This chronic disease of the adult skeleton, formerly known as osteitis deformans, is characterized by bowing and irregular flattening of the bones. Any or all skeletal bones may be affected, but the tibia, skull, and pelvis are the most frequent sites. Usually, multiple bones are affected, but in 15%, only one is involved. The disease is symptomatic in 15% to 20% of affected individuals. Pain is the most common symptom. Except for the skeletal deformities and pain, the disease causes disability only when the skull or spine is involved.

The skull and the bones in other parts of the body are occasionally involved by a process characterized by small areas of bone destruction or massive sclerotic overgrowth. The clinical picture of fibrous dysplasia is related to the site and extent of the bone overgrowth. Fibrous dysplasia can involve one (monostotic form) or multiple (polyostotic form) bones. Both types may be associated with hyperfunctional endocrinopathies and café au lait lesions referred to as the McCune-Albright syndrome. Fibrous dysplasia and McCune-Albright syndrome are caused by a sporadic postzygotic missense mutation in the somatic cells of the GNAS complex locus located on chromosome 20q13. Overall, this leads to defects in osteoblast differentiation and proliferation of osteoblast progenitors leading to abnormal bone. The bones of the skull most often affected are the frontal (56%) and sphenoid (48%) bones. A recent Danish case series of 26 subjects revealed that 80% had involvement of craniofacial bones. Diffuse involvement of the entire skull produces leontiasis ossea, with exophthalmos, optic atrophy, and cranial nerve palsies (Fig. 122.2).

In addition to the disfiguration of the skull in the polyostotic form, symptoms of the monostotic form of the disease include headache, convulsions, exophthalmos, optic atrophy, and deafness. Most patients are, however, asymptomatic. Symptoms may begin at any age, but onset usually occurs in early adult life. The family history is negative, and there is no racial or sexual predominance.

Treatment is limited. Surgical intervention can be used to treat fracture and bony deformities. Although not well studied, bisphosphonates have been used to treat bone pain. Results are mixed and no randomized clinical trial has been done.

Achondroplasia (chondrodystrophy) is the most frequent form of skeletal dysplasia causing dwarfism. It is characterized by short arms and legs, lumbar lordosis, and enlargement of the head caused by mutations in the fibroblast growth factor receptor 3 gene (FGFR3). The gene product is expressed in cartilage. A frequent FGFR3 mutation is a Gl 138A codon mutation with GGG to AGG or CGG substitutions, resulting in an exchange of glycine at position 380 in the FGFR3 protein to arginine. This mutation results in a gain of negative function, producing an inactive FGFR and resultant dwarfism. The disease is rare and is estimated to occur in 15 of 1 million births in the United States. It is inherited as an autosomal dominant trait, although 80% of cases are sporadic.

Symptoms of involvement of the nervous system sometimes develop as a result of hydrocephalus, compression of the medulla and cervical cord at the level of the foramen magnum, compression of the spinal cord by ruptured intervertebral disk, and bone
compression of the lower thoracic or lumbar cord. Seizures, ataxia, and paraplegia are the most common symptoms. Mental development is usually normal. Mortality rates are significantly elevated secondary to accidental, neurologic, and heart diseaserelated causes.

The diagnosis is made from the characteristic body configuration of short arms and legs, normal-sized trunk, enlargement of the head, and changes in the radiographs of the skeleton. Previously, CT was used to evaluate neurologic complications of achondroplasia. Currently, MRI of the brain and spine best define the presence of hydrocephalus and degree of ventricular compensation as well as whether cord compression is present. Somatosensoryevoked potential may be useful for detecting cervical myelopathy. Many affected infants die in the perinatal period, although a normal life span is possible for patients with less severe involvement of the bones.

Shunting procedures may be needed for hydrocephalus caused by involvement of the bones at the base of the skull. Laminectomy is indicated for signs of cord compression. The mutations in the FGFR3 gene at 4p are usually new mutations and result in autosomal dominant inheritance.

Ankylosing spondylitis is considered the prototype of the spondyloarthropathies. It typically occurs in younger persons and men are affected two to three times more commonly than women. Its etiology is likely secondary to multiple genetic and environmental factors including a strong association with the gene for human leukocyte antigen (HLA)-B27. The condition is common, affecting an estimated 1.4% of the general population. Neurologic symptoms have been considered to be uncommon but have only received limited study. A recent study investigated this question further among 24 patients recruited from an Egyptian outpatient rheumatologic clinic compared to age and sex matched controls. Neurologic manifestations occurred in 25% of the patients; 8.3% had myelopathy and 16.7% had radiculopathy. Subclinical neurologic complications as evident by neurophysiologic test abnormalities were common, as over 70% had at least one abnormal finding.

This inflammatory disorder affects ligamentous insertions into bones; at first, it usually affects the sacroiliac joints and lumbar spine. In some patients, the entire spine is involved, with ossification of the ligaments and fusion of the vertebra. The spine becomes rigid and susceptible to a variety of disorders that may affect the spinal cord, including fractures and dislocations, atlanto-occipital dislocation, and spinal stenosis.

A cauda equina syndrome may appear in patients with longstanding spondylitis. Signs and symptoms are symmetric, with weakness, wasting, and sensory loss in lumbosacral myotomes. Autonomic dysfunction and more specifically parasympathetic dysfunction may occur. Bladder and bowel are commonly affected, and pain may be severe. The mechanism is not clear. Although concomitant arachnoiditis has been suspected as the cause, the syndrome appears late, when there is little evidence that the underlying spondylitis is active. Moreover, there is little inflammation at postmortem examination, which is likely to show chronic fibrosis. There is erosion of posterior bone elements, and, in earlier days, myelography showed enlargement of the caudal sac and prominent diverticulae of the arachnoid. CT shows similar pathology, but MRI is more illuminating, showing nerve root thickening and sometimes enhancement of dura and nerve roots; that pattern suggests inflammation of the arachnoid structures, supporting the earlier theory. Surgery is generally ineffective and has sometimes been deleterious, although there have been rare reports of some relief. Steroid therapy has been similarly without benefit. Physical therapy may be useful. Studies suggest the use of nonsteroidal anti-inflammatory drugs (NSAIDs) or selective cyclo-oxygenase-2 inhibitors for symptomatic patients. Tumor necrosis factor (TNF) inhibitors are useful for patients whose symptoms persist despite treatment with NSAIDs.