Camurati-Engelmann disease is a skeletal condition that is characterized by abnormally thick bones (hyperostosis) in the arms, legs, and skull.

The thick limb bones can lead to bone pain and muscle weakness in the arms and legs and cause individuals with Camurati-Engelmann disease to tire quickly. Bone pain ranges from mild to severe and can increase with stress, activity, or cold weather. Leg weakness can make it difficult to stand up from a seated position and some affected individuals develop a waddling or unsteady walk. Additional limb abnormalities include joint deformities (contractures), knock knees, and flat feet (pes planus). Swelling and redness (erythema) of the limbs and an abnormal curvature of the spine can also occur.

Individuals with Camurati-Engelmann disease may have an unusually thick skull, which can lead to an abnormally large head (macrocephaly) and lower jaw (mandible), a prominent forehead (frontal bossing), and bulging eyes with shallow eye sockets (ocular proptosis). These changes to the head and face become more prominent with age and are most noticeable in affected adults. In about a quarter of individuals with Camurati-Engelmann disease, the thickened skull increases pressure on the brain or compresses the spinal cord, which can cause a variety of neurological problems, including headaches, hearing loss, vision problems, dizziness (vertigo), ringing in the ears (tinnitus), and facial paralysis.

The degree of hyperostosis varies among individuals with Camurati-Engelmann disease as does the age at which they experience their first symptoms.

Other, rare features of Camurati-Engelmann disease include abnormally long limbs in proportion to height, a decrease in muscle mass and body fat, delayed teething (dentition), frequent cavities, delayed puberty, a shortage of red blood cells (anemia), an enlarged liver and spleen (hepatosplenomegaly), thinning of the skin, and excessively sweaty (hyperhidrotic) hands and feet.

Mutations in the TGFB1 gene cause Camurati-Engelmann disease. The TGFB1 gene provides instructions for producing a protein called transforming growth factor beta-1 (TGFβ-1). The TGFβ-1 protein triggers chemical signals that regulate various cell activities, including the growth and division (proliferation) of cells, the maturation of cells to carry out specific functions (differentiation), cell movement (motility), and controlled cell death (apoptosis).

The TGFβ-1 protein is found throughout the body but is particularly abundant in tissues that make up the skeleton, where it helps regulate the formation and growth of bone and cartilage, a tough, flexible tissue that makes up much of the skeleton during early development. TGFβ-1 is involved in different processes in other tissues.

The TGFB1 gene mutations that cause Camurati-Engelmann disease result in the production of an overly active TGFβ-1 protein. This abnormal TGFβ-1 protein activity causes an increase in signaling, which leads to more bone formation. As a result, the bones in the arms, legs, and skull are thicker than normal, contributing to the movement and neurological problems often experienced by individuals with Camurati-Engelmann disease.

Some individuals with Camurati-Engelmann disease do not have an identified mutation in the TGFB1 gene. In these cases, the cause of the condition is unknown.

Normal Function

The TGFB1 gene provides instructions for producing a protein called transforming growth factor beta-1 (TGFβ-1). The TGFβ-1 protein triggers chemical signals that regulate various cell activities inside the cell, including the growth and division (proliferation) of cells, the maturation of cells to carry out specific functions (differentiation), cell movement (motility), and controlled cell death (apoptosis).

The TGFβ-1 protein is found throughout the body but is particularly abundant in tissues that make up the skeleton, where it helps regulate the formation and growth of bone and cartilage, a tough, flexible tissue that makes up much of the skeleton during early development. TGFβ-1 is also involved in the formation of blood vessels, development of muscle tissue and body fat, wound healing, inflammatory processes in the immune system, and prevention of tumor growth.

Health Conditions Related to Genetic Changes

Camurati-Engelmann disease

At least 12 mutations in the TGFB1 gene have been found to cause Camurati-Engelmann disease. This condition is characterized by abnormally thick bones (hyperostosis) in the arms, legs, and skull. Hyperostosis can cause bone pain, muscle weakness, and increased pressure on the brain that results in neurological problems, including headaches and hearing and vision problems.

Most of the TGFB1 gene mutations change single protein building blocks (amino acids) in the TGFβ-1 protein. Three mutations account for approximately 75 percent of cases of Camurati-Engelmann disease. Two of these mutations change the amino acid arginine at position 218 in the protein. One replaces arginine with the amino acid cysteine (written as Arg218Cys or R218C) and the other replaces arginine with the amino acid histidine (written as Arg218His R218H). The third mutation replaces the amino acid cysteine with the amino acid arginine at protein position 225 (written as Cys225Arg C225R).

All TGFB1 gene mutations that cause Camurati-Engelmann disease result in the production of an overly active TGFβ-1 protein. This abnormal TGFβ-1 protein activity causes an increase in signal transduction, which leads to more bone formation. As a result, the bones in the arms, legs, and skull are thicker than normal, contributing to the movement and neurological problems often experienced by individuals with Camurati-Engelmann disease.

Idiopathic pulmonary fibrosis

MedlinePlus Genetics provides information about Idiopathic pulmonary fibrosis

Cancers

Changes in the TGFB1 gene have been reported to be associated with certain cancers. These variants are acquired during a person's lifetime and are present only in certain cells. Studies have shown that TGFB1 gene variants are associated with breast, colorectal, lung, liver, and prostate cancer. The altered protein expression may increase several cell processes that promote cancer formation such as cell proliferation, cell motility, and the development of new blood vessels (angiogenesis) that nourish a growing tumor.

Other Names for This Gene

• TGF-beta 1 protein
• TGF-beta-1
• TGFB
• TGFB1_HUMAN
• TGFbeta
• transforming growth factor, beta 1

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

Some people who have the altered gene never develop the condition, a situation known as reduced penetrance.

People with Camurati-Engelmann disease have increased bone density, particularly affecting the long bones of the arms and legs (tibia, femur, humerus, ulna, radius). In some cases, the skull and hip bones are also affected. The thickened bones can lead to pain in the arms and legs, a waddling walk, muscle weakness, and extreme tiredness. An increase in the density of the skull results in increased pressure on the brain and can cause a variety of neurological problems, including headaches, hearing loss, vision problems, dizziness (vertigo), ringing in the ears (tinnitus), and facial paralysis. The added pressure that thickened bones put on the muscular and skeletal systems can cause abnormal curvature of the spine (scoliosis), joint deformities (contractures), knock knees, and flat feet (pes planus). Other features of Camurati-Engelmann disease include abnormally long limbs in proportion to height, a decrease in muscle mass and body fat, and delayed puberty. In the most severe cases, the mandibula (jaw), vertebrae, thoracic cage, shoulder girdle, and carpal (hands, wrist) and tarsal (foot, ankle) bones are involved.

Radiographically (on X-ray), the shafts of long bones show symmetric and progressive widening and malformation (diaphyseal dysplasia). Vascular (Raynaud's phenomenon) and hematological (anemia, leukopenia (low level of white blood cells), increased erythrocyte sedimentation rate) features and hepatosplenomegaly are commonly associated with the disease.

The age at which affected individuals first experience symptoms varies greatly; however, most people with this condition develop pain or weakness by adolescence.

Diagnosis of Camurati-Engelmann disease is based on physical examination and radiographic findings and can be confirmed by molecular genetic testing. TGFB1 is the only gene known to be associated with Camurati-Engelmann disease. Sequence analysis identifies mutations in TGFB1 in about 90% of affected individuals and is clinically available.

Individuals with a family history of Camurati-Engelmann disease or symptoms associated with this condition may wish to consult with a genetics professional. Visit the Find a Specialist section on this page to learn how you can locate a genetics professional in your community.

Treatment for Camurati-Engelmann disease depends on the symptoms and severity in each person. Several medications, including corticosteroids, biphosphonates, and non-steroidal anti-inflammatory drugs (NSAIDs), have been used to manage the symptoms of Camurati-Engelmann disease (CED). NSAIDs and bisphosphonates have not been proven to be effective for most people with CED. Corticosteroids may relieve some of the symptoms such as pain and weakness, and can also improve gait and exercise tolerance. However, they have serious side effects with long-term use.

More recently, losartan, an angiotensin II type 1 receptor antagonist, has been reported to reduce limb pain and increase muscle strength in multiple case reports. However, the use of losartan needs more study to determine if it is effective and safe for those with CED. Exercise programs, when tolerated, have also been found to be beneficial.

Surgical procedures may also be needed in people with CES. Craniectomy, which involves removing a portion of the skull to relieve pressure on the brain, may be needed to reduce intracranial pressure and relieve symptoms in some people. Myringotomy, a procedure used to relieve pressure within the middle ear, may improve conductive hearing loss from fluid build-up in the ear.

Ongoing surveillance by various specialists may be needed to monitor signs and symptoms and make sure medical therapies remain safe to use. Depending on each person's symptoms and treatment, a person with CES may need periodic blood pressure checks, blood tests, neurologic exams, hearing evaluations, eye exams, bone density scans, or other types of surveillance. Children with CES should have routine growth monitoring, and those with cranial involvement (including those treated surgically) should continue to be monitored for signs and symptoms of increased intracranial pressure.

Please note: Case reports detail the signs and symptoms in individual cases. It is important to keep in mind that the features documented in these case reports are based on specific individuals and may not necessarily apply to others with the same disease.

Around half of people with Camurati-Engelmann disease have skull base thickening and around one-fourth of these people develop symptoms. Symptoms may be constant or come and go. Some patient's symptoms stabilize, while other's worsen with time. Signs and symptoms reported in the medical literature, include;

• Hearing loss
• Headache
• Bulging eyes
• Prominent forehead

Less common signs and symptoms, include;

• Vision changes
• Vertigo
• Facial weakness
• Symptomatic brain stem compression
• Facial numbness
• Loss of smell

Treatment of symptoms due to skull base thickening may involve aggressive decompression surgery in carefully selected patients. Corticosteroids and bisphosphates that may improve symptoms in the arms, legs, and torsos of some patients, have not been shown to improve symptoms caused by skull base thickening. Decompression surgery is challenging and patients are at an increased risk for complications with surgery. The form of decompression surgery will vary depending on the skull involvement and symptoms experienced by the patient. Likewise the risks for complications vary depending on these factors.

Following surgery it is possible for the bone to regrow. A recent review article found that 3 of 28 cases reported in the literature described bony regrowth following decompression surgery.