflammatory drugs (NSAIDs), steroids or narcotics (on rare occasions) are generally used. These medications are somewhat conducive in the early stages of the disease, but may be less so for the severely inflicted. These medications are sometimes helpful in the early stages of the chronic progression of the disease but may be less so for the severely affected. However, some patients have shown benefit in either symptoms or on bone scans. The disorder is progressive, with the ultimate severity of symptoms often depending on age of onset. In severe cases, amputation has been performed when conservative measures such as physical therapy and regional anesthetics have been ineffective.

Prognosis
The disease is of varies in severity, but tends to follow a progressively chronic path in adults. However, it trends a more rapid course in children, incidentally resulting in substantial disability from joint contractures or deformities. Melorheostosis is not life-threatening, but can greatly affect quality of life. This is due to chronic pain that can intensify or resurface, even after surgical treatment.

Research
In April 2018, the U.S. Department of Health and Human Services reported that researchers at the National Institutes of Health worked with 15 patients from around the world to divulge the genetic basis of melorheostosis. Fifteen unrelated adults with this disease, worldwide, volunteered to come to the NIH Clinical Center to receive biopsies of both affected and unaffected bones. Researchers were able to compare samples of both healthy and diseased bone from each participant to look for differences in the exome, the portion of the genome that codes for proteins. The comparison of the genetic material in each sample allowed the team to pinpoint the lowest levels of the mutations. Researchers from NIAMS and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) worked together on this study.

This analysis showed that 8 of the 15 participants had mutations in the MAP2K1 gene in the affected bone only. MAP2K1 produces the protein MEK1. The gene MAP2K1 has previously been linked to some types of cancerous growths as well as to conditions that lead to abnormal blood vessel formation in the head, face or neck.

In melorheostosis, all the identified MAP2K1 mutations affect a portion of the MEK1 protein that normally subdues its activity, hence they cause MEK1 to become overactive. The bone growth is non-malignant and does not spread to other areas of the body.