Camurati–Engelmann disease (CED) is a very rare

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...

that causes characteristic anomalies in the

skeleton A skeleton is the structural frame that supports the body of most animals. There are several types of skeletons, including the exoskeleton, which is a rigid outer shell that holds up an organism's shape; the endoskeleton, a rigid internal fra ...

. It is also known as progressive diaphyseal dysplasia. It is a form of

dysplasia Dysplasia is any of various types of abnormal growth or development of cells (microscopic scale) or organs (macroscopic scale), and the abnormal histology or anatomical structure(s) resulting from such growth. Dysplasias on a mainly microscopic ...

. Patients typically have heavily thickened bones, especially along the shafts of the

long bone The long bones are those that are longer than they are wide. They are one of five types of bones: long, short, flat, irregular and sesamoid. Long bones, especially the femur and tibia, are subjected to most of the load during daily activities ...

s (called diaphyseal dysplasia). The

skull The skull, or cranium, is typically a bony enclosure around the brain of a vertebrate. In some fish, and amphibians, the skull is of cartilage. The skull is at the head end of the vertebrate. In the human, the skull comprises two prominent ...

bones may be thickened so that the passages through the

that carry

nerve A nerve is an enclosed, cable-like bundle of nerve fibers (called axons). Nerves have historically been considered the basic units of the peripheral nervous system. A nerve provides a common pathway for the Electrochemistry, electrochemical nerv ...

s and

blood vessel Blood vessels are the tubular structures of a circulatory system that transport blood throughout many Animal, animals’ bodies. Blood vessels transport blood cells, nutrients, and oxygen to most of the Tissue (biology), tissues of a Body (bi ...

s become narrowed, possibly leading to sensory deficits,

blindness Visual or vision impairment (VI or VIP) is the partial or total inability of visual perception. In the absence of treatment such as corrective eyewear, assistive devices, and medical treatment, visual impairment may cause the individual difficul ...

, or

deafness Deafness has varying definitions in cultural and medical contexts. In medical contexts, the meaning of deafness is hearing loss that precludes a person from understanding spoken language, an audiological condition. In this context it is writte ...

. This

disease A disease is a particular abnormal condition that adversely affects the structure or function (biology), function of all or part of an organism and is not immediately due to any external injury. Diseases are often known to be medical condi ...

often appears in

childhood A child () is a human being between the stages of childbirth, birth and puberty, or between the Development of the human body, developmental period of infancy and puberty. The term may also refer to an unborn human being. In English-speaking ...

and is considered to be inherited; however, many patients have no previous history of CED within their family. The disease is slowly progressive and, while there is no cure, there is treatment. It is named for M. Camurati and G. Engelmann.

Signs and symptoms

Patients with CED complain of chronic bone pain in the legs or arms, muscle weakness (

myopathy In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. ''Myopathy'' means muscle disease ( Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meaning implies that the primary defec ...

) and experience a waddling gait. Other clinical problems associated with the disease include increased fatigue, weakness, muscle spasms, headache, difficulty gaining weight, and delay in puberty. Some patients have an abnormal or absent

tibia The tibia (; : tibiae or tibias), also known as the shinbone or shankbone, is the larger, stronger, and anterior (frontal) of the two Leg bones, bones in the leg below the knee in vertebrates (the other being the fibula, behind and to the outsi ...

, may present with a flat foot, or have

scoliosis Scoliosis (: scolioses) is a condition in which a person's Vertebral column, spine has an irregular curve in the coronal plane. The curve is usually S- or C-shaped over three dimensions. In some, the degree of curve is stable, while in others ...

. This disease may also cause bones to become abnormally hardened which is referred to as sclerosis. This hardening may affect the bones at the base of the skull or those in the hands, feet, or jaw. This causes ongoing pain and aching within the body parts that are affected. The pain has been described as either a hot electric stabbing pain, an ever-increasing pressure sensation around the bones (especially before electrical storms) or as a constant ache that radiates through several long bones at once. Pain may also occur in the hips, wrists, knees and other joints as they essentially lock up (often becoming very stiff, immobile and sore), mostly when walking up or down staircases, writing for extended periods of time, or during the colder months of the year. Those with the disease tend to have a very characteristic walk medically diagnosed as a 'waddling gait'. This is observed by the broad-based gait with a duck-like waddle to the swing phase, the pelvis drops to the side of the leg being raised, notable forward curvature of the lumbar spine and a marked body swing. The pain is especially severe during a flare-up, which can be unpredictable, exhausting and last anywhere from a few hours to several weeks. This is a common occurrence for several CED patients, often causing myopathy and extensive sleep deprivation from the chronic, severe and disabling pain. Patients may even require the use of a wheelchair (or additional carer's help with getting dressed, showering, mobility/shopping, preparing meals or lifting heavy items) especially when bedridden or housebound for days or weeks at a time. Flare-ups may be attributed to, or exacerbated by growth spurts, stress, exhaustion, exercise, standing or walking for too long, illness, infection, being accidentally knocked/hurt or injured, after surgery/anaesthetics, cold weather, electrical storms, and sudden changes in barometric pressure. CED may also affect internal organs, the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

and

spleen The spleen (, from Ancient Greek '' σπλήν'', splḗn) is an organ (biology), organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The spleen plays important roles in reg ...

, which may become enlarged. A loss of vision and/or hearing can occur if bones are adversely affected by the hardening in the skull. Hence proactive specialist check-ups, X-rays, diagnostic tests/scans, and regular blood tests are recommended on an annual basis to monitor the CED bony growth and secondary medical issues that may arise from this condition.

Cause

Camurati-Engelmann disease is caused by autosomal dominant mutations in the gene

TGFB1 Transforming growth factor beta 1 or TGF-β1 is a polypeptide member of the transforming growth factor beta superfamily of cytokines. It is a secreted protein that performs many cellular functions, including the control of cell growth, cell proli ...

, localized at chromosome 19q13.

Diagnosis

Classification

There are two forms: * Type 1 is associated with

* Type 2 is not associated with TGFB1 Type 1 Camurati-Engelmann Disease is associated with an error occurring in the TGFB1 protein. Affected individuals shared a

haplotype A haplotype (haploid genotype) is a group of alleles in an organism that are inherited together from a single parent. Many organisms contain genetic material (DNA) which is inherited from two parents. Normally these organisms have their DNA orga ...

between D19S881 to D19S606. TGFB1 protein is encoded by the TGF-B1 gene, which occurs on chromosome 19q13.1-13.3. This protein is responsible for a multitude of functions, one of which includes regulating the function of

osteoblasts Osteoblasts (from the Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts functi ...

and

osteoclasts An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated ...

, which decreases

bone resorption Bone resorption is resorption of bone tissue, that is, the process by which osteoclasts break down the tissue in bones and release the minerals, resulting in a transfer of calcium from bone tissue to the blood. The osteoclasts are multi-nuclea ...

and increases

bone formation Ossification (also called osteogenesis or bone mineralization) in bone remodeling is the process of laying down new bone material by cells named osteoblasts. It is synonymous with bone tissue formation. There are two processes resulting in th ...

.Saito, T., Kinoshita, A., Yoshiura, K. I., Makita, Y., Wakui, K., Honke, K., ... & Taniguchi, N. (2001). Domain-specific mutations of a transforming growth factor (TGF)-β1 latency-associated peptide cause Camurati-Engelmann disease because of the formation of a constitutively active form of TGF-β1.Journal of Biological Chemistry, 276(15), 11469-11472. These functions can be affected by a series of mutations that occur on exon 4, near the carboxyl terminus of the latency associated peptide, or LAP. TGFB1 is expressed as a latent form, a mature form and a B1-LAP. Mutations to R218H affect the association of the B1-LAP and the mature form of TGFB1 by conformational changes to B1-LAP. These mutations can lead to a buildup of mature TGFB1, which accumulates in the mutant R218H fibroblasts. Fibroblasts are a type of cell that creates

collagen Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...

and the

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and bio ...

. This suggests that R218H mutation causes a disassociation between mature-TGFB1 and B1-LAP. Mutations at the LLL12-13ins and Y81H regions decrease the secretion of TGFB1, which leads to intracellular buildup of TGFB1. Type 2 Camurati-Engelmann Disease is still speculative, with no distinct evidence to credit its existence. There are many similarities between Type 2 CED and hyperostosis generalisata with striations of the bones (HGS), with some speculating they are two phenotypic variations of the same disease.

Treatment

Camurati–Engelmann disease is somewhat treatable. Glucocorticosteroids, which are

anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation, fever or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs reduce pain by inhibiting mechan ...

and immunosuppressive agents, are used in some cases. This form of medication helps in bone strength; however, it can have multiple side effects. In several reports, successful treatment with glucocorticosteroids was described, as certain side effects can benefit a person with CED. This drug helps with pain and fatigue as well as some correction of radiographic abnormalities. Alternative treatments such as massage, relaxation techniques (meditation, essential oils, spa baths, music therapy, etc.), gentle stretching, and especially heat therapy have been successfully used to an extent in conjunction with pain medications. A majority of CED patients require some form of analgesics, muscle relaxant, and/or sleep inducing medication to manage the pain, specifically if experiencing frequent or severe flare-ups (e.g. during

winter Winter is the coldest and darkest season of the year in temperate and polar climates. It occurs after autumn and before spring. The tilt of Earth's axis causes seasons; winter occurs when a hemisphere is oriented away from the Sun. Dif ...

).Jadhav, A. T. U. L., & Ghanekar, J. A. I. S. H. R. E. E. (2013). Camurati–Engelmann disease. Indian Journal of Clinical Practice, 24(2).

Notable persons

* John Belluso, writer for the CBS television show ''

Ghost Whisperer ''Ghost Whisperer'' is an American supernatural television series, which ran on CBS from September 23, 2005, to May 21, 2010. The series follows the life of Melinda Gordon ( Jennifer Love Hewitt), who has the ability to see and communicate w ...

'', used a wheelchair from the age of 13 because of Camurati–Engelmann syndrome. He died on February 10, 2006, at the age of 36 in New York City.

References

External links

{{DEFAULTSORT:Camurati-Engelmann Disease Extracellular ligand disorders Skeletal disorders Rare diseases Autosomal dominant disorders Diseases named after discoverers